CEREBRAL OXYGEN TRANSPORT WITH STABILIZED CELL FREE HEMOGLOBIN

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Oxygen transport to the brain is ordinarily well regulated in that decreases in arterial 02 content associated with anemic, hypoxic and CO hypoxia result in reciprocal increases in cerebral blood flow. In the case of anemia, it remains unclear if increased cerebral blood flow is a consequence of decreased viscosity or 02 availability. Differentiating these mechanisms is important because anemia is a common form of clinical hypoxia, hemodilution is routinely employed during cardiopulmonary bypass, and positive evidence of reduced infarction with hemodilution in experimental focal cerebral ischemia has prompted clinical trials in patients with stroke. Exchange transfusion with red cell free oxyhemoglobin provides a unique physiological tool for dissociating effects of 02 carrying capacity from viscosity when hematocrit is reduced. Chemical stabilization of hemoglobin preserves its tetrameric form and 02 binding cooperatively, and increases its circulating half- life compared to untreated hemoglobin. Our overall goal is to determine the mechanism of hematocrit-induced changes in the cerebral circulation under normal and ischemic conditions in anesthetized cats. First, we will determine the effect of reducing hematocrit with or without reductions in O2 carrying capacity on cerebral blood flow, cerebral 02 extraction and cerebral tissue oxyhemoglobin content, measured by near-infrared spectroscopy in vivo. After reducing hematocrit with free oxyhemoglobin or albumin, we will determine how well cerebral O2 transport is regulated when arterial PO2 is reduced. Second, we will show whether circulating free hemoglobin alters endothelial dependent and independent pial arteriolar dilation in vivo or alters blood-brain barrier permeability. Third, by using 31P magnetic resonance spectroscopy to measure brain high energy phosphates and intracellular pH, we will demonstrate if the threshold for producing cerebral ischemia is improved by reducing hematocrit and oxyhemoglobin affinity to augment O2 distribution and unloading. Fourth, we will determine whether free hemoglobin transfusion reduces the progression of cerebral infarction during middle cerebral artery occlusion by increasing tissue oxygenation as a consequence of increased perfusion of free hemoglobin in the ischemic territory. New insights derived from transfusions with oxyhemoglobin of different O2 affinities will distinguish viscosity, O2 carrying capacity, and O2 unloading mechanisms in the regulation of cerebral O2 transport during anemia and ischemia and will provide new strategies for increasing cerebral O2 availability.