[Contributions and prospects of hemoglobin derivatives]

Anoxia-reoxygenation leads to severe metabolic alterations, which result in a generalized inflammatory reaction and multiple organ dysfunction. Direct blood transfusion limits these alterations, but is accompanied by risk of transmission of infections or viral diseases. To avoid these risks, "blood substitutes" have been designed. The modified hemoglobins are not true blood substitutes because they do not possess the complex functions of erythrocytes. They are only oxygen carriers, with a short intravascular life, adapted for temporary use. They are stable, devoid of toxicity and antigenicity, and are able to carry and deliver O2 without regulation of this oxygen transport and without chemical reaction with O2. They possess rheologic properties and an oncotic pressure like those of blood. The use of natural hemoglobin solutions, obtained after lysis of erythrocytes, remains "at risk" because these solutions easily form methemoglobin, increase the oncotic pressure, present renal toxicity, and possess a too high affinity for O2. For these reasons, 5 types of modified hemoglobin solutions have been designed, prepared from human or bovine hemoglobin or by genetic engineering. These hemoglobins are highly purified to eliminate trace amounts of stroma, lipids and endotoxins, which are responsible for acute toxicity. They are modified by internal cross-linking between the monomers, or by binding to macromolecules. Afterwards, they can be polymerized or encapsulated in liposomes. The purpose of these modifications is to modulate the affinity for O2 (by decreasing the binding of O2 and increasing its delivery to tissue), to reduce the dissociation into monomers and to guard against oxidation into methemoglobin. Encapsulation in liposomes allows co-encapsulation of effector molecules and protective substances. Genetic engineering allows the production of recombinant hemoglobin with selective modifications. The modified hemoglobin solutions are essentially used in hemorrhagic shock and perioperative hemodilution. Experimental work in animals has afforded good results: restoration of normal O2 pressure and no toxicity. These assays allow frequent observation of an unexpected rapid hypertensive effect, transient, 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 effects, etc.). In humans, studies with healthy volunteers have been completed, while phase II clinical studies are under way in hypovolemic shock, in major abdominal, orthopedic and cardiac surgery, in stroke and in intensive care patients after surgery. The detailed results are awaited, but the modified hemoglobin solutions already appear to be without toxicity and present the same hypertensive effect as observed in animals. However, until now only low doses have been used, and the catabolism of these solutions remains largely unknown.