A review of clinical trials of hypothermia treatment for severe traumatic brain injury.

Clinical trials of hypothermia treatment of traumatic brain injury can be divided into (1) trials designed to abort the biochemical cascade after injury-neuroprotection, (2) trials primarily designed to test the effect of hypothermia in reducing elevated intracranial pressure (ICP), and (3) trials with features of both neuroprotection and elevated ICP control. Three of the four clinical trials testing hypothermia induction after failure of conventional means of ICP control showed decreased mortality rate, though sample sizes were small and findings were not always statistically significant. Nine randomized trials have tested hypothermia as a neuroprotectant, inducing it from 2.5 to 15 hours after injury and continuing it for a predetermined period of time regardless of ICP. Eight of these nine trials have been negative with three finding an effect in patients with evacuated hematomas, two of these if hypothermia is rendered before or soon after craniotomy. Despite extensive clinical testing over a range of treatment windows after injury, there is no evidence for the use of hypothermia as a neuroprotectant in patients with diffuse brain injury. Four randomized trials have features of neuroprotection and ICP control, randomizing and initiating hypothermia within 15 hours of injury and continuing hypothermia for the duration of ICP elevation. All found improved outcome and reduced ICP. Based on these findings and the negative results of neuroprotection trials that extended hypothermia for a defined period of time, it is likely that the mechanism of protection in these combined mechanism trials was early control of ICP. This literature suggests the need for clinical trials with two distinct objectives-(1) testing hypothermia for ICP control when conventional means (sedation and paralysis, mannitol, hyperventilation, and cerebrospinal fluid drainage) fail and (2) testing early induction of hypothermia before hematoma evacuation individualizing the duration of hypothermia to the patient's ICP responses.