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For more than 30 years, the concept of “brain death” has been an operable – if still controversial – paradigm for defining death by neurological criteria, a concept first given institutional blessing by the Ad Hoc Committee of the Harvard Medical School in its 1968 report, “A Definition of Irreversible Coma” (JAMA 1968;205:337–340).

But an illuminating new historical analysis of the concept published in Neurology last month reveals that the Harvard committee was actually predated by reports in the literature as early as 1959 that described “death of the nervous system” and “coma depasse” (beyond coma), and by the pioneering work of one Belgian surgeon who introduced a set of brain death criteria for use in carrying out transplantation in 1963.

The “Historical Neurology” report by neurologist Calixto Machado, MD, PhD, demonstrates how once morally difficult notions may become the norm as a result of the influences of technology and evolving opinion – and how the canonization of those norms by respected societal institutions is often predated by the pioneering work of individuals who dare to “push the envelope” of what is acceptable.

For his report, Dr. Machado received AAN's prestigious Lawrence C. McHenry Award for History of Neurology at this year's AAN Annual Meeting in Miami Beach. The award recognizes excellence in research in the history of neurology.


Dr. Machado, who is with the Institute of Neurology and Neurosurgery in Havana, Cuba, told Neurology Today in a phone interview: “The concept of brain death emerged because of the development of intensive care, which allowed us to give life support and save patients whose heart was beating but who had no brain activity,” Dr. Machado said. “The concept of brain death and the practice of organ transplantation had a parallel development, though at some point in history they crossed over. But brain death did not appear as a concept in order to benefit the practice of organ transplantation.”


In his paper, Dr. Machado reviews work by P. Wertheimer and colleagues in 1959 characterizing “death of the nervous system,” and by P. Mollaret and collaborators that same year describing “coma depasse.” In particular, Dr. Machado features the work of Belgian surgeon Guy Alexandre, MD, at the Catholic University of Louvain, who drew on those early conceptual formulations to develop criteria for brain death that could be used in transplantation.

When Dr. Alexandre and his team performed the landmark kidney transplant in 1963, they did not discontinue mechanical ventilation and wait for the donor's heart to stop beating, as had been the practice among pioneering transplant surgeons in the late 1950s and early 1960s.

“It was the first transplantation ever to make use of a heart-beating, brain-dead donor,” Dr. Machado reported.


In his investigation of these events, Dr. Machado reviewed the little-known proceedings of a Ciba Symposium held in London in March 1966. It was there that Dr. Alexandre presented five criteria for determining brain death in potential transplant donors with severe craniocerebral injuries.

In his review, Dr. Machado also features personal correspondence with Dr. Alexandre himself, and with other physicians involved in the 1963 kidney transplant and with the Ciba Symposium.

At the 1966 symposium, Dr. Alexandre told physicians in attendance that he and his team had by that time used nine patients with head injuries, whose hearts had not stopped, to do kidney transplantations.

Five conditions were met in those cases: complete bilateral mydriasis; complete absence of reflexes, complete absence of spontaneous respiration five minutes after mechanical respiration has been stopped; falling blood pressures, necessitating increasing amounts of vasopressive drugs; and a flat EEG.

The conversations at the symposium surrounding this somewhat audacious presentation provide a glimpse into the earliest gestation of a radical idea that would in time become widely accepted. While some physicians offered tentative support for Dr. Alexandre's conception, many others were suspicious of – or repelled outright by – a proposition that they feared could be used to exploit trauma patients for harvesting transplantable organs.

“I doubt if any of the members of our transplant team could accept a person as being dead as long as there was a heart beat,” responded liver transplant pioneer Thomas Starzl, MD. “We have been discussing this practice in relation to renal homografts. Here, a mistake in evaluation of the ‘living cadaver’ might not necessarily lead to an avoidable death since one kidney could be left. But what if the liver or heart were removed? Would any physician be willing to remove an unpaired vital organ before circulation had stopped?”

Sir Roy Calne, MD, another transplant pioneer, said, “Although Dr. Alexandre's criteria are medically persuasive, according to traditional definitions of death he is in fact removing kidneys from live donors. I feel that if a patient has a heart beat, he cannot be regarded as a cadaver.”

At the end of the symposium, Dr. Machado reports, attendees were asked if they would be willing to abide by Dr. Alexandre's criteria. “I was the only one to raise my hand,” Dr. Alexandre told Dr. Machado. “All the others did not.”


But it would be only two years later that the Harvard Ad Hoc Committee would write its landmark report, closely mirroring the criteria set out by Dr. Alexandre. In his paper, Dr. Machado quoted remarks by Dr. Starzl as evidence of the rapid evolution in thinking.

“At first this idea appalled me because I envisioned that the care of a trauma victim could be jeopardized by virtue of his or her candidacy to become an organ donor,” Dr. Starzl is quoted as saying. “These fears were unfounded. The chances of a seriously injured patient being carefully cared for were actually greatly increased when death was defined by the disappearance of brain function rather than the criteria of cessation of heart beat and respiration.”


Neurologists who reviewed Dr. Machado's paper agree fears of exploitation of trauma patients – and suspicions that brain-death criteria generally, and the Harvard report specifically, were influenced heavily by transplant surgeons – have proven to be groundless.

James Kelly, MD, Visiting Professor of Neurosurgery at the University of Colorado School of Medicine where Starzl performed the first liver transplant, told Neurology Today that Dr. Starzl was early on convinced that “we must not go down that slippery slope of not doing everything possible for the trauma patient.”

Actually, Dr. Kelly said, the slope has proven not to be so slippery after all. “In fact, we have been extraordinarily careful not to do anything inappropriate.”

Advances in technology continue to refine the criteria originally set out by Dr. Alexandre. Today, the flat EEG is not routinely required for a determination of brain death if the other criteria are met, Dr. Kelly said.

“The EEG initially played a larger role,” he said. “Now it's one of the tests we can use if there is something that you can't adequately examine because of the nature of what has happened to the trauma patient. This is the result of technology, some of which didn't exist [in Dr. Alexandre's time], that is now available as confirmation to help with clinical certainty.”

Dr. Kelly said that Dr. Machado's paper provides a revealing look at the early evolution of a controversial idea. “His contribution is to start at the very beginning with the idea of coma depasse, which some people found intriguing and which set in motion the movement toward a more careful analysis of the condition and its ethical implications as well as its usefulness in organ donation.”

George K. York, III, MD, a member of the McHenry Award Committee, said Dr. Machado's work was “a good example of how someone who is not a professional historian can do an important piece of historical research.”

Dr. York, a neurologist with Kaiser Permanente in Stockton, CA, formerly was Chair of the AAN History Section, and writes the “Accidental Historian” column for Neurology Today.

“At the time that Dr. Alexandre produced his criteria, the concept of brain death was foreign even to people in the field, and Dr. Alexandre was one of only a few who thought that such a thing could even be ethical,” Dr. York told Neurology Today. “But within a very short period of time the world changed. What had been morally suspect within ten or 15 years became the moral rule.”


  • ✓ A historical review of the concept of brain death traces its early development to a 1959 report that described “death of the nervous system” and “coma depasse” (beyond coma).

Dr. Calixto Machado: “The concept of brain death emerged because of the development of intensive care, which allowed us to give life support and save patients whose heart was beating but who had no brain activity.”


• Calixto M. The first organ transplant from a brain-dead donor. Neurology 2005;64:1938–1942.
• A definition of irreversible coma: Report of the Ad Hoc Committee of the Harvard Medical School to examine the definition of brain death. JAMA 1968;205:337–340.