The goals of these studies are to examine the delivery and utilization of oxygen in the brain of the developing sheep under both normal and pathologic circumstances as well as begin to gain an understanding of mechanisms of brain injury. Two studies are designed to answer basic physiologic questions about the regulation of the cerebral circulation. Making use of radiolabelled microsphere methodology and a sagittal sinus catheter to sample cerebral venous drainage in fetal and neonatal sheep, cerebral blood flow, O2 delivery, O2 consumption, and fractionational O2 extraction will be measured or calculated. The first of these studies seeks to demonstrate that the steeper response of the cerebral circulation to changes in PaCO2 in the adult sheep compared to the fetal sheep is due to a difference in hemoglobin O2 affinity rather than an intrinsic difference in vascular reactivity between immature and mature brain. The second study will examine the clinically relevant issue of potential harmful effects of therapeutically induced hypocarbia, specifically whether or not cerebral O2 consumption falls during severe hypocarbia. Three studies are designed to consider mechanisms of brain injury after asphyxia. The central hypothesis is that much of the brain injury associated with asphyxia occurs after rather than during the event. These studies will utilize a neonatal lamb asphyxia model. One protocol will consider the response of cerebral blood flow and O2 metabolism after asphyxia to hypoxia and hypotension using radiolabelled microspheres and a sagittal sinus catheter. An inability to maintain O2 delivery and O2 consumption with these perturbations is potentially an important means of post asphyxial brain injury. A second study will focus on the roles of eicosanoid and free radical production in the etiology of post asphyxial cerebral blood flow and O2 metabolism abnormalities. Preliminary data will also be collected on these products role in the generation of cerebral edema, and mitochondria dysfunction. Finally the effect of preasphyxial blood glucose concentration and subsequent lactate accumulation during asphyxia on post asphyxial blood flow and O2 metabolism abnormalities will be evaluated utilizing glucose clamp technology. The importance of these studies is that glucose concentration, eicosanoid and free radical production are potentially altered therapeutically so an understanding of their role in brain injury lends itself to future therapeutic advances.
