Ischemic rescue with hemoglobin-based oxygen carriers

Abstract

Experimental studies indicate that hemoglobin-based oxygen carriers (HBOCs) can be effective in rescuing ischemic tissue with residual collateral blood flow after occlusion of a major artery supply. Much of the work showing positive effects of HBOC transfusion has been performed in middle cerebral artery occlusion models of stroke, although some evidence supports their use during ischemia in heart and peripheral tissue. Strategies for improving convective oxygen transport through collateral arteries with HBOCs include (1) boosting blood oxygen carrying capacity, (2) decreasing hematocrit and blood viscosity while limiting the decrease in oxygen carrying capacity, and (3) augmenting dilation of collateral arteries. In addition, plasma-based HBOCs may enhance the delivery of oxygen from the microcirculation to the ischemic parenchymal cells by (1) increasing oxygen flux through individual capillaries that have a disproportionately low flux of red blood cells but persistent plasma flow, (2) filling the capillary spaces between red blood cells with an oxygen source that increases the effective capillary surface area for oxygen diffusion, and (3) facilitating oxygen transport from the red blood cell to the endothelium through the plasma. Newer formulations of HBOCs with carbon monoxide, S-nitrosylation, and superoxide dismutase-mimetic activity endowed by polynitroxylation can be effective at relatively low plasma concentrations, possibly because they may serve to stabilize endothelial function and limit inflammation and reperfusion injury. Future development of HBOCs as a therapeutic for ischemic organs will require determining the precise mechanisms of action of each type of HBOC and the optimal dosage and timing for the specific application.