A Review of Blood Substitutes: Examining The History, Clinical Trial Results, and Ethics of Hemoglobin-Based Oxygen Carriers

Abstract

The complications associated with acquiring and storing whole blood for transfusions have launched substantial efforts to develop a blood substitute. The history of these efforts involves a complicated mixture of science, ethics, and business. This review focuses on clinical trials of the three hemoglobin-based oxygen carriers (HBOC) that have progressed to Phase II or III clinical trials: He-mAssist (Baxter; Deerfield, IL, US), PolyHeme (Northfield; Evanston, IL, US), and Hemopure (Biopure; Cambridge, MA, US). Published animal studies and clinical trials carried out in a perioperative setting have demonstrated that these products successfully transport and deliver oxygen, but all may induce hypertension and lead to unexpectedly low cardiac outputs. Overall, these studies suggest that HBOCs resulted in only modest blood saving during and after surgery, no improvement in mortality and an increased incidence of adverse reactions. To date, the results from these perioperative studies have not led to regulatory approval. All three companies instead chose to focus their efforts on large trials of trauma patients in the pre-hospital setting.Baxter abandoned the development of HemAssist after a trial in the U.S. was prematurely halted when the first 100 patients showed significantly increased mortality rates as compared to patients treated with blood products. Northfield’s PolyHeme trial demonstrated a non-significant trend towards increased mortality and a very modest reduction in the subsequent need for blood. The testing of Biopure’s Hemopure for trauma patients has been halted for several years because of FDA concerns over trial design and study justification. Ethical concerns have also been raised regarding the design and implementation of all HBOC clinical trials.Thus, the available evidence suggests that HemAssist, Polyheme, and Hemopure are associated with a significant level of cardiovascular dysfunction. The next generation of HBOCs remains under development.

Enhancing Nitrite Reductase Activity of Modified Hemoglobin: Bis-tetramers and Their PEGylated Derivatives

“…This is a lower oxygen affinity than that of native RBCs. It also has an increased molecular weight, with an average of 250 kDa (Range: 130-500) (36). There are a number of parallels between these products.…”

Manipulating hemoglobin oxygenation using silica nanoparticles: a novel prospect for artificial oxygen carriers

“…1 Blood substitutes have to overcome the acute renal toxicity associated with the delivery of free hemoglobin in the circulatory system and to prevent fast clearance from the bloodstream, vasoconstriction, and severe cardiac effects.…”

“…However, the rapid clearance from the bloodstream of the carrier, its degradation leading to the release of free hemoglobin, or the uncontrolled change of the oxygen-binding properties of hemoglobin impairing its oxygen delivery efficiency have limited their clinical application. 1,5,12 In their meta-analysis of 16 clinical trials of hemoglobin-based blood substitutes, Natanson and coworkers concluded that the use of HBOCs is associated with a significant increase of the risk for myocardial infarction and death. 2 The development of HemAssist was later abandoned by Baxter, and the clinical trial of Hemopure on trauma patients in the United States was halted by the US Food and Drug Adminsitration.…”

Repeated Injection of High Doses of Hemoglobin-Encapsulated Liposomes (Hemoglobin Vesicles) Induces Accelerated Blood Clearance in a Hemorrhagic Shock Rat Model

“…Hemoglobin-based artificial oxygen carriers (HBOCs), which include cross-linked (Chen et al, 2009), polymerized (Jahr et al, 2008), and polymer-conjugated Hb (Smani, 2008), have been developed to overcome problems associated with blood transfusion, such as crossmatching, blood-bone infections (human immunodeficiency virus and hepatitis virus), and the shortage of donated blood. Several of these HBOCs are currently in the final stages of clinical evaluation.…”