OPTIMAL DEPTH AND DURATION OF MILD HYPOTHERMIA IN A FOCAL MODEL OF TRANSIENT CEREBRAL-ISCHEMIA - EFFECTS ON NEUROLOGIC OUTCOME, INFARCT SIZE, APOPTOSIS, AND INFLAMMATION

Background and Purpose-Mild hypothermia is possibly the single most ef fective method of cerebroprotection developed to date. However, many q uestions regarding mild hypothermia remain to be addressed before its potential implementation in the treatment of human stroke. Here we rep ort the results of 2 studies designed to determine the optimal depth a nd duration of mild hypothermia in focal stroke and its effects on inf arct size, neurological outcome, programmed cell death, and inflammati on. Methods-Rats underwent a 2-hour occlusion of the left middle cereb ral artery. In the first study (I) animals were kept (intraischemicall y) at either 37 degrees C (n=8), 33 degrees C (n= 8), or 30 degrees C (n=8). Study II consisted of 4 groups: (1) controls (37 degrees C, n=1 0), (2) 30 minutes of hypothermia started at ischemic onset (33 degree s C, n=9), (3)1 hour (33 degrees C, n=8), and (4) 2 hours (33 degrees C, n=8). Brain temperature was measured by a thermocouple probe placed in the contralateral cortex. After suture removal, all animals were r ewarmed and reperfused for 22 hours (I) or 70 hours (II). Results-Mild hypothermia to 33 degrees C or 30 degrees C was neuroprotective (17+/ -7% and 27+/-6%, respectively) relative to controls (53 +/- 8%, P<0.02 ), but 33 degrees C was better tolerated and recovery from anesthesia was faster. The neurological score of hypothermic animals was signific antly better than that of controls (I & II) at both 24 and 72 hours po stischemia except for the 30-minute group (II), which showed no improv ement. In Study II, 2 hours of hypothermia reduced injury by 59%, 1 ho ur reduced injury by 84% whereas 30 minutes did not reduce injury. Nor malized for infarct size, 2 hours of mild hypothermia decreased neutro phil accumulation by 57% whereas both 1 hour and 30 minutes had no eff ect. At 72 hours, 1 and 2 hours of mild hypothermia decreased transfer ase dUTP nick-end labeling (TUNEL) staining by 78% and 99%, respective ly, and 30 minutes of hypothermia had no effect. Conclusions-Intraisch emic mild hypothermia must be maintained for 1 to 2 hours to obtain op timal neuroprotection against ischemic cell death due to necrosis and apoptosis.