A technique used with increasing frequency in the neurosurgical operating room is temporary occlusion of a major intracranial vessel to facilitate the obliteration of a vascular lesion (e.g. cerebral aneurysm). While this is of great help technically, it produces a potential for cerebral infraction (stroke). Under these conditions, collateral blood flow is present, which distinguishes this type of ischemic insults from complete, global ischemia as produced by cardiac standstill. I proposed to explore means of protecting cerebral tissue from such partial or """"""""focal"""""""" ischemia, using measures designed to maximize energy supply via collaterals, and to minimize the energy requirements of the tissue. These techniques are designed to prevent rather than to treat ischemia and have been generally under-utilized. In the initial phase of the proposed study, I will refine an existing model of focal cerebral ischemia in the rabbit to mimic the conditions present when treating patients with cerebrovascular disease, and I will test the effects of three protective measures used singly and in combination. Induced systemic hypertension and intravenous mannitol will be used to improve energy supply by improving collateral blood flow. Mild hypothermia will be used to reduce energy requirements. In the second phase of the study, I propose to use the focal in vivo ischemia model to test the protective effect of replacing the rabbit's red blood cells with polymerized bovine hemoglobin. The resulting reduction in viscosity, without a reduction in oxygen carrying capacity, is expected to increase substantially the rate of blood flow and oxygen delivery (energy supply) via collaterals to ischemic brain tissue. During the later phase of study, several pharmacologic agents which suppress neuronal metabolism will be combined and delivered prior to the induced ischemia. Since it is anticipated that some of the most useful agents will not readily pass the blood-brain-barrier, intra-arterial mannitol will be given prior to the agents to transiently open the barrier and increase the penetration. If effective, this would provide a new method for avoiding cerebral tissue injury and would have the potential for direct application in the operating room where agents could be given prior to an interval of """"""""planned"""""""" focal brain ischemia.
