Physiological Strategies Hypothermia

As with all molecular and biochemical pathways, the major mechanisms of cell death are temperature-dependent. Hypothermia can protect against multiple deleterious processes, including oxidative stress, inflammation, lipid peroxidation, and activation of cysteine or serine proteases.88-94 Each degree of temperature decline reduces the rate of cellular respiration, oxygen demand, carbon dioxide production by 10%.95 Preclinical and clinical results have been encouraging, making hypothermia an attractive physiological therapy that targets multiple injury mechanisms. However, the therapeutic time window for hypothermia is narrow.96 In one study, hypothermia proved beneficial if initiated 30 minutes before stroke onset, but not 10 minutes after stroke onset.97

While moderate hypothermia (28-32°C) is technically difficult and fraught with complications, recent experimental studies have shown that small decreases in the core temperature (from normothermia to 33-36°C) are safe and sufficient to reduce neuronal death. In humans, improved functional recovery and reduced mortality were achieved in two randomized clinical trials of mild hypothermia in survivors of out-of-hospital cardiac arrest.98,99 With prolonged cooling (12-48 hours), substantial neuroprotection can be achieved in focal as well as global cerebral ische-mia.100,101 In a nonrandomized pilot study of 25 patients with acute, large, complete MCA infarction, mild hypothermia significantly reduced intracranial pressure from 20.9 to 13.4 mm Hg, leading to an increase in cerebral perfusion pressure from 68 to 78 mm Hg. Mortality was reduced to 44% versus approximately 80% in historical controls.102 Radiologically, moderate hypothermia attenuates infarct volumes on MRI in rats103 and causes regression of ischemic injury in humans with MCA stroke.104

Based on these results, additional controlled trials are now underway to test the therapeutic impact of hypothermia combined with thrombolysis. The results of a recent trial (Cooling for Acute Ischemic Brain Damage [COOL-AID])105 suggest that the combination of intra-arterial thrombolysis plus mild hypothermia via external cooling is safe, although mean time to achieve the target temperature was 3.5 ± 1.5 hours. Use of an intravascular inferior vena cava heat exchange catheter is also safe, and cooling may be achieved more quickly (77 ± 44 minutes).106 The two COOL-AID trials (external cooling vs. inferior vena cava cooling) were not designed to determine efficacy. Use of a cooling helmet has also been found to be safe, and can achieve brain temperature reduction of 1.84°C/hours of cooling, requiring a mean of 3.4hours to achieve temperatures below 34°C.107 Several single- and multi-center randomized trials are underway in patients with ischemic and hemorrhagic stroke: Intravascular Cooling for the Treatment of Stroke-Longer window (ICTuS-L), Nordic Cooling Stroke Study (NOCSS), Controlled Hypothermia in Large Infarction (CHILI), and the Combined Cytoprotection rt-PA Stroke Trial investigating the efficacy of caffeine, ethanol, and cooling via a femoral catheter for 24 hours with or without rt-PA.

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