HEMOGLOBIN-BASED RED-BLOOD-CELL SUBSTITUT ES

Although the attempts to develop an oxygen-carrying alternative to red blood cells (RBC) have spanned the last 100 years, it has proven diff icult to develop a clinically useful haemoglobin-based oxygen carrier. Four major problems have been shown to compromise the use of haemoglo bin outside the RBC as an oxygen carrier: (1) the increased oxygen aff inity due to the loss of 2,3-diphosphoglycerate; (2) dissociation into dimers and monomers with consequent renal and capillary loss of hemog lobin; (3) insufficient concentrations of prepared solutions under iso -oncotic conditions, and thereby reduced oxygen-carrying capacity; and (4) toxicity. Most of these limitations have been overcome by differe nt modifications of haemoglobin, including pyridoxylation, intra- and intermolecular crosslinking, polymerisation, liposome encapsulation, c onjugation to inert macromolecules, and genetic engineering. Questions of toxicity are not completely answered at present, especially with r egard to renal toxicity, interactions with the nitric oxide system, an d antigenicity. Therefore, the issues preventing clinical application are those of safety and not of efficacy of haemoglobin-based RBC subst itutes. Potential clinical applications include fluid resuscitation, t reatment of anaemia and ischaemia, support in extracorporeal circulati on, and organ preservation. Based on promising and reproducible result s obtained from animal studies, clinical phase I and II trials with ne wer haemoglobin solutions have been started in the United States. Subs tantial knowledge has been gained the development, in production, and evaluation of haemoglobin-based oxygen carriers during the past years. It will probably not take another century before oxygen-carrying RBC substitutes will become available for clinical use.