Blood Substitute!

06/20/00- Updated 12:57 PM ET

Blood substitute may be anticipated break

By Robert Davis, USA TODAY

When Herbert Kay faced major surgery in January to repair an aortic aneurysm, 
he told his doctor that he did not want to receive a blood transfusion unless his life 
was in danger. The risk of contracting HIV, hepatitis C or even ''mad cow disease'' 
from donated blood was a concern to the 70-year-old research psychologist. 
''I wanted them to use a transfusion only as a last resort,'' he said.

Kay got his wish: His operation was done using a milky white substance that scientists 
hope will prove to be a major breakthrough in the effort to find a viable blood substitute. 
If it does, ''bloodless surgery'' - preferred by increasing numbers of patients and doctors 
could become commonplace.

Kay, of West Caldwell, N.J., was part of the clinical trial that is testing the substance, 
called Oxygent. The concoction, which looks somewhat like baby formula, has been 
used in hundreds of patients around the world during clinical trials and appears to be 
headed for federal approval and widespread use.

''I'm convinced that within the next year or so we will have a licensed product,'' said 
Harvey Klein, chief of the department of transfusion medicine at the National Institutes 
of Health. NIH funds some research in the field, but most is done by private companies.

Doctors and scientists call Oxygent an oxygen carrier, not a blood substitute. 
They cannot yet come close to matching the miraculous jobs that blood cells perform in 
our bodies. But Oxygent, made by Alliance Pharmaceutical Corp. of San Diego, appears 
to do a key, lifesaving job well: It delivers oxygen in ways that are often better than the 
body's own red cells. Beyond use in surgery, doctors see the substance as being a lifesaver
for heart attack and stroke victims and severe trauma patients who can die in the minutes 
that it takes to identify the patient's blood type, acquire donated blood that matches and 
deliver a transfusion.

Federal officials caution that it is too early to know whether further clinical testing will find 
unexpected downsides, but there is growing optimism that Oxygent and other oxygen  
carriers may finally provide a safe alternative for donated blood and ease the strain on 
the nation's already overtaxed blood banks.

The U.S. blood supply is chronically low; American blood banks are expected to come 
up about 250,000 units short this year. Officials are forecasting a national shortage in July, 
when regular donors go on vacation and college students scatter.

Because the nation has a robust and competitive blood collection system, shortages are 
usually filled before lives are threatened. But coming up short means that elective surgeries 
and other noncritical needs are not met. The supply is so fragile - donated blood is only good
for about 42 days, and less than 5% of eligible donors give blood - that severe weather such 
as snowstorms or hurricanes often lead to surgeries being canceled.

And while blood is a scarce resource, it also comes with a risk. New viral screening processes 
are being tested, but so far scientists have not been able to call donated blood 100% safe. 
Hepatitis C is transmitted about once in every 100,000 transfusions, and HIV, the AIDS virus, 
about once in every 676,000. There are 11 million transfusions a year.

Long, difficult road

Attempts over the past 25 years to create a safe blood substitute have seen high hopes turn 
to tragic disappointment. Some experts predicted in the mid-1990s that Baxter Healthcare's 
HemAssist, a hemoglobin-based substitute, would be approved within a few years. But the 
company halted its clinical trial suddenly when trauma patients died at an unexpected rate. 
Of the 52 trauma patients who got HemAssist, 24 died.

When doctors and scientists looked more closely at what had happened, they were surprised 
to see that the blood substitute had caused the blood pressure to rise dramatically. ''It reflected 
that we didn't understand what these things were doing at the cellular level,'' Klein said.

Baxter has moved to a new generation of hemoglobin-based substitutes. The company is 
genetically engineering hemoglobin cells but has not begun human testing. Baxter cautiously 
predicts its new version could be on the market by 2007.

Unlike other competitions within the drug industry, where successes and failures largely remain 
trade secrets, the rest of the industry has learned from Baxter's failure. The Food and Drug 
Administration held public meetings so all scientists could learn from one other.

Baxter gets high praise from federal officials for sharing its lessons. ''We're much further ahead 
than we were when Baxter stopped their trials,'' Klein said.

The Alliance trial of Oxygent is typical of the way trials have been redesigned since HemAssist 
failed in emergency rooms. Test subjects now are picked from stable surgery patients instead 
of those who are fighting for their lives, reducing chances that unexpected medical complications 
will skew the tests.

The product is administered in the operating room under the supervision of top anesthetists 
instead of in the chaotic emergency room. That allows the doctor at the head of the operating 
table to watch the patient closely for trouble.

Instead of determining the value of the substitute largely by patient survival, today's studies 
allow doctors to monitor all of the patient's vital signs and blood functions closely before, 
during and for many days after surgery. That allows doctors to track more subtle changes 
in the body after the substitute is given.

Doctors involved in the study say the early results are remarkable, with great benefit to the 
patients and no signs of serious side effects. But others say that the big hurdle - testing in 
trauma patients - remains. Baxter's HemAssist passed similar, well-controlled surgical trials 
only to fail the real test of trauma cases.

Alliance said that the problems that led to the HemAssist failure were seen on a smaller 
scale in the surgical trials and that there have been no serious side effects of Oxygent
But some blood experts caution that today's enthusiasm for blood substitutes is not unlike 
the previous waves of excitement.

''I would be surprised if something got through the FDA in two years,'' said Linda Chambers, 
a senior medical officer at the Red Cross. ''It's been a long road with a lot of bumps. 
The FDA will be very careful approving any of these.''

Competing with nature

Human blood is a perfect stew of platelets and red and white cells in plasma. It performs 
countless life-sustaining tasks, not all of which are fully understood.

Blood transfusions are used for many medical purposes today. But it's when a patient is in 
shock, when medics need to deliver oxygen throughout the body within seconds to save  
a life, that blood transfusions can take too long. Blood must be preserved carefully, so it's  
not always handy. Blood must be matched to each recipient, and those tests take time.

This urgent need for an oxygen delivery device has driven scientists down two general paths:  
modifying the blood's own hemoglobin and developing synthetic substitutes. Hemoglobin-based  
substitutes such as HemAssist and others require donated blood from either people or cows;  
Alliance's Oxygent is made primarily of inexpensive, easy-to-produce fluorocarbons.

They dissolve gases, moving oxygen from the lungs to vital organs and remote regions of the  
body and cleansing the body of carbon dioxide. In surgery, the fluorocarbon delivers to the body  
about twice as much  twice as fast as the same amount of the blood's own hemoglobin. And  
because these particles are tiny compared to the body's red blood cells, they can swirl  
freely through the body's 60,000 miles of capillaries and breeze through blocked arteries in  
heart attack or stroke victims.

If Oxygent is approved for use in surgery, experts say, doctors will begin using it ''off label''  
for other purposes, such as getting oxygen into a damaged brain.

''There is potential for this to be used in stroke patients where you want to deliver oxygen   
to an area where the blood vessel is severely compromised,'' said Ronald Pellegrini, a surgeon  
who has given Oxygent to some of his patients at the University of Pittsburgh Medical Center.  
''It can get through very small spots.''

Pellegrini and other doctors who are using the oxygen carrier say the benefits are obvious.  
But some downsides are noticeable, too. Patients sometimes get flu-like symptoms as their  
bodies try to filter the substance from the blood. And the number of platelet cells in the  
blood - key for forming blood clots - drops several days after Oxygent has been given.  

Alliance said neither is a significant side effect, but federal officials say much more analysis is  
needed before the product can be judged for safety.

Alliance hopes to have tested Oxygent on more than 1,000 patients by the end of the year.  
And more trials, including emergency cases, will likely follow. Even so, side effects that only  
occur once in every 10,000 cases may remain hidden. Eventually, the FDA must decide if the  
risk of what is still unknown outweighs the benefit of a substitute for blood. Officials say  
more tests on more patients will be needed to make such a decision.

''This is unlike any other biologic product out there,'' said the FDA's Abdu Alayash.  
''We're going against nature, so we are constantly surprised by some of the things that we  
discover as we go along. This is really new science.

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