HBOC-201 Vasoactivity in a Phase III Clinical Trial in Orthopedic Surgery Subjects—Extrapolation of Potential Risk for Acute Trauma Trials

Abstract

Our limited HEM-0115 safety analysis shows that key potentially vasoactivity-related adverse safety signals were more frequent with HBOC-201 than RBC in older patients undergoing orthopedic surgery with rapid access to safe blood transfusions. That incidences of these safety signals were generally lower and group differences narrowed in subpopulations with stable trauma, hypotension, and younger age, suggests an acceptable safety profile in younger acute trauma populations, especially in settings where rapid access to safe blood transfusions is unavailable; confirmation in controlled clinical trials is urgently warranted.

Clinical practice guideline: Red blood cell transfusion in adult trauma and critical care*

“…These products may also deliver more oxygen per unit mass than an equivalent amount of Hb from RBCs, providing the potential to sustain life in certain clinical situations. A number of problems remain, including short biological half-life, which may limit the application to times when the patient is most acutely anemic (i.e., in the intraoperative or immediate perioperative phase) or for emergent use, vasoactivity (245) and concern regarding possible risks of MI and death examined in a recent meta-analysis (246). There is concern, however, that heterogeneity in HBOCs and controls in these studies preclude combining in a meta-analysis, and lack of information on criteria used to diagnose MIs within these trials was a limitation as well.…”

Sodium nitroprusside ameliorates systemic but not pulmonary HBOC-201-induced vasoconstriction: An exploratory study in a swine controlled haemorrhage model

“…2 However, adverse events, including myocardial infarctions, related to systemic and pulmonary vasoconstriction were reported in HBOC clinical trials. 7,8 Indeed, increased afterload from systemic vasoconstriction, and ventilation-perfusion mismatch causing blood deoxygenation and decreased venous return and cardiac output from pulmonary vasoconstriction could theoretically contribute to cardiac ischemia. HBOC vasoactivity mechanisms have been put forth, including vasoconstriction due to hyperoxia (high P50), endothelin release, adrenergic receptor activation, and arachidonic acid interaction, but nitric oxide (NO) scavenging by extracellular HBOC is considered the primary mechanism.…”

Biophysical Properties and Oxygenation Potential of High-Molecular-Weight Glutaraldehyde-Polymerized Human Hemoglobins Maintained in the Tense and Relaxed Quaternary States

“…However, vasoconstriction and hypertension still remain significant side effects. [1][2][3][4] Although the exact mechanism of vasoconstriction upon HBOC transfusion is not known, there are two major hypotheses in the literature, namely, nitric oxide (NO) scavenging (by far the most popular one of the two) and oxygen oversupply. [5][6][7] To limit/prevent vasoconstriction by either mechanism, the size (i.e., molecular weight, MW) of the HBOC should be increased and free hemoglobin (Hb) and low-MW components should be removed from solution to reduce the interaction of the HBOC with the endothelium.…”