Current status of blood substitute research: towards a new paradigm.

For many reasons, haemoglobin, modified to prolong its circulation time, seems to be the optimal choice for a cell-free O2 carrier (blood substitute) because of its capacity to reversibly bind O2 in the lung and release it in tissue. After refining methods to prepare highly purified haemoglobin solutions and to chemically or genetically modify haemoglobin to overcome renal toxicity and to prolong retention time, a number of unwanted effects were observed in human clinical trials. These included symptoms referable to the GI tract, elevated pancreatic enzymes and hypertension, presumed to be the result of vasoconstriction. Studies on the mechanism of vasoconstriction induced by haemoglobin, using new techniques to investigate the microcirculation have led to a surprising new paradigm for the design of safe and effective solutions. These include increased O2 affinity (low P50) and increased viscosity and oncotic pressure. These second-generation solutions hold greater promise for clinical development.