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Solubility of inert gases in PFC blood substitute, blood plasma, and mixtures.

Measurements are reported of the solubility of nonreactive gases, e.g., hydrogen and xenon, in the following liquids: (a) Oxypherol (FC-43 emulsion) blood substitute, (b) blood plasma, (c) mixtures of Oxypherol and blood plasma, and (d) perfluorotributylamine. Typical results for Ostwald solubility at 25 degrees C for Xe gas in various liquids are 0.118 in H2O, 0.12 in blood plasma, and 1.51 in N(C4F9)3. Observed solubilities for the mixtures can be calculated from the relation: L(mixture) = L(emulsion)xv(emulsion) + L (plasma)xv(plasma), in which the v's are the volume fractions in the mixture. This linear relation implies that the gas dissolves independently in each liquid in the mixture. The effect of the emulsifier (Pluronic F-68, 2.6%), on gas solubility in the mixture, is small. Results for the temperature dependence of Ostwald solubility, L(T), in the range 10-37 degrees C are reported.

Blood Substitutes

Canadian Red Cross lecture. Current concepts of oxygen-transporting blood substitutes.

Blood substitutes are being developed that will provide oxygen-transporting capabilities as well as volume replacement. Perfluorochemical and hemoglobin solutions have potential clinical use. A perfluorochemical blood substitute, Fluosol-DA 20%, is being used in clinical trials in several countries. These blood substitutes are not capable of totally replacing the need for blood transfusions but could be used temporarily in situations where blood is contraindicated or not available. They may be useful for a wide range of clinical conditions other than blood replacement, such as impending tissue ischemia. Before large-scale clinical use of these products is realized, more information is needed about drug efficacy and safety so that intelligent decisions can be made about indications for this type of transfusion therapy.

Animals

Blood transfusion or blood substitution?

Blood transfusion has become a universally accepted, life-saving procedure in modern clinical medicine. In addition, specific blood fractions are widely used in the therapeutic treatment of haematological disorders. Problems are, however, encountered in conventional transfusion practice and in the clinical use of blood components. This paper outlines some of those problems and considers how plasma expanders and oxygen-carrying blood substitutes may be used to overcome some of them. The extent to which acceptable blood substitutes have been developed and tested in both animal and human studies is especially emphasized.

Blood Substitutes

"Bloodless" rats through the use of artificial blood substitutes.

Artificial blood substitutes have been prepared with liquid fluorocarbons, Pluronic polyols, hydroxyethyl starch, electrolytes, and bicarbonate buffer. Dispersing the fluorocarbons is by sonication in the presence of the polyols. A CO-2 atmosphere is provided to prevent the formation of fluoride ions which otherwise form. Viscosity, oncotic pressure, osmotic pressure, and pH are adjusted to that of rat blood. With such preparations all of the normal blood of rats can be replaced. Such animals survive, carry out usual functions, regenerate blood cells and plasma protein, and continue to grow and develop. Volumes up to 30 times the blood volume of the rat have been perfused. Perfluorotributylamine has been the most successful of the fluorocarbons, in spite of its prolonged retention in the tissues, but progress has been made with the perfluorodecalins which leave the tissues rapidly. "Bloodless" rats show no reaction to dextran which ordinarily causes acute hypersensitivity reactions in normal rats. Rabbit antirat serum, which has little effect on normal rats, is toxic to "bloodless" rats. Lack of circulating enzymes in "bloodless" rats. Lack of circulating enzymes in "bloodless" rats allows a) specific enzymes to be given to achieve the enzyme profile desired; and b) enzyme-labile compounds to be kept in circulation. "Bloodless" rats made possible by artificial blood substitutes afford a new biomedical research tool.

Adenosine Triphosphate

Hemodynamic effects and oxygen transport properties of a new blood substitute in a model of massive blood replacement.

Recent concerns regarding the safety of the national blood supply have rekindled interest in the development of blood substitutes. Clinical studies have dampened the initial enthusiasm for fluorocarbon solutions as blood substitutes. The potential of hemoglobin solutions as blood substitutes has continued to stimulate investigations. However, the development of an ideal hemoglobin-derived blood substitute has eluded investigators for the past century. A persistent problem has been the inability to develop hemoglobin solutions that provide adequate oxygen and carbon dioxide exchange, while avoiding toxicity that precludes clinical safety and long-term survival. Traditionally, investigators have focused on human hemoglobin solutions. The use of outdated banked blood or pedigree human donor blood as a hemoglobin source poses continued disease transmission risks and a prohibitively limited supply. We evaluated the hemodynamic and gas transport effects of a new purified, polymerized bovine hemoglobin preparation. Bovine hemoglobin oxygen affinity is regulated by chloride ion. The concentration of chloride ions in human plasma results in excellent oxygen transport properties in a stroma-free environment. In addition, unlike human blood, bovine blood is a more disease-free hemoglobin source that is available in large supply. We exchange-transfused eight conscious sheep with this new polymerized bovine hemoglobin solution. All animals tolerated greater than or equal to 95% exchange transfusion to reach a final ovine hematocrit of 2.4 +/- 0.5% with stable hemodynamics and no clinical evidence of distress. The exchange transfusion with bovine hemoglobin polymer resulted in a final plasma hemoglobin concentration of 6.1 +/- 1.6 gm/dl, which supported oxygen consumption at baseline levels. All animals that were exchange transfused with this preparation survived long term with rapid resynthesis of ovine erythrocytes.

Animals

Binding of warfarin by human albumin in the presence of a perfluorochemical blood substitute.

The effect of a perfluorochemical blood substitute on ligand binding by human albumin was examined using warfarin as a model drug. Binding of warfarin by four per cent human albumin solutions diluted with either buffer or blood substitute, and by blood substitute diluted with buffer was examined. Solutions containing 2 or 10 micrograms/ml warfarin were quantitated by liquid scintillation counting using 14C-warfarin. The per cent warfarin free at room temperature was determined by centrifugation followed by supernatant ultrafiltration. Warfarin was weakly bound by the blood substitute and the overall effect of albumin dilution with the blood substitute was an increase in per cent warfarin free. Blood substitute binding of warfarin may explain the decrease of per cent warfarin free observed when albumin solutions were diluted to 50 and 75% v/v with blood substitute rather than buffer. However, the per cent warfarin free increased when albumin solutions were diluted to 25% v/v with blood substitute rather than buffer. The fraction free increased by 39.0% and 30.4% at total warfarin concentrations of 2 and 10 micrograms/ml, respectively. This relative increase in per cent warfarin free may be the result of a direct and/or indirect displacement of albumin bound warfarin by a component(s) of the blood substitute.

Blood Substitutes

Plasma-mediated alterations of erythrocyte deformability by perfluorochemical blood substitutes.

The effect of perfluorochemical blood substitutes (eg, Oxypherol or Fluosol-DA) on red cell deformability was investigated because these emulsions are in direct contact with red cells when they are used as temporary circulatory aids. Erythrocyte deformability was assessed by a constant volumetric flow rate filtration method. The results of in vitro incubation experiments indicate that perfluorotributylamine causes the deformability of human red cells to decrease significantly in the presence of plasma. However, there is no obvious loss in the deformability when washed cells are used. Neither mean cell volume nor white cells appear to be responsible for the observed effects of perfluorotributylamine. Perfluorodecalin and perfluorotripropylamine, two perfluorochemical compounds that are widely applied clinically, do not induce significant changes in red cell deformability with or without plasma. These results indicate the need for in vitro testing in the development of perfluorochemicals as blood substitutes.

Blood Substitutes