Haemoglobin-based oxygen carriers.

Haemoglobin-based oxygen carriers are being developed for use in blood replacement therapies, either for perioperative haemodilution or for resuscitation from haemorrhagic blood loss. There is a high demand for these products because of risks associated with blood transfusions and pending worldwide blood shortages. Development of these products has required new technologies in protein engineering; since the haemoglobin is cell-free in solution, the molecule must be modified to be retained within blood circulation. Three classes of haemoglobin are under development: intramolecular cross-linked, intermolecular polymerised and surface conjugated with polyethylene glycol. Two products based on cross-linking chemistry have been discontinued because of serious adverse events and/or increased mortality rate in Phase III clinical trials. Three products based on polymerisation chemistry are in ongoing Phase III clinical trials. A new product based on surface conjugation is in preclinical evaluation. Although cross-linked and polymerised products have shown to be safe in preclinical and early Phase I/II clinical trials, they have had difficulty in proving efficacy. The primary adverse effect for the majority of cross-linked or polymerised products is a haemodynamic response, leading to increased vascular resistance to blood flow. The physiological mechanisms are still incompletely understood, so that safety and efficacy cannot be completely dissociated. New understandings on the mode of action of these products will help to define their utility and application. New products are under development, designed specifically to maximise blood flow and tissue perfusion and therefore, oxygenation.