Gerald S. Moss

The first randomized trial of human polymerized hemoglobin as a blood substitute in acute trauma and emergent surgery

BACKGROUNDnHuman polymerized hemoglobin (PolyHeme) is a universally compatible, disease-free, oxygen-carrying resuscitative fluid. This is the first prospective, randomized trial to compare directly the therapeutic benefit of PolyHeme with that of allogeneic red blood cells (RBCs) in the treatment of acute blood loss.nnnSTUDY DESIGNnForty-four trauma patients (33 male, 11 female) aged 19-75 years with an average Injury Severity Score (ISS) score of 21+/-10 were randomized to receive red cells (n = 23) or up to 6 U (300 g) of PolyHeme (n = 21) as their initial blood replacement after trauma and during emergent operations.nnnRESULTSnThere were no serious or unexpected adverse events related to PolyHeme. The PolyHeme infusion of 4.4+/-2.0 units (mean +/- SD) resulted in a plasma [Hb] of 3.9+/-1.3 g/dL, which accounted for 40% of the total circulating [Hb]. There was no difference in total [Hb] between the groups before infusion (10.4+/-2.3 g/dL control vs. 9.4+/-1.9 g/dL experimental). At end-infusion the experimental RBC [Hb] fell to 5.8+/-2.8 g/dL vs. 10.6+/-1.8 g/dL (p < 0.05) in the control, although the total [Hb] was not different between the groups or from pre-infusion. The total number of allogeneic red cell transfusions for the control and experimental groups was 10.4+/-4.2 units vs. 6.8+/-3.9 units (p < 0.05) through day 1, and 11.3+/-4.1 units vs. 7.8 +/-4.2 units (p = 0.06) through day 3.nnnCONCLUSIONSnPolyHeme is safe in acute blood loss, maintains total [Hb] in lieu of red cells despite the marked fall in RBC [Hb], and reduces the use of allogeneic blood. PolyHeme appears to be a clinically useful blood substitute.

The life-sustaining capacity of human polymerized hemoglobin when red cells might be unavailable

BACKGROUNDnHuman polymerized hemoglobin (PolyHeme, Northfield Laboratories, Evanston, IL) is a universally compatible, immediately available, disease-free, oxygen-carrying resuscitative fluid being developed as a red cell substitute for use in urgent blood loss. PolyHeme should be particularly useful when red cells may be temporarily unavailable. This article assesses survival at life-threatening RBC hemoglobin concentration ([Hb]) in massively bleeding patients who do not receive red cells.nnnSTUDY DESIGNnThere were 171 patients who received rapid infusion of 1 to 20 units (1,000 g, 10 L) of PolyHeme in lieu of red cells as initial oxygen-carrying replacement in trauma and urgent surgery. The protocol simulated the unavailability of red cells, and the progressive fall in RBC [Hb] in bleeding patients was quantified. Thirty-day mortality was compared with a historical control group of 300 surgical patients who refused red cells on religious grounds.nnnRESULTSnA total of 171 patients received rapid infusion of 1 to 2 units (n = 45), 3 to 4 units (n = 45), 5 to 9 units (n = 47), or 10 to 20 units (n = 34) of PolyHeme. Forty patients had a nadir RBC [Hb] < or = 3 g/dL (mean, 1.5 +/- 0.7 g/dL). But total [Hb] was adequately maintained (mean, 6.8 +/- 1.2 g/dL) because of plasma [Hb] added by PolyHeme. The 30-day mortality was 25.0% (10/40 patients) compared with 64.5% (20/31 patients) in historical control patients at these RBC [Hb] levels.nnnCONCLUSIONSnPolyHeme increases survival at life-threatening RBC [Hb] by maintaining total [Hb] in the absence of red cell transfusion. PolyHeme should be useful in the early treatment of urgent blood loss and resolve the dilemma of unavailability of red cells.

Clinical Development of Human Polymerized Hemoglobin as a Blood Substitute

Abstract. Although the efficacy of hemoglobin-based oxygen carriers was established more than 60 years ago, all prior clinical trials have demonstrated significant toxicity characterized by renal dysfunction, gastrointestinal distress, and systemic vasoconstriction. The mechanisms of these toxicities now appear to be understood. Tetrameric forms of the hemoglobin molecule extravasate from the circulation and interact with endothelium-derived relaxing factor, leading to unopposed vasoconstriction. Although numerous efforts are under way to chemically modify the native tetramer, it is likely that all tetrameric forms of the hemoglobin molecule will continue to extravasate. We have focused on developing a polymerized form of hemoglobin that is virtually free of unreacted tetramer. The development and characterization of this polymerized pyridoxylated hemoglobin solution (Poly SFH-P) is described. Clinical trials have been completed successfully in volunteers and are now under way to assess the safety and efficacy of Poly SFH-P as a clinically useful red blood cell substitute for treatment of acute blood loss in the setting of trauma and surgery.

The development of hemoglobin solutions as red cell substitutes: Hemoglobin solutions

Although the efficacy of hemoglobin-based oxygen carriers was established more than 60 years ago, all prior clinical trials have demonstrated significant toxicity characterized by renal dysfunction, gastrointestinal distress, and systemic vasoconstriction. The mechanisms of these toxicities now appear to be understood. Tetrameric forms of the hemoglobin molecule extravasate from the circulation and interact with endothelial derived relaxing factor, leading to unopposed vasoconstriction. Although numerous efforts are underway to chemically modify the native tetramer, it is likely that all tetrameric forms of the hemoglobin molecule will continue to extravasate. We have focused on developing a polymerized form of hemoglobin that is virtually free of unreacted tetramer. The development and characterization of this polymerized pyridoxylated hemoglobin solution (Poly SFH-P) is described. Clinical trials have been completed successfully in volunteers, and are now underway to assess the safety and efficacy of Poly SFH-P as a clinically useful red cell substitute in the treatment of acute blood loss in the setting of trauma and surgery.

Metabolism of lactic acid in the macacus rhesus monkey in profound shock

Abstract This is a comparative study of the metabolism of radioactive lactic acid in monkeys in profound shock (5 to 8 hours after induction of shock) after attempting resuscitation with Ringers lactate or Ringers acetate-gluconate solutions. After infusing Ringers lactate solution there was depression of lactic acid metabolism. Lactate concentrations were inversely proportional to serum potassium and sodium, indicating fixation of cations. If this model can be extrapolated clinically, Ringers lactate infusions can be deleterious to patients in prolonged shock.

Endotoxin effect on respiration of rat liver mitochondria.

Abstract Isolated rat liver mitochondria in sucrose medium were subjected to challenge by the endotoxins of various bacterial species, particularly the lipopolysaccharide extracted from Escherichia coli 026:B6 by the Boivin method. Manometric and oxygen electrode studies showed a marked inhibition of respiration in the challenged mitochondria when the oxygen uptake was stimulated by citrate, α-ketoglutarate, or pyruvate (with malate as a primer). Little or no inhibition was observed when the respiration-stimulating substrate was succinate or glutamate.

Decline in pancreatic insulin release during hemorrhagic shock in the baboon.

Hyperglycemia has been noted in man and animal during hemorrhagic shock. Studies in the dog demonstrated that this hyperglycemia is accompanied by elevated levels of serum immunoreactive insulin, suggesting increased insulin resistance (2). However, recent shock studies by Carey (3) in man, and from our laboratory in the baboon (6) have shown a different pattern. Insulin levels have been depressed despite hyperglycemia, suggesting suppression of insulin release rather than increased insulin resistance.

Technic of iced saline gastric lavage in upper gastrointestinal hemorrhage

Abstract Effective gastric lavage to control hemorrhage requires large volumes, such as 10 L, of saline at 0 °c to produce local hypothermia. For efficient irrigation, a technic is presented that utilizes a double lumen nasogastric tube for simultaneous introduction of irrigant and aspiration of fluid and clots.