[A new procedure for donating hearts and other organs is saving
lives. But for some it challenges the definition of death.]
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SUNDAY SCIENCE: GIVING HEART  
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Jennifer Couzin-Frankel
May 11, 2023
Science
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_ A new procedure for donating hearts and other organs is saving
lives. But for some it challenges the definition of death. _

Tony Donatelli (foreground) was the first person ever to receive a
heart, liver, and kidney through a new donation procedure. “I cannot
tell you how lucky I am,” he says., Sandy Huffaker

 

A version of this story appeared in Science, Vol 380, Issue
6645.Download PDF
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On a chilly holiday Monday in January 2020, a medical milestone passed
largely unnoticed. In a New York City operating room, surgeons gently
removed the heart from a 43-year-old man who had died and shuttled it
steps away to a patient in desperate need of a new one.

More than 3500 people in the United States receive a new heart each
year. But this case was different—the first of its kind in the
country. “It took us 6 months to prepare,” says Nader Moazami,
surgical head of heart transplantation at New York University (NYU)
Langone Health, where the operation took place. The run-up included
oversight from an ethics board, education sessions with nurses and
anesthesiologists, and lengthy conversations with the local
organization that represents organ donor families. Physicians spent
hours practicing in the hospital’s cadaver lab, prepping for organ
recovery from the donor. “We wanted to make sure that we controlled
every aspect,” Moazami says.

That’s because this donor, unlike most, was not declared dead
because of loss of brain function. He had been suffering from
end-stage liver disease and was comatose and on a ventilator, with no
hope of regaining consciousness—but his brain still showed activity.
His family made the wrenching choice to remove life support. Following
that decision, they expressed a wish to donate his organs, even
agreeing to transfer him to NYU Langone Health before he died so his
heart could be recovered afterward.

In individuals declared brain dead, organs can be recovered before
life support is disconnected, as these people have already died; such
machinery keeps organs oxygenated and healthy prior to transplant. But
for this man the donation process would be altered: Life support had
to be withdrawn for death to occur. His heart stopped, and his
circulation with it.

As is customary regardless of whether organs will be donated,
physicians waited 5 minutes to ensure that the heart didn’t start
beating again on its own. It did not, and the man was declared dead.
The baton then passed to the organ recovery and transplant team. They
clamped blood vessels running from the torso to the brain and
reconnected his body to machines that circulated oxygenated blood,
causing the heart to begin pumping again.

These two interventions—initiating a heartbeat after death is
declared and taking steps to prevent blood flow to the brain—are at
the core of a raging debate about the ethics of such donations. To
some people, the approach risks disrupting the dying process; to
others, it allows that process to continue as the family desires,
while also honoring individual or family wishes for organ donation.

The debate touches on the definition of death, Moazami says. “When
the heart stops, we say, ‘time of death, 5:20 a.m.’” But, “The
fact of the matter is, death is a process. Death is not a time
point.” Cells can take hours to die. Sophisticated machinery can
induce a heartbeat hours after death, but does that make a person
“alive”?

Just over a year after his triple transplant, Donatelli is back to
surfing and wrestling with his sons. Sandy Huffaker

An expanding number of hospitals and organ procurement organizations
(OPOs), which work with donor families, support this novel category of
donations, and the number performed in the U.S. is growing. “I had
about 3 months, tops,” left to live, says Tony Donatelli, 41, who
lives near San Diego with his wife and two young children, and who
developed a rare disease that causes a dangerous buildup of protein in
the body. On Valentine’s Day 2022, he became the first person in the
world known to receive a heart, liver, and kidney from a donor whose
organs were perfused after circulatory death. Donatelli is back to
surfing, woodworking, and wrestling on the floor with his sons. “I
cannot tell you how lucky I am,” he says.

Yet professional groups have expressed dueling
[[link removed]] views
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the organ donation strategy, and a paper in press urges more research.
Some countries are holding off on these organ donations, whereas
others embrace them. One OPO says families who welcome donation do so
without regard for the organ recovery technique, as such gifts can
bring comfort after a terrible loss; another worries that without more
research and greater attention to legal and ethical questions,
there’s a risk fewer people may volunteer to be organ donors.
Meanwhile, surgeons say this category of donors could increase heart
transplants by up to 30%, saving lives with organs that would
otherwise go unused.

“There is definitely that initial reaction that there’s something
different” about this, says Anji Wall, an abdominal transplant
surgeon and bioethicist at Baylor University Medical Center. Although
Wall acknowledges the complexities, she supports such transplants and
has performed them herself. “At the end of the day, the donor is
dead,” she says. “What you do does not make them alive again.”

ORGAN TRANSPLANTATION has evolved and flourished from its first
success in 1954, when a 23-year-old in Boston donated a kidney to his
identical twin. In the years since, the number of transplants has
surged, but demand invariably outstrips supply. In the U.S., which
performs more transplants than any other country, about 104,000 people
are awaiting a new organ, and, on average, 17 die each day before they
get one. “We are a system that has always operated with scarcity,”
says Alexandra Glazier, an attorney and president and CEO of New
England Donor Services. Her system is one of 56 OPOs, each covering a
geographic region across the U.S., that coordinate organ donations by
working with hospitals and donor families.

The transplant system relies on public trust and the generosity of
these families at an excruciating and disorienting time. In 2013,
Emily Stillman, a 19-year-old college student in Michigan, was
rendered brain dead by a meningitis infection. When her mother, Alicia
Stillman, was approached about donating Emily’s organs, her first
reaction was one of horror. “I said, ‘Absolutely not, tell them to
stay away.’ … I remember screaming.”

But she quickly had second thoughts, believing her daughter would have
wanted organ donation; a call to the family’s rabbi also helped.
Emily’s organs were donated to five people, and the family bonded
with four of them. The heart recipient, a young physician in Ohio,
named his baby girl after Emily. On the anniversary of Emily’s death
in February, the mothers of the heart and kidney recipients reached
out to Alicia, “telling me, mother to mother, how grateful they are
that they had these 10 years,” she says. Gifting Emily’s organs
“was a huge part of our healing. It always gave us something
positive to grab onto.”

Until recently, virtually all organ donors in the U.S. were like
Emily. Following a grievous injury or some other catastrophe, they
were left brain dead—which is defined as lacking any brain function,
including the ability to breathe on one’s own. Their organs,
however, can be protected by keeping donors on supportive machinery.

But in the 1990s, doctors grew interested in another potential
category of donors: people who retained some brain activity after a
serious illness or accident but who died when their circulation
ceased—normally because, like the heart donor at NYU, their families
had opted to withdraw life support when there was no hope of
meaningful recovery. The lungs, liver, and kidneys, surgeons learned,
could be recovered and function after transplant. This became known as
“donation after circulatory death,” or DCD donation. Initially
uncommon, the number of DCD donors has soared; today, about
one-quarter of the kidneys transplanted in the U.S. are from DCD
donors.

The heart was another story. Circulatory death could severely injure
the organ. To address the problem, companies experimented with
machinery that would run blood through a heart after it was removed
from the body and stimulate its electrical activity. In 2014,
Australia was the first to test one such device, made by the company
TransMedics, after circulatory death. Five years later, a TransMedics
clinical trial began in the U.S. Regulators there approved the system
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this purpose in 2022.

Heart of the matter

Typically, organs are recovered after brain death. A newer approach
allows donations from people whose relatives choose to withdraw life
support, following an unsurvivable illness or injury. After death is
declared due to loss of circulation, machines are connected to
oxygenate the blood and allow the heart to restart, while clamps
prevent blood from reaching the brain. The circulation keeps organs
healthy until they are recovered for transplant.

1 A clamp is placed across three arteries that supply blood to the
brain, to focus perfusion on the organs being recovered and to avoid
interfering with the dying process.

2 Deoxygenated blood travels from right atrium to an external
reservoir.

3 Blood is warmed and oxygenated before returning to the body.

A. Mastin / SCIENCE

“It gave us access to hearts that no one else was using,” says
Ashish Shah, chief of cardiac transplantation at Vanderbilt
University, who participated in the trial. But using the device costs
between $65,000 and $85,000 each time. Recovering organs from DCD
donors can also be logistically complex, as surgeons race to remove
them before they succumb to a lack of oxygen. Sometimes, one organ is
recovered but another can’t be saved.

Shah, like Moazami, had been scrutinizing reports from colleagues in
Europe and the United Kingdom about another kind of DCD donation. It
entailed initiating oxygenated blood flow to the organs intended for
transplant while they were still in the donor’s body. For the heart,
that meant starting it beating again after a declaration of death.

The strategy, called normothermic regional perfusion–DCD (NRP-DCD)
and sometimes abbreviated to NRP, was yielding promising results. In
2020, a team at Royal Papworth Hospital in Cambridge, England,
published outcomes on three categories of heart recipients
[[link removed](20)31765-4/fulltext]:
those who received a heart from a donor after brain death, those whose
heart was from a DCD donor and placed on an external device, and those
whose donor organ was recovered after NRP, with perfusion within the
body. All 22 people who received NRP hearts were still alive 1 year
later. For the group receiving hearts maintained on external
machinery, the 1-year survival rate was 86%. For people receiving
hearts from donors assessed as brain dead, 1-year survival was 89%. A
March study reported comparable outcomes
[[link removed](23)00064-0/fulltext] after
157 NRP-DCD heart transplants spanning several countries and 673 heart
transplants from donors declared brain dead.

These weren’t randomized trials, but nonetheless “the results were
great” for NRP, says Stephen Large, a cardiothoracic surgeon at
Royal Papworth. Large pioneered these heart transplants in the U.K.
beginning in 2015, after years of deliberation by authorities. The
inspiration, he recalls, came in 2006 when a family approached him
after their 57-year-old wife and mother had suffered a devastating
stroke. The relatives intended to remove life support and wished to
donate her heart, but DCD heart donations weren’t possible at the
time. The family reached for the next best option, asking Large
whether he wanted to study her heart instead. He did, testing NRP
for the first time in a human being
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IN DOING SO, Large learned that the strategy allows a surgeon to, in
effect, audition the heart. You could “see how the heart was
performing” in the body after restarting perfusion, he says.
Moazami, the first to adopt the technique in the U.S., had the same
reaction: “I can look at the pressure the heart is generating, what
the chambers are doing.” In addition, surgeons believe that when
oxygenated blood circulates through several organs at once, it can
help them recover function lost during the dying process and their
time without oxygen.

In September 2021, Moazami’s team announced that its first eight
NRP-DCD heart recipients
[[link removed](21)01316-7/fulltext] were
all still alive. Earlier that year, Vanderbilt, one of the biggest
heart transplant centers in the world, had launched its own NRP
program. “We found ourselves traveling all over the country getting
hearts,” Shah says. “There was a demand from the donor
side—these families want these hearts donated. … Our job is to
find a way to use” them. And use them he did. In 2022, Vanderbilt
performed 40 heart transplants from NRP donors.

NRP technology is being used for other organs as well. Aleah Brubaker
was a new liver transplant surgeon at the University of California,
San Diego (UCSD), in the fall of 2021 when she was dispatched to get
her first liver from an NRP donor. Immediately, the impact “was very
evident to me,” she says. Patients are “unquestionably” getting
organs more quickly, including some who might die waiting—among them
Donatelli, for whom Brubaker was on the transplant team.

Heather Santiago listens to her son Jordan’s heart beat inside the
person who received it. After Jordan died in a hit-and-run, his organs
were donated to five people.SOUTHWEST TRANSPLANT ALLIANCE

UCSD has accepted livers from NRP donors in their late 60s, above the
usual age cutoff, because perfusion inside the body helped doctors
determine that the organs would be usable. Research on NRP kidney
[[link removed]] and liver
[[link removed](18)32632-1/fulltext] recipients
shows they have improved organ function and less chance of needing a
second transplant than patients who get those organs via conventional
DCD. “The results were much better,” says Beatriz Domínguez-Gil,
director general of the Spanish National Transplant Organization.
Spain has used NRP for abdominal organs for many years and began NRP
heart donations in 2020. Unlike the heart, the liver and kidneys can
be sustained with blood flow just to the abdomen, and without inducing
a heartbeat, which eases some ethical concerns.

Transplant programs are fiercely competitive, vying for the lowest
wait times and highest survival rates. At the same time, the surgeons
participating in NRP donations say they wouldn’t touch them without
full support from their institutions and confidence that they are
ethical. The people who become NRP donors “are in this terrible
state,” Shah says, most often with a devastating brain injury. They
have no prospect of meaningful recovery.

“We have to put ourselves back into the context that this family has
already accepted their loved one will not live and wants us to go
forward with donation,” says Brad Adams, an attorney who is also
president and CEO of the Southwest Transplant Alliance. His OPO
oversaw seven NRP donations in the first quarter of this year compared
with nine in all of 2022.

AS NRP DONATIONS ramp up in the U.S., some other countries are
pumping the brakes. In the U.K., the first place to use NRP for heart
donation, they ground to a halt in 2019. Concern bubbled up at a
meeting between U.K. and Canadian physicians about whether, despite
the clamping of vessels to the brain before organ recovery, some blood
could still reach it.

In an attempt to study this, Large and his colleagues examined three
NRP donors, looking for blood in tiny arteries that thread up to large
vessels feeding the brain. In one person, there was detectable blood
flow in these vessels, estimated at 50 milliliters per minute, about
7% of the normal rate. Whether blood actually reached the brain
wasn’t tested. “There was a heated argument” among physicians,
Large says, about how much blood, if any, could get to the brain, and
its significance
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Following Large’s observations, the donation and transplant
communities paused NRP for heart donations in the U.K. The country
continues to support NRP for liver and kidney donors, as vessels there
are clamped lower in the abdomen and the chance of blood reaching
beyond the torso is considered remote.

A knotty and mind-bending question is whether such flow would matter.
“The clamping of the vessels is … a postmortem intervention,”
says Marat Slessarev, a specialist in critical care and organ donation
at Western University in Canada. Like colleagues who work in intensive
care units, he’s comfortable with the standard of declaring death 5
minutes after the heart stops following a withdrawal of life support.
A recent study that included 480 patients whose life support was
withdrawn backs this up. Transient heart activity resumed
spontaneously in 67, but the longest lag time was 4 minutes and 20
seconds [[link removed]],
investigators reported in _The New England Journal of Medicine _in
2021.

But could blood flow to the brain after circulatory death still spark
brain activity or function? Because dying is a process, “the best
way to put it is, we don’t know,” Slessarev says. He wants to
prove that circulatory death guarantees rapid brain death, which he
suspects is the case, and that clamping guarantees zero blood flow to
the brain.

Slessarev and colleagues began to address the first challenge in a
pilot study of eight people
[[link removed](23)00064-3/fulltext] after
the withdrawal of life support. They found that brain activity
actually ceased before the heart stopped beating—on average, 78
seconds earlier. “Blood pressure falls below a certain level, then
the brain stops, then circulation stops,” Slessarev says.
“That’s sort of the sequence of events.” To see whether these
results hold up, he’s now co-leading a larger effort across Canada
that aims to enroll about 90 people. His goal is to inform organ
donation policies in his country, which does not permit NRP donations
but is weighing them.

Slessarev is also co-leading a Canadian team preparing to probe
whether there’s any blood flow to the brain after clamping. He’s
reassured by a January 2022 paper from a team in Denmark, showing that
in pigs, 8 minutes without circulation followed by clamping prevented
all blood flow
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brain activity when the heart restarted. Animals that did not receive
any clamping showed brain waves on monitors.

At the end of the day, the donor is dead. … What you do does not
make them alive again. ANJI WALL, BAYLOR UNIVERSITY MEDICAL CENTER

Others are conducting similar studies. Moazami recently hunted for
cerebral blood flow with a transcranial doppler machine in two NRP
heart donors. “We could not detect any,” he says, and he plans to
examine this in more cases.

In the U.K., a team at Royal Papworth will study NRP donors in the
coming months, using a test called a CT angiogram to see whether any
blood appears in cerebral arteries and returns through the veins. The
latter could indicate perfusion through tissues. “I will be really
surprised” if there is cerebral blood flow to any meaningful degree,
says Antonio Rubino, an intensivist at the hospital who is leading the
trial. But he still wants the work to be done.

FOR NOW, “the global ethics of this have not been resolved,”
Moazami says, and even in the U.S., controversy is erupting. “The
definition of death is kind of broken,” says Brendan Parent, an NYU
bioethicist who helped his hospital and several others consider the
ethics of NRP. Irreversible loss of either all circulation or all
brain function qualifies as death in the U.S. But circulation can, in
theory, be reinstituted by machinery even many hours after a death,
Parent notes, rendering the circulatory death definition, practically
speaking, meaningless.

As NRP donations increased in the U.S., debate emerged in spurts and
crescendoed this spring. An early salvo came in April 2021, when the
American College of Physicians, which represents internal medicine
doctors, deemed NRP unethical
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part because it can reestablish a heartbeat. Wall, Shah, and others
published a response arguing that NRP meets ethical standards
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consent and organ donation. On the legal front came a volley from
Alexander Capron, a law professor at the University of Southern
California, and Glazier of the New England OPO, arguing that NRP is
inconsistent with U.S. legal standards
[[link removed](22)08196-5/fulltext] because
it involves restarting circulation whose permanent absence prompted
the declaration of death in the first place. Adams, Parent, and others
shot back that NRP is consistent with U.S. legal standards of death
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the technique is limited to perfusing organs and doesn’t impact the
determination of death. Glazier, who says her OPO is one of a few that
don’t yet permit NRP for the organ recoveries they coordinate,
emphasizes that her concerns are more about a “misalignment rather
than a big violation.” Can these potential donors return to what is
considered meaningful life with NRP interventions? “Absolutely
not,” she says. But she still has significant concerns about the
strategy.

Glazier thinks death in the U.S. should be redefined as a permanent
loss of brain function, period, with no separate definition for
circulatory death. She joined authors from eight countries, including
some, such as France and Spain, where NRP has long been practiced, on
a paper in press in _Transplantation_. They urged all countries to
adopt a brain-based definition of death, which could be determined by
a permanent absence of circulation to the brain. This would ease
concerns about NRP if studies like those planned in Canada and the
U.K. confirm that clamping prevents any blood flow to the brain.

In March, the U.S. National Institutes of Health and the Organ
Donation and Transplantation Alliance held separate meetings to
discuss NRP. Interest in the topic was so great that the alliance was
forced to find a larger venue. Elizabeth Pomfret, chief of transplant
surgery at the University of Colorado School of Medicine, which
recovers organs with NRP, welcomes the discussion. But Pomfret, who is
president-elect of the American Society of Transplant Surgeons,
worries about “confusion that’s arisen around these questions of
the permanence of death. … This whole conversation is sort of
reeling out of control.”

Parent stresses that protecting the potential donor’s interests is
the highest priority. But he adds, “It’s not as simple as just
trying harder to save that person’s life,” because doing so can
become futile and cause more suffering. For individuals who expressed
a wish to be a donor and whose life cannot be saved, “what would be
in their best interest is preserving their organs” for others who
need them, he says. Parent is now developing a project to study public
and donor family perceptions of NRP.

Alicia Stillman and her husband didn’t have to make a decision about
NRP donation for Emily. But if they had, she imagines that the
distinction between circulatory and brain death would not have been so
important to her. “Nothing was going to bring Emily back,” she
says. “There was nothing I could have done to save her.” Donor
families “should be at the head of the table” helping make these
decisions, she believes.

Across the country in Texas, another family agrees. Andrew Santiago
doesn’t know what he and his wife Heather Santiago would have done
in this situation, but he suggests these donations “be positioned as
an optional deal,” with the family making that call. His 25-year-old
son Jordan was left brain dead almost 3 years ago after a hit-and-run.
Jordan’s organs, like Emily’s, were donated to five people, and
“that’s what’s keeping us going,” his mother says. Both
the Stillmans [[link removed]] and the Santiagos
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include organ donor advocacy.

Early next month, the American Transplant Congress will convene in San
Diego, about a 15-minute drive from Donatelli’s home near the
Pacific Ocean; he may be speaking there. Pomfret, meanwhile, is
organizing a symposium for the conference’s opening day to develop a
formal position statement on NRP and lay plans for national data
collection on NRP cases and universal standards for recovering those
organs, such as clamping techniques. “We’re showing the community
that we’re responsible,” Pomfret says. “This isn’t just a
free-for-all.”

UCSD Jacobs Medical Center, the site of the institute’s transplant
surgeries, is a short drive up the coast from the convention center
where surgeons will gather. In one of the hospital’s beds, another
triple-organ transplant patient is currently recovering. His new
heart, liver, and kidney were given by an NRP donor.

_JENNIFER COUZIN-FRANKEL is a reporter at Science, covering
biomedical research._

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