Resuscitation of the injured patient with polymerized stroma-free hemoglobin does not produce systemic or pulmonary hypertension

doi:10.1016/S0002-9610(98)00275-X

The American Journal of Surgery

Volume 176, Issue 6, December 1998, Pages 612-617

Presented at the 50th Annual Meeting of the Southwestern Surgical Congress, San Antonio, Texas, April 19–22, 1998.

https://doi.org/10.1016/S0002-9610(98)00275-X Get rights and content

Abstract

Background: Hemoglobin-based blood substitutes appear poised to deliver the promise of a universally compatible, disease-free alternative to banked blood. However, vasoconstriction following administration of tetrameric hemoglobins has been problematic, likely because of nitric oxide binding. Polymerized hemoglobin is effectively excluded from the abluminal space because of its size, and is thus less likely to perturb vasorelaxation. We therefore hypothesized that hemodynamic responses would be no different in injured patients receiving polymerized hemoglobin versus banked blood.

Methods: Injured patients requiring urgent transfusion were randomized to receive either polymerized hemoglobin or banked blood. Systemic arterial pressure, pulmonary arterial pressure, cardiac index, pulmonary capillary wedge pressure, systemic vascular resistance, and pulmonary vascular resistance were measured serially.

Results: There was no difference in any of the measured hemodynamic parameters between patients resuscitated with polymerized hemoglobin versus blood.

Conclusions: Polymerized hemoglobin given in large doses to injured patients lacks the vasoconstrictive effects reported in the use of other hemoglobin-based blood substitutes. This supports the continued investigation of polymerized hemoglobin in injured patients requiring urgent transfusion.

Section snippets

Materials and methods

Injured patients greater than 17 years of age with an anticipated need for urgent transfusion were eligible for this study. The protocol was approved by the Colorado Multiple Institutional Review Board, and patients were enrolled only after informed consent was obtained from the patient or family. Patients were then randomized to receive either polymerized hemoglobin (up to 6 units, approximately 4,500 mg/kg) or banked red blood cells as their initial oxygen carrying resuscitative fluid.

Results

Seven patients received banked packed red blood cells, and 6 received polymerized hemoglobin as their initial oxygen-carrying fluid. All patients had suffered serious blunt injuries (motor vehicle collision or pedestrian struck by auto). The groups were not statistically different with respect to injury severity (blood group ISS 19.9 ± 1.7 versus PolyHeme group ISS 23.5 ± 1.5) or age (blood group 37.0 ± 4.7 versus PolyHeme group 30.3 ± 3.3). Further, at the beginning of central hemodynamic

Comments

Several formulations of hemoglobin are now poised to deliver the promise of a universally compatible, immediately available, disease-free substitute for red cells in the resuscitation of the injured patient. Many problems associated with transfusion of the naturally occurring tetramer have been alleviated through chemical modification; however, pressor effects remain a critical hurdle for tetrameric formulations to overcome. For example, in an animal study modeling resuscitation from

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The low dose of GU-HP-Hb was proven to be protective again cardiac ischemia when compared with the high dose, which was verified by the overall impaired cardiac function [208]. Similarly, in another study conducted by Heneka et al., polymerized Hb was found to reinstate cardio and glomerular function in an endotoxin-induced animal model [209,210]. Polymerized bovine Hb (HBOC-201) was compared with Hetastarch concerning resuscitation performance in pig models [211].
Blood transfusion is the key to life in case of traumatic emergencies, surgeries and in several pathological conditions. An important goal of whole blood or red blood cell transfusion is the fast delivery of oxygen to vital organs and restoration of circulation volume. Whole blood or red blood cell transfusion has several limitations. Free haemoglobin not only loses its tetrameric configuration and extracts via the kidney leading to nephrotoxicity but also scavenges nitric oxide (NO), leading to vasoconstriction and hypertension. PFC based formulations transport oxygen in vivo, the contribution in terms of clinical outcome is challenging. The oxygen-carrying capacity is not the only criterion for the successful development of haemoglobin-based oxygen carriers (HBOCs). This review is a bird's eye view on the present state of the PFCs and HBOCs in which we analyzed the current modifications made or which are underway in development, their promises, and hurdles in clinical implementation.
The USA Multicenter Prehosptial Hemoglobin-based Oxygen Carrier Resuscitation Trial: Scientific Rationale, Study Design, and Results
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The ideal control group to assess efficacy of an oxygen carrier when blood is not available would comprise severely injured, massively bleeding patients who have critically low [Hb] levels and substantially delayed access to blood and the resulting high mortality. Prior clinical experience with PolyHeme in hospitalized patients26–28,48,49,52,74–78 has shown that PolyHeme can provide life-sustaining oxygen-carrying capacity at otherwise life-threatening Hb levels.52 Because of the possibility that the control group would include patients who had mixed injury severity, variable volumes of blood loss, and early access to blood, dual primary end points of superiority and noninferiority were employed.
Human polymerized hemoglobin (PolyHeme) is a universally compatible oxygen carrier developed for use when red blood cells are unavailable and oxygen-carrying replacement is needed to treat life-threatening anemia. This multicenter phase III trial assessed survival of patients resuscitated with a hemoglobin-based oxygen carrier starting at the scene of injury. Patients resuscitated with PolyHeme had outcomes comparable to those receiving the standard of care including rapid access to stored red blood cells. Although there were more adverse events in the PolyHeme group compared with control patients receiving blood, the observed safety profile is acceptable for the intended population. The benefit-to-risk ratio of PolyHeme is favorable when blood is needed but is not available or an option.
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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.
Human Polymerized Hemoglobin for the Treatment of Hemorrhagic Shock when Blood Is Unavailable: The USA Multicenter Trial
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But the overall incidence of substantially abnormal episodes of systolic and diastolic hypertension on arrival at the hospital or through 6 hours postinjury was low (5% PolyHeme versus 3% control and 7% PolyHeme versus 7% control, respectively). The lack of significant evidence of vasoconstriction is consistent with our previous work.46 The incidence of renal failure was also low and comparable between groups (3% PolyHeme, 2% control).
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.
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.
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.
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.
Hypovolemic Shock
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Dissociation of local nitric oxide concentration and vasoconstriction in the presence of cell-free hemoglobin oxygen carriers
2006, Blood
Citation Excerpt :
Hb extravasation into the vessel wall is presumed to cause NO scavenging.4,5 Polymerization of the protein that limits extravasation has in some cases elicited6,7 or prevented8 hypertension. In general, large conjugated or polymerized Hbs with increased effective molecular radii appear to be inversely correlated with the hypertensive response.9
Cell-free hemoglobin's (CFH) high affinity for nitric oxide (NO) could limit CFH's use as an oxygen-carrying blood replacement fluid because it scavenges NO, causing vasoconstriction and hypertension. However, the extent to which perivascular NO levels change following intravascular administration of hemoglobin (Hb) with different molecular dimensions correlates with vasoconstrictive responses in the microcirculation is unknown. The study objective was to determine vasoconstrictive effects following bolus infusions of (1) αα cross-linked Hb; (2) polymerized bovine Hb; or (3) polyethylene glycol-decorated Hb (PEG-Hb), by measurements of in vivo microvessel diameter, blood flow, perivascular NO concentration, and systemic hemodynamic parameters. All CFHs caused reductions in perivascular NO levels, not correlated to microvascular responses. PEG-Hb (largest molecular volume) maintained blood flow, while the others caused vasoconstriction and reduced perfusion. All solutions increased mean arterial pressure due to vasoconstriction and blood volume expansion, except for PEG-Hb, which increased blood pressure due to blood volume expansion and maintenance of cardiac output. In conclusion, perivascular NO reduction is similar for all Hb solutions because NO binding affinities are similar; however, effects on vascular resistance are related to the type of molecular modification, molecular volume, and oxygen affinity.

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^☆: This work was supported in part by National Institutes of Health Grants P50GM49222 and T32GM08315.

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Scientific PapersResuscitation of the injured patient with polymerized stroma-free hemoglobin does not produce systemic or pulmonary hypertension☆

Abstract

Section snippets

Materials and methods

Results

Comments

J Thorac Cardiovasc Surg

Crit Care Clin

Free Rad Biol Med

The clinical utility of human polymerized hemoglobin as a blood substitute following trauma and emergent surgery

J Trauma

Hemoglobin solution in the treatment of hemorrhagic shock

Crit Care Med

Mechanism of NO-induced oxidation of myoglobin and hemoglobin

Biochemistry

Scientific Papers
Resuscitation of the injured patient with polymerized stroma-free hemoglobin does not produce systemic or pulmonary hypertension☆