PolyHeme

Abstract: Background Human polymerized hemoglobin (PolyHeme, Northfield Laboratories) is a universally compatible oxygen carrier developed to treat life-threatening anemia. This multicenter phase III trial was the first US study to assess survival of patients resuscitated with a hemoglobin-based oxygen carrier starting at the scene of injury. Study Design Injured patients with a systolic blood pressure≤90 mmHg were randomized to receive field resuscitation with PolyHeme or crystalloid. Study patients continued to receive up to 6 U of PolyHeme during the first 12 hours postinjury before receiving blood. Control patients received blood on arrival in the trauma center. This trial was conducted as a dual superiority/noninferiority primary end point. Results Seven hundred fourteen patients were enrolled at 29 urban Level I trauma centers (79% men; mean age 37.1 years). Injury mechanism was blunt trauma in 48%, and median transport time was 26 minutes. There was no significant difference between day 30 mortality in the as-randomized (13.4% PolyHeme versus 9.6% control) or per-protocol (11.1% PolyHeme versus 9.3% control) cohorts. Allogeneic blood use was lower in the PolyHeme group (68% versus 50% in the first 12 hours). The incidence of multiple organ failure was similar (7.4% PolyHeme versus 5.5% control). Adverse events (93% versus 88%; p=0.04) and serious adverse events (40% versus 35%; p=0.12), as anticipated, were frequent in the PolyHeme and control groups, respectively. Although myocardial infarction was reported by the investigators more frequently in the PolyHeme group (3% PolyHeme versus 1% control), a blinded committee of experts reviewed records of all enrolled patients and found no discernable difference between groups. Conclusions Patients resuscitated with PolyHeme, without stored blood for up to 6 U in 12 hours postinjury, had outcomes comparable with those for the standard of care. Although there were more adverse events in the PolyHeme group, the benefit-to-risk ratio of PolyHeme is favorable when blood is needed but not available.

Abstract: We have previously documented the safety of 1 unit (50 gram) of human polymerized hemoglobin (Poly SFH-P) in healthy volunteers. This report describes the first patient trial to assess the therapeutic benefit of Poly SFH-P in acute blood loss. Thirty-nine patients received 1 In = 14), 2 In = 2), 3 In = 15), or 6 In = 8) units of Poly SFH-P instead of red cells as part of their blood replacement after trauma and urgent surgery. There were no safety issues related to the infusion of Poly SFH-P. The plasma hemoglobin concentration ([Hb]) after the infusion of 6 units (300 gram) of Poly SFH-P was 4.8 ± 0.8 g/dL (mean ± SD). Although the red cell [Hb] fell to 2.9 ± 1.2 g/dL, the total [Hb] was maintained at 7.5 ± 1.2 g/dL. Poly SFH-P maintained total [Hb], despite the marked fall in red cell [Hb] due to blood loss. The utilization of O 2 (extraction ratio) was 27 ± 16% from the red cells and 37 ± 13% from the Poly SFH-P. Twenty-three patients (59%) avoided allogeneic transfusions during the first 24 hours after blood loss. Poly SFH-P effectively loads and unloads O 2 and maintains total hemoglobin in lieu of red cells after acute blood loss, thereby reducing allogeneic transfusions. Poly SFH-P seems to be a clinically useful blood substitute.

Abstract: Donor blood is a limited resource and its transfusion is associated with significant adverse effects. Therefore, alternatives have been searched, the ultimate being artificial oxygen (O2) carriers. There are two main groups of artificial O2 carriers: hemoglobin based and perfluorocarbon emulsions. The hemoglobin molecule in hemoglobin based artificial O2 carriers needs to be stabilized to prevent dissociation of the alpha2beta2-hemoglobin tetramer into alphabeta-dimers in order to prolong intravascular retention and to eliminate nephrotoxicity. Other modifications serve to decrease O2 affinity in order to improve O2 off-loading to tissues. In addition, polyethylene glycol may be surface conjugated to increase molecular size. Finally, certain products are polymerized to increase the hemoglobin concentration at physiologic colloid oncotic pressure. Perfluorocarbons are carbon-fluorine compounds characterized by a high gas dissolving capacity for O2 and CO2 and chemical and biologic inertness. Perfluorocarbons are not miscible with water and therefore need to be brought into emulsion for intravenous application. Development, product specification, physiologic effects, efficacy to decrease the need for donor blood in surgery and side effects of the following products are described: Diaspirin cross-linked hemoglobin (HemAssist), human recombinant hemoglobin (rHb1.1 and rHb2.0), polymerized bovine hemoglobin-based O2 carrier (HBOC-201), human polymerized hemoglobin (PolyHeme), hemoglobin raffimer (Hemolink), maleimide-activated polyethylene glycol-modified hemoglobin (MP4) and perflubron emulsion (Oxygent). In addition, enzyme cross-linked poly-hemoglobin, hemoglobin containing vesicles (nano-dimension artificial red blood cells) and an allosteric modifier (RSR13) are discussed. The most advanced products are in clinical phase III trials but no product has achieved market approval yet in the US, Europe or Canada.