From the standpoint of the clinician and the transfusion service, the ideal red cell substitute should deliver oxygen, cause few undesirable effects, require no compatibility testing, remain stable during prolonged storage, persist in the circulation, be easily reconstituted, and be available at a reasonable cost. From the standpoint of the patient, or better of the general public, any alternative to transfusion that would lower the risk of transfusion-transmitted infection would be worth a substantial cost increment. Most candidate red cell substitutes would undergo some pathogen inactivation treatment and nanofiltra-tion process that would address this important issue. Candidate substitutes would also avoid the compatibility issues, the logistic problems with multiple blood types, and many of the problems of storing, transporting, and transfusing refrigerated cells that are at great risk for immune, mechanical and thermal lysis. The other risks of transfusion that might be avoided (fever, urticaria, TRALI, hypotension, anaphylaxis, immunomodulation) would have to be balanced against the potential toxicities of the candidate replacement. Although head-to-head comparisons are difficult, the question of immediate delivery and release of oxygen by stored red cells has long been an issue, particularly for the pediatric surgeon, and small molecules that deliver oxygen might address that concern.
Where might a red cell substitute be most valuable? Probably where blood is not immediately available. Trauma outside of the hospital, including in the military setting, comes to mind immediately. Refrigerated group O cells cannot be readily stored and transported on ambulances across the country. A similar application involves acute, unanticipated blood loss in surgery, and moderate blood loss during and after surgery, especially during periods of blood shortage or for patients who are difficult to transfuse. The product can be used as a bridge for patients with multiple antibodies or rare blood types until compatible blood can be located. An oxygen carrier can also bridge the period of potential hypoxic coma and death in patients with severe autoimmune hemolytic anemia until treatment effects remission of the disease (Mullon et al., 2000).
The largest potential use involves 'blood sparing' or 'blood avoidance' during surgery - a primary study endpoint for some early clinical trials. For elective surgery, the potential exists to reduce an estimated 5 million units of perioperative red cells transfused annually in the United States. However, the short 12-48-hour half-life of these small molecules limits their blood-sparing utility. Mathematical modeling suggests that benefits will be confined primarily to non-anemic patients who undergo extreme hemodilution and sustain large perioperative blood losses (Brecher et al., 1999). The potential applications (in North America) include an estimated 600 000 cardiac surgery patients, 625 000 orthopedic surgery patients, and 70 000 men undergoing radical prostatectomy. While the short half-life of current candidate substitutes all but precludes their use for managing chronic anemia, a 'second generation' product with a longer intravascular survival might find substantial application for the estimated 40 per cent of patients with lung or ovarian cancers who develop chemotherapy-induced anemia.
The largest potential market for oxygen carriers as red cell substitutes is in those parts of the world that can least afford to pay for it. In the developing world, 25 per cent of maternal deaths from pregnancy-related causes are associated with loss of blood (WHO, 2001). Pediatric deaths from malaria-induced anemia are entirely preventable (English et al., 2002). Operational problems, infrastructure costs and cultural issues pose seemingly insurmountable hurdles to building modern blood delivery systems in the same regions. Even if they could, a sizable fraction of the donor population carries infectious agents and donations would have to undergo a pathogen inactivation process. Inexpensive blood substitutes, even those that fail to meet the rigorous safety standards applied to blood in the developed world, would allow patients to receive treatments ordinarily requiring blood transfusion, and could improve health dramatically in many developing countries. Whether such a practice, or even clinical trials of such products, is ethically acceptable remains a subject of intense debate. If the problems of their high cost and short intravascular half-life can be solved, these drugs will save countless lives in the developing world.
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