INTRODUCTION

The development of a “perfect” blood substitute has been in progress for many years. Such a product would have advantages over human red cells that included rapid and widespread availability, fewer requirements with regard to storage, transport, and compatibility testing, a longer shelf life, and a more consistent supply. An ideal substitute would be less antigenic than allogeneic red cells, and would have less risk of disease transmission. Two main types of blood substitutes are in development, hemoglobin solutions and perfluorocarbon emulsions. Of the hemoglobin solutions, two products are in phase III clinical trials, and the companies behind the products predict FDA approval in the near future.

HEMOGLOBIN SOLUTIONS

Unmodified cell-free hemoglobin has known limitations, such as: an oxygen affinity that is too high for effective tissue oxygenation; a half-life within the intravascular space that is too short to be clinically useful; and a tendency to undergo dissociation into dimers with resultant renal tubular damage and toxicity. Because of these limitations, hemoglobins used to make solutions must be modified. A number of modification techniques have been developed.  Hemoglobin can be cross-linked (a covalent bond between 2 globin chains is made through chemical modification), and then polymerized using reagents such as glutaraldehyde. These modifications result in a product that has a higher P50 than that of normal hemoglobin, and an increase in the plasma half life of up to 30 hours. The source of the hemoglobin used for the solutions can be human (outdated donated blood), bovine, or recombinant. The solution is prepared from highly purified hemoglobin, and taken through processes which eliminate phospholipids, endotoxins, and viral contaminants.

Currently, two products are in advanced clinical trials. Hemolink^® by Hemosol Inc. (Toronto, Ontario (416)-798-0700) is a hemoglobin solution that contains cross-linked and polymerized human hemoglobin. The intravascular half-life is 18 to 20 hours. The mode of excretion is not entirely clear, but a small amount is renal. Phase I clinical trials in healthy male volunteers showed that the drug is fairly well tolerated, with abdominal pain of moderate to severe intensity at doses greater than 0.4 mg/kg. This abdominal pain was alleviated with muscle relaxants. A dose-dependent increase in mean arterial pressure was also seen (1). According to the company, 8 clinical trials have been completed, including a pivotal phase III trial in CABG patients in the United Kingdom and Canada. A phase III clinical trial in CABG patients is currently underway in the United States.

Hemopure^® (HBOC-201) by Biopure (Cambridge, Massachusetts (617)-234-6500) is also in phase III clinical trials. This hemoglobin solution contains cross-linked and polymerized hemoglobin, however the source of the hemoglobin is bovine. The intravascular half-life is approximately 24 hours, and the excretion is non-renal. Administration of the solution to 10 patients with severe anemia resulted in a 60% survival rate at hematocrits as low as 4.4%. The authors did emphasize that the product served as a bridge over days, until blood became available, or the patient’s own red cells were regenerated (2). As with all hemoglobin solutions, administration of Hemopure^® leads to vasopressor effects that may increase systemic and pulmonary vascular resistance with resultant decreases in cardiac index. The use of HBOC-201 in a small study of patients undergoing pre-operative hemodilution for vascular surgery showed limited efficacy (3). More studies are warranted to determine whether or not this type of solution can be used in patients undergoing pre-operative hemodilution for other procedures.

ADVERSE EFFECTS

As stated above, the main potential adverse effect of these solutions is an increase in systemic and pulmonary vascular resistance that may lead to a  decrease in cardiac index. Decreases in the cardiac index may impair optimum oxygen delivery and outweigh the advantage of an oxygen-carrying solution (3). One of the main mechanisms underlying such vasopressor effects is cell-free hemoglobin acting as a scavenger of nitric oxide. Animal studies show that if nitric oxide is placed back into the system, the vasopressor effects are reversed. In general the patient populations currently chosen for studies with these solutions are relatively stable, and may be undergoing high blood-use surgery such as elective AAA repair or orthopedic surgery. One study examined the utility of these solutions in the acute resuscitation phase of unstable trauma patients. However the study design was poor and any role of the solutions in influencing ultimate patient outcome was unclear (4). Further trials in unstable trauma patients have not been attempted, thus the benefit or harm of hemoglobin solutions in these patients stands as an unanswered question.

USES AND LIMITATIONS

In general, these solutions have been shown to reduce or eliminate the need for allogeneic blood transfusions in patients undergoing orthopedic surgery, elective abdominal surgery, and coronary artery bypass graft surgery. Hemoglobin solutions may also serve as a bridge to transfusion in patients for whom blood is temporarily difficult to find. They may also serve as a bridge in the temporary support of a patient who will not accept blood and who has a reasonable chance of recovering an adequate hemoglobin/ hematocrit within a few days.

The major limitation of hemoglobin solutions is the short intravascular half-life. A transfused red cell can persist in the circulation for several weeks in a patient with no active bleeding or hemolysis. A hemoglobin solution, in comparison, can last several hours and requires frequent replacement. As these solutions are not yet available, the price compared to the cost of a unit of blood is unknown.

OTHER CONSIDERATIONS

Because these solutions have a dark red color, they can hinder the ability of blood bank staff to obtain an ABO type or antibody screen once the solution has been infused. It is highly recommended that a patient sample be sent to the blood bank for type and screen prior to infusion of the hemoglobin solution.

PERFLUOROCARBON EMULSIONS

Perfluorocarbon emulsions contain synthetic fluorinated hydrocarbons that are capable of dissolving oxygen and delivering oxygen to tissues.  The transport and release of gases by perfluorocarbons is based on physical solubility, and the quantity of gas dissolved is linearly related to its partial pressure. Because the hydrocarbons are immiscible in water, they require administration as an emulsion. They are chemically inert, and are not metabolized in vivo. The intravascular half-life depends on the molecular weight of the compound, but in general is hours to days. The compounds are eliminated unchanged by the lungs after passing through the reticuloendothelial system. Ongoing clinical trials show a transient and dose-dependent flu-like illness, and transient decrease in platelet count as the main adverse effects. Oxygent^® by Alliance pharmaceutical corporation (San Diego, CA (858)-410-5200) is currently in phase II clinical trials.

SUMMARY

Hemoglobin solutions contain modified hemoglobins that have comparable properties to normal adult hemoglobin. Two solutions containing cross-linked, polymerized hemoglobin are in phase III clinical trials. The main adverse effects of the solutions stem from the ability of cell-free hemoglobin to scavenge nitric oxide. These effects include an increase in vascular resistance with subsequent decrease in cardiac index. The major limitation of these solutions, compared to red cells, is their short intravascular half-life. Because of this limitation, hemoglobin solutions serve mainly as a bridge to transfusion, rather than as a replacement for blood.

Perfluorocarbon emulsions are inert compounds, capable of dissolving and delivering oxygen to tissues. Phase II clinical trials are ongoing.  Currently the half-life of these compounds is hours to days, which is significantly shorter than the lifetime of a transfused red cell.

REFERENCES

1.     Carmichael F.J.L. et al. A phase I study of oxidized raffinose cross-linked human hemoglobin. Crit Care Med 2000; 28: 2283-92.

2.     Jacobs E.E. et al. Use of Hemoglobin Based Oxygen Carrier-201 when blood is not available or not acceptable. Transfusion 2000; 40: 41S.

3.     Kasper S.M. et al. The effects of increased doses of bovine hemoglobin on hemodynamics and oxygen transport in patients undergoing preoperative hemodilution for elective abdominal aortic surgery. Anesth Analg 1998; 87: 284-91.

4.     Koenigsberg D. et al. The efficacy trial of diaspirin cross-linked hemoglobin in the treatment of severe traumatic hemorrhagic shock. Acad Emerg Med 1999; 6: 379-80.

5.     Creteur J. et al. Hemoglobin solutions- not just red blood cell substitutes. Crit Care Med 2000; 28:3025-34.

6.     Winslow R.M. Diaspirin cross-linked hemoglobin: Was failure predicted by preclinical testing? Vox Sang 2000; 79: 1-20.

7.     Remy B. et al. Red blood cell substitutes: fluorocarbon emulsions and haemoglobin solutions. British Medical Bulletin 1999; 55: 277-98.