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Abstract
In this review the current status of what commonly are termed “blood substitutes” is discussed. The term blood substitute is a misnomer because the formulations under development at this time transport respiratory gases but do not perform the metabolic, regulatory, and protective functions of blood. Either hemoglobin or a perfluorochemical form the base to transport oxygen; die advantages and disadvantages of each base are discussed.
The availability of a blood substitute in the U.S. will require approval by the Food and Drug Administration (FDA) and, by law, both its efficacy and safety must be demonstrated prior to approval. Showing efficacy of any blood substitute is complicated by the oxygen reserve and the compensatory mechanisms to acute blood loss in man. The challenge is to prove that the administration of these formulations offer clinical advantages compared with replacement of volume alone. Several efficacy models, the most attractive among them being perioperative hemodilution, should provide data that would bring these formulations into clinical practice.
When hemoglobin is not within the favorable environment of the red cell, whether the hemoglobin is derived from expression vectors developed through recombinant biotechnology or from lysed human red cells, it acquires a left-shifted oxygen disassociation curve. Further, because the tetramer disassociates when injected intravenously and the resulting dimers are cleared rapidly from the circulation by the kidneys, intravascular dwell time is brief. Hemoglobins have been modified chemically and linked intramolecularly, intermolecularly, and to macromolecules to correct these problems. While these manipulations have normalized the p50 and extended the dwell time significantly, some toxicity problems remain unresolved. The binding of nitric oxide to hemoglobin preparations and the presumably resultant systemic and pulmonary hypertension observed in animals may be the most difficult to overcome, although the implications of these reactions in man is poorly understood.
Perfluorochemicals (PFC) provide a fundamentally different and simpler approach to oxygen transport than hemoglobin formulations. Typically, the PFCs used are liquids composed of 8 to 10 carbon atoms that dissolve oxygen and obey Henry's law. Thus, the recipient's inspired oxygen and cardiac output assume importance. Because they are insoluble in water, PFCs are administered as emulsions, that is, as small droplets about 0.1 to 0.2 μm in diameter. In this respect, they are very similar to the lipid emulsions widely used for parenteral nutrition. Egg yolk phospholipid and poloxamers are most commonly used as emulsifiers. PFCs are not metabolized and are excreted unchanged by the lungs, following temporary storage by the monocyte-macrophage system (MMS). The formulation of a PFC emulsion is largely defined by its intended use: military applications might dictate a high PFC concentration, whereas perioperative hemodilution may be successfully undertaken with emulsions of lower concentration. Injected PFC emulsions essentially increase the oxygen-carrying capacity of the plasma compartment and, because the oxygen is dissolved and not bound, virtually all is extracted by the tissues before hemoglobin is offloaded. Several efficacy studies have indicated that PFC emulsions deliver significant oxygen to the tissues and maintain satisfactory tissue oxygenation even at low hematocrits. The various studies suggesting these preparations are not effective result from poorly designed trials and a failure to recognize the limitations of the products. These carriers should augment the effectiveness of allogenic blood avoidance strategies and provide an additional margin of safety during perioperative hemodilution. The toxicity of PFC emulsions have been minimal, although fever and malaise have been described following their injection into awake subjects. These effects are believed to be generic and associated with uptake of particles by the MMS and are largely relieved by steroid and cyclooxygenase inhibitor drugs, and thus are believed to be manageable.
The road to achieving a satisfactory injectable oxygen carrier has been long and arduous and more difficulties have been encountered than expected. That this is the case reflects the incompleteness of the fundamental knowledge about the physiology of oxygen transport and of the toxicity of some of the formulations. The extensive research currently underway in this field should lead to decisive results with one or more oxygen carriers within the foreseeable future.