Figure 1Hypothermia for traumatic brain injury. Immediate hypothermia is compared with normothermia. The outcome was death at final follow-up stratified by trial quality. CI, confidence interval; M-H, Mantel-Haenszel. Reproduced with permission from [80]. Copyright …The meta-analysis of Axitinib melanoma Peterson and colleagues [78] included eight trials that studied comparable patient groups at baseline. Hypothermia was shown to reduce mortality by 20%, although this was not statistically significant (RR 0.80, 95% CI 0.59 to 1.09). Subgroup analysis showed that this effect was significantly greatest when hypothermia was maintained for more than 48 hours (RR 0.51, 95% CI 0.33 to 0.79). Hypothermia was also associated with a non-significant increase of 25% in neurological outcome when measured by the Glasgow Outcome Scale at 6 months (RR 1.

25, 95% CI 0.96 to 1.62). Despite not reaching statistical significance, results showed an increased likelihood of improved neurological outcome when cooling was maintained for more than 48 hours (RR 1.91, 95% CI 1.28 to 2.85). Another key finding of this meta-analysis is that hypothermia was of significant benefit only to those patients who had not received barbiturate therapy (RR 0.58, 95% CI 0.40 to 0.85).A criticism of these analyses is that most failed to take account of important differences in patient groups (such as those with or without intracranial hypertension) and of differences in treatment protocols, except the use of hypothermia.

Only one differentiated between studies that enrolled patients with normal ICP and those that enrolled patients with intracranial hypertension and that analysis found no neurological improvement associated with hypothermia [77]. Only two assessed effects of treatment duration and speed of re-warming [73,74], concluding that cooling for more than 48 hours and rewarming rates of 24 hours, or 1��C/4 hours, were key factors in reducing mortality (RR 0.70, 95% CI 0.56 to 0.87) and improving neurological outcome (RR 0.79, 95% CI 0.63 to 0.98), respectively.In summary, the evidence from previous research shows that induced hypothermia may be effective in patients with severe TBI and intracranial hypertension provided that the treatment is continued for long enough (between 48 hours and 5 days) and that patients are rewarmed slowly (1��C/4 hours).

Experience with cooling also appears to be important if complications that may outweigh the benefits of hypothermia are to be avoided.Rationale for Eurotherm3235TrialThe Eurotherm3235Trial will enrol TBI patients who have an ICP Entinostat of more than 20 mm Hg for at least 5 minutes after first-line treatments with no obvious reversible cause (for example, patient position, coughing, or inadequate sedation). Three stages of TBI management have been developed to support the trial and are based upon the best evidence available (Figure (Figure2)2) [73,81].