Cerebral oxygen delivery by liposome-encapsulated hemoglobin: a positron-emission tomographic evaluation in a rat model of hemorrhagic shock

Abstract

Liposome-encapsulated Hb (LEH) is being developed as an artificially assembled, low-toxicity, and spatially isolated Hb-based oxygen carrier (HBOC). Standard methods of evaluating oxygen carriers are based on surrogate indicators of physiology in animal models of shock. Assessment of actual delivery of oxygen by HBOCs and resultant improvement in oxygen metabolism at the tissue level has been a technical challenge. In this work, we report our findings from 15O-positron emission tomographic (15O-PET) evaluation of LEH in a rat model of 40% hypovolemic shock. In vitro studies showed that PEGylated LEH formulation containing approximately 7.5% Hb and consisting of neutral lipids (distearoylphosphatidylcholine:cholesterol:alpha-tocopherol, 51.4:46.4:2.2) efficiently picks up 15O-labeled oxygen gas. The final preparation of LEH contained 5% human serum albumin to provide oncotic pressure. Cerebral PET images of anesthetized rats inhaling 15O-labeled O2 gas showed efficient oxygen-carrying and delivery capacity of LEH formulation. From the PET images, we determined cerebral metabolic rate of oxygen (CMR(O2)) as a direct indicator of oxygen-carrying capacity of LEH as well as oxygen delivery and metabolism in rat brain. Compared with control fluids [saline and 5% human serum albumin (HSA)], LEH significantly improved CMR(O2) to approximately 80% of baseline level. Saline and HSA resuscitation could not improve hypovolemia-induced decrease in CMR(O2). On the other hand, resuscitation of shed blood was the most efficient in restoring oxygen metabolism. The results suggest that 15O-PET technology can be successfully employed to evaluate potential oxygen carriers and blood substitutes and that LEH resuscitation in hemorrhage enhances oxygen delivery to the cerebral tissue and improves oxygen metabolism in brain.