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Can a brain dead person recover?

Can a brain dead person recover?


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Many times I have heard someone having to pull the plug because the patient was declared brain dead before the body healed fully? Why do they pull the plug without first waiting till the body/brain has a full recovery? What situations if not recoverable would they allow the body to fully heal before pulling the plug?


No.

Brain death is permanent damage to the brain. Depending on the specific definition, it may refer to either cerebral death or to failure of the brainstem to maintain functions like respiration.

It could be possible for mistakes to be made and for brain death to be declared in a patient who has not actually experienced brain death. However, this is incredibly incredibly rare: zero cases have been reported when appropriate guidelines are followed (Wijdicks et al. 2010). If someone is diagnosed as brain dead after a trauma, the medical staff involved in making that decision are stating that there is effectively no chance for recovery. Brain death is not diagnosed lightly.


Wijdicks, E. F., Varelas, P. N., Gronseth, G. S., & Greer, D. M. (2010). Evidence-based guideline update: determining brain death in adults: report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology, 74(23), 1911-1918.


@Bryan Krause answered your question prior to the edit. Your new question is relatively easy to answer.

Why do they pull the plug without first waiting till the body/brain has a full recovery?

Some organs have a high regenerative capacity (you can donate part of your liver and it will mostly grow back), some have a high compensatory ability (you could live with one lung), etc. However, the brain isn't one of those organs.

Until relatively recently, it was thought that the brain had no regenerative ability at all. We now know that to be untrue. Still, compared with most other organs, the brain doesn't "heal" well.

It's one thing to keep a comatose patient alive (e.g. after a bad stroke) to see if time will help. Neurons do form new synapses that allow for a degree of recovery. But most times with a stroke, only part of the brain is involved, and the brain does have compensatory abilities (new synapse formation.)

But brain death is much more than a coma.

When there is so much damage that a patient can be declared to have undergone brain death, people don't recover from that. There isn't any reason to let someone heal all their other organs - or the brain - fully when the one organ that makes us who we are is dead and the only way to stay 'alive' is by artificial means (ventilators, total parenteral nutrition or a g-tube, etc.)

What situations if not recoverable would they allow the body to fully heal before pulling the plug?

Family inability to allow a hospital to "pull the plug" leads to prolonged life support and recovery time for such patients. This is not necessarily good, however. Some patients who were declared brain dead (less rigorous criteria) survived post life support, but none has gone on to become functional (and usually stay in a vegetative - or minimally conscious - state at best.)

Regeneration of Hippocampal Pyramidal Neurons after Ischemic Brain Injury by Recruitment of Endogenous Neural Progenitors

The Challenges of Defining and Diagnosing Brain Death

A new Johns Hopkins support team helps clinicians and families understand a difficult diagnosis.

A woman lies in a bed at The Johns Hopkins Hospital. Aided by a ventilator, her lungs inflate, deflate, and fill again. Her heart beats and her skin is warm. But her eyes stay closed and she does not react to stimuli such as pain and light.

If you’re unsure, or if the question makes you uncomfortable, you’re not alone. The hypothetical case described here reflects a real problem: the inherent difficulties of diagnosing and accepting brain death.

The topic was the focus of a September Ethics for Lunch discussion in the Chevy Chase Bank Auditorium of The Johns Hopkins Hospital, hosted by the Berman Institute of Bioethics.

The panel was moderated by anesthesiologist and critical care specialist Robert Stevens, who says the line between life and death, once clearly perceptible in the form of a beating heart, is now sometimes harder to see because of advances in lifesaving technologies.

The modern intensive care unit can keep a person with severe brain injuries alive, he says, but may also mask evidence that the person has died. The shift from a deep coma to brain death—permanent cessation of all brain function—may not be immediately obvious to an untrained observer. Yet recognizing this transition from life to death is critical for families, the medical team and potential organ recipients.

When a patient dies, doctors stop treatment and instead focus on organ viability. The body is kept on life-support machinery if the patient was a registered organ donor or while the family makes decisions about organ donation.

To help clinicians make a brain death diagnosis, The Johns Hopkins Hospital in June 2016 created a Determination of Death by Neurological Criteria Support Team.

Here’s how it works: A patient arrives in the emergency room after an overdose, car accident or other trauma that caused extensive brain injury. Doctors do everything they can to stabilize the patient, but his brain may have suffered irreversible damage.

When attending physicians suspect a patient is brain-dead, they may opt to call a consultant—a Johns Hopkins neurologist, neurosurgeon or critical care specialist with experience and training in two different, but related, areas: the techniques used to determine death, and communicating the nuances of the difficult situation with primary care teams and family members.

The consultant performs a full neurological examination to determine if there are any signs of brain or brainstem function. This includes assessing the drive to take a breath, determining whether pupils react to light, and swabbing the back of the throat to elicit a gag reflex. The neurological examination must be repeated at least once after a minimum interval of six hours, to ensure that brain function is not temporarily suppressed by factors such as high doses of narcotics or intense cold.

The support team helps those consultants by providing guidance and answering questions. “Our only advantage is experience, because we handle more of these cases,” says neurologist and neurocritical care specialist Adrian Puttgen, who forms the group with anesthesiologist and neurocritical care specialist Adam Schiavi, and neurologists Rafael Llinas and Brett Morrison. “This team is written into our hospital policy. We monitor in the background and come in as needed when there’s a question.”

Because of that support, brain death determinations take less time than in the past. “We owe it to the families to resolve the question of whether a patient is alive or dead as quickly as possible,” says Puttgen. “Otherwise, it’s a state of limbo.”

A brain death diagnosis is nearly always confusing and overwhelming to family members. In a few states, though not Maryland, doctors must accommodate the preferences of families who refuse to accept the diagnosis for religious reasons.

That happened in 2013, when the parents of Jahi McMath moved the13-year-old from a California hospital to one in New Jersey after a brain death diagnosis following tonsillectomy complications. Her body remains attached to life-support machinery.

“Most people have this notion that you’re recognizably alive and then you’re recognizably dead,” says Schiavi. “What’s happened is that our technological ability to sustain life has moved faster than our moral capacity to deal with the implications.”

The support team is helping. “We are taking active steps to change the culture, not only for families but for physicians as well,” he says.


Nearly brain-dead woman survives after being removed from life support

Moments after a Michigan man made the heart-wrenching decision to take his wife off life support, she started breathing on her own.

Michele De Leeuw, 57, was rendered nearly brain dead by a heart attack she suffered in August while at home with her husband. Days later, one of her doctors told her husband, Karl De Leeuw that, "the woman that you know as your wife is not there anymore," he said.

Less than four months later, she's made an almost full recovery.

Michele De Leeuw was without oxygen for 15 minutes before Sterling Heights paramedics were able to resuscitate her, Karl De Leeuw said.

She was then rushed to St. John Macomb Hospital, at which point Karl alerted his two adult children.

"When my father called me after she was rushed to the hospital, was that he felt that she was dead. It was the most earth-shattering phone call of my young life," said Michele's daughter, Myles De Leeuw, 24. "It was horrible to see my mother on more IVs and tubes than you can ever imagine."

"I’ve never seen that many IVs," Karl Leeuw, 58, echoed.

Six days after Michele's heart attack, her distraught family was told she had only 5 percent brain function and 25 percent heart function.

At that point, Karl De Leeuw was charged with making what he called the "hardest decision of my life."

"I took her off the ventilator. I unplugged her," he told NBC News.

"When we pulled the plug, it was just so sad to start living with the reality that my mom is dead," said Myles De Leeuw.

But that wasn't the reality.

"She started breathing on her own," Karl De Leeuw said.

Michele De Leeuw hadn't gained consciousness though, and doctors didn't expect her to recover so she was placed in "comfort care" for patients who are expected to pass away.

"Two days later, the doctor called me on the phone and said, 'We’ve had an unexpected event happen,'" Karl De Leeuw said. His wife's eyes had opened.

Two days after that, she was talking.

"She told the nurse she’s hungry," Karl De Leeuw said. "I said, 'well feed her.'"

"Two days later she was sitting up in bed feeding herself," Karl De Leeuw said

Still, Michele De Leeuw had a long way to go. She didn't know where she was, wasn't making sense and still had blockages in her veins.

Today though, after open heart surgery, speech and physical therapy, she's nearly fully recovered.

On Tuesday, she was awarded the Sterling Heights Fire Department’s “Survival Coin” at an event that brings heart attack survivors together with the first responders who treated them.

"You wouldn’t believe it if you didn’t know what she’s gone through." Karl De Leeuw said. "She’s a miracle lady."

He said his wife came home from her heart surgery on their 26th anniversary and it got him thinking about marriage vows.

Karl said through the years, the couple's bond has survived "for richer or for poorer." And over the past four months, they've overcome "in sickness and in health."

"For me though, I don’t think there are a lot of couples who can pass the last one," Karl De Leeuw said. "Till death do us part."


How do hospitals determine if someone is brain dead?

The rules for judging when a patient is brain dead vary widely from hospital to hospital, despite the existence of national standards created to ensure accuracy, a new study has found.

The American Academy of Neurology adopted a set of updated guidelines in 2010 for judging whether a person has lost all brain function and is being kept alive solely through hospital machinery, said lead researcher Dr. David Greer, a professor of neurology at the Yale School of Medicine, in New Haven, Conn.

There are no legitimate reports of any patient ever being declared brain dead when they weren't, Greer said, but such judgments need to be made with "100 percent certainty."

"That's why we want to provide a very high level of accountability for this, and that's why we created the guidelines to be so specific, so straightforward and cookbook," Greer said. "Basically, you might call it 'Brain Death For Dummies.' You should be able to take this checklist to the bedside, follow it point by point and be able to get through it."

But hospitals have been slow to adopt the brain death standards in their policies, Greer and colleagues found in a national review.

They reviewed 508 hospital policies regarding brain death, representing hospitals and health systems in all 50 states. The results were published online Dec. 28 in the journal JAMA Neurology.

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To rule a person brain dead, physicians must make two judgments, Greer said.

They have to prove there's no brain function at all, even to regulate automatic processes in the body. "Even the most basic things such as taking a breath constitutes brain function," he said.

They must also rule out any chance that the person might recover brain function. For example, doctors have to make sure the person isn't suffering from a condition that resembles brain death, Greer said.

"If there's any chance that, by continuing to treat the patient or by eliminating some unknown factor, the patient might retain some brain function, then you don't declare them," he said.

But the rules for both judgments vary widely between hospitals, and often do not stick to the guidelines, researchers found.

For example, only 56 percent of hospital policies required doctors to rule out hypotension -- severely low blood pressure -- as a factor that might create the illusion of brain death, according to review findings.

In addition, one out of every five policies did not require doctors to rule out hypothermia -- abnormally low body temperature -- as a possible factor.

Dr. James Bernat, a neurologist with Dartmouth's Geisel School of Medicine in Hanover, N.H., said he was surprised to learn that about one in 10 hospital policies did not require doctors to make sure that a patient can no longer breathe on his or her own before declaring brain death -- otherwise known as an "apnea test."

"That is an absolute requirement," Bernat said. "No one should ever do a brain death determination without an apnea test. Determining apnea is essential."

Many differences among hospitals can be chalked up to variations in community standards and state law, said Dr. John Combes, senior vice president of the American Hospital Association.

"There are different state and legal requirements that hospitals must follow," Combes said. "I think that inherently there is going to be variation."

But the updated national requirements take such variations into account, Greer said. For example, the guidelines provide flexibility regarding which type of doctor can judge brain death, how many doctors need to be involved and how many examinations should occur.

"However, there are core requirements that should not be debatable whatsoever," he said. "The core things absolutely have to be there. If there are things stipulated by the state on top of that, then that's fine."

The review researchers are concerned that organ donations could drop off if potential donors become fearful that the proper steps aren't being followed to make sure brain death has occurred, Greer said.

"That's why we're all working together, to make sure this is done right 100 percent of the time," he said. "If the public were to lose faith in what we're doing on the medical side, then that would have disastrous implications for organ donation."

Greer said the review results show that hospitals are moving in the right direction, but still have more to do.

Combes agreed. "This article encourages [hospitals] to review their procedures to make sure they meet the current standard of evidence and medical knowledge," he said.

Hospitals might be quicker to adopt solid policies if they were required to do so by the Joint Commission, the body that accredits hospitals, Bernat said.

"I can tell you if the Joint Commission insists this be done in a certain way, then it will be done," he said.

First published on December 28, 2015 / 5:31 PM

© 2015 HealthDay. All rights reserved. This material may not be published, broadcast, rewritten, or redistributed.


Brain Dead Patients Waking Up

Although rare, there have been cases of patients who were declared brain dead waking up suddenly, sometimes after spending years in a coma. Colleen Burns was diagnosed by doctors with irreversible brain damage. However, just as she was about to be taken back for her organs to be donated, she woke up on her own. Another woman, Taylor Hale, was in an accident where she fell off the hood of a car. Her doctors told the family there was no way she could come back from that kind of brain damage. However, after some prayer, she woke up. Despite having no memories from before the accident, she lives a normal life.


When a patient enters a vegetative state

Sixty-one-year-old Darrel Young underwent heart transplant surgery on Sept. 21, 2018, at Newark Beth Israel Medical Center. Young never awoke from surgery, instead falling into a vegetative state. If he had died, the hospital's heart transplant program survival rate would have dropped to 84.2% — which would have triggered scrutiny by the federal government.

In a recording, transplant program director Dr. Mark Zucker said the team would "need to keep [Young] alive till June 30 at a minimum." It was then that a federally funded organization that tracks transplant survival rates would file its next report. "If he's not dead in this report, even if he's dead in the next report, it becomes an issue that moves out six more months," Zucker said in a recording.

So Young was kept alive in a vegetative state. But what exactly does that mean? The term "vegetative state" sounds a lot like "coma" or "brain-dead," but there are actually clear distinctions between each of these conditions.


Get Smart: Brain Cells Do Regrow, Study Confirms

March 6, 2000 (Boston) -- Here's hope for those who fear they lost too many brain cells to youthful dissipation: Researchers at Cornell University have demonstrated that cells from an area of the brain essential for learning and memory can regenerate in a laboratory dish. In the future, the discovery might lead to strategies for replacing brain cells lost to diseases such as Alzheimer's.

Until recently, conventional medical wisdom held that we are born with all the brain cells, or neurons, that we'll ever have and when they're gone, they're gone for good. Over the last few years, though, researchers have shown that in at least one area of the brain, a region known as the hippocampus, there is continual turnover of cells throughout most of our lives.

In the latest study, Steven A. Goldman, MD, from Cornell University Medical College in New York City, and colleagues took samples of tissues from the hippocampus that had been removed from patients undergoing surgery to repair brain disorders. They were able to tease out cells from a certain area where populations of "seed," or precursor, cells are found. The researchers were able to separate these precursor cells from mature cells, which can no longer divide. They were able to aid the cells in continuing to divide and grow.

Jack P. Antel, MD, and colleagues from McGill University in Montreal write in an editorial accompanying the study that this approach could ultimately lead to new strategies for repairing and restoring cells lost to diseases or trauma in the hippocampus, and perhaps other regions of the brain.

But in an interview with WebMD, Goldman cautions that "it's a bit early in the game to think in practical terms of using these cells for transplantation purposes."

Among the problems that need to be tackled, Goldman says, are how best to deliver these cells to the brain and ensure that they will survive in sufficient numbers after transplant, and how to direct them to the parts of the brain where they will do the most good.

Many researchers think that memory impairment associated with aging is caused by damage to the hippocampus brought on by lifelong exposure to stress hormones. Several studies have shown that elderly people and rats with significant and prolonged elevation of these stress hormones have smaller hippocampal regions and show declines in memory due to damage to the hippocampus.

"It's a very interesting system," says Ronald McKay, PhD, chief of the laboratory of molecular biology at the National Institute of Neurological Disorders and Stroke. McKay, who has previously demonstrated that reducing stress hormone levels in aged rats can restore the production rate of brain cells in the hippocampus, reviewed the current study for WebMD.

"The hippocampus has these cells . which are replaced throughout life from dividing cells, so that whole process of division, . maturation and death seems to be going on all the time in this structure."

Although it's tempting to think that seed cells could be grown in the lab to restore cells damaged by neurodegenerative disorders such as Alzheimer's disease, much needs to be learned before such therapies are practical, Goldman and McKay say.

Instead, these precursor cells are likely to have their first uses in drug-testing labs, where researchers could explore whether specific drugs or combinations could be used to stimulate the growth of new brain cells within the hippocampus, Goldman says.


Hypoglycemia, functional brain failure, and brain death

Division of Endocrinology, Metabolism and Lipid Research, Washington University School of Medicine, St. Louis, Missouri, USA.

Address correspondence to: Philip E. Cryer, Campus Box 8127, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, Missouri 63110, USA. Phone: (314) 362-7635 Fax: (314) 362-7989 E-mail: [email protected]

Related article:

Hypoglycemic neuronal death is triggered by glucose reperfusion and activation of neuronal NADPH oxidase

Hypoglycemic neuronal death is triggered by glucose reperfusion and activation of neuronal NADPH oxidase

Abstract

Hypoglycemic coma and brain injury are potential complications of insulin therapy. Certain neurons in the hippocampus and cerebral cortex are uniquely vulnerable to hypoglycemic cell death, and oxidative stress is a key event in this cell death process. Here we show that hypoglycemia-induced oxidative stress and neuronal death are attributable primarily to the activation of neuronal NADPH oxidase during glucose reperfusion. Superoxide production and neuronal death were blocked by the NADPH oxidase inhibitor apocynin in both cell culture and in vivo models of insulin-induced hypoglycemia. Superoxide production and neuronal death were also blocked in studies using mice or cultured neurons deficient in the p47phox subunit of NADPH oxidase. Chelation of zinc with calcium disodium EDTA blocked both the assembly of the neuronal NADPH oxidase complex and superoxide production. Inhibition of the hexose monophosphate shunt, which utilizes glucose to regenerate NADPH, also prevented superoxide formation and neuronal death, suggesting a mechanism linking glucose reperfusion to superoxide formation. Moreover, the degree of superoxide production and neuronal death increased with increasing glucose concentrations during the reperfusion period. These results suggest that high blood glucose concentrations following hypoglycemic coma can initiate neuronal death by a mechanism involving extracellular zinc release and activation of neuronal NADPH oxidase.

Authors

Sang Won Suh, Elizabeth T. Gum, Aaron M. Hamby, Pak H. Chan, Raymond A. Swanson

Hypoglycemia commonly causes brain fuel deprivation, resulting in functional brain failure, which can be corrected by raising plasma glucose concentrations. Rarely, profound hypoglycemia causes brain death that is not the result of fuel deprivation per se. In this issue of the JCI, Suh and colleagues use cell culture and in vivo rodent studies of glucose deprivation and marked hypoglycemia and provide evidence that hypoglycemic brain neuronal death is in fact increased by neuronal NADPH oxidase activation during glucose reperfusion (see the related article beginning on page 910). This finding suggests that, at least in the setting of profound hypoglycemia, therapeutic hyperglycemia should be avoided.

Hypoglycemia, including iatrogenic hypoglycemia in people with diabetes, causes brain fuel deprivation that initially triggers a series of physiological and behavioral defenses but if unchecked results in functional brain failure that is typically corrected after the plasma glucose concentration is raised. Rarely, profound, and at least in primates prolonged, hypoglycemia causes brain death.

Given the survival value of maintaining physiological plasma glucose concentrations, it is not surprising that mechanisms that normally very effectively prevent or rapidly correct symptomatic hypoglycemia have evolved ( 1 ). As a result, hypoglycemia is a distinctly uncommon clinical event except in people who use drugs that lower the plasma glucose concentration ( 2 ). Although there are other drugs, and several relatively uncommon conditions, that cause hypoglycemia ( 2 ), in the vast majority of instances the offending drug is an insulin secretagogue or insulin used to treat diabetes mellitus ( 2 , 3 ). As a result of the interplay of relative or absolute therapeutic insulin excess and compromised physiological and behavioral defenses against falling plasma glucose concentrations, hypoglycemia is the limiting factor in the glycemic management of diabetes ( 3 ). It causes recurrent morbidity in most people with type 1 diabetes mellitus (T1DM) and in many with advanced T2DM and is sometimes fatal. Furthermore, hypoglycemia, as well as prior exercise and sleep, further compromise glycemic defenses by causing hypoglycemia-associated autonomic failure and thus a vicious cycle of recurrent hypoglycemia. Finally, the barrier of hypoglycemia precludes maintenance of euglycemia over a lifetime of diabetes and thus full realization of the long-term vascular benefits of glycemic control.

Recent interest in alternative brain fuels (including lactate derived from glucose largely within the brain refs. 4 –6) notwithstanding, glucose is an obligate metabolic fuel for the brain under physiological conditions ( 7 ). Because the brain cannot synthesize glucose or store substantial amounts as glycogen in astrocytes, the brain requires a virtually continuous supply of glucose from the circulation. Facilitated diffusion of glucose from the blood into the brain is a direct function of the arterial plasma glucose concentration. The rate of blood-to-brain glucose transport exceeds the rate of brain glucose metabolism at normal (or elevated) plasma glucose levels, but it falls and becomes limiting to brain glucose metabolism when arterial glucose concentrations fall to low levels ( 8 ). Thus, hypoglycemia causes brain fuel deprivation and, as a result, functional brain failure.

The sequence of responses to falling plasma glucose concentrations ( 1 ) is illustrated in Figure 1. Initially, declining plasma glucose levels activate defenses against hypoglycemia. Physiological defenses normally include decrements in pancreatic β cell insulin secretion as glucose levels decline within the physiological postabsorptive plasma glucose concentration range (approximately 3.9–6.1 mmol/l [70–110 mg/dl]). The glycemic threshold for decreased insulin secretion is approximately 4.5 mmol/l (81 mg/dl). Increments in pancreatic β cell glucagon and adrenomedullary epinephrine secretion (among other neuroendocrine responses) normally occur as glucose levels fall just below the physiological range (threshold equal to approximately 3.8 mmol/l [68 mg/dl]). If these defenses fail to abort the hypoglycemic episode, lower glucose levels trigger a more intense sympathoadrenal response that causes neurogenic (or autonomic) symptoms neuroglycopenic symptoms occur at about the same glucose level (threshold equal to approximately 3.0 mmol/l (54 mg/dl). The perception of symptoms, particularly neurogenic symptoms, prompts the behavioral defense, the ingestion of food. If all of these defenses fail, lower glucose levels cause overt functional brain failure that can progress from measurable cognitive impairments (threshold equal to approximately 2.8 mmol/l [50 mg/dl]) to aberrant behaviors, seizure, and coma. Coma can occur at glucose levels in the range of 2.3–2.7 mmol/l (41–49 mg/dl) ( 9 ) as well as at lower glucose levels. All of these responses are typically corrected after the plasma glucose concentration is raised.

Sequence of responses to falling arterial plasma glucose concentrations. The solid horizontal line indicates the mean and the dashed horizontal lines the upper and lower limits of physiological postabsorptive plasma glucose concentrations in humans. The glycemic thresholds for decrements in insulin secretion, increments in glucagon and epinephrine secretion, symptoms, and decrements in cognition have been defined in healthy humans ( 1 ) (see text). Those for seizure and coma and for neuronal death are extrapolated from clinical observations of humans ( 9 ) and studies in monkeys ( 12 ) as well as in other experimental animals ( 13 – 15 ). In this issue of the JCI, Suh and colleagues ( 13 ) report that glucose reperfusion increased brain neuronal death in their rodent model of profound hypoglycemia.

Episodes of hypoglycemia are a fact of life for most people with T1DM and many with advanced T2DM ( 3 ). In T1DM, plasma glucose concentrations may be less than 2.8 mmol/l (50 mg/dl) as much as 10% of the time the average patient suffers two episodes of symptomatic hypoglycemia per week and one episode of severe, temporarily disabling hypoglycemia per year. Although iatrogenic deaths do result from the adverse effects of drug therapy ( 9 , 10 ) (the mechanisms are unclear but could include cardiac arrhythmias), seemingly complete recovery from hypoglycemia-induced functional brain failure after the plasma glucose concentration is raised is the rule ( 3 , 11 ). Permanent neurological damage is rare ( 11 ).

Profound, prolonged hypoglycemia can cause brain death. In studies of insulin-induced hypoglycemia in monkeys, 5–6 hours of blood glucose concentrations of less than 1.1 mmol/l (20 mg/dl) were required for the regular production of neurological damage ( 12 ) the average blood glucose level was 0.7 mmol/l (13 mg/dl). Fortunately, hypoglycemia of that magnitude and duration occurs rarely in people with diabetes.

The mechanisms of the common, hypoglycemia-induced functional brain failure and of the rare, hypoglycemia-induced brain death that occurs at very low, and at least in primates prolonged, plasma glucose concentrations (Figure 1) differ. The former is the result of brain fuel deprivation per se, but the latter is not. As summarized by Suh and colleagues in their study reported in this issue of the JCI ( 13 ), a variety of mechanisms are thought to be involved in the pathogenesis of hypoglycemic neuronal death. These include glutamate release and activation of neuronal glutamate receptors, production of reactive oxygen species, neuronal zinc release, activation of poly(ADP-ribose) polymerase, and mitochondrial permeability transition.

In their current report, Suh and colleagues ( 13 ) describe additional studies of the mechanisms of hypoglycemia-induced neuronal necrosis. Based on systematic cell culture and in vivo rodent studies of glucose deprivation followed by glucose provision, they provide evidence that hypoglycemic superoxide production and neuronal death are increased by NADPH oxidase activation during glucose reperfusion. These effects were reduced by an inhibitor of NADPH oxidase, deficiency of a subunit of the enzyme, and blockade of NADPH regeneration, among other findings. Notably, superoxide formation and neuronal death increased with increasing glucose concentrations during the posthypoglycemic reperfusion period. That finding is generally consistent with earlier findings by these investigators ( 14 ) and by others ( 15 ).

In order to reproducibly cause the study endpoints, including neuronal death, these studies ( 13 ) were generally performed at glucose concentration extremes. In the cell culture studies, glucose deprivation conditions were established by the use of a medium containing no glucose, while conditions of glucose provision were established by adding glucose to the medium at 10.0 mmol/l (180 mg/dl), several-fold greater than normal brain extracellular fluid glucose concentrations. In the in vivo studies, blood glucose concentrations averaged 0.4 mmol/l (7 mg/dl), causing an isoelectric EEG, during hypoglycemia and approximately 7.5 mmol/l (135 mg/dl) during glucose reperfusion that was documented to cause detrimental effects. Superoxide production, and presumably neuronal death, occurred as a result of hypoglycemia, but these occurred to a greater extent with glucose reperfusion, less so when posthypoglycemic blood glucose concentrations were raised to the range of 1.0–2.0 mmol/l (18–36 mg/dl) than when they were raised to the range of 5.0–10.0 mmol/l (90–180 mg/dl). Studies involving less profound hypoglycemia were not reported.

The distinction between the common hypoglycemia-induced functional brain failure and the rare hypoglycemia-induced brain death drawn here is admittedly arbitrary. Plasma glucose concentrations of less than 1.0 mmol/l (18 mg/dl) occur occasionally in people with diabetes ( 9 ), and dying brain cells, presumably neurons, have been reported following episodes of hypoglycemia at plasma glucose levels of 1.7–1.9 mmol/l (30–35 mg/dl) — but not following episodes of hypoglycemia at plasma glucose levels of 2.5 mmol/l (45 mg/dl) — in rats ( 16 ). Thus, it could be reasoned that these categories are not binary and that there is a continuous spectrum with increasing risk of neuronal death at progressively lower plasma glucose concentrations. Nonetheless, seemingly complete recovery follows the vast majority of episodes of clinical hypoglycemia.

The appropriate clinical extrapolation of these data is not entirely clear. As the authors point out ( 13 ), plasma glucose concentrations must be raised in hypoglycemic patients. In the common clinical setting of hypoglycemia-induced functional brain failure, plasma glucose levels should be raised into the physiological range promptly with the expectation that recovery of brain function will follow. At this point there is no clear evidence that posttreatment hyperglycemia is detrimental to recovery, but there is no reason to think it is beneficial in that setting. On the other hand, undertreatment will delay recovery. In the rare clinical setting of profound, prolonged hypoglycemia, where the risk of neuronal death is higher, the data suggest that plasma glucose levels should be raised cautiously with avoidance of hyperglycemia ( 13 – 15 ). Nonetheless, it would seem reasonable to raise the plasma glucose level into the physiological range (e.g., >3.9 mmol/l [70 mg/dl]) promptly. Clearly, additional studies of this important issue are needed.

The author’s work cited was supported, in part, by US Public Health Service/NIH grants R37 DK27085, M01 RR00036, P60 DK20579, and T32 DK07120 and by a fellowship award from the American Diabetes Association. Janet Dedeke prepared this manuscript.

Nonstandard abbreviations used: T1DM, type 1 diabetes mellitus.

Conflict of interest: The author has served on advisory boards of Novo Nordisk Inc., Takeda Pharmaceuticals North America Inc., MannKind Corp., and Merck and Co. and as a consultant to TolerRx Inc., Amgen Inc., and Marcadia Biotech in recent years.

Reference information: J. Clin. Invest.117:868–870 (2007). doi:10.1172/JCI31669.


Brain Activity in 'Unresponsive' Patients May Predict Recovery

by Judy George, Senior Staff Writer, MedPage Today June 27, 2019

About one in six clinically unresponsive ICU patients showed electroencephalography (EEG) patterns of brain activity when spoken to soon after acute brain injury, a single-center study showed.

In 16 of 104 (15%) unresponsive patients, a machine-learning algorithm that analyzed EEG recordings detected brain activation following researchers' verbal commands a median of 4 days after injury, according to Jan Claassen, MD, of Columbia University in New York City, and colleagues.

Half of these 16 patients improved to the point that they were physically able to follow commands a median of 6 days later, the researchers reported in the New England Journal of Medicine. The injured patients who showed early brain activity were four times more likely to achieve partial independence at 12 months than similar patients with no activity, they added.

If confirmed, these findings "could inform prognostication of acute brain injury and potentially provide a means of communication with patients who seem unresponsive on the basis of a conventional clinical examination," wrote David Menon, MD, PhD, and Srivas Chennu, PhD, both of the University of Cambridge in England, in an accompanying editorial.

Not being able to follow commands early after an acute, severe brain injury traditionally has been thought to mean either that damage is too severe for consciousness to return or that the ability to follow commands and other signs of consciousness may recover over time as injury and sedative effects fade, Menon and Chennu noted.

"However, a third possibility exists: there is activation of cerebral neural circuits for perception of commands that is not accompanied by corresponding motor responses," they wrote.

This phenomenon, known as cognitive&ndashmotor dissociation, is seen in about 15% of chronically unresponsive patients, with fMRI or EEG indicating cerebral activation during motor imagery tasks in patients who demonstrated no motor responses to commands. Other studies in chronic disorders of consciousness have shown a related phenomenon known as "covert cognition," when brain activation occurs in unresponsive patients during cognitive tasks that do not require the patient to attempt to move.

In this study, Claassen and colleagues looked for cognitive-motor dissociation in patients shortly after brain injury, since the absence of an ability to follow commands at that point may affect decisions about withdrawing life-sustaining therapies.

They identified 104 patients with acute brain injury from 2014 to 2107 who were unable to follow spoken commands, excluding patients with seizures, hyperglycemia, abnormal sodium, and renal or fulminant liver failure. Before each EEG assessment, they rated each patient on the 23-point Coma Recovery Scale&ndashRevised (CRS-R), and classified sedation as minimal, low, or moderate. If deemed safe, sedation was reduced for an EEG assessment.

The researchers acquired a total of 240 EEG recordings while issuing verbal commands such as "open and close your hand." During half (52%) of the recordings patients were comatose 54 recordings occurred (22%) while patients were in a vegetative state, and 60 (25%) while patients were in a minimally conscious state&ndashminus category.

The machine-learning algorithm (support vector machine) detected cognitive&ndashmotor dissociation on at least one recording a median of 4 days after ICU admission in 16 of 104 (15%) patients. These 16 patients had injury from subarachnoid hemorrhage (five people), traumatic brain injury (three), intracerebral hemorrhage (four), cardiac arrest (two), neurosarcoidosis (one), and bupropion overdose (one).

Eight of these 16 patients (50%) and 23 of 88 patients (26%) without brain activity improved to the point where they were able to follow commands before discharge. At 12 months, 7 of 16 patients (44%) with brain activity and 12 of 84 patients (14%) without brain activity had a Glasgow Outcome Scale&ndashExtended level of 4 or higher, indicating they were able to function independently for 8 hours (OR 4.6 95% CI 1.2-17.1).

Six patients with cognitive&ndashmotor dissociation (38%) and 50 without (60%) were dead at 12 months. Four of six patients with cognitive&ndashmotor dissociation who died did so after life-sustaining therapy was withdrawn.

While some responses were inconsistent, the findings are intriguing, especially since EEG is more easily used and more widely available than fMRI in the ICU, Menon and Chennu wrote. The verbal commands used were similar to ones used in bedside clinical examination to determine whether a patient is unresponsive, they pointed out: "It is noteworthy that [the researchers'] methods were designed to reduce the risk of false discovery of cognitive&ndashmotor dissociation."

But questions remain and replicating this study is essential, they said. "Future studies should explore spatial patterns of EEG activation, quantify false positive detection rates of the EEG classifier, understand the basis of inconsistent responses within patients, and provide details and evaluation of the specifics of support vector algorithms," Menon and Chennu wrote. It's also unclear whether sedation or arousal played a role in the outcomes.

"A better understanding of the neural substrates for cognitive&ndashmotor dissociation could identify neurotransmitter systems as targets to restore behavioral responsiveness," they added.

This study was supported by the Dana Foundation and the James S. McDonnell Foundation.


The mental health effects of having Covid

While most people are dealing with more mental health issues than usual during the pandemic, the anxiety and stress that come with a Covid diagnosis is significant, even for those who recover.

Researchers wrote that the prevalence of mental health conditions among Covid survivors "reflects, at least partly, the psychological and other implications of a Covid-19 diagnosis rather than being a direct manifestation of the illness."

Previous research from the same group at Oxford found that people who were diagnosed with Covid were more likely to be diagnosed with a mental health issue than people coping with other health issues during the pandemic. For example, those recovering from Covid-19 were twice as likely to be diagnosed with a mental health disorder as compared with someone who had the flu.

Almost 20% of Covid patients who recovered were diagnosed with a mental illnesses within three months.

Harrison, the lead author for both studies, said that the findings lay bare the need for mental health services for the large number of people who may be experiencing symptoms.



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