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New research by Sam Parnia, MD, PhD, associate professor of medicine and director of critical care and resuscitation research at �ٺ���Ƶ, is aiming to create measurements and methods to better capture end-of-life phenomena such as cognitive lucidity and to identify novel approaches to enhance the quality of resuscitation after cardiac arrest.

Deciphering Paradoxical Lucidity in Terminal Patients

Over the past two decades, Dr. Parnia has led pioneering research into the recalled experiences of death, particularly among survivors of cardiac arrest. The groundbreaking AWARE (AWAreness during REsuscitation) I and AWARE II studies from the closely examined the experiences of hundreds of patients with cardiac arrest who had biologically crossed over the threshold of death before being resuscitated. Among the many intriguing findings, many survivors reported lucid and well-structured thought processes. They described seeing deceased relatives and reviewing their actions and intentions toward others throughout their lives, and afterward, many recalled details of their resuscitation.

The lab’s compelling research caught the eye of the National Institutes of Health, which has recognized a similar but poorly understood phenomenon among patients with advanced dementia called paradoxical lucidity (PL). Caregivers have routinely reported that such patients begin to have unexpected periods of cognitive clarity and verbal communication, particularly near the end of life. “The common unresolved question for both of these areas of research is how do you have lucidity at a time when the brain is assumed to not be functioning?” Dr. Parnia says. “A major subgroup of people who go through this have had advanced end-stage dementia and maybe have had no lucidity for years.”

Under a five-year grant from the National Institute on Aging, Dr. Parnia and colleagues are aiming to create the first-ever definition and measurement scale for the PL phenomenon. “The downstream effect of this is that we might be able to identify new pathways for lucidity in patients with dementia. We may also be able to find new ways to treat disorders of consciousness as well as better understand the cognitive experience of death, what it’s like to approach death,” he says. “So it could further multiple goals.”

For the study, Dr. Parnia’s group will collaborate with �ٺ���Ƶ experts in geriatrics and dementia, including Joshua Chodosh, MD, the Michael L. Freedman Professor of Geriatric Research and professor of population health, and Lindsey J. Gurin, MD, assistant professor of neurology, psychiatry, and rehabilitation medicine. Multiple experts from other institutions, including the Visiting Nurse Service of New York’s hospice services, will also participate. Together they will track about 500 terminally ill patients who have dementia and a life expectancy of 1 week or less. The researchers will connect each to an in-home video electroencephalography (EEG) device, which measures electrical activity in the brain and simultaneously records video and audio of the patient. “We’re going to be monitoring these people, so if we see a sign that looks like paradoxical or terminal lucidity, we can capture what it’s like visually and auditorily, and also in terms of the underlying brain biomarkers that no one has ever understood,” Dr. Parnia says. In addition, the novel study will ask caregivers to a fill out a symptom diary of their observations and record the instances they think are suggestive of PL in their loved ones.

Finally, the collaborators will examine the EEG measurements to assess whether any electrocortical biomarkers correspond to brain activity before, during, or after a period of PL. Some data suggest these lucid episodes may correlate with surges in electrocortical activity, which could offer mechanistic insights and biological plausibility for PL in severe dementia. “That may be significant because if we could find some structural change, then we might be able to use that as a novel therapeutic target for people who regularly have dementia, or other disorders of consciousness, by trying to activate that circuit and maybe give them more lucidity,” Dr. Parnia says.

Fine-Tuning Physiological Feedback to Improve CPR Outcomes

Although the development of cardiopulmonary resuscitation (CPR) revolutionized emergency medicine by allowing patients with cardiac arrest to be resuscitated within 5 or 10 minutes of death, Dr. Parnia says the lifesaving technique has advanced little over the past 60 years. Cardiac arrest survival rates haven’t improved in decades, and anoxic brain injury remains a major health burden for those who survive to hospital discharge.

“One of the problems with the way it’s currently practiced is that physicians usually don’t have biomarkers to guide their treatment and just use one approach—advanced cardiac life support—for everyone,” says Dr. Parnia. Although an accelerometer can measure a patient’s chest movements during CPR compressions, Dr. Parnia and other researchers believe this measurement provides only a rough gauge of the quality of the intervention. “What we need to do is to find a navigation system that provides data to the practitioners in real time that tells them how much blood and oxygen is getting into the brain and how effective their treatments are,” he says.

The Parnia Lab has pioneered the use of noninvasive brain monitoring of regional cerebral oxygenation (rSO2) using near-infrared spectroscopy, and of end-tidal carbon dioxide (ETCO2) as sensitive physiological markers of circulation quality and perfusion to the brain and vital organs during CPR. A new trial funded by the National Heart, Lung, and Blood Institute is building on that work with a study of more than 500 in-hospital patients with cardiac arrest to better understand the optimal physiological resuscitation target for reducing ischemic injuries and for predicting survival and the possible level of brain damage.

For the multidisciplinary project, Dr. Parnia will collaborate with neurologists and intensive care unit (ICU) specialists at �ٺ���Ƶ. “Our overall hypothesis is that with a better-quality resuscitation, we’d expect to see less biomarkers of brain injury,” he says. In addition, the study will analyze how different levels of brain oxygen delivered during a cardiac arrest resuscitation influence biomarkers of brain injury and inflammation in patients in the ICU. “If a patient’s oxygen levels during cardiac arrest stay above a certain threshold, how much brain injury does the patient suffer, or what can we measure in terms of brain injury biomarkers in the first few days in the ICU?” Dr. Parnia explains.

Once the researchers have identified a brain resuscitation “gold standard,” Dr. Parnia aims to launch a randomized controlled trial of 150 patients. The trial, he says, will compare the outcomes of patients who receive conventional CPR with those who receive CPR directed by this research’s suggested feedback. “What’s novel about our study is that we’re using a physiological target that reflects what’s happening inside the body in real time, as opposed to more artificial, movement-based feedback,” he says. If successful, the research could help clinicians take another big step in improving both survival and neurological outcomes of patients with cardiac arrest.