Nearly all ischemic events are modulated by temperature, and cerebroprotection from hypothermia is believed to increase resistance against multiple deleterious pathways including oxidative stress and inflammation [189-195]. Generally, most biological processes exhibit a Q10 of approximately 2.5, which means that a 1°C reduction in temperature reduces the rate of cellular respiration, oxygen demand, and carbon dioxide production by approximately 10% [196]. Reduced temperature also slows the rate of pathological processes such as lipid peroxidation, as well as the activity of certain cysteine or serine proteases. However, detoxification and repair processes are also slowed, so the net outcome may be complex. Hence, hypothermia appears to be an attractive therapy that targets multiple injury mechanisms.

Brain cooling can be achieved more rapidly (and spontaneously) when blood flow to the entire brain ceases following cardiac arrest, and thermoregulation may be abnormal due to hypothalamic dysfunction. If only a segment of brain is ischemic, nonin-jured brain remains a metabolically active heat source. While moderate hypothermia (28-32 °C) is technically difficult and fraught with complications, recent experimental studies have shown that small decreases in core temperature (from normothermia to 33-36 °C) are sufficient to reduce neuronal death. The consensus from preclinical data suggests that the opportunity to treat does not extend beyond minutes after reversible MCA occlusion when hypothermia is maintained for a short duration (a few hours) [197]. In a global model of hippocampal ischemia, hypothermia is beneficial if begun 30 min before but not 10 min after stroke onset [198]. However, if cooling is prolonged (12-48 h), protection against injury is substantial following focal as well as global cerebral ischemia [199,200]. In humans, encouraging positive results were recently reported in two randomized clinical trials of mild hypothermia in survivors of out-of-hospital cardiac arrest [201,202]. Cooling significantly improved outcomes despite a relatively delayed interval (105 min) from ischemic onset until the initiation of cooling. Based on these results, additional controlled trials are now underway to test the therapeutic impact of hypothermia in focal ischemia and embolic stroke when combined with thrombolysis. Preliminary data justify enthusiasm. In a study of 25 patients with acute, large, complete MCA infarction, mild hypothermia (33°C maintained for 4872 h) significantly reduced morbidity and improved long-term neurologic outcome [203]. The results of a recent trial [Cooling for Acute Ischemic Brain Damage (COOL-AID)] [204] suggest that the combination of intra-arterial thrombolysis plus mild hypothermia is safe; however, complications such as cardiac arrhythmia, deep vein thrombosis, and pneumonia have been reported previously [205]. Several single and multicenter randomized trials are underway in patients with ischemic and hemorrhagic stroke.

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