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The risks of transfusion-associated infectious disease have made increased efforts to avoid homologous transfusion imperative. Little attention has been focused on efforts to accelerate erythropoiesis as a method of reducing homologous blood use. Recombinant human erythropoietin (rHuEPO) has been shown to enhance erythropoiesis. The purpose of this study was to evaluate the effects of perioperative rHuEPO administration on postoperative erythropoiesis. Fifteen baboons were divided into three groups of five each. Group I received no rHuEPO. Group II received five daily preoperative doses of rHuEPO (1000 U/kg). Group III received five daily preoperative doses and 14 daily postoperative doses of rHuEPO (1000 U/kg). All animals underwent a laparotomy followed by an exchange transfusion to a final hematocrit of 15%. The time in days required to recover to hematocrits of 20% was significantly shorter in both groups that received preoperative doses of rHuEPO when compared with that of controls (3.3 vs 5.7 days, p less than 0.01). The recovery times to hematocrits of 25%, 30%, and baseline levels were all significantly shorter in the group that received both preoperative and postoperative doses of rHuEPO. The data show that perioperative dosage of rHuEPO significantly accelerates postoperative erythropoiesis. Perioperative administration of rHuEPO may reduce the requirements for homologous transfusion.

Risks of transfusion are minimized with autologous blood. However, autologous donation programs require 2 to 5 weeks to yield only 2.2 units per patient. Recombinant human erythropoietin (r-HuEPO) has been shown to increase erythropoiesis. This study evaluated the effects of r-HuEPO on an aggressive autologous donation program. Twelve adult male baboons were randomized into two groups of six. All animals were studied three times per week for 5 weeks. A unit of blood was donated when on any study day the hematocrit was greater than 30%. Animals received intravenously either 750 units/kg of r-HuEPO (n = 6) or placebo (n = 6) on each study day. Iron dextran was given intravenously to replace 150% of shed iron. The r-HuEPO group had an earlier onset of reticulocytosis (2.7 vs 5.5 days, p less than 0.01) and donated 35% more blood (13.5 vs 10.0 units, p = 0.01) than the control group. No adverse reactions to r-HuEPO were observed. The data show that an aggressive autologous donation program can yield 10 units of blood over a 5-week period. Further, r-HuEPO increases that yield by an additional 35%. This aggressive autologous donation program with r-HuEPO may significantly reduce the need for homologous transfusion and its attendant risks.

The two acellular oxygen carriers currently being evaluated as red cell substitutes are hemoglobin solutions and fluorocarbon emulsions. We have shown that both products can maintain normal levels of oxygen consumption, CO2 production, and circulatory dynamics in primates in the virtual absence of the red blood cell. Although each solution thus satisfies the most important criteria for a red cell substitute, development continues with both products. The clinical trials with the fluorocarbons have been discontinued due to the lack of efficacy of Fluosol-DA--20% in the setting of acute blood loss. Our current hemoglobin preparation is a polymerized, pyridoxylated product that has a normal oxygen-carrying capacity. Clinical testing must await further evaluation of the safety and efficacy of this product. Alternative uses for both of these oxygen carriers continue to be explored, and may eventually be the area of their greatest utility in the clinical setting.

The risk of homologous blood may cause physicians to withhold red cell treatment after acute blood loss. We believe that in the euvolemic patient with acute anemia, the heart is the principal organ at risk. The cardiac compensation to extreme anemia is unknown and is the purpose of this report. Fourteen adult baboons were anesthetized, paralyzed, and ventilated with room air. Left atrial and coronary sinus catheters were inserted surgically. Experimental animals (n = 7) were hemodiluted at constant left atrial pressure with 5% human serum albumin. Control animals (n = 7) underwent similar volume exchanges with fresh, cross-matched, homologous red blood cells resuspended in human serum albumin, also at constant left atrial pressure. Six of seven experimental animals survived until hematocrit levels were 4%. Adequate cardiac compensation was observed until hematocrit levels were less than 10%. Increased flow, without increases in the O2 extraction ratio, was the mechanism of compensation used by the healthy heart with patent coronary vessels.

Development continues for a safe and effective hemoglobin solution to be used as a temporary red cell substitute. Our own efforts have progressed from the unmodified tetramer, to the pyridoxylated tetramer, to our current product--polymerized, pyridoxylated hemoglobin (Poly SFH-P). We recently completed two studies to evaluate the efficacy of Poly SFH-P. The results document that Poly SFH-P supports life in the absence of red cells while maintaining baseline hemodynamics and O2 consumption. In addition, Poly SFH-P achieves a near-normal plasma [Hb], and has a longer intravascular persistence than any unpolymerized product. Poly SFH-P thus is an improved red cell substitute for use in the clinical setting.

Polymerization of pyridoxylated stroma free hemoglobin (poly SFH-P) yields a solution with a normal hemoglobin concentration, normal colloid osmotic pressure (COP), and a suitable P50. In the present study we compared its in vivo O2-carrying capacity and intravascular persistence with those of pyridoxylated hemoglobin (SFH-P), following a partial exchange transfusion (900 ml) in adult baboons (n = 4 in each group). Poly SFH-P in plasma had an O2-carrying capacity that was 77% greater than that achieved with SFH-P (8.0 versus 4.5 vol%). Furthermore, poly SFH-P provided 5.0 vol% at the end of 24 hours and 2.5 vol% at the end of 48 hours; in contrast SFH-P provided only 2.2 vol% at the end of 6 hours and none within 24 hours. A normal COP was maintained throughout the postexchange period with poly SFH-P despite a 68% increase in plasma protein concentration (from 7.1 to 11.9 gm/dl). The plasma P50 of poly SFH-P decreased from 16 torr immediately after exchange to 12 torr at the end of 48 hours. The in vivo rate of conversion to methemoglobin was similar with both solutions. Polymerized pyridoxylated hemoglobin is currently the only modification of hemoglobin solution that approximates the O2-carrying capacity of whole blood and can be infused without altering the plasma COP.

Efforts to produce a clinically acceptable hemoglobin solution that could function as a temporary oxygen carrier have evolved through several stages. Beginning with the simple tetramer, we have lowered the affinity state by pyridoxylation and then polymerized the modified tetramer. This new substance, polyhemoglobin, has a normal oxygen capacity and a half-life of 38 hours. Issues of nephrotoxicity and immunocompetence after infusion remain to be defined.