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What the Post-Mortem Pig Brain Study Really Says About Brain Death

Article In Brief

A report on cellular activity in the brain of a pig post-mortem prompted some misreporting in the media about what the finding suggests about brain death, experts in neurocritical care say.

Researchers at Yale Medical School's Institute for Neuroscience used an experimental blood substitute and a novel perfusion system to partially “restore” brain microcirculation and neural cell integrity in young pigs, up to four hours after their death.

Although the investigators observed some neuronal, glial, and vascular cell activity, they emphasized in the April 17 report in Nature that they found no organized global electrical activity indicative of brain function, consciousness, perception, or awareness.

“Based on our findings, we can conclude that this is not a living brain, but it is a cellularly active brain,” senior author Nenad Sestan, MD, PhD, told Neurology Today. “We are still in early stages, and this technology cannot be applied to humans. More importantly, applying this to the human brain is not within our goals at the moment.”

Nonetheless, many news outlets, including some major organizations, either misread the study, misinterpreted the results, or misunderstood the limited significance of the findings, especially with regard to brain death determination in humans, independent experts told Neurology Today.

Responding to a story in the Wall Street Journal, past AAN President MD, FAAN, FAHA, together with James Russell, DO, FAAN, and Leon G. Epstein, MD, FAAN, the chair and vice chair of the AAN's Ethics, Law, and Humanities Committee, respectively, sent a letter to the editor of the newspaper, calling the article inaccurate and misleading.

Primarily funded by the National Institutes of Health's BRAIN Initiative, the Yale scientists developed BrainEx—an experimental system employing a series of computerized pumps, warmers, reservoirs, and filters—to perfuse a hemoglobin-based, acellular, non-coagulative, cytoprotective blood substitute capable of delivering oxygen and other neuroprotective compounds to the pigs' brains.

Tested in more than one hundred dead pigs to date, the system restored some brain architecture and prevented the degradation of brain cells by enabling recovery from anoxia, preventing edema, and metabolically supporting brain energy needs, according to Dr. Sestan, professor of neuroscience and executive director of the Genome Editing Center at Yale's Kavli Institute for Neuroscience.

“We observed attenuation of cell death and preservation of anatomical and neural cell integrity. We also found that specific cellular functions were restored, as indicated by vascular and glial responsiveness to pharmacological and immunogenic interventions, spontaneous synaptic activity, and active cerebral metabolism.”

While the findings have no immediate clinical application, he told Neurology Today, the approach, or a similar technique, might one day help search for ways to salvage brain function after stroke, or test new therapies for cellular recovery after brain injury.

Asked whether or not mainstream media had correctly reported the findings, Dr. Sestan had this to say: “Overall, we are pleased that the overwhelming majority of the media reports understood the goals of the study, which were not to restore consciousness but to test whether it is possible to restore circulation and cellular activity in the post-mortem brain,” he said. “Of course, due to the nature of the work, it is easy to let one's imagination run loose with sensationalism.”

AAN Position

Dr. Russell, a neurologist at Lahey Hospital and Medical Center in Burlington, MA, and a clinical professor at Tufts University School of Medicine, said that he has concerns about media misinterpretation of the paper's findings and its impact on the public's trust in brain death.

“There were concerns that the findings would be seen as injurious to the public trust in the AAN's position,” said Dr. Russell, who played a key role in the Academy's updated brain death position statement published last January in Neurology.

The statement called for uniform brain death laws, policies, and practices to define brain death in accordance with the Uniform Determination of Death Act as “death due to irreversible loss of function of the entire brain, or death due to irreversible loss of function of the circulatory system, including the heart.”

It also said that uniform policies in medical facilities across the country would ensure compliance with established brain death guidelines.

“The AAN is not aware of any cases in which compliance with these guidelines led to inaccurate determination of death with return of any brain function, including consciousness, brainstem reflexes or breathing,” he said. “The fear is that public misunderstanding could potentially erode trust in current brain death policies, with wide-reaching implications. Cellular preservation does not translate into organ or organism restoration as reported or implied,” he told Neurology Today.

He said that the AAN's position, while recognizing the beneficence of organ donation and transplantation, unequivocally identifies that the AAN member's primary responsibility is to their brain injured patient, he noted.

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“Many have taken the finding way beyond the authors' conclusions, but from a purely scientific perspective, this is really exciting and shows great future potential in how we approach brain injuries. That said, being able to use similar technology in humans is years, if not decades, down the road.”

—DR. DAVID GREER

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“I'm concerned about how this study was reported. ...With all the hoopla, I wouldn't be surprised if families start asking whether this technology can be used to ‘wake up’ loved ones.”

—DR. ARIANE LEWIS

David Greer, MD, FAAN, professor and chief of neurology at Boston University School of Medicine, has been involved in drafting AAN's brain death guidelines since the mid-1990s.

“I think that what the researchers reported is pretty groundbreaking. It's never been done before,” he said. “Many have taken the finding way beyond the authors' conclusions, but from a purely scientific perspective, this is really exciting and shows great future potential in how we approach brain injuries. That said, being able to use similar technology in humans is years, if not decades, down the road.”

Misinterpretation Hazards

In an editorial posted on the bioethics.net website, renowned bioethicist Arthur L. Caplan, PhD, also criticized many news reports for including opinions that exaggerated or misstated the findings.

“[Some] commentators suggested that the pigs' brains were somehow made partly alive, that concerns about consciousness recurring in the dead now needed to be addressed, and that the experiment called into question the current understanding of brain death,” said Dr. Caplan, professor and founding head of the Division of Medical Ethics at the NYU School of Medicine in New York City.

“The experiment did not justify any of these conclusions,” he wrote. “Worse, comments about partial life may frighten people into thinking their loved ones were declared dead when they were not, or that they and their loved ones should not agree to serve as organ or tissue donors due to new doubts over the validity of brain death.

“Restoring some form of disorganized, non-functional electrical activity in the cells of a long-dead brain does not cast doubt on the notion of brain death, which requires the total, irreversible loss of brain function. Nor is there any such state as ‘partially alive,’” he said.

The study “should not be a source of wild, irresponsible speculation about reanimating the dead, creating new states of partial life, or tossing out brain death definitions,” Dr. Caplan said. “Pronouncing death and organ donation are too important to permit a demonstration that cells can be stimulated to fire up in some way drawn from a most certainly deceased pig to declare that a conceptual revolution has just occurred.”

Ariane Lewis, MD, associate professor of neurology and neurosurgery, and director of neurocritical care at NYU Langone Medical Center, is among a number of AAN experts who shared Dr. Caplan's views.

“I'm concerned about how this study was reported,” she told Neurology Today. “The authors carefully stated what their findings meant and didn't mean. They were very cautious, and emphasized that the findings should not be misinterpreted. But many articles did just that—extrapolated far beyond what the study actually shows. With all the hoopla, I wouldn't be surprised if families start asking whether this technology can be used to ‘wake up’ loved ones,” she told Neurology Today.

Michael Rubin, MD, MA, assistant professor of neurology and chair of the University of Texas Southwestern University Hospital ethics committee in Dallas said: “Many people seem to view this study in terms of some kind of brain death resuscitation machine, but the researchers clearly indicate that this was not their intent, and none of their findings support restoration of neurological or cognitive function,” he told Neurology Today.

“If they were trying to restore rather than preserve cell function, they would have tested the approach not after four hours post-mortem but after four days or four weeks,” he noted. “Instead, their findings demonstrate that some neural architecture and some cellular function appear to have more resiliency after death than we might have expected, and that their system appears able to be able to tap into that,” he said.

“I think what they showed corroborates brain death declaration standards as established by the AAN. Furthermore, it supports the catastrophic brain injury guidelines of the Neurocritical Care Society, which encourage continued resuscitation for 24 to 48 hours before assuming that further efforts are futile. I look at this as an experimental animal model, no more and no less—one that should encourage further research into acute resuscitation after neurologic injury.”

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“The fear is that public misunderstanding could potentially erode trust in current brain death policies, with wide-reaching implications. Cellular preservation does not translate into organ or organism restoration as reported or implied.”

—DR. JAMES RUSSELL

Disclosures

None of the sources quoted in this story had competing conflicts.

Link Up for More Information

•. Vrselja Z, Daniele S, Silbereis J, et al. Restoration of brain circulation and cellular functions hours post-mortem https://www.nature.com/articles/s41586-019-1099-1. Nature 2019;568(7752):336–343.
•. Caplan A. When pigs fly. April 22,2019; www.bioethics.net/2019/04/when-pigs-fly/2
    •. Russell JA, Epstein LG, Greer DM. Brain death, the determination of brain death, and member guidance for brain death accommodation requests: AAN position statement http://n.neurology.org/content/neurology/early/2019/01/02/WNL.0000000000006750.full.pdf. Neurology 2019;92:228–232.
    •. Wijdicks EF, Varelas PN, Gronseth GS, Greer DM. Evidence-based guideline update: Determining brain death in adults: Report of the Quality Standards Subcommittee of the American Academy of Neurology https://n.neurology.org/content/74/23/1911. Neurology 2010;74(23):1911–1918.
    •. Lewis A, Bernat JL, Blosser S, et al. An interdisciplinary response to contemporary concerns about brain death determination https://n.neurology.org/content/90/9/423.long. Neurology 2018;90(9):423–426.