“Coming Back from the Dead” Is No Longer Science Fiction
Last year, there were widespread reports of a 53-year-old Frenchman who had suffered a cardiac arrest and "died," but was then resuscitated back to life 18 hours after his heart had stopped.
The once black-and-white line between life and death is now blurrier than ever.
This was thought to have been possible in part because his body had progressively cooled down naturally after his heart had stopped, through exposure to the outside cold. The medical team who revived him were reported as being "stupefied" that they had been able to bring him back to life, in particular since he had not even suffered brain damage.
Interestingly, this man represents one of a growing number of extraordinary cases in which people who would otherwise be declared dead have now been revived. It is a testament to the incredible impact of resuscitation science -- a science that is providing opportunities to literally reverse death, and in doing so, shedding light on the age-old question of what happens when we die.
Death: Past and Present
Throughout history, the boundary between life and death was marked by the moment a person's heart stopped, breathing ceased, and brain function shut down. A person became motionless, lifeless, and was deemed irreversibly dead. This is because once the heart stops beating, blood flow stops and oxygen is cut off from all the body's organs, including the brain. Consequently, within seconds, breathing stops and brain activity comes to a halt. Since the cessation of the heart literally occurs in a "moment," the philosophical notion of a specific point in time of "irreversible" death still pervades society today. The law, for example, relies on "time of death," which corresponds to when the heart stops beating.
The advent of cardiopulmonary resuscitation (CPR) in the 1960s was revolutionary, demonstrating that the heart could potentially be restarted after it had stopped, and what had been a clear black-and-white line was shown to be potentially reversible in some people. What was once called death—the ultimate end point— was now widely called cardiac arrest, and became a starting point.
From then on, it was only if somebody had requested not to be resuscitated or when CPR was deemed to have failed that people would be declared dead by "cardiopulmonary criteria." Biologically, cardiac arrest and death by cardiopulmonary criteria are the same process, albeit marked at different points in time depending on when a declaration of death is made.
The apparent irreversibility of death as we know it may not necessarily reflect true irretrievable cellular damage inside the body.
Clearly, contrary to many people's perceptions, cardiac arrest is not a heart attack; it is the final step in death irrespective of cause, whether it be a stroke, a heart attack, a car accident, an overwhelming infection or cancer. This is how roughly 95 percent of the population are declared dead.
The only exception is the small proportion of people who may have suffered catastrophic brain injuries, but whose hearts can be artificially kept beating for a period of time on life-support machines. These people can be legally declared dead based on brain death criteria before their hearts have stopped. This is because the brain can die either from oxygen starvation after cardiac arrest or from massive trauma and internal bleeding. Either way, the brain dies hours or possibly longer after these injuries have taken place and not just minutes.
A Profound Realization
What has become increasingly clear is that the apparent irreversibility of death as we know it may not necessarily reflect true irretrievable cellular damage inside the body. This is consistent with a mounting understanding: it is only after a person actually dies that the cells in the body start to undergo their own process of death. Intriguingly, this process is something that can now be manipulated through medical intervention. Being cold is one of the factors that slows down the rate of cellular decay. The 53-year-old Frenchman's case and the other recent cases of resuscitation after prolonged periods of time illustrate this new understanding.
Last week's earth-shattering announcement by neuroscientist Dr. Nenad Sestan and his team out of Yale, published in the prestigious scientific journal Nature, provides further evidence that a time gap exists between actual death and cellular death in cadavers. In this seminal study, these researchers were able to restore partial function in pig brains four hours after their heads were severed from their bodies. These results follow from the pioneering work in 2001 of geneticist Fred Gage and colleagues from the Salk Institute, also published in Nature, which demonstrated the possibility of growing human brain cells in the laboratory by taking brain biopsies from cadavers in the mortuary up to 21 hours post-mortem.
The once black-and-white line between life and death is now blurrier than ever. Some people may argue this means these humans and pigs weren't truly "dead." However, that is like saying the people who were guillotined during the French Revolution were also not dead. Clearly, that is not the case. They were all dead. The problem is not death; it's our reliance on an outdated philosophical, rather than biological, notion of death.
Death can no longer be considered an absolute moment but rather a process that can be reversed even many hours after it has taken place.
But the distinction between irreversibility from a medical perspective and biological irreversibility may not matter much from a pragmatic perspective today. If medical interventions do not exist at any given time or place, then of course death cannot be reversed.
However, it is crucial to distinguish between biologically and medically: When "irreversible" loss of function arises due to inadequate treatment, then a person could be potentially brought back in the future when an alternative therapy becomes available, or even today if he or she dies in a location where novel treatments can slow down the rate of cell death. However, when true irreversible loss of function arises from a biological perspective, then no treatment will ever be able to reverse the process, whether today, tomorrow, or in a hundred years.
Probing the "Grey Zone"
Today, thanks to modern resuscitation science, death can no longer be considered an absolute moment but rather a process that can be reversed even many hours after it has taken place. How many hours? We don't really know.
One of the wider implications of our medical advances is that we can now study what happens to the human mind and consciousness after people enter the "grey zone," which marks the time after the heart stops, but before irreversible and irretrievable cell damage occurs, and people are then brought back to life. Millions have been successfully revived and many have reported experiencing a unique, universal, and transformative mental state.
Were they "dead"? Yes, according to all the criteria we have ever used. But they were able to be brought back before their "dead" bodies had reached the point of permanent, irreversible cellular damage. This reflects the period of death for all of us. So rather than a "near-death experience," I prefer a new terminology to describe these cases -- "an actual-death experience." These survivors' unique experiences are providing eyewitness testimonies of what we will all be likely to experience when we die.
Such an experience reportedly includes seeing a warm light, the presence of a compassionate perfect individual, deceased relatives, a review of their lives, a judgment of their actions and intentions as they pertain to their humanity, and in some cases a sensation of seeing doctors and nurses working to resuscitate them.
Are these experiences compatible with hallucinations or illusions? No -- in part, because these people have described real, verifiable events, which, by definition are not hallucinations, and in part, because their experiences are not compatible with confused and delirious memories that characterize oxygen deprivation.
The challenge for us scientifically is understanding how this is possible at a time when all our science tells us the brain shuts down.
For instance, it is hard to classify a structured meaningful review of one's life and one's humanity as hallucinatory or illusory. Instead, these experiences represent a new understanding of the overall human experience of death. As an intensive care unit physician for more than 10 years, I have seen numerous cases where these reports have been corroborated by my colleagues. In short, these survivors have been known to come back with reports of full consciousness, with lucid, well-structured thought processes and memory formation.
The challenge for us scientifically is understanding how this is possible at a time when all our science tells us the brain shuts down. The fact that these experiences occur is a paradox and suggests the undiscovered entity we call the "self," "consciousness," or "psyche" – the thing that makes us who we are - may not become annihilated at the point of so-called death.
At New York University, the State University of New York, and across 20 hospitals in the U.S. and Europe, we have brought together a new multi-disciplinary team of experts across many specialties, including neurology, cardiology, and intensive care. Together, we hope to improve cardiac arrest prevention and treatment, as well as to address the impact of new scientific discoveries on our understanding of what happens at death.
One of our first studies, Awareness during Resuscitation (AWARE), published in the medical journal Resuscitation in 2014, confirmed that some cardiac arrest patients report a perception of awareness without recall; others report detailed memories and experiences; and a few report full auditory and visual awareness and consciousness of their experience, from a time when brain function would be expected to have ceased.
While you probably have some opinion or belief about this based upon your own philosophical, religious, or cultural background, you may not realize that exploring what happens when we die is now a subject that science is beginning to investigate.
There is no question more intriguing to humankind. And for the first time in our history, we may finally uncover some real answers.
The Only Hydroxychloroquine Story You Need to Read
In the early days of a pandemic caused by a virus with no existing treatments, many different compounds are often considered and tried in an attempt to help patients.
It all relates back to a profound question: How do we know what we know?
Many of these treatments fall by the wayside as evidence accumulates regarding actual efficacy. At that point, other treatments become standard of care once their benefit is proven in rigorously designed trials.
However, about seven months into the pandemic, we're still seeing political resurrection of a treatment that has been systematically studied and demonstrated in well-designed randomized controlled trials to not have benefit.
The hydroxychloroquine (and by extension chloroquine) story is a complicated one that was difficult to follow even before it became infused with politics. It is a simple fact that these drugs, long approved by the Food and Drug Administration (FDA), work in Petri dishes against various viruses including coronaviruses. This set of facts provided biological plausibility to support formally studying their use in the clinical treatment and prevention of COVID-19. As evidence from these studies accumulates, it is a cognitive requirement to integrate that knowledge and not to evade it. This also means evaluating the rigor of the studies.
In recent days we have seen groups yet again promoting the use of hydroxychloroquine in, what is to me, a baffling disregard of the multiple recent studies that have shown no benefit. Indeed, though FDA-approved for other indications like autoimmune conditions and preventing malaria, the emergency use authorization for COVID-19 has been rescinded (which means the government cannot stockpile it). Still, however, many patients continue to ask for the drug, compelled by political commentary, viral videos, and anecdotal data. Yet most doctors (like myself) are refusing to write the prescriptions outside of a clinical trial – a position endorsed by professional medical organizations such as the American College of Physicians and the Infectious Diseases Society of America. Why this disconnect?
It all relates back to a profound question: How do we know what we know? In science, we use the scientific method – the process of observing reality, coming up with a hypothesis about what might be true, and testing that hypothesis as thoroughly as possible until we discover the objective truth.
The confusion we're seeing now stems from an inability to distinguish between anecdotes reported by physicians (observational data) and an actual evidence base. This is understandable among the general public but when done by a healthcare professional, it reveals a disdain for reason, logic, and the scientific method.
The Difference Between Observational Data and Randomized Controlled Trials
The power of informal observation is crucial. It is part of the scientific method but primarily as a basis for generating hypotheses that we can test. How do we conduct medical tests? The gold standard is the double-blind, randomized, placebo-controlled trial. This means that neither the researchers nor the volunteers know who is getting a drug and who is getting a sugar pill. Then both groups of the trial, called arms, can be compared to determine whether the people who got the drug fared better. This study design prevents biases and the placebo effect from confounding the data and undermining the veracity of the results.
For example, a seemingly beneficial effect might be seen in an observational study with no blinding and no control group. In such a case, all patients are openly given the drug and their doctors observe how they do. A prime example is the 36-patient single-arm study from France that generated a tremendous amount of interest after President Trump tweeted about it. But this kind of a study by its nature cannot answer the critical question: Was the positive effect because of hydroxychloroquine or just the natural course of the illness? In other words, would someone have recovered in a similar fashion regardless of the drug? What is the role of the placebo effect?
These are reasons why it is crucial to give a placebo to a control group that is as similar in every respect as possible to those receiving the intervention. Then we attempt to find out by comparing the two groups: What is the side effect profile of the drug? Are the groups large enough to detect a relatively rare safety concern? How long were the patients followed for? Was something else responsible for making the patients get better, such as the use of steroids (as likely was the case in the Henry Ford study)?
Looking at the two major hydroxychloroquine trials, it is apparent that, when studied using the best tools of clinical trials, no benefit is likely to occur.
All of these considerations amount to just a fraction of the questions that can be answered more definitively in a well-designed large randomized controlled trial than in observational studies. Indeed, an observational study from New York failed to show any benefit in hospitalized patients, showing how unclear and disparate the results can be with these types of studies. A New York retrospective study (which examined patient outcomes after they were already treated) had similar results and included the use of azithromycin.
When evaluating a study, it is also important to note whether conflicts of interest exist, as well as the quality of the peer review and the data itself. In the case of the French study, for example, the paper was published in a journal in which one of the authors was editor-in-chief, and it was accepted for publication after 24 hours. Patients who fared poorly on hydroxychloroquine were also left out of the study altogether, skewing the results.
What Randomized Controlled Trials Have Shown
Looking at the two major hydroxychloroquine trials, it is apparent that, when studied using the best tools of clinical trials, no benefit is likely to occur. The most important of these studies to announce results was part of the Recovery trial, which was designed to test multiple interventions in the treatment of COVID-19. This trial, which has yet to be formally published, was a randomized controlled trial that involved over 1500 hospitalized patients being administered hydroxychloroquine compared to over 3000 who did not receive the medication. Clinical testing requires large numbers of patients to have the power to demonstrate statistical significance -- the threshold at which any apparent benefit is more than you would expect by random chance alone.
In this study, hydroxychloroquine provided no mortality benefit or even a benefit in hospital length of stay. In fact, the opposite occurred. Hydroxychloroquine patients were more likely to stay in the hospital longer and were more likely to require mechanical ventilation. Additionally, smaller randomized trials conducted in China have not shown benefit either.
Another major study involved the use of hydroxychloroquine to prevent illness in people who were exposed to COVID-19. These results, published in The New England Journal of Medicine, included over 800 patients who were studied in a randomized double-blind controlled trial and also failed to show any benefit.
But what about adding the antibiotic azithromycin in conjunction with hydroxychloroquine? A three-arm randomized controlled study involving over 500 patients hospitalized with mild to moderate COVID-19 was conducted. Its results, also published in The New England Journal of Medicine, failed to show any benefit – with or without azithromycin – and demonstrated evidence of harm. Those who received these treatments had elevations of their liver function tests and heart rhythm abnormalities. These findings hold despite the retraction of an observational study showing similar results.
Additionally, when used in combination with remdesivir – an experimental antiviral – hydroxychloroquine has been shown to be associated with worse outcomes and more side effects.
But what about in mildly ill patients not requiring hospitalization? There was no benefit found in a randomized double-blind placebo-controlled trial of 400 patients, the majority of whom were given the drug within one day of symptoms.
Some randomized controlled studies have yet to report their findings on hydroxychloroquine in non-hospitalized patients, with the use of zinc (which has some evidence in the treatment of the common cold, another ailment that can be caused by coronaviruses). And studies have yet to come out regarding whether hydroxychloroquine can prevent people from getting sick before they are even exposed. But the preponderance of the evidence from studies designed specifically to find benefit for treating COVID-19 does not support its use outside of a research setting.
Today – even with some studies (including those with zinc) still ongoing – if a patient asked me to prescribe them hydroxychloroquine for any severity or stage of illness, with or without zinc, with or without azithromycin, I would refrain. I would explain that, based on the evidence from clinical trials that has been amassed, there is no reason to believe that it will alter the course of illness for the better.
Failing to recognize the reality of the situation runs the risk of crowding out other more promising treatments and creating animosity where none should exist.
What has been occurring is a continual shifting of goalposts with each negative hydroxychloroquine study. Those in favor of the drug protest that a trial did not include azithromycin or zinc or wasn't given at the right time to the right patients. While there may be biological plausibility to treating illness early or combining treatments with zinc, it can only be definitively shown in a randomized, controlled prospective study.
The bottom line: A study that only looks at past outcomes in one group of patients – even when well conducted – is at most hypothesis generating and cannot be used as the sole basis for a new treatment paradigm.
Some may argue that there is no time to wait for definitive studies, but no treatment is benign. The risk/benefit ratio is not the same for every possible use of the drug. For example, hydroxychloroquine has a long record of use in rheumatoid arthritis and systemic lupus (whose patients are facing shortages because of COVID-19 related demand). But the risk of side effects for many of these patients is worth taking because of the substantial benefit the drug provides in treating those conditions.
In COVID-19, however, the disease apparently causes cardiac abnormalities in a great deal of many mild cases, a situation that should prompt caution when using any drugs that have known effects on the cardiac system -- drugs like hydroxychloroquine and azithromycin.
My Own Experience
It is not the case that every physician was biased against this drug from the start. Indeed, most of us wanted it to be shown to be beneficial, as it was a generic drug that was widely available and very familiar. In fact, early in the pandemic I prescribed it to hospitalized patients on two occasions per a hospital protocol. However, it is impossible for me as a sole clinician to know whether it worked, was neutral, or was harmful. In recent days, however, I have found the hydroxychloroquine talk to have polluted the atmosphere. One recent patient was initially refusing remdesivir, a drug proven in large randomized trials to have effectiveness, because he had confused it with hydroxychloroquine.
Moving On to Other COVID Treatments: What a Treatment Should Do
The story of hydroxychloroquine illustrates a fruitless search for what we are actually looking for in a COVID-19 treatment. In short, we are looking for a medication that can decrease symptoms, decrease complications, hasten recovery, decrease hospitalizations, decrease contagiousness, decrease deaths, and prevent infection. While it is unlikely to find a single antiviral that can accomplish all of these, fulfilling even just one is important.
For example, remdesivir hastens recovery and dexamethasone decreases mortality. Definitive results of the use of convalescent plasma and immunomodulating drugs such as siltuxamab, baricitinib, and anakinra (for use in the cytokine storms characteristic of severe disease) are still pending, as are the trials with monoclonal antibodies.
While it was crucial that the medical and scientific community definitively answer the questions surrounding the use of chloroquine and hydroxychloroquine in the treatment of COVID-19, it is time to face the facts and accept that its use for the treatment of this disease is not likely to be beneficial. Failing to recognize the reality of the situation runs the risk of crowding out other more promising treatments and creating animosity where none should exist.
Dr. Adalja is focused on emerging infectious disease, pandemic preparedness, and biosecurity. He has served on US government panels tasked with developing guidelines for the treatment of plague, botulism, and anthrax in mass casualty settings and the system of care for infectious disease emergencies, and as an external advisor to the New York City Health and Hospital Emergency Management Highly Infectious Disease training program, as well as on a FEMA working group on nuclear disaster recovery. Dr. Adalja is an Associate Editor of the journal Health Security. He was a coeditor of the volume Global Catastrophic Biological Risks, a contributing author for the Handbook of Bioterrorism and Disaster Medicine, the Emergency Medicine CorePendium, Clinical Microbiology Made Ridiculously Simple, UpToDate's section on biological terrorism, and a NATO volume on bioterrorism. He has also published in such journals as the New England Journal of Medicine, the Journal of Infectious Diseases, Clinical Infectious Diseases, Emerging Infectious Diseases, and the Annals of Emergency Medicine. He is a board-certified physician in internal medicine, emergency medicine, infectious diseases, and critical care medicine. Follow him on Twitter: @AmeshAA
Drugs That Trick Older People’s Bodies to Behave Younger Might Boost the Effectiveness of a COVID-19 Vaccine
In our April 23rd editorial for this magazine, we argued that addressing the COVID-19 pandemic requires that we both fight the SARS-CoV-2 virus and fortify the human hosts who are most vulnerable to it.
Two recent phase 2 studies in older adults have suggested that a new category of drugs called rapalogues can in some cases increase the immunization capacity of older adults.
Because people over 70 account for more than 80 percent of reported COVID-19 deaths globally, this means we must do everything possible to protect our elders.
A range of recent studies have suggested that systemic knobs might metaphorically be turned to slow the cellular aging process, making us better able to fight off the many diseases correlated with aging. These types of systemic changes might be used to stem the specific decline in immunity caused by aging and to increases the biological capacity of elderly people to effectively fight viral infection.
But while helping make older people more resilient in the face of a viral infection is critical, that's not the only way geroscience can help in our fight against this deadly pandemic.
As we move toward hopefully developing one or more COVID-19 vaccines, researchers must more fully appreciate the ways in which traditional vaccines can be less effective in older people than in younger ones.
Repeated studies have shown that the flu vaccine, for example, has lower efficacy in older people than in younger ones. Older people tend to develop fewer antibodies after being vaccinated because a subset of their white blood cells, called T cells, have become less responsive over time. Some inflammatory peptides that increase with aging are also preventing the action of those T cells.
This is why there's a distinct possibility that a future COVD-19 vaccine, particularly one utilizing the traditional attenuated virus approach, could be less effective in older people than in younger ones.
Given the extreme urgency of developing vaccines that work well for everyone, we need to make sure that researchers are exploring all of the ways our elders can be best protected. While generating a vaccine that works equally well for people of all ages would be ideal, we can't count on that.
One way to bridge this gap might be to trick the bodies of older people into behaving as if they are younger just at the moment what a vaccine is delivered by giving them pre-immunization boosters.
Two recent phase 2 studies in older adults have suggested that a new category of drugs called rapalogues can in some cases increase the immunization capacity of older adults. Use of the drug for a short time period before flu shot immunization increased the antibody production for the flu and resulted in a 52 percent decrease in the occurrence of severe diseases needing medical help or hospitalization. This short-term pre-immunization intervention can also decrease the severity of serious respiratory tract infections, the deadliest manifestations of COVID-19, by similar magnitude. These patients also had almost half the incidence of the non-COVID-19 coronaviruses associated with the common cold.
The fact that those people were protected by treatment before hospitalization suggests metformin may have a role in boosting the vaccination of older people.
An inexpensive generic drug called metformin similarly targets the decline in immunity and inflammation (and extends health span and lifespan) in animals and has been used for decades to protect against the flu. A recent paper from a hospital in Wuhan, China showed that mortality of elderly COVID-19 diabetic patients on metformin was 25 percent less than that of patients with diabetes but not on metformin.
Another study from the U.S. showed that COVID-19 patients on metformin had a 20 percent decrease in mortality and lower inflammation. The fact that those people were protected by treatment before hospitalization suggests metformin may have a role in boosting the vaccination of older people.
We don't yet know whether rapalogues or metformin could be used as COVID-19 immunization boosters, not least because we don't have those vaccines. But we can and should make sure that all vaccine trials including older subjects also consider offering a subset of those subjects appropriate doses of rapalogues or metformin to explore whether doing so can boost the efficacy of a given vaccine.
If we weren't in the middle of the worst pandemic in a century, we would have more time to test our vaccines slowly and sequentially. In the context of the current crisis, however, testing whether immunization boosters might increase the efficacy of potential COVID-19 vaccines for older adults is at the very least a hypothesis worth exploring.