For much of history an end to breathing and a beating heart, marked death.
This all changed in the last half of the 20th century when cardiopulmonary resuscitation, mechanical ventilation and, more recently, extracorporeal membrane oxygenation (ECMO) and other means for sustaining life, became available.
These techniques proved their worth for keeping the body going, if not always the brain, and in doing so, have blurred the transition between life and death.
In the United States and Canada most organs suitable for transplant come from patients who suffer from severe traumatic or hypoxic and/ischemic injuries to the brain.
The result is that harvesting human organs for transplantation purposes cannot proceed until internationally agreed upon criteria for brain death are met.
But useful as those criteria are, they are not perfect. A few patients considered brain dead, unaware and unresponsive using traditional clinical methods, have been found to respond to questions using tools such as functional MRI (fMRI) or AI analysis of the electrical activity of the brain.
Both of those methods are capable of detecting activation of regions in the brain that are functionally related to specific questions. Thus, what seemed to be iron-clad criteria for brain death became a little murky.
Then there is the vital question: how long can brain cells survive when their blood supply and thus source of oxygen and glucose is cut?
For decades science taught that cutting off the brain’s supply of glucose and oxygen for more than a few minutes, causes irreversible death of nerve cells. However, recent evidence suggests brain cells may survive much longer in some cases.
For example, removing a clot blocking a major brain artery such as the middle cerebral artery, as long as six to 12 hours following a stroke, occasionally may be associated with surprisingly good recovery of parts of the brain affected by the stroke.
Then there is the all-important delay between harvesting suitable organs and reconnecting those organs to the circulation of the intended recipient.
Too long a delay compromises the viability of the organ because the organ is no longer perfused with oxygen and other essential nutrients. This raises two questions: What can be done to shorten the delay? And what can be done to protect the viability of the organ in the time between harvesting and implantation?
The journal Nature published a blockbuster study in 2019 challenging long-held views about how well the brain survives complete loss of its blood supply and thus oxygen source.
In that study, pig brains were harvested from a commercial slaughterhouse after which the brains were without circulation, and thus oxygen, for four hours. Then the circulation to the brain was restored using a mechanical pump and the brain perfused with a special artificial hemoglobin-like molecule to restore oxygen to the brain.
The artificial perfusate, which they called BrainEx, included drugs to suppress electrical activity in the brain and block potential inflammatory and immune responses.
The results were stunning. Many brain cells showed signs of recovery including restoration of their natural transmembrane potentials, mitochondrial function and homeostasis – despite being without oxygen and any circulation for four hours and far beyond the several minutes after which brain cells deprived of oxygen, were hitherto thought to die irreversibly.
This study may have been macabre, but the implications were huge and fully justified the accompanying thorough reviews and critiques by invited editorials in Nature, including contributions from ethicists.
The latest study, in the Aug. 3 edition of Nature, was designed to see whether a similar approach might help cells survive in organs such as kidneys, livers and even hearts.
In this case, pigs were deeply sedated, placed on a ventilator after which the heart was stopped and the ventilator turned off for one hour.
When the hour was up, the ventilator was turned on and a pump was used to circulate a mix of the pig’s own blood with a perfusate similar to BrainEx, called OrganEx, for six hours. Afterward, the hearts, livers and kidneys were examined.
The study showed that the cells in the heart, kidneys and liver of pigs recovered and survived surprisingly well when their tissues were perfused with OrganEx.
For comparison, the cellular structure and function in pigs whose circulation was supported by extracorporeal membrane oxygenation or given no treatment at all, fared far worse.
This study is important because it suggests that the survival of harvested human organs could be prolonged by several hours before transplanting them into hosts, thus increasing the chance of successful transplants and effectively boosting the number of viable organs for transplantation.
Beyond humans as the sole source of organs for transplantation is the possibility of using genetically modified pig organs as a common source for kidney and heart transplants in humans – a step now under consideration by the U.S. Food and Drug Administration.
Dr. William Brown is a professor of neurology at McMaster University and co-founder of the InfoHealth series at the Niagara-on-the-Lake Public Library.