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.