Recent developments in hemoglobin-based oxygen carriers – an update on clinical trials

doi:10.1016/S0955-3886(00)00122-3

Transfusion and Apheresis Science

Volume 24, Issue 1, February 2001, Pages 17-21

https://doi.org/10.1016/S0955-3886(00)00122-3 Get rights and content

Abstract

Considerable progress has been made in the development of the hemoglobin based oxygen carriers (HBOCs), with a number of products in the final stages of clinical development prior to licensing application. This follows many years of concentrated study. Although there are limitations to the clinical use of the currently studied HBOCs, there are a number of advantages that suggest that these products will have an important role in future clinical practice. It is anticipated that these products will be commercially available within two years.

Section snippets

History of oxygen carriers

The realization of commercially available hemoglobin-based oxygen carriers (HBOCs), which are often historically referred to as blood substitutes, appears to be near at hand. This follows a long and somewhat arduous search for a safe and effective alternative for the oxygen carrying capacity of hemoglobin (Hb) that is currently provided by red blood cell transfusion. Initial exploration into this arena focused on cell-free hemoglobin preparations. Unfortunately these early preparations

Oxygen carriers in development

There are currently two major classes of oxygen therapeutics in clinical development, the HBOCs, and the perfluorocarbon emulsions (PFCs) [1], [2]. HBOCs, like red blood cells, depend on the chemical and physical properties of hemoglobin to bind and release oxygen under specific physiologic conditions. Potential sources of the acellular Hb for HBOCs include outdated human red cells, bovine Hb and recombinant technologies using an E. coli expression system. In contrast, PFCs are independent of

Potential benefits of HBOCs

The HBOCs are a distinct group of compounds with important advantages over donor red cells. A significant advantage of HBOCs is that they are virtually pathogen free as a result of pasteurization and viral filtration. These processes remove viruses, such as HIV, hepatitis A, B, and C, and other pathogens. Further, the HBOCs do not contain residual RBC membranes, thus they do not contain the blood antigen molecules, so do not need to be cross-matched, and may be given to patients of all blood

Limitations of HBOC clinical use

Although HBOCs represent a significant therapeutic advance, there are some limitations to the clinical application of these preparations. Cell-free hemoglobin, including HBOCs is known to bind the endogenous vasodilator, nitric oxide (NO). Locally released NO can be scavenged by hemoglobin thus preventing NO from exerting a tonic vasodilator action, thereby allowing vasoconstrictor mechanisms to dominate [2]. This results in an increase in blood pressure in patients treated with HBOCs. These

Hemolink™

Hemolink™, a human-derived hemoglobin-based HBOC, is cross-linked and polymerized with o-raffinose [3], [4].

As of March 2000, seven clinical trials of Hemolink™ had been completed: one Phase I safety study, six Phase II studies (two in cardiac surgery, three in orthopedic surgery and one in anemia). In addition, enrollment in a pivotal Phase III trial in coronary artery bypass grafting (CABG) surgery in Canada and UK was completed in March 2000 and a similar trial is currently underway in the

Clinical applications of HBOCs

When one anticipates where blood substitutes will be used in the future, one only has to ask where are RBC's used today. Roughly 50% of transfused RBCs are used for medical treatment of anemias of various etiologies, and the remainder in surgery and trauma. The companies currently in Phase III trials are expected to submit for regulatory approval with the anticipation that these products will be available in the market place in one to two years, world wide. With approval, where will these

Summary and conclusions

Significant progress has been made in the development of HBOCs within the past few years. The converging evidence from studies with HBOCs has demonstrated that they are a safe and effective means of providing hemoglobin and oxygen carrying capacity to tissues in times of acute hemoglobin deficiency. Therefore it is anticipated that HBOCs will dramatically change transfusion practice and emerge as major alternatives to the use of allogeneic or donor red blood cells in a number of clinical

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Free hemoglobin has enormous affinity for NO and can reduce the plasma level of NO to the point of causing symptoms. This reduction has been demonstrated in clinical trials where the administration of cell-free hemoglobin solutions to healthy people is associated with development of abdominal pain and esophageal spasm.55 Under normal conditions, hemoglobin is sequestered by the erythrocyte membrane, which minimizes the scavenging of NO. In PNH, the intravascular hemolysis results in release of large amounts of free hemoglobin into the plasma.
Perioperative Blood Transfusion and Blood Conservation in Cardiac Surgery: The Society of Thoracic Surgeons and The Society of Cardiovascular Anesthesiologists Clinical Practice Guideline
2007, Annals of Thoracic Surgery
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Combinations of ANH with other blood conservations may be beneficial. For example, use of synthetic fluorocarbons or hemoglobin based oxygen carrier products in conjunction with ANH shows clinical promise in most published trials [520–524]. Additionally, several studies suggest that a combination of blood conservation interventions is likely to provide the best reduction in blood transfusion [469, 525–530].
A minority of patients having cardiac procedures (15% to 20%) consume more than 80% of the blood products transfused at operation. Blood must be viewed as a scarce resource that carries risks and benefits. A careful review of available evidence can provide guidelines to allocate this valuable resource and improve patient outcomes.
We reviewed all available published evidence related to blood conservation during cardiac operations, including randomized controlled trials, published observational information, and case reports. Conventional methods identified the level of evidence available for each of the blood conservation interventions. After considering the level of evidence, recommendations were made regarding each intervention using the American Heart Association/American College of Cardiology classification scheme.
Review of published reports identified a high-risk profile associated with increased postoperative blood transfusion. Six variables stand out as important indicators of risk: (1) advanced age, (2) low preoperative red blood cell volume (preoperative anemia or small body size), (3) preoperative antiplatelet or antithrombotic drugs, (4) reoperative or complex procedures, (5) emergency operations, and (6) noncardiac patient comorbidities. Careful review revealed preoperative and perioperative interventions that are likely to reduce bleeding and postoperative blood transfusion. Preoperative interventions that are likely to reduce blood transfusion include identification of high-risk patients who should receive all available preoperative and perioperative blood conservation interventions and limitation of antithrombotic drugs. Perioperative blood conservation interventions include use of antifibrinolytic drugs, selective use of off-pump coronary artery bypass graft surgery, routine use of a cell-saving device, and implementation of appropriate transfusion indications. An important intervention is application of a multimodality blood conservation program that is institution based, accepted by all health care providers, and that involves well thought out transfusion algorithms to guide transfusion decisions.
Based on available evidence, institution-specific protocols should screen for high-risk patients, as blood conservation interventions are likely to be most productive for this high-risk subset. Available evidence-based blood conservation techniques include (1) drugs that increase preoperative blood volume (eg, erythropoietin) or decrease postoperative bleeding (eg, antifibrinolytics), (2) devices that conserve blood (eg, intraoperative blood salvage and blood sparing interventions), (3) interventions that protect the patient's own blood from the stress of operation (eg, autologous predonation and normovolemic hemodilution), (4) consensus, institution-specific blood transfusion algorithms supplemented with point-of-care testing, and most importantly, (5) a multimodality approach to blood conservation combining all of the above.
Blood substitutes: Hemoglobin-based oxygen carriers
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Resuscitation with a blood substitute causes vasoconstriction without nitric oxide scavenging in a model of arterial hemorrhage
2004, Journal of the American College of Surgeons
The purpose of this study was to determine if a hemoglobin-based oxygen carrier, HBOC-201 (Hemopure, Biopure Corp), alters endothelial function and nitric oxide physiology when used for hemorrhagic shock.
Female swine (Sus scrofa) underwent catheterization of the femoral, circumflex iliac, and pulmonary arteries. Control animals (n = 3) underwent instrumentation only. Study animals underwent hemorrhage to mean arterial pressure of 30 ± 5 mmHg, were maintained for 45 minutes, and resuscitated to the baseline mean arterial pressure for 4 hours. Resuscitation fluids included: shed blood (SB) (n = 8), lactated Ringers plus shed blood (LRSB) (n = 8), and HBOC (n = 8). At baseline, 1, and 4 hours after resuscitation, acetylcholine was infused into the proximal iliac artery and endothelial-dependent relaxation was measured with M-mode ultrasonography. Nitric oxide levels were determined using a chemiluminescent assay.
HBOC, SB, and LRSB provided equivalent survival and resuscitation as measured by mean arterial pressures (65.3 ± 2.48 mmHg); pulmonary artery mean pressures (15.8 ± 0.84 mmHg); and lactate levels (1.22 ± 0.19 mmol/L). HBOC group animals required the lowest resuscitation volume (SB, 41.5 ± 3.5 mL/kg; LRSB, 76.4 ± 1.1 mL/kg, HBOC, 14.6 ± 2.1 mL/kg, p < 0.001). Response to acetylcholine was normal in the SB and LRSB groups, but the HBOC group had diminished acetylcholine response (29.5% endothelial-dependent relaxation end resuscitation, p < 0.001). Arterial nitric oxide levels did not differ between study groups (p = 0.69).
HBOC might be an alternative resuscitation agent in patients with hemorrhagic shock. Resuscitation with HBOC requires less volume than blood or crystalloid. These data suggest HBOC-201 has a vasoconstrictive effect that cannot be attributed soley to nitric oxide scavenging.
The novel hemoglobin-based oxygen carrier HRC 101 improves survival in murine sickle cell disease
2007, Anesthesiology
Erythrocyte transfusion decreases morbidity in sickle cell disease, but is not without risk. Use of a hemoglobin-based oxygen carrier could offer the benefits of erythrocyte transfusion while reducing related complications. The authors tested the hypothesis that the novel hemoglobin-based oxygen carrier, HRC 101, would improve survival during exposure to acute hypoxia in a murine model of sickle cell disease, the transgenic mouse expressing hemoglobin SAD (α₂^humanβ₂^{S,Antiles,D-Punjab}).
Wild-type (n = 30) and transgenic SAD (n = 36) mice received 0.02 ml/g HRC 101 (hemoglobin concentration, 10 g/dl) or an equal volume of 5% albumin. Thirty percent or 6% oxygen was administered to spontaneously breathing mice during halothane anesthesia (inspired concentration, 0.5%). The time to cessation of cardiac electrical activity was recorded. Survival was compared using Kaplan-Meier analysis.
Control mice survived the 60-min study period, whether breathing 30% or 6% oxygen. In contrast, all SAD mice given albumin and 6% oxygen died, with a median survival time of 9.0 min (interquartile range, 6.9–11.6 min; P < 0.0001). HRC 101 significantly increased survival in SAD mice breathing 6% oxygen. Of 12 SAD mice given HRC 101 and 6% oxygen, 4 survived the entire study period and 8 died, with a median survival time of 48 min (19–60 min; P < 0.0001 vs. albumin).
HRC 101 significantly decreased sickle-related mortality during exposure to acute hypoxic stress in transgenic mice expressing hemoglobin SAD. HRC 101 warrants further evaluation as a therapeutic modality in sickle cell disease.
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