Hemorrhage is the leading cause of death in immediate survivors of severe injury, whether in a combat or civilian setting. Reexpansion of the vascular volume can be achieved by conventional colloids or crystalloids, but unless O2 is resupplied to tissue within the first hour following injury, irreversible metabolic events lead to cell death, organ failure, and death of the victim. The ideal resuscitation solution would combine reestablished tissue perfusion with effective O2 supply. So far, an O2 carrier that is sterile, safe, effective and environmentally compatible is not available, but remains a high priority for both civilian and military trauma research. Development of hemoglobin-based O2 carriers has been impeded by hitherto insurmountable obstacles, chief of which is exacerbation of vasoconstriction, a normal component of shock. NO scavenging is commonly believed to underlie this vasoconstriction, but inconsistent observations, both in the literature and our own laboratory, have led to an alternate (or additional) theory of hemoglobin-induced vasoconstriction, based on O2 signaling in the microcirculation (the """"""""autoregulatory theory""""""""). Using this concept, we have produced a series of novel hemoglobin molecules that are not vasoactive and which promote O2 delivery to tissue, both by the molecules themselves and, of equal importance, by red blood cells. As such, the molecules we have produced are not """"""""blood substitutes"""""""" per se, but a new class of therapeutic agent, effective in small volume, that """"""""target"""""""" O2 to capillaries and hypoxic tissues. The biochemical approach to the modification of hemoglobin is the surface attachment of polyethylene glycol (PEG) in such a way as to obtain values of O2 affinity, viscosity and oncotic pressure optimized for tissue perfusion and O2 delivery to capillary networks. The strength of the proposal is its breadth and depth: we will prepare and characterize the molecules, study their O2 transport properties in vitro (Aim 1), their diffusive behavior in simulated capillaries (Aim 2), their hemodynamic effects (Aim 3), and their rate of extravasation (Aim 4) in rats, and their performance in a swine model of prehospital or military use (Aim 5). The research described in this proposal will focus on molecules and formulations specifically tailored for use in prehospital and trauma settings.
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