Spontaneous intracerebral hemorrhage (ICH) is a common and often fatal disease with no effective treatment. While the intracerebral hematoma resolves spontaneously after several weeks, the pathophysiologic mechanisms responsible for ICH mortality, morbidity and factors defining the reversibility of induced brain changes are complex and remain poorly understood. This proposal seeks to study ICH in pigs, a species which -- because large hematoma volumes may be studied --permits blood aspiration following in situ clot lysis. Hematoma aspiration using this new promising surgical technique will take place after different time intervals and with and without adjunct pharmacologic treatments aimed at extending the window of opportunity for surgical treatment. Differences in outcome will aid in defining the optimal time for surgical hematoma removal and determine the effectiveness of pharmacologic treatment. Serial topographic brain biochemical and water content determinations will help define the sequence of pathophysiologic and pathochemical events causing death and tissue injury. Cerebral blood flow, cerebral tissue pressure and EEG will be monitored and correlated with outcome. We will test the hypothesis that an inverse time-dependent relationship is present between hematoma evacuation (aspiration after in situ clot lysis) and ICH outcome (mortality, neurologic deficit, extent of tissue necrosis). Secondly, we hypothesize that ICH activates a series of multifactorial pathophysiologic and pathochemical cascades in the marginal zone adjacent to the hematoma which ultimately lead to perifocal ischemia and the development of brain edema and tissue necrosis. Specifically, these pathochemical mechanisms include: delayed perifocal ischemia resulting in marked energy depletion and lactic acidosis, elevation of extracellular concentrations of glutamate due to high levels in the hematoma and from endogenous release, and oxygen free radical production directly by blood components or by tissue adjacent to the hematoma depleting antioxidants and inducing membrane lipid peroxidation. Lastly, we propose that pharmacologic treatments that interrupt these brain damaging pathochemical cascades, including buffers, glutamate receptor antagonists, free radical scavengers and lipid peroxidation inhibitors will extend the window of opportunity for surgical intervention to salvage viable brain tissue.
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