As a matter of biology, brain death is catastrophic for the body.
Yes, the heart can still beat and a ventilator can provide oxygen, but there is no brain to coordinate the tasks of staying alive. Hormones that tell organs what to do are out of whack. Inflammatory molecules flood the body. Cells die. “You can see the kidneys don’t work as well, the lungs don’t work was well, and the heart can look stunned,” says Darren Malinoski, a trauma surgeon at Oregon Health and Science University.
There’s nothing to do for the dead patient at this point. But his or her organs can be saved, and because most transplanted organs in the United States come from brain-dead donors, these minutes are crucial. For this reason, researchers have wanted to study the use of drugs or procedures in brain-dead donors, halting organ damage that happens in the minutes after death.
But this kind of research is almost impossible to do in the United States. The ethics of so-called donor-intervention research are incredibly fraught. How do you get informed consent and from whom? The dead donor? The live recipient—or possibly dozens of live recipients getting tissues or organs from a single donor, fanned out across the country at different hospitals each with their own ethics review boards? All this would unfold against intense time pressure. Every minute of delay is a minute in which the organ is deteriorating.
In 2015, Malinoski and his co-investigator Claus Niemann, a transplant doctor at University of California San Francisco, published results from a rare donor-intervention trial. The reaction to their study became an object lesson in why doctors avoid this kind of research.
The research team wanted to see if cooling the body temperature of brain-dead donors by about 4.5 degrees Fahrenheit—aka hypothermia—could improve the function of transplanted kidneys. Since kidneys are put on ice after they’re taken out of the body, perhaps cooling the kidneys while still in the body could help preserve them. Every institution involved in human subjects research has an institutional review board, and UCSF’s board decided doctors did not have to ask for informed consent. In the case of the donors, the board reasoned they were dead and thus not human research subjects. In the case of the organ recipients, it reasoned the hypothermia protocol posed only minimal risk to them.
Then in April 2016, Public Citizen, a consumer advocacy organization, blasted UCSF’s decision as a “disturbing failure.” It wrote a letter asking the federal Office for Human Research Protections, which oversees institutional review boards at hospitals and universities, to investigate. The OHRP has not yet made any public statements about the hypothermia trial.
The letter sent a chill through the transplantation community though. “Already there were perceived barriers and real barriers [to donor invention research] and now there’s concern about regulatory compliance,” says Alexandra Glazier, president and CEO of New England Donor Services, an organ-procurement organization that helps arrange donations.
Public Citizen’s condemnation was especially harsh, but disagreement over how to handle donor-intervention research is real. In 2016, Glazier, Feng, and others published the results of a survey of transplant surgeons, institutional review board (IRB) members, and organ procurement organization professionals. They found a wide range of views on the many unresolved questions, such as whether the donor or recipient’s hospital IRB should review the trial, who is a human research subject, and what kind of consent is necessary.
In one hypothetical scenario they asked about, a researcher wants to test a drug already used in dead organ donors to find the optimal dose to improve heart transplants. In their survey, 82 percent IRB members thought the trial was human subjects research. In contrast, 58 percent of transplant surgeons and 19 percent of organ procurement organization professionals agreed. IRBs are supposed to oversee human subjects research, so the community does not agree on a question as basic as whether an IRB should even oversee this research.
Practically, this confusion means the research rarely happens. “It gets shut down because everybody understands there is no pathway to doing this research,” says Sandy Feng, a transplant surgeon at UCSF who has written extensively about this issue. Funding agencies don’t want to fund it. Pharmaceutical companies don’t want to pursue it. Doctors shy away, not wanting to risk their reputations.
Douglas Hanto, a transplant surgeon at VA St. Louis Health-Care System, told me his research on using carbon monoxide to improve kidney transplants has been stymied. While toxic in high doses, carbon monoxide at low doses seemed to improve kidney function in pigs. They never got to test it in human donors, he says, because the company interested in carbon monoxide realized such trials would be impossible to do. It didn’t help that carbon monoxide is usually known a poison.
In contrast, the handful of donor-intervention trials that have gone through, like the hypothermia trial, have been minimal-risk. Usually, they have involved drugs already used in live patients. These trials are obviously not controversy-free, but if researchers are serious about testing new drugs that could radically change the quality of organs, Feng says the United States definitely needs a better system for ethical review.
For example, what if a new drug preserves the lungs but could potentially damage other organs? Would you need consent from the heart, kidney, liver, pancreas, intestinal, and tissue recipients, too? Would you need each recipient’s hospital IRB to approve the trial? Organs are not even allocated until after the drug would need to be given. It would be nearly impossible to go to each individual IRB in the time the organ is viable for transplant.
One solution is a central IRB, whose decisions would be accepted by every hospital in the country or at least in a region. That would logistically simplify a donor-intervention trial. IRB members also tend to be generalists, not experts on transplants. “This is a sufficiently niche area of research that there are compelling arguments for establishing donor-intervention research IRBs that could regulate all donor-intervention trials around the country,” says Scott Halpern, a doctor and bioethicist at University of Pennsylvania.
In the fall, the National Academy of Medicine—a nonprofit group that advises the federal government—is expected to issue a report on how to handle the ethical and regulatory issues of donor-intervention research. A national IRB is one of the recommendations it is considering.
To doctors like Malinoski, clear guidelines for donor-intervention research—guidelines that can cut through the mess of diverging opinions—can’t come soon enough. He and Niemann had planned a follow-up trial. Cooling the donor’s body did appear to improve kidney transplant success, and now they wanted to compare it to an alternative technique that uses a machine to pump liquid through the kidney outside the body.
But after the Public Citizen letter came out, potential collaborators were suddenly shaky. “When there’s controversy, people don’t want to touch it with a 10-foot pole,” says Malinoski. “It really set our study back over a year, year and a half.” After a lot of meetings and consultations, UCSF eventually gave them the go-ahead. The National Academy of Medicine can provide an authoritative answer for the whole country.
“We’re looking forward to clarity,” he says, “Whatever is decided, we’re happy to follow it.”