Adverse HBOC-Endothelial Dysfunction Synergism: A Possible Contributor to Adverse Clinical Outcomes?

Abstract

Adverse outcomes in clinical trials on Hemoglobin Based Oxygen Carriers (HBOCs) appear to have occurred more frequently in HBOC treated than in control treated subjects. The differential may be related to many factors, including study complexity and compliance issues. Adverse outcomes also appear to be related to chronic comorbidities in subjects undergoing elective surgery. Frequently occurring comorbidities in these populations are those related to aging, cardiovascular and metabolic disease (hypertension, atherosclerosis, diabetes, etc.). These are highly prevalent among many population subsets. These conditions have been extensively studied and are characterized by dysfunction of important endothelial vasoregulatory mechanisms, including impaired nitric oxide bioavailability, excessive generation of reactive oxygen species (ROS) and possibly enhanced vasoconstrictor mechanisms. Although less extensively studied, HBOCs have properties that may have an important amplifying effect upon mechanisms operating in endothelial dysfunction, by scavenging nitric oxide, generating further excess of ROS which in turn react with nitric oxide, inhibit nitric oxide synthase and possibly stimulate the release of vasoconstrictors such as endothelin. It is likely that amplification of vasoconstrictor effects is not uniformly operative in all vascular beds, and that some protective autoregulatory mechanisms maintain sufficient blood flow in vital organs as long as sufficient vasodilator reserve is available. When the latter is exhausted in the presence of arterial disease with physical obstructions, blood flow to vital organs may become compromised. This paper suggests avenues of further exploration to elucidate whether the combination of HBOC and endothelial dysfunction is a contributing factor in HBOC related adverse outcomes.