Dr. Guy Alexandre (1934-2024), gave birth to brain death in deceased organ transplantation

 The father of brain death has died.

Here's the NYT obit.

Guy Alexandre, Transplant Surgeon Who Redefined Death, Dies at 89. His willingness to remove kidneys from brain-dead patients increased the organs’ viability while challenging the line between living and dead.  By Clay Risen

"Guy Alexandre, a Belgian transplant surgeon who in the 1960s risked professional censure by removing kidneys from brain-dead patients whose hearts were still beating — a procedure that greatly improved organ viability while challenging the medical definition of death itself — died on Feb. 14 at his home in Brussels. He was 89.

...

"Dr. Alexandre was just 29 and fresh off a yearlong fellowship at Harvard Medical School when, in June 1963, a young patient was wheeled into the hospital where he worked in Louvain, Belgium. She had sustained a traumatic head injury in a traffic accident, and despite extensive neurosurgery, doctors pronounced her brain dead, though her heart continued to beat.

"He knew that in another part of the hospital, a patient was suffering from renal failure. He had assisted on kidney transplants at Harvard, and he understood that the organs began to lose viability soon after the heart stops beating.

"Dr. Alexandre pulled the chief surgeon, Jean Morelle, aside and made his case. Brain death, he said, is death. Machines can keep a heart beating for a long time with no hope of reviving a patient. His argument went against centuries of assumptions about the line between life and death, but Dr. Morelle was persuaded.

...

"Over the next two years, Dr. Alexandre and Dr. Morelle quietly performed several more kidney transplants using the same procedure. Finally, at a medical conference in London in 1965, Dr. Alexandre announced what he had been doing.

...

"In 1968, the Harvard Ad Hoc Committee, a group of medical experts, largely adopted Dr. Alexandre’s criteria when it declared that an irreversible coma should be understood as the equivalent of death, whether the heart continues to beat or not.

"Today, Dr. Alexandre’s perspective is widely shared in the medical community, and removing organs from brain-dead patients has become an accepted practice.

“The greatness of Alexandre’s insight was that he was able to see the insignificance of the beating heart,” Robert Berman, an organ-donation activist and journalist, wrote in Tablet magazine in 2019.

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And here's the story from Tablet magazine, interesting in a number of respects:

The Man Who Remade Death. Guy Alexandre was the first surgeon to remove organs from a patient with a beating heart. His colleagues thought him a murderer; Alexandre disagreed and revolutionized our understanding of death.  BY ROBBY BERMAN, Feb 4, 2019

"I met Alexandre a few months ago in his home in an upscale suburb of Brussels. The octogenarian is charming, affable and avuncular but he does not mince words: The physicians who accused him of murder “were hypocrites. They viewed their brain dead patients as alive yet they had no qualms about turning off the ventilator to get the heart to stop beating before they removed kidneys. In addition to ‘killing’ the patient, they were giving the recipients damaged kidneys that suffered ischemia … oxygen deprivation. The kidneys did not work well; they did not last long.”

"Given that brain death was not well known by the public in 1963, I asked Alexandre how he succeeded in getting consent from families to donate the organs. “It was simple. I didn’t ask. I told the families the situation was grim and I removed the organs in the middle of the night. When the family returned the next morning I told them their loved one had died during the night.”

"In 1961, Alexandre was in his third year of surgical training. He left Brussels for Boston to attend Harvard Medical School where he studied under professor Joseph Murray, the surgeon famous for performing the first successful kidney transplant between twins in 1954. After Alexandre successfully executed a number of kidney transplants between dogs in the laboratory, he was invited by Murray to join him in the operating room to operate on humans. It was there that Alexandre noticed a curious phenomenon.

"Murray turned off the ventilator in order to cause the heart to stop beating and only then did he extract the organs. Alexandre felt there was no need to damage the kidneys by depriving them of oxygen. He believed when looking at a human body with a dead brain that he was looking at a corpse that was suffering from a bizarre medical condition: a beating heart. In other words, the organism was dead but the organs remained alive."

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Earlier:

Friday, January 18, 2019

Fifty years of "brain death"

Brain death for organ donation, and its relation to controversy about abortion

 Here's a summary of the current discussion of brain death (and its possible connection to the debate on whether a fetus is a living person), in JAMA. Maybe it will reach some resolution this year...

Truog, Robert D., and David C.  Magnus. The Unsuccessful Effort to Revise the Uniform Determination of Death Act. JAMA. 2023;330(24):2335–2336. doi:10.1001/jama.2023.24475

"In 1968, a Harvard committee proposed a new approach for determining death, one based on the irreversible loss of neurological functions.1 This concept was instantiated into law in 1980 when the Uniform Law Commission endorsed The Uniform Determination of Death Act.2 The act, which a large majority of states have adopted in whole or with some variations, says, in part, that an individual is dead if the individual has sustained (1) irreversible cessation of circulatory and respiratory functions, or (2) irreversible cessation of all functions of the entire brain, including the brain stem. A determination of death must be made in accordance with accepted medical standards.

"In 2020, the commission was asked to consider updating the act, based in part on concerns that the act does not fully align with current medical practice.3 A draft of its revision was presented and discussed at the commission’s annual meeting on July 26, 2023.4 Herein, we summarize the major issues that led to the decision to draft a revision, the alternatives that were considered, why there was failure to reach consensus, and what this means for the future.

"The Uniform Determination of Death Act defines neurological death, commonly known as brain death, as the complete absence of all functions of the entire brain. The current diagnostic criteria, however, test for only a subset of brain functions, and most notably do not include testing for neurosecretory hypothalamic functions, which are retained by many patients who have been diagnosed as brain dead.5 In addition, the law requires the “irreversible” cessation of biological functions, whereas in practice the standard has been “permanence,” with the distinction being that irreversible implies that the function cannot be restored, whereas permanence means that the function will not be restored because no attempt will be made to do so.

...

"n order for medical practice to be in compliance with the law, the commissioners considered either changing the guidelines to conform with the law, or changing the law to conform with the guidelines. Under the first approach, the guidelines would require physicians to diagnose the irreversible cessation of all brain functions, not just selected functions. This would be challenging, given the difficulty of detecting and measuring all of the brain’s many functions. Alternatively, the law could be revised to be coherent with current practice guidelines. At the annual meeting of the Uniform Law Commission, the committee considered the following draft alternative to the existing Uniform Determination of Death Act4: “An individual is dead if the individual has sustained: (1) permanent cessation of circulatory and respiratory functions; or (2) permanent (A) coma, (B) cessation of spontaneous respiratory functions, and (C) loss of brainstem reflexes.”

"This proposal would harmonize the law with the practice guidelines. Instead of requiring the absence of all brain functions, this revision would have required only the absence of specific brain functions, namely the capacity for consciousness and spontaneous respiration.

"The proposed revision also would have replaced the requirement for irreversible cessation with permanent cessation, thereby anticipating the trajectory of new developments in resuscitation research, including work demonstrating the potential for restoration of neuronal function in brains, even many hours after the loss of brain perfusion.6 Using the permanence standard, death can be determined in these patients on the grounds that function will not be restored rather than the requirement that it cannot be restored.

"Finally, the proposed revision also included a section that would have required hospitals to respect the refusal of patients or their surrogates to having death determined by neurological criteria. This position was supported by various constituencies, including the Catholic Medical Association, as well as several of the Uniform Law Commission commissioners, who saw it as a way to respect the diversity of opinions surrounding the determination of death while still supporting the concept of brain death. At the same time, this approach was strongly condemned by most mainstream physician and transplant organizations, given the burden that it would place on hospitals and intensive care units and its potential negative impact on organ procurement.

...

"in an email on September 22, 2023, the committee leadership announced that they had decided to pause the process, saying that “although we will continue to hope mid-level principles will become apparent, no further drafting committee meetings will be scheduled at this time.”

"Perhaps this outcome could have been predicted from the beginning, given the polarization that has evolved in the US around issues at the beginning and end of life. Commissioner James Bopp emphasized these connections in asserting that the controversies around brain death and abortion are an “identical debate, just in a different context.”7

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Earlier:

Wednesday, October 18, 2023

Peter Singer on brain death

Peter Singer on brain death

 Here's Peter Singer's op-ed in the Washington Post on the debate over brain death, presently used to decide when deceased donor organs can be used for transplantation:

What is the line between life and death? Here’s my answer.  By Peter Singer  October 17, 2023 

"When it is justifiable to end a human life?

"Here’s my answer: When consciousness has gone, never to return. Other bioethicists have different views. No surprise there. But on this we should all agree: These differences need to be hammered out in public, not behind closed doors by a body that few people have heard of.

"The last effort to define death in the United States was in 1980, and at that time there was remarkable consensus on a decision so consequential. Then, the commission proposed a new Uniform Determination of Death Act establishing that in addition to the traditional determination of death by the heart ceasing to beat, a person is dead when their whole brain has irreversibly ceased to function. All 50 states and D.C. adopted the act’s central proposition — which is staggering, really, given today’s battles over when life begins."

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Earlier:

Sunday, October 8, 2023

Dead or alive? Debates about defining brain death and circulatory death in the medical literature

Sunday, May 21, 2023

Defining death for deceased organ donation

Thursday, April 13, 2023

Brain Death

Friday, August 21, 2020

Brain death (death by neurological criteria)

Brain Death

 Before there was the possibility of organ transplantation, determining that someone was dead could be a relatively leisurely affair. But transplants depend on organs remaining alive after the potential organ donor has died.  If the death is due to irreversible absence of circulation and respiration (Donation after Circulatory Death – DCD), it has to be declared quickly, so that preparation for organ recovery can begin promptly. If the declaration of death is based on brain death, i.e. on irreversible absence of whole brain function (Donation after Death declared by Neurologic Criteria - DDNC), then it must occur while the potential donor is on a ventilator, so that his/her organs continue to be oxygenated.  This means that the declaration of death occurs while the ventilator is still maintaining many of the signs (respiration, heartbeat) that are usually evidence of a living person.  So deciding when someone is brain dead requires both expertise and consensus.

Here's a recent discussion of all this, including some controversy, in JAMA: 

The Uncertain Future of the Determination of Brain Death, by Robert D. Truog, JAMA. 2023;   329(12): 971-972. doi:10.1001/jama.2023.1472

"In 1980, the US Uniform Law Commission (ULC) established the Uniform Determination of Death Act (UDDA), which was subsequently adopted (with some modifications) by all 50 states.1 The law states that death is defined as either (1) the irreversible cessation of circulatory and respiratory functions or (2) the irreversible cessation of all functions of the entire brain, including the brainstem.

...

"The framers of the UDDA rejected the claim that this was a new way of defining death.2 Instead, they pointed to evidence at the time suggesting that the brain is necessary for maintaining biological functioning and that when this brain regulation is absent, homeostatic mechanisms fail, with cardiac arrest invariably occurring within 1 to 2 weeks at most. In other words, brain death and cardiopulmonary arrest were seen as equivalent and equally valid criteria for diagnosing the biological death of a patient.

"However, with improvements in critical care medicine, this equivalency has been called into question. With modern intensive care unit support, some patients can be stabilized and, if provided with mechanical ventilation and tube feedings, their bodies may survive for many years.

...

"In fact, patients with brain death may retain most of the capacities of living people, including the ability to absorb nutrition, excrete waste, heal wounds, grow, undergo puberty, and even gestate. This has led many families to reject the diagnosis and insist on the continuation of medical support for their loved ones.

"In addition, a second issue has been that, although the UDDA requires “the irreversible absence of all functions of the entire brain,” the current guidelines from the American Academy of Neurology (AAN) test for only a select number of functions and most notably do not test for hypothalamic functions, which are sometimes present in patients who are diagnosed with brain death

"In the wake of an increasing number of legal challenges related to the determination of brain death, ULC began a process in 2021 to assess whether the UDDA should be revised.1 At least 3 distinct proposals have been considered.

"Proposal 1: Revise the Guidelines to Align With the Current Definition

"One option would be to leave the UDDA intact, but revise the AAN guidelines to include testing for the absence of hypothalamic function.

...

"Proposal 2: Revise the Definition to Align With the Current Guidelines

"A second proposal has been to change the definition of brain death to be in alignment with the guidelines.

...

"Revising the UDDA so that it required not the irreversible loss of all brain functions, but rather only those functions that support consciousness and spontaneous respiration, would bring the UDDA into alignment with the AAN guidelines. This approach also has precedent, in that it is the definition that was adopted by the United Kingdom in 2008.

...

"Proposal 3: Maintain the Status Quo

"If the position endorsed by commissioner Bopp were to prevail, some states could choose to entirely eliminate the determination of death by neurologic criteria. The impact would be 2-fold: in those states it would no longer be permissible to procure transplantable organs from patients diagnosed with brain death and physicians could be required to continue to provide intensive care unit beds and life support to patients who will never regain consciousness. Such an outcome could have disastrous consequences for our existing systems of organ procurement and transplantation, leading to thousands of otherwise avoidable deaths.

"This has led some commissioners to lean in favor of not making any major revisions to the UDDA, leaving well enough alone."

Dead pigs and live brain cells--with implications still to be understood

Dramatic scientific announcements get press coverage before they are well (or at all) understood, but that can still be exciting.  Here's some press coverage of an article that was published yesterday in Nature about restoring some cellular activity in the brains of pigs which had been slaughtered and decapitated.  It may eventually have implications for brain injuries, brain death and (hence) deceased organ donation.
(The Nature article and two commentaries published with it are also linked below.)

NY Times:
‘Partly Alive’: Scientists Revive Cells in Brains From Dead Pigs
In research that upends assumptions about brain death, researchers brought some cells back to life — or something like it.

"In a study that raises profound questions about the line between life and death, researchers have restored some cellular activity to brains removed from slaughtered pigs.

"The brains did not regain anything resembling consciousness: There were no signs indicating coordinated electrical signaling, necessary for higher functions like awareness and intelligence.

"But in an experimental treatment, blood vessels in the pigs’ brains began functioning, flowing with a blood substitute, and certain brain cells regained metabolic activity, even responding to drugs. When the researchers tested slices of treated brain tissue, they discovered electrical activity in some neurons."
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Washington Post:
Scientists restore some brain cell functions in pigs four hours after death
Ethicists advise caution with research that blurs the line between life and death.

"The researchers are mindful that this is controversial territory with great potential to stoke outrage or, simply, the heebie-jeebies. Such a head-snapping experiment inevitably generates nightmarish scenarios involving live brains in vats, brain transplants, the Zombie Apocalypse, and other mad-scientist story lines (brilliantly crafted, somehow, by neurons firing away inside the skulls of conventionally living human beings).
"The findings also lead to ethical quandaries, some of which are outlined in two commentaries simultaneously published by Nature. The ethicists say this research can blur the line between life and death, and could complicate the protocols for organ donation, which rely on a clear determination of when a person is dead and beyond resuscitation."
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Guardian:
Researchers 'reboot' pig brains hours after animals died
Scientists say ability to revive some brain functions will not change definition of death



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And here's the article in Nature:
Published: 17 April 2019

Restoration of brain circulation and cellular functions hours post-mortem
Zvonimir Vrselja, Stefano G. Daniele, John Silbereis, Francesca Talpo, Yury M. Morozov, André M. M. Sousa, Brian S. Tanaka, Mario Skarica, Mihovil Pletikos, Navjot Kaur, Zhen W. Zhuang, Zhao Liu, Rafeed Alkawadri, Albert J. Sinusas, Stephen R. Latham, Stephen G. Waxman & Nenad Sestan
Naturevolume 568, pages336–343 (2019) | Download Citation

Abstract
The brains of humans and other mammals are highly vulnerable to interruptions in blood flow and decreases in oxygen levels. Here we describe the restoration and maintenance of microcirculation and molecular and cellular functions of the intact pig brain under ex vivo normothermic conditions up to four hours post-mortem. We have developed an extracorporeal pulsatile-perfusion system and a haemoglobin-based, acellular, non-coagulative, echogenic, and cytoprotective perfusate that promotes recovery from anoxia, reduces reperfusion injury, prevents oedema, and metabolically supports the energy requirements of the brain. With this system, we observed preservation of cytoarchitecture; attenuation of cell death; and restoration of vascular dilatory and glial inflammatory responses, spontaneous synaptic activity, and active cerebral metabolism in the absence of global electrocorticographic activity. These findings demonstrate that under appropriate conditions the isolated, intact large mammalian brain possesses an underappreciated capacity for restoration of microcirculation and molecular and cellular activity after a prolonged post-mortem interval.
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Here are two commentaries published in the same issue of Nature:
COMMENT  17 APRIL 2019
Part-revived pig brains raise slew of ethical quandaries
Researchers need guidance on animal use and the many issues opened up by a new study on whole-brain restoration, argue Nita A. Farahany, Henry T. Greely and Charles M. Giattino.
^^^^^^^^^

COMMENT  17 APRIL 2019
Pig experiment challenges assumptions around brain damage in people
The restoration of some structures and cellular functions in pig brains hours after death could intensify debates about when human organs should be removed for transplantation, warn Stuart Youngner and Insoo Hyun.