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Medical Meeting Reports

American College of Surgery Clinical Congress

October 10-15, 1999

font=>By Karen Sandrick

A. Gerson Greenburg, MD, of Brown University, Providence, RI, traced the many accomplishments in development of hemoglobin-based red cell substitutes over the last 25 years. To date, more than 2,000 patients have been exposed to various forms of hemoglobin solutions throughout the world without any evidence of nephrotoxicity or coagulopathy. If current and planned clinical trials prove these solutions to be effective, red cell substitutes could replace allogeneic and autologous blood for most patients undergoing elective, urgent, or emergent surgery.

Early Investigations

The modern era of development of red cell substitutes began in the 1960s with the discovery that if the toxic stroma of the hemoglobin molecule were removed, hemoglobin-based solutions would be safe.

Dr. Greenburg first became involved in testing red cell substitutes in 1973. He gave a stroma-free hemoglobin-based solution to resuscitate animals in hemorrhagic shock and found that the solution was equivalent to whole blood in the degree to which it improved mitochondrial function and efficacy.

He then began a series of chemical modifications of hemoglobin. He rejuvenated red blood cells before making a stroma-free hemoglobin solution, changed the oxygen delivery capacity so the hemoglobin solution would remain in the circulation longer. He used o-raffinose to alter conditions within the hemoglobin molecule, examined the mechanism of vasoconstriction in studies of the Ao ring and endothelin-1, and evaluated access to the heme binding site.

The result of his studies is Hemolink, a solution containing 10g Hgb/dL and less than 10% meth-hemoglobin. Hemolink is not a pure tetramere; it is an oligomere that has been modified as a beta-beta crosslink.

Clinical Trials

The first phase I trial of Hemolink in 1995 showed a relationship between concentration of the red cell substitute and intravascular persistence. The circulation half life ranged from four to 14 hours depending on the amount of grams of hemoglobin infused. A slight increase in blood pressure, possibly dose-related, occurred immediately following infusion of the hemoglobin-based solution, but it subsided within 24 hours. Changes in creatinine clearance and total bilirubin were minor. Serum calcium and serum phosphorus decreased, but the declines in concentration were not dose-related. Although pancreatic enzyme activity increased in association with the dose of the blood substitute, patients did not develop clinical signs of pancreatitis.

The result of this trial led to a phase II investigation of Hemolink in patients having elective orthopedic surgery. Patients received 3/4 to 1L of the hemoglobin-based solution for hemodilution and replacement when transfusion was indicated. The blood substitute decreased the exposure of these patients to allogeneic red cells by 60-80%. A phase III trial is beginning in Canada and the United Kingdom that will study the extent to which Hemolink can reduce the need for allogeneic transfusion. The study also will document the incidence of any central nervous system events, such as stroke and delirium.

Trials with Other Red Cell Substitutes

Five groups at the present time are testing other types of red cell substitutes in phase I, II, and III clinical investigations of sepsis, coronary artery bypass, and vascular surgery. One of these using a polymerized form of hemoglobin blood substitute showed that total hemoglobin concentration could be maintained in 27 patients who had red cell hemoglobin concentrations less than 3 gm/dL, which is considered to be a lethal clinical situation. Mortality was less than 15%, however, after delivery of the hemoglobin solution.

Future Directions

Dr. Greenburg predicted that second generation hemoglobin-based red cell substitutes will have further modifications of the heme pocket, liposome composition and structure, and they will come from a variety of sources including plants, yeasts, bacteria, and transgenic animals. The goal is to produce a solution that has enough oxygen-carrying capacity and volume expansion in sufficient quantities to replace the current use of allogeneic and autologous blood in the pre- and postoperative periods for 60% of patients having surgery.

Ortho Biotech

Funded through an unrestricted educational grant by Ortho Biotech.

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