MODIFIED HEMOGLOBINS - CONTRIBUTIONS AND PERSPECTIVES

Anoxia-reoxygenation leads to severe metabolic alterations, which resu lt in a generalized inflammatory reaction and multiple organ dysfuncti on. Direct blood transfusion limits these alterations, but is accompan ied by risk of transmission of infections or viral diseases. To avoid these risks, <<blood substitutes>> have been designed. The modified he moglobins are not true blood substitutes because they do not possess t he complex functions of erythrocytes. They are only oxygen carriers, w ith a short intravascular life, adapted for temporary use. They are st able, devoid of toxicity and antigenicity, and are able to carry and d eliver O-2 without regulation of this oxygen transport and without che mical reaction with O-2. They possess theologic properties and an onco tic pressure like those of blood. The use of natural hemoglobin soluti ons, obtained after lysis of erythrocytes, remains ''at risk'' because these solutions easily form methemoglobin, increase the oncotic press ure, present renal toxicity, and possess a too high affinity for O-2. For these reasons, 5 types of modified hemoglobin solutions have been designed, prepared from human or bovine hemoglobin or by genetic engin eering. These hemoglobins are highly purified to eliminate trace amoun ts of stroma, lipids and endotoxins, which are responsible for acute t oxicity. They are modified by internal cross-linking between the monom ers, or by binding to macromolecules. Afterwards, they can be polymeri zed or encapsulated in liposomes. The purpose of these modifications i s to modulate the affinity for O-2 (by decreasing the binding of O-2 a nd increasing its delivery to tissue), to reduce the dissociation into monomers and to guard against oxidation into methemoglobin. Encapsula tion in liposomes allows co-encapsulation of effector molecules and pr otective substances. Genetic engineering allows the production of reco mbinant hemoglobin with selective modifications. The modified hemoglob in solutions are essentially used in hemorrhagic shock and perioperati ve hemodilution. Experimental work in animals has afforded good result s: restoration of normal O-2 pressure and no toxicity. These assays al low frequent observation of an unexpected rapid hypertensive effect, t ransient, reversible, and that could be controlled by antihypertensive drugs. The mechanisms of this hypertensive effect remain controverted (stimulation of endothelin production, inhibition of nitric oxide eff ects, etc.). In humans, studies with healthy volunteers have been comp leted, while phase II clinical studies are under way in hypovolemic sh ock, in major abdominal, orthopedic and cardiac surgery, in stroke and in intensive care patients after surgery. The detailed results are aw aited, but the modified hemoglobin solutions already appear to be with out toxicity and present the same hypertensive effect as observed in a nimals. However, until now only low doses have been used, and the cata bolism of these solutions remains largely unknown.