Many patients with severe COVID-19 recover consciousness, but recovery can take days or even weeks

The study, which is published in the Annals of Neurology, involved a retrospective analysis of 795 patients with severe COVID-19 who were treated with mechanical ventilators in the intensive care units of the investigators' medical centers for at least six days. After respiratory support ended, clinicians performed daily assessments to see whether patients could respond purposefully to a verbal command, a standard measure of consciousness.

Of the 795 patients, 72% survived and ultimately recovered consciousness prior to hospital discharge. For those who survived, 25% recovered consciousness 10 or more days after ventilator support was stopped, and 10% took more than three weeks to recover.

"When we examined the potential causes of delayed recovery of consciousness, we found that low blood oxygen levels correlated with the time to recovery, even after accounting for other factors such as exposure to sedatives," says co-senior author Brian L. Edlow, MD, associate director of the Center for Neurotechnology and Neurorecovery at MGH and associate professor of neurology at Harvard Medical School. "This relationship was dose-dependent -- the more episodes of low blood oxygen that a patient experienced, the longer it took them to wake up."

Most patients had normal brain scans, suggesting that the prolonged time to recover consciousness was not related to stroke, swelling, or bleeding in the brain. "These observations were consistent across all three medical centers and during the first and second surges of the COVID-19 pandemic," says Jan Claassen, MD, a co-leader of the study and associate professor of neurology at Columbia University Vagelos College of Surgeons and Physicians.

Additional research is needed to understand the mechanisms behind the link between low blood oxygen levels and prolonged time to recover consciousness. "We've seen similar phenomena in rare patients with cardiac arrest who were treated with hypothermia," says Nicholas D. Schiff, MD, a co-leader of the study and the Jerold B. Katz Professor of Neurology and Neuroscience in the Feil Family Brain and Mind Research Institute and co-director of the Consortium for the Advanced Study of Brain Injury (CASBI) at Weill Cornell Medicine and an attending neurologist at NewYork-Presbyterian/Weill Cornell Medical Center. "Hypothermia appears to protect cardiac arrest patients from neurological damage in ways we still don't understand. We're now moving forward with studies aimed at uncovering common underlying mechanisms of neuroprotection that might connect these two groups of patients."

Regardless of the underlying mechanisms yet to be uncovered, the study's results could have an immediate clinical impact. "These findings provide us with more accurate information to guide families who are deciding whether to continue life-sustaining therapy in unconscious COVID-19 patients," says Edlow. "The fact that delayed recovery of consciousness was consistently seen at three different medical centers, across two surges of COVID-19, suggests that we should consider the possibility of delayed recovery when making life-of-death decisions for these patients in the intensive care unit."

The results may also be applied to critically ill patients with other medical conditions. "We are trying to determine whether the lessons learned from patients with severe COVID-19 can inform our approach to oxygenation targets and sedation management in the intensive care unit for the broad spectrum of patients who require mechanical ventilation," says co-author Emery N. Brown, MD, PhD, professor of anesthesia at Harvard Medical School, anesthesiologist at MGH, and professor of medical engineering and computational neuroscience at Massachusetts Institute of Technology.

Co-first author Megan E. Barra, PharmD, a clinical pharmacy specialist in neurocritical care at MGH, notes that additional research is also needed to determine the degree of functional recovery in patients with COVID-19 or other conditions who experience prolonged unconsciousness after ventilator support is stopped. "We did not look at long-term recovery of cognition or functional independence in our study, but this is an important consideration for patients and their families," she says.

Additional study co-authors include Greer Waldrop, MD, ScM; Seyed A. Safavynia, MD, PhD; Sachin Agarwal, MD, MPH; David A. Berlin, MD; Amelia K Boehme, PhD, MSPH; Daniel Brodie, MD; Jacky M. Choi, MPH; Kevin Doyle, MA; Joseph J. Fins, MD; Wolfgang Ganglberger, MSc; Katherine Hoffman, MS; Aaron M. Mittel, MD; David Roh, MD; Shibani S. Mukerji, MD, PhD; Caroline Der Nigoghossian, PharmD,; Soojin Park, MD; Edward J. Schenck, MD; John Salazar-Schicchi, MD; Qi Shen, PhD; Evan Sholle, MS; Angela G. Velazquez, MD; Maria C. Walline, MD; M. Brandon Westover, MD, PhD; Jonathan Victor, MD, PhD.

The study was supported by the James S. McDonnell Foundation.