WASHINGTON -- Duke University Medical Center researchers report that an
important step has been achieved in the development of a blood substitute
for use during surgery.
The phase II trial tested a genetically modified version of hemoglobin, the oxygen-carrying protein in human red blood cells.
According to the Duke researcher who led the clinical trial, such a blood substitute could lead to lowered medical costs for patients and hospitals, and reduced demand for banked human blood. A viable oxygen carrier would not only eliminate the possibility, however slight, of disease transmission, but also a common side effect of donated blood -- immunosuppression in the recipient.
"The potential benefits to patients of a viable blood substitute are enormous," said Dr. Bruce Leone, associate professor of anesthesiology at Duke. "Anything we can do to decrease the external sources of blood is significant. We could now have something else to offer patients other than donated human blood.
"While routine use of such a product is three to five years off, this is an important and exciting first step," he said. "This is the first time a recombinant form of hemoglobin has been used as a pre-surgical volume replacement."
Leone prepared the results of the Duke trial for presentation Sunday (March 10) at the 70th Clinical and Scientific Congress of the International Anesthesia Research Society.
The phase II clinical trial suggested the safety of administration of large doses of the recombinant hemoglobin during surgery. Previous phase I studies conducted elsewhere demonstrated that the small doses of the product were safe in healthy, non-surgical patients. Future larger-scale clinical trials are needed to fully document the effectiveness of the recombinant hemoglobin, Leone said.
The blood substitute used in the trial was developed by Somatogen Inc., a biotechnology company based in Boulder, Colo. The product, rHb 1.1, is trademarked under the name Optro.
Somatogen creates rHb 1.1 by inserting the gene for the altered hemoglobin into the common bacteria E. coli., which then produces large quantities of the recombinant hemoglobin through the fermentation process, much like recombinant insulin is produced today.
The trial, which was conducted at Duke Hospital, involved 10 patients who underwent total hip replacements, a surgical procedure that usually entails blood transfusions either during or after surgery.
In the trial, physicians removed two units of blood from each patient immediately before surgery and replaced it with a mixture of saline solution and rHb 1.1 (up to 50 grams), creating a solution the color of a "red zinfandel wine," Leone said. The rHb 1.1 is designed to fulfill the oxygen-carrying responsibilities of the red blood cells for the duration of the procedure, which normally lasts about six to eight hours. If patients needed additional blood after surgery, they received their own.
"None of the patients experienced any significant side effects or adverse reactions from the product, and all of the procedures went without problems," Leone said. "Patients couldn't tell the difference, the surgeons couldn't tell the difference. Based on this small population of patients, the recombinant hemoglobin appeared to be safe and effective. Furthermore, none of the patients required donor blood."
In the pursuit of a viable blood substitute, companies and researchers have pursued two general strategies -- one that makes use of the oxygen-carrying capability of the hemoglobin molecule, and another that creates emulsions of perflourocarbons.
Scientists have been able to isolate the hemoglobin molecule for more than 50 years. However, efforts to use the molecule -- either human or animal -- have largely been unsuccessful for two main reasons -- kidney toxicity and inefficient oxygen carrying capability.
When administered directly into humans, free hemoglobin molecules quickly break down into two components that cause renal failure when they interact with kidney tissue, Leone said. Also, hemoglobin isolated from its natural environment within red blood cells loses its effectiveness in carrying oxygen through the blood and "off-loading" it to tissues.
Attempts to overcome these problems using strategies that chemically alter cow hemoglobin or extract the hemoglobin molecule from banked human blood that has passed its expiration date have met with limited success, Leone said.
In addition, the yields from both sources are considered to be too low to provide a reliable and practical blood source of hemoglobin, Leone said. He added that it is not certain that the processes used to retrieve and sterilize the hemoglobin from the "expired" human blood will completely remove the threat of disease transmission.
"Somatogen has taken a novel approach to this problem," Leone said. "The genetic modification in essence 'glues' the hemoglobin protein together so it doesn't break into its toxic parts once inside the body. This recombinant form of hemoglobin also carries oxygen efficiently outside the environment of the red blood cell.
"The method can create large quantities of recombinant hemoglobin without the threats of any disease, so it appears to be viable blood substitute," Leone added.
In 1978, the Green Cross Corp. developed an oxygen-carrying substance based on an emulsion of perflourocarbons. While the substance received FDA approval 11 years later, it was quickly removed from the market for lack of effectiveness.
Since then, researchers have developed newer and more efficient emulsions that are showing promise in various clinical trials being conducted in the United States and abroad.
While Leone said it is too early to calculate specific dollar savings from the recombinant hemoglobin, there are definite clinical benefits to the recombinant hemoglobin as another tool to help surgical patients avoid exposure to donor blood.
"Although the risks of infection are exceedingly rare (1 in 3,000 for hepatitis or 1 in 500,000 for HIV), there are other consequences," Leone continued. "Transfused blood can cause immunosuppression in the recipient. Many studies have demonstrated an increased rate of infections in people who have received transfusions. Until now, we have had no alternatives."
For example, about half of all Duke's hip replacement patients pre-donate their own blood before surgery, mainly out of fear of contracting a blood-borne disease. This process usually involves numerous visits over a period of weeks to a blood bank, which is inconvenient for the patient and adds the blood processing and storage expenses.
Joining Leone in the trial from Duke were Cynthia Chuey, clinical research nurse; David Gleason, certified registered nurse anesthetist; Dr. Susan Steele, and Dr. Roy Greengrass. From Somatogen, researchers were Dr. Robert Caspari and Rebecca Scanga.