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

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 mm 3 [mean±SD], respectively) than in normothermic rats (14.4±12.7 and 42.4±19.2 mm 3 ) and in animals with 39°C hyperthermia (16.5±28.7 and 40.9±34.3 mm 3 ) ( 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.