DURHAM, N.C. -- A Phase II clinical trial conducted at Duke University Medical Center and five other U.S. institutions has shown that an agent made of purified human hemoglobin appears safe and may be effective when used instead of transfused human blood to replace blood lost during heart surgery.
If the benefits of the agent, known as hemoglobin raffimer, are proven in subsequent Phase III clinical trials, physicians would not need to use as much donated blood during surgery, the researchers said. An estimated 20 percent of all human blood transfused in the U.S. is associated with heart surgery, so the Duke researchers believe that an efficient "oxygen therapeutic" could play an important role in reducing the need for transfused blood.
The results of the trial were published today (Dec. 13, 2002) in the Journal of Cardiothoracic and Vascular Anesthesia.
The study also showed although hemoglobin raffimer -- like other oxygen therapeutics or blood substitutes tested to date -- produced elevated blood pressures during surgery, it was the only significant side effect and was manageable.
"Our data suggests that hemoglobin raffimer, when used during bypass surgery, is well tolerated and may be effective in reducing blood transfusions," said Duke anesthesiologist Steven Hill, M.D. "Although elevated blood pressure was more frequent in patients given hemoglobin raffimer when compared to controls, aggressive management kept blood pressures under control.
"If we had an agent that could temporarily sustain oxygen delivery to the body during surgery without having to use donated blood, that could have significant long-term potential for our patients," he said.
Hill said the importance of developing an effective oxygen therapeutic is not only because of the decreasing donor pool for human blood and fears of disease transmission, but also because transfused blood may lead to worse outcomes after heart surgery. He cited the results of a recent study conducted at the Medical College of Ohio, which showed that five years after heart surgery, 15 percent of patients receiving blood transfusions had died, compared to a seven percent mortality rate for those who didn't receive a transfusion.
"It may be that transfusion is not as safe as we think," Hill said. "So if we had a product that we could pull off the shelf at any time, and not have to worry about the possibilities of any infectious agents or immune responses, that could be a major step forward in improving outcomes."
Hemoglobin raffimer is produced by removing hemoglobin, an oxygen-carrying molecule, from human red blood cells that have "expired," or passed their 42-day shelf life. After 42 days, Hill explained, stored red blood cells begin to break down and are no longer used in human transfusions.
"For hemoglobin raffimer, the hemoglobin is extracted and the other components of the red blood cells are discarded," Hill said. "The hemoglobin is then heat-treated and filtered, which eliminates risks of infectious agents."
In bypass procedures, some of a patient's own blood may be removed just prior to being placed on the heart-lung machine -- which takes over for the heart during surgery. The blood is replaced by a colloid solution. Then, the patients' own blood can be returned at a later point during the surgery, preferably after blood loss has ceased. This blood preservation strategy is frequently used to reduce the need for transfused blood.
"To avoid transfusion during cardiac surgery, however, we do have to remove a significant amount of the patients' own blood," Hill said. "A hemoglobin-based oxygen carrier would provide additional circulating hemoglobin to facilitate safe removal of the patient's blood and support oxygen delivery to the body during the three to four hours of surgery."
In the Duke study, 60 patients undergoing coronary artery bypass operations at six U.S. medical centers were randomized to receive either varying doses of hemoglobin raffimer or colloid during surgery. Of those receiving hemoglobin raffimer, 44 percent did not need a blood transfusion, while 18 percent of the control group avoided transfusion. Other than elevated blood pressures, the researchers found no other significant negative side effects from the agent.
There are two other ongoing trials of hemoglobin raffimer -- a Phase III trial being conducted in Canada and the United Kingdom, as well as a Phase II trial in the U.S., which is examining the effectiveness of the agent at higher doses.
The clinical trial was funded by Hemosol, Inc., Toronto, which developed hemoglobin raffimer. Hill has no financial interest in Hemosol.
Joining Hill in the study were Katherine Grichnik, M.D., from Duke and Lewis Gottschalk, M.D., University of Texas Medical School, Houston.
Materials provided by Duke University Medical Center. Note: Content may be edited for style and length.
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