Polymerized Hemoglobin Maintains Cardiac Function After Extreme Anemia

Abstract

BackgroundBlood transfusion as a treatment for anemia is vital in ensuring oxygen (O2) carrying capacity. However, fears of blood shortages and adverse reactions to stored blood transfusion have driven the development of oxygen carrying alternatives to blood. One class of alternatives to blood for transfusion medicine are hemoglobin (Hb) based oxygen carriers (HBOCs), which have been in development for decades. A recent advancement in the development of HBOCs is the discovery that their O2 affinity can be tightly regulated by locking Hb in the T state (low O2 affinity), or R state (high O2 affinity). By regulating O2 affinity, O2 extraction by tissues can be controlled, and targeted O2 delivery to hypoxic tissues is made possible. As the heart is one of the most sensitive organs to changes in oxygenation due to its high metabolic rate, the objective of this study was to test the efficacy of high and low O2 affinity HBOCs in maintaining cardiac function and systemic O2 delivery during severe anemia.MethodsPolymerized hemoglobin (PolyHb), the most scalable method of producing HBOCs, was synthesized in the high and low O2 affinity state (R and T, respectively) with glutaraldehyde and then subjected to 8–9 cycles of diafiltration as previously described. This resulted in a PolyHb solution containing only polymerized Hb molecules > 500kDa suspended in Lactated Ringers solution. Rats were instrumented with a pressure‐volume catheter to monitor cardiac function. Severe anemia was induced via a 50% isovolumic hemodilution with 5% human serum albumin. Rats were then resuscitated by a 40% isovolumic infusion of a 10 g/dL solution of R PolyHb, T PolyHb, or fresh blood (drawn from the animal during the first exchange).ResultsSevere anemia resulted in impaired cardiac function and O2 delivery. Transfusion of fresh blood, T PolyHb, and R PolyHb restored vascular resistance, blood pressure, and cardiac contractility. T PolyHb also promoted increased O2 extraction and myocardial energy utilization. Severe anemia did not cause significant changes in blood electrolytes relative to baseline. Severe anemia resulted in blood acidification that only recovered for animals resuscitated with T PolyHb. Furthermore, resuscitation with T PolyHb resulted in higher arterial pO2 and lower pCO2 than other groups. R PolyHb increased lactate and glucose, suggesting that the high O2 affinity prevented proper O2 release to some tissues, despite maintaining cardiac function.ConclusionsBoth T and R PolyHb maintain myocardial O2 extraction compared to fresh blood. T PolyHb appears to be the optimal molecule for increasing O2 delivery during anemic conditions. Although R PolyHb apparently decreased systemic O2 extraction during anemia, it can be potentially useful to increase O2 uptake in the lungs during hypoxic‐hypoxia. This study indicates that PolyHb is as efficacious as fresh blood in restoring cardiac function and oxygenation in rats during severe anemia.Support or Funding InformationThis work was supported by the NIH Heart Lung and Blood Institute under Grants T32‐HL105373, R01‐HL126945, and R01‐HL138116.