Bloodless Coup

There'll be no waivers for patients in this experimental blood-substitute program

The LifeFlight emergency helicopter swoops down to the accident scene. It's bad -- the unconscious victim has lost a lot of blood. An ambulance crew is already there and checking the victim's pulse and blood pressure.

The chopper's blades still whirring, the LifeFlight techs hop out and survey the scene. One of them slips a nondescript envelope out of the emergency kit and rips it open. Inside is a document telling them whether the victim has just been enrolled in an experimental research program. If so, the techs will begin transfusion of an unproven blood substitute, without the victim's knowledge.

The victim, like most Houstonians over 18, has been automatically entered in research conducted by the University of Texas Health Science Center at Houston and Memorial Hermann Hospital's LifeFlight.

The study began last month as part of a nationwide program sponsored by Northfield Laboratories, an Illinois-based drug company seeking approval for its blood substitute, PolyHeme. Northfield trials are already under way in Denver, and the company hopes to conduct trials in 15 or 20 other cities.

Under the informed consent laws, most experimental programs require that participants first be told about the research, and then give written approval before becoming a test subject. For this blood substitute program, the U.S. Food and Drug Administration has issued a waiver so that medical personnel don't need the patients' permission to administer the product to trauma victims. Excluded are patients under 18, pregnant women, the severely brain-injured, those requiring CPR to maintain their heartbeat, those with "unsurvivable injuries" and patients known to object to blood transfusions (e.g., Jehovah's Witnesses) or resuscitation.

Everyone else -- that goes for most readers of this article -- is automatically included. The LifeFlight study aims to administer PolyHeme to 50 patients.

The rare waiver underscores the importance of the research: Companies know that whoever designs the best product will revolutionize emergency medicine -- and make billions of dollars in the process.


Trauma-related injury is a leading cause of death for Americans under 45, according to the UT Health Science Center, which is overseeing the LifeFlight trials.

In these cases, blood is the most critical resource. But donated blood expires after 42 days. Blood cannot be safely transfused at accident scenes and is therefore not usually carried in emergency vehicles, says Tom Flanagan, assistant vice president for emergency services at Memorial Hermann.

Hospitals are required to have O-negative blood, the universal donor, at all times. This is to be administered until the hospital can determine the patient's blood type -- about a 40-minute procedure.

The first 60 minutes following a trauma injury are the most vital -- doctors call it the golden hour. Loss of blood means loss of oxygen to the organs. Between transportation to the hospital and waiting for blood typing, each minute can literally mean life or death.

But even transfusions carry risk -- potentially leading to viral infection and organ failure, Flanagan says.

Seeing the need to find a safe, transportable, universally compatible alternative to donated blood, medical research companies in the 1980s raced to put blood substitutes on the market, ranging from derivatives of cow's blood to completely synthetic fluids.

Blood substitutes are intended to keep patients alive long enough to reach a hospital and gain access to real blood. They are not meant to replace donated blood and, if ultimately approved, could increase the need for donations, says Robin Davidson, public relations manager for the Gulf Coast Regional Blood Center. Davidson, who supports the research, says more trauma patients would reach more hospitals more of the time -- meaning more blood would be needed than ever before.

The companies are expected to conduct stringent clinical trials, on both animals and voluntary human subjects, before seeking FDA permission to waive the informed consent rule. In 1998, Illinois-based Baxter Healthcare Corporation's HemAssist was the first to receive the waiver.

That waiver gave Baxter the lead at the time in cracking what blood substitute companies estimate to be a $5 billion to $10 billion worldwide market. In 2001 alone, American hospitals transfused 14 million pints of whole blood and red blood cells, the National Blood Data Resource Center reports. The volume of transfused blood is increasing 6 percent a year. In Houston, the regional blood center sells red blood cells for $188 per pint, depending on supply and the season; some blood substitute companies projected their prices at up to $1,000 per pint.

Ben Taub General Hospital was to be among 17 hospitals involved in the trials, but before they started at Ben Taub, Baxter ceased testing because the initial results showed a higher-than-anticipated mortality rate. Twenty-four of 52 patients given HemAssist died, compared to eight out of 46 in a control group. HemAssist's death rate was 4 percent higher than Baxter expected. The deaths were believed to be caused by blood vessel constriction.

Then Northfield Laboratories became the front-runner when it received federal research approval for PolyHeme. Northfield CEO Dr. Steven Gould says Memorial Hermann was selected to be in those trials because it's a level-one trauma center that has the necessary resources for proper testing.

But the study is actually under the auspices of Dr. Frederick Moore, general surgery director at the UT Health Science Center.

Gould says PolyHeme is made by extracting hemoglobin, the oxygen- carrying molecules in red blood cells, from expired whole blood.

In 2002, the Journal of the American College of Surgeons reported the results of Northfield's first controlled human trials. The study compared 171 trauma patients who received PolyHeme to statistics from an earlier, unrelated study in which, for religious reasons, 300 trauma patients did not receive any blood products.

Gould, who was proud of the results, anticipated criticism from the fact that he had to rely on a historical control group.

In order for doctors to compare patients who received PolyHeme to patients who didn't receive any blood or red blood cells, the researchers would have had to deny life-saving blood products to a control group. Because such denial would have been unethical, Gould relied on the historical data.

Ultimately, 18 of the 171 PolyHeme patients died (10.5 percent), compared to 48 deaths in the control group (16 percent). "None of the deaths was considered due to the PolyHeme," the study states, citing other factors, such as multiple organ failure.

Dr. Ronald Maier, a Seattle doctor, published a critical review of the study: "Unfortunately…the use of historical controls raises significant concern for the reliability of the final comparisons….[I]t is unlikely that the difference is as great as is demonstrated using selected historical control groups," he wrote.

But based in part on the report, and after analysis by review boards at the UT Health Science Center, the study to transfuse PolyHeme without consent was granted.


Dr. Laurence McCullough, a medical ethicist at Baylor University, calls it a classic moral dilemma: the clash between two good, yet incompatible, ideas -- the fundamental right to informed consent versus the need to improve emergency medical care through means that cannot allow for that consent.

"Emergency medicine has developed by innovation, without confidence in all cases that the innovation is doing patients any good," McCullough says. "So if we can't do research to improve emergency medicine, then we're left with a real major ethical problem on our hands; we may be doing things to patients in emergency medicine that may not benefit them and, even worse, may harm them."

In 1996, the FDA began allowing waivers with the belief that, as McCullough says, "If you stick to an absolute requirement of consent, you may oblige doctors and nurses in places like emergency rooms or in ambulances to deliver care that is substandard."

The ultimate goal of medicine is to establish "evidence-based standards" of care, where factors such as geography -- how far away a person lives from a hospital -- would not affect the level of care for patients.

"The kind of medical care you get for a heart attack or for a stroke shouldn't be a function of where you live, right?" McCullough asks. "That's irrelevant. What's relevant is your medical diagnosis, and that's how you should be managed."

But in order to get there, researchers must be allowed to conduct trials where informed consent is difficult or impossible. Waivers are not issued lightly. Committees of medical experts and community members outside the medical field extensively reviewed UT's application.

Larry Scott, UT's assistant vice president for Human Subjects Research, called the proposal "a conundrum," adding that "on the one hand, research [was] needed to be done in these emergent life-threatening situations, but the usual kinds of safeguards that were put in place to protect research participants just weren't gonna work."

Marianne Fanning, a health care consultant who sat on one of the review committees, says she put herself "in the role of the patient or the patient's family members…When they say, 'let's waive consent,' it's a fundamental right that you are waiving…you take those real seriously as they come through."

(There is a provision where members of the general public can avoid becoming test subjects by calling the UT Health Science Center at 713-500-7277. Callers will receive bracelets exempting them from the possibility of receiving a blood substitute.)

To gauge community reaction, the UT committees also held meetings last summer with about ten churches and civic organizations, including the Metropolitan Community Church of the Resurrection and the Chinese Community Center.

Vicki Gibbs, pastor's assistant at Metropolitan, was among two dozen people who attended the August meeting. She supported the waiver.

"I would like informed consent, but I know that that's not always necessary -- and if you're trying to save a life, save the life," she says.

Theresa Hong Chen, the CCC's community services director, says 66 people attended their meeting in July. "They explained it very well, they were clear," she says of the university's committee members. She says the explanations were clear and she would have no problem receiving PolyHeme without consent.

"What you do when you want to sacrifice one good to achieve another," McCullough says, "is you set up very rigorous review processes to reach a judgment that the one good is worth sacrificing for the other. And you make people justify that."

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