In this feasibility proposal we are seeking support for the development of a comprehensive clinical and basic science head-injury research center. We will study the therapeutic value and potential mechanisms of action of moderate hypothermia administered after head injury. Data from our laboratories suggest that mild to moderate cerebral hypothermia used after global cerebral ischemia in dogs improves outcome and reduces mortality. Recent studies in a rodent fluid percussion model also suggest that hypothermia improves outcome, and that hypothermia may be more effective than many other types of therapy. In our clinical projects we will randomize adult victims of severe closed-head-injury to a normothermia group or a group cooled to 32-33 degree centigrade for 24 hours after their injury. Emphasis will be placed on cooling as soon as possible following the injury. Physiologic, metabolic and blood flow measurements will be made at frequent intervals during the first five days after injury, and the influence of hypothermia on these parameters will be assessed through statistical comparison of values from the experimental and control groups. Clinical outcome in both groups will also be carefully assessed and recorded. In our basic science projects we will define potential mechanisms through which hypothermia may be effective, determine the time interval following injury during which hypothermia might be expected to be effective, and determine if the use of high-dose steroids might enhance the efficacy of moderate hypothermia. These projects will complement the clinical projects by systematically analyzing ventricular cerebrospinal fluid (CSF) and brain tissue specimens obtained from human head-injured subjects for interleukin-1, glutamate and aspartate to define their role as mediators of secondary brain injury, and the effect of hypothermia on their concentration in CSF and brain tissue. In a rodent focal cerebral contusion model we will use microdialysis to investigate the time course of appearance of these neurochemicals in the extracellular space, and the effect of hypothermia on suppression of their production. In this same experimental paradigm we also will investigate the effects of hypothermia on nerve growth factor concentrations, and density and function of NMDA receptors. Using behavioral and histological analysis we will define the time interval after blunt head injury in rats and epidural compression injury in dogs during which hypothermia might still be efficacious. Finally, we will determine if a combination of high-dose steroids and moderate hypothermia will prolong the therapeutic window during which treatment can be administered. The projects submitted in this head-injury center proposal are designed to answer fundamental questions about the mechanisms of action of hypothermia in head injury, and its effect on cerebral physiology, metabolism and blood flow. Our results will provide the groundwork for a multicenter clinical trial of moderate hypothermia.
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