Abstract
Currently there are limited therapeutic interventions that have been reported to improve functional outcomes in patients with traumatic brain injury (TBI) in terms of successful Phase 3 randomized controlled clinical trials. Therapeutic hypothermia (controlled induced hypothermia) and targeted temperature management (32–36 °C) have been evaluated in a variety of experimental and clinical situations indicating that this is a potentially important strategy for limiting secondary injury mechanisms. Indeed, studies using clinically relevant animal models of acute CNS injury conducted by multiple laboratories have repeatedly shown that while therapeutic hypothermia is protective and improves functional outcomes, mild elevations in temperature can produce detrimental consequences. Based on these preclinical investigations, clinical studies have been initiated including both single institutional and multicenter TBI trials. Unfortunately, while some mild-to-moderate hypothermia TBI studies and trials have reported improvements in neurological outcomes in certain patient populations, larger randomized multicenter trials have failed to show significant improvements in severe TBI patients when comparing normothermic and hypothermic treatments. Various explanations for these failures have been discussed and include issues concerning patient heterogeneity, a limited therapeutic window for cooling effectiveness, and uncertainty regarding optimal cooling levels, duration as well as rewarming protocols. Nevertheless, there remains significant interest in determining better ways to apply hypothermia as well as determining which patients may be responsive or non-responsive to this powerful therapeutic intervention. This chapter summarizes the preclinical and clinical literature emphasizing the importance of brain temperature in modifying secondary injury mechanisms after TBI. Emphasis is also placed on recent studies that are helping to clarify specific factors that may be critical in the successful use of this powerful treatment intervention.