THERAPEUTIC MANAGEMENT OF CEREBRAL ISCHEMIA

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We have designed a baboon model which closely parallels the most common manifestations of human cerebrovascular disease. Using our unique vascular occluder, we can reversibly obstruct flow in the middle cerebral artery (MCA) of the unanesthetized baboon. With this model we are able to test the potential of various therapies to alter the outcome of a standardized ischemic insult. Our initial goal during the proposed funneling period is to examine the critical question of whether outcome from ischemic infarction can be improved by reperfusion in the semiacute or chronic stage of evolution without increasing morbidity and mortality. Microvascular extracranial-intracranial (EC-IC) bypass is now a viable clinical option in the treatment of patients suffering from focal cerebral ischemia. Multiple case reports have appeared describing the reversal of chronic neurologic deficits following such revascularization procedures. These reports suggest that it is possible for neurons to remain clinically viable although functionally silent for prolonged periods distal to the area of occlusion in a cerebral vessel. Astrup et al have termed this area of viable but silent neurons the "ischemic penumbra." If areas critical to neurologic function are located within this penumbra, then increasing blood flow should improve neurologic outcome. Because of the risks of increasing cerebral edema in the area of infarct, the earliest that most neurosurgeons would attempt microsurgical revascularization is at 10 days, with the majority preferring to delay such a procedure for 6 weeks. Using our primate model we plan to occlude the MCA in 30 animals: EC-IC bypass will then be carried out at 10 days and 6 weeks after occlusion in two groups (10 animals/group). Results of?neurologic and neuropathologic scores in these two groups will be compared with those in a series of 10 controls without revascularization. If the ischemic penumbra exists and is of any clinical significance, then a difference among these groups should be apparent. In the second stage of this protocol we plan to evaluate three therapies with a potential benefit in the treatment of acute focal cerebral ischemia: 1) the calcium antagonist nimodipine, 2) hypervolemic hemodilution with Dextran-40, and 3) use of Fluosol-DA. These therapies will be evaluated in our primate model with both six hour and permanent MCA occlusion. Neurologic and neuropathologic evaluations will be compared with the results in controls at two weeks.