[Modified hemoglobins as oxygen transporting blood substitutes ].

Although the attempts to develop an oxygen-carrying alternative to red blood cells (RBC) have spanned the last 100 years, it has proven difficult to develop a clinically useful haemoglobin-based oxygen carrier. Four major problems have been shown to compromise the use of haemoglobin outside the RBC as an oxygen carrier: (1) the increased oxygen affinity due to the loss of 2,3-diphosphoglycerate; (2) dissociation into dimers and monomers with consequent renal and capillary loss of hemoglobin; (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 different modifications of haemoglobin, including pyridoxylation, intra- and intermolecular cross-linking, polymerisation, liposome encapsulation, conjugation to inert macromolecules, and genetic engineering. Questions of toxicity are not completely answered at present, especially with regard to renal toxicity, interactions with the nitric oxide system, and antigenicity. Therefore, the issues preventing clinical application are those of safety and not of efficacy of haemoglobin-based RBC substitutes. Potential clinical applications include fluid resuscitation, treatment of anaemia and ischaemia, support in extracorporeal circulation, and organ preservation. Based on promising and reproducible results obtained from animal studies, clinical phase I and II trials with newer haemoglobin solutions have been started in the United States. Substantial knowledge has been gained in the development, 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.