Early transfusion history described the miraculous recovery of patients suffering life-threatening hemorrhage. However, equally dramatic reports revealed unexpected, unexplained, and occasionally lethal complications. The emergence of HIV as a transfusion-transmitted virus was only the latest such complication and certainly not the last. Little wonder that the medical establishment, the public, and, more recently, the biotechnology industry place such high hopes on development of safer alternatives to blood. Despite more than 40 years of focused research and the recent infusion of hundreds of millions of venture capital dollars, no credible replacement for blood has yet been approved for use in the United States.
The term "blood substitute" is a misnomer. So-called blood substitutes in fact replace only one or possibly two functions of transfused blood. By this definition, several blood substitutes are already in common use: dextran(Drug information on dextran) and starch solutions that act as volume expanders; recombinant proteins that replace, among other things, coagulation factors; and even anticoagulants, such as warfarin(Drug information on warfarin) and heparin(Drug information on heparin), that are used on occasion to substitute for naturally-occurring anticoagulant proteins. For other functions of blood, those of the platelets and leukocytes, no substitutes are likely to emerge in the near future.
Whereas, the "holy grail" of blood substitute research has been to develop a red cells substitutea small molecule that delivers oxygen (O2) efficiently, requires no compatibility testing, can be sterilized, has a long shelf-life at room temperature, reconstitutes easily, persists in the circulation for days or weeks, and can be provided at a price competitive with that of human blood. No such substance is on the near horizon.
Candidate red cell substitutes generally fall into three classes: perfluorochemicals, hemoglobin-based oxygen carriers, and liposome-encapsulated hemoglobin. Although it is convenient to review these drugs as "classes," each formulation should be considered a unique drug with its own physical characteristics, biologic activities, and adverse reaction profile. General characteristics of these classes are reviewed in Tables 1 and 2.
Perfluorochemicals are synthetic, inert, hydrophobic molecules with an almost unlimited ability to dissolve gases including oxygen. Because these molecules are structurally similar to hydrocarbons, they are not water-soluble and therefore must be emulsified with surfactants before they are suitable for intravenous use. This property has complicated their preparation and storage, and the nature of the emulsifier turns out to be as important as the perfluorochemical itself. The classic early experiments in which a mouse was submerged in a beaker of preoxygenated perfluorochemical emulsion and shown to breathe liquid continues to fascinate medical journalists and catch the public eye. Similarly, the exchange-transfused "bloodless rat" experiments seemed to promise a quick transition to a clinically useful oxygen transport drug. However, early perfluorochemical formulations were impure, persisted for long periods in the reticuloendothelial system, and proved unsuitable for clinical trials.
Broad application of perfluorochemicals as red cell substitutes may be limited by their oxygen-loading and off-loading properties (Figure 1). Unlike blood and hemoglobin constructs, perfluorochemicals dissolve O2 in a linear fashion directly related to the partial pressure of O2. In practice this means that these emulsions can carry a great deal of O2, but only if the patient inspires high concentrations of supplemental O2. Furthermore, the compounds may release much of the O2 as blood passes through less well-oxygenated environments and long before it reaches the most ischemic tissues. The latter property, the need for refrigerated storage, and the relatively short circulating half-life have led some investigators to postulate that these chemicals will prove most suitable for hospital use.
During a 10-year period, thousands of patients with a wide variety of illnesses received an early perfluorochemical formulation, Fluosol DA. This agent was even licensed for use in coronary artery balloon angioplasty. However in controlled clinical trials, patients receiving Fluosol failed to show substantial physiologic benefit and were plagued with adverse reactions attributed by some to complement activation. In any case, production of this drug ceased in 1994. An excellent review of this drug and other early perfluorochemicals has been published by Keipert.