Tissue oxygenation after exchange transfusion with ultrahigh-molecular-weight tense- and relaxed-state polymerized bovine hemoglobins

Abstract

Hemoglobin (Hb)-based O2 carriers (HBOCs) constitute a class of therapeutic agents designed to correct the O2 deficit under conditions of anemia and traumatic blood loss. The O2 transport capacity of ultrahigh-molecular-weight bovine Hb polymers (PolybHb), polymerized in the tense (T) state and relaxed (R) state, were investigated in the hamster chamber window model using microvascular measurements to determine O2 delivery during extreme anemia. The anemic state was induced by hemodilution with a plasma expander (70-kDa dextran). After an initial moderate hemodilution to 18% hematocrit, animals were randomly assigned to exchange transfusion groups based on the type of PolybHb solution used (namely, T-state PolybHb and R-state PolybHb groups). Measurements of systemic parameters, microvascular hemodynamics, capillary perfusion, and intravascular and tissue O2 levels were performed at 11% hematocrit. Both PolybHbs were infused at 10 g/dl, and their viscosities were higher than nondiluted blood. Restitution of the O2 carrying capacity with T-state PolybHb exhibited lower arterial pressure and higher functional capillary density compared with R-state PolybHb. Central arterial O2 tensions increased significantly for R-state PolybHb compared with T-state PolybHb; conversely, microvascular O2 tensions were higher for T-state PolybHb compared with R-state PolybHb. The increased tissue Po2 attained with T-state PolybHb results from the larger amount of O2 released from the PolybHb and maintenance of macrovascular and microvascular hemodynamics compared with R-state PolybHb. These results suggest that the extreme high O2 affinity of R-state PolybHb prevented O2 bound to PolybHb from been used by the tissues. The results presented here show that T-state PolybHb, a high-viscosity O2 carrier, is a quintessential example of an appropriately engineered O2 carrying solution, which preserves vascular mechanical stimuli (shear stress) lost during anemic conditions and reinstates oxygenation, without the hypertensive or vasoconstriction responses observed in previous generations of HBOCs.