The purpose of the mechanical brain injury and therapy laboratory is to provide an experimental facility for resolving issues which are closely allied with the thrust of the clinical trial. As such, experiments targeted for therapy evaluation are designed to more closely simulate actual conditions at time of injury as well as incorporating delays in treatment which normally occur. In the previous application, we tested the hypothesis that mechanical injury results in the development of tissue acidosis which can adversely effect the external and in-internal milieu necessary for cell functi on we measured, using magnetic resonance spec-troscopy (MRS) and and microsphere CBF, the metabolic response to experimental brain injury and observed that CBF was inadequate to meet oxidative demand resulting in relative ischemia which we attributed to impaired vasoreactivity. Based on this evidence, this application is based on the hypothesis that relative ischemia may be avoided either by improving vessel reactivity or decreasing energy requirements. Two drugs, (PEG-SOD) and THAM proposed for use in the ICU will be evaluated as to their effectiveness in reducing impairment of vessel reactivity and improving CBF to meet demand. We will also provide data to clarify the mechanism by which THAM overcomes the deleterious effect of sustained hyperventilation to allow safe use of this therapy for ICP control. A third drug, Etomidate, will be tested in its ability to lower metabolism and ameliorate relative ischemia by reducing blood flow requirements in the well-defined model of fluid percussion injury. Our goal is to provide data to help determine the effectiveness and the mechanism by which these drugs operate in a well-defined model of experimental brain injury. In this way, we can optimize current deliveryy of therapy and suggest new avenues of treatment for improvement f outcome and morbidity.
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