Acellular hemoglobin-based oxygen carrier mediated blood pressure elevation and vasoconstriction: A review of proposed mechanisms and contributing factors

Abstract

A key impediment to regulatory approval of HBOCs appears to be an undesirable BP elevation (hypertension) often observed following IV administration in preclinical and clinical studies. The HBOC-mediated hypertension, as it occurs without increased cardiac output, appears to be primarily mediated by systemic vasoconstriction. In fact, a recent statement by FDA indicates that all HBOC products reviewed are vasoactive at the doses proposed for clinical use. Acute BP elevation could cause serious adverse effects (AEs) in vulnerable patients. Because vasoconstriction can cause suboptimal blood flow to affected organs, a crucial question is whether HBOC-mediated vasoconstriction is directly or indirectly responsible for some of the adverse events observed in recent clinical trials. There are many theories and hypotheses but little evidence that definitively links HBOC to observed adverse events. The pathophysiology involved in trauma, hemorrhage, ischemia and reperfusion is extremely complex and etiology of HBOC treatment associated AEs has not been elucidated. In this chapter, key currently proposed mechanisms for the HBOC-mediated BP elevation/vasoconstriction are reviewed. A most widely accepted mechanism for most HBOC-mediated vasoconstriction cases is Hb inactivation of endothelial NO, a potent vasodilator constitutively produced in the vascular endothelium. However, other mechanisms that may also play a more prominent role or multiple mechanisms may participate in concert under certain clinical conditions. In addition, a variety of factors that contribute to the manifestation of HBOC-mediated vasoactivity are also discussed.