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The Reason for Cautious Optimism in Recovery of Intubated COVID-19 Patients

Article In Brief

The findings of two prospective studies show that, in the absence of structural brain injury, patients who were sedated and intubated during the first wave of the COVID-19 pandemic did recover and improve. They just needed more time and supportive care.

Two large studies of patients hospitalized during the first wave of the COVID-19 pandemic have found recovery rates that were mostly reassuring and, in some cases, surprising.

The first study, published online ahead of print on March 7 in the Annals of Neurology, involved 795 patients who required endotracheal intubation for at least seven days. For the 571 patients who eventually recovered command following, the median time to recovery was far longer than is usual for patients with other illnesses requiring intubation: 30 days. Even so, nearly half of those who did recover were discharged home or sent to a rehabilitation facility.

The authors and other neurocritical-care neurologists said the findings show that in the absence of structural brain injury, physicians and families should remain cautiously optimistic when COVID-19 patients who required intubation and sedation take more than the usual amount of time to awaken.

The other study, published online ahead of print on March 21 in Neurology, followed the trajectories of neurologic recovery in 174 patients who had been hospitalized for COVID-19 and completed both six- and 12-month follow-ups. Its most worrisome finding was that at 12 months, 87 percent of patients still had at least one ongoing abnormality in functional, cognitive, emotional, or quality-of-life metrics. In particular, half were still experiencing abnormal cognition, despite having had no prior history of cognitive abnormality.

On the bright side, however, the same study found that 56 percent of patients showed significant improvement in cognitive scores from the six-month to 12-month marks, while 45 percent significantly improved over that period on a measure of anxiety.

Another surprisingly welcome finding was that encephalopathy or other neurologic complications during hospitalization did not increase the likelihood of having cognitive, emotional or other dysfunctions at 12 months compared to those who did not have any neurological complications during hospitalization, except for increased scores on a measure of fatigue.


“What surprised me is that so many of these people actually got better. These were all hospitalized patients, most of them very, very sick. These papers are giving a related message: that patients can improve, and you just need to give them time and supportive care. Thats a very important message to convey to physicians.”—DR. AVINDRA NATH

“That's encouraging,” said the first author of that study, Jennifer Frontera, MD, professor of neurology in the division of neurocritical care and stroke at New York University's Grossman School of Medicine. “The fact that there was significant improvement from six to 12 months suggests that neurodegeneration is not at play, at least in the majority of patients.”

Panayiotis N. Varelas, MD, PhD, FAAN, FNCS, president of the Neurocritical Care Society, who was not involved with either paper, told Neurology Today that the two studies, together, were “amazing.”

“These studies answer two major questions that we get in the ICU when we talk with the families of patients,” said Dr. Varelas, who is also professor and chair of the department of neurology at Albany Medical College. “One is, for patients who are in a coma: Is our relative going to wake up, doctor? The other question is: Will they be exactly as they were before, or are you expecting any deficits?”

Prolonged Recovery from Unconsciousness

Data for the study on prolonged unconsciousness in COVID-19 patients came from three medical centers in New York and Boston during the first wave of the pandemic, from March to July of 2020: NewYork-Presbyterian Hospital/Columbia University Irving Medical Center, Massachusetts General Hospital, and New York-Presbyterian Hospital/Weill Cornell Medical College.

The retrospective cohort study involved 795 patients who were admitted to one of the three hospitals during the study period with severe COVID-19 requiring intubation for at least seven days, and who had an impairment of consciousness (Glasgow Coma Scale motor score <6). Nearly one-third of the cohort, 224 patients, never recovered the ability to follow commands.


“The fact that there was significant improvement from six to 12 months suggests that neurodegeneration is not at play, at least in the majority of patients.”—DR. JENNIFER FRONTERA

The median 30-day time to recovery of command-following for the remaining 571 patients was measured from the time of intubation. Even from the time that mechanical ventilation was ended, one-fourth of the patients took at least 10 days to recover.

A key variable in those who recovered and those who did not was the incidence of hypoxemia. The time to recovery of command following, for instance, increased by 16 days for patients with at least one episode of an arterial partial pressure of oxygen (PaO2) ≤55mmHg (p<0.001), and each additional day of hypoxemia decreased the likelihood of recovery.

The findings on recovery time were confirmed in a subgroup analysis of 322 patients for whom imaging by CT or MRI was available; 199 of those in the subgroup had no evidence of structural brain injury. The findings were additionally confirmed in a second cohort of 427 patients during the second surge, between October of 2020 and April of 2021.

“Prolonged time to recovery of command-following, as observed in our study, should be considered in goals-of-care discussions between clinicians and surrogate decision-makers,” the paper concluded. “Our results indicate that most survivors of severe COVID-19 recover command-following, but that recovery may occur beyond 30 days and may be days or weeks after patients no longer require mechanical ventilation. Our results highlight the need for a cautious approach to neuroprognostication in patients with severe COVID-19. Decisions to withdraw life-sustaining therapies should not be based solely on prolonged periods of unconsciousness, as patients may harbor prospects for recovery. Importantly, the degree of functional recovery remains unknown and warrants further investigation.”

“The data speaks for itself,” said a senior author of the paper, Nicholas D. Schiff, MD, the Jerold B. Katz Professor of Neurology and Neuroscience at Weill Cornell Medicine. “People can take an incredibly long time to recover consciousness after successful COVID-19 treatment. You have to be very cautious about withdrawing life support.”

Dr. Schiff said the mechanism by which neurons remain quiescent for such a lengthy period remains unknown. “It's hard to understand what's going on,” he said, “but there seems to be a neuroprotective effect in these patients comparable to when hypothermia protects against anoxia.”

Follow-Up Through 12 Months

Dr. Frontera and colleagues conducted a prospective, longitudinal cohort study of patients with and without neurologic complications during hospitalization for COVID-19. They followed up at six and 12 months by calling patients and conducting the modified Rankin Scale (mRS); the Barthel Index of Activities of Daily Living; the telephone Montreal Cognitive Assessment (t-MoCA); and Neuro-QoL batteries for anxiety, depression, fatigue, and sleep.

The study included patients hospitalized for COVID-19 who completed the 12-month follow-ups. The median age was 65, males accounted for 64 percent, and 34 percent were intubated (in contrast to the other study, in which all patients were intubated). Although 242 patients completed the 12-month follow-up, only 174 of them also had completed the six-month follow-up.

At the one-year mark, 87 percent had more than one abnormal metric, consisting of either an mRS score greater than zero (75 percent), a Barthel Index less than 100 (64 percent), a t-MoCA score of 18 or less (50 percent), high anxiety (7 percent), depression (4 percent), fatigue (9 percent), or poor sleep (10 percent).

Although the study had been designed specifically to compare the effect of having or not having a neurologic complication during hospitalization, it found that the 12- month mRS scores did not differ significantly among them after adjusting for age, sex, race, pre-COVID mRS, and intubation status (adjusted OR 1.4). Those with neurologic complications, however, did have severe fatigue scores (T-score 47 versus 44, p=0.037).

The researchers observed significant improvements—from the time of the six-month follow-up to the 12-month follow-up—in the t-MoCA scores (56 percent with a median improvement of one point on the scale, p=0.002). The Neuro-QoL anxiety scores also improved among 45 percent (p=0.003). Other non-significant improvements also occurred in fatigue (48 percent), sleep (48 percent), and depression (38 percent). Barthel and mRS scores remained unchanged in half of the patients.

Dr. Frontera said she was surprised that such a high proportion of patients still had at least one abnormality a full year after being discharged from the hospital, even though two-thirds of the patients had not been sick enough to require ventilation.

“These are people who were capable of completing the batteries,” she said. “The people in nursing homes couldn't complete these assessments. I would have expected fewer than 87 percent would still have abnormalities on objective testing at 12 months.”

Expert Commentary

Avindra Nath, MD, FAAN, senior investigator in the section of infections of the nervous system at the National Institute of Neurological Disorders and Stroke, said he was not surprised that most of the patients in Dr. Frontera's study still had deficits a year later.

“What surprised me is that so many of these people actually got better,” he said. “These were all hospitalized patients, most of them very, very sick.”

Together with the study from Dr. Schiff and colleagues, he added, “These papers are giving a related message: that patients can improve, and you just need to give them time and supportive care. That's a very important message to convey to physicians.”


“These studies answer two major questions that we get in the ICU when we talk with the families of patients. One is, for patients who are in a coma: Is our relative going to wake up, doctor? The other question is: Will they be exactly as they were before, or are you expecting any deficits?”—DR. PANAYIOTIS N. VARELAS

Sherry H-Y Chou, MD, associate professor of neurology and chief of neurocritical care at Northwestern University, told Neurology Today that both papers were “fantastic.”

“Some people may say that these studies look back at the first wave of COVID-19, and that the world has changed with the treatments and vaccines we now have,” Dr. Chou said. “I don't think so. Given the low vaccination rate we have in many parts of the country and around the world, severe COVID-19 will remain relevant for the foreseeable future.”

Regarding the paper by Dr. Schiff and colleagues on recovery times in patients who were intubated, Dr. Chou said she was surprised that so many of the patients were discharged to home even after weeks of prolonged unconsciousness.

“They found it took a month on average before these people started to wake up and follow commands,” she said. “These were 60-year-old people. If you are intubated for seven days and then it takes you another three weeks to wake up and follow commands, the fact that a good number of them went home at discharge is very impressive. I would have thought the number would be close to zero. What I learn from this paper, as a neuro-intensivist, is that if I consult with another COVID-19 patient who is not responsive for days and weeks after they come off mechanical ventilation, I will tell their families exactly what this paper found: it may take a long time for them to wake up.”

Dr. Chou said she would advise all neurologists consulting on such cases to be cautious in how they prognosticate such patients.

“If we had a very pessimistic view of these patients and we told their families they won't wake up, many of these patients may end up dead,” she said.

Dr. Varelas expressed a similar point of view. “Fourteen days is usually the timeframe within which we have to finalize goals-of-care discussions with families, for example whether to proceed with tracheostomy and percutaneous feeding tube placement,” he said. “Based on this data, you can tell families that the patient has quite a successful chance to wake up but may need more time.”


“They say that people can take an incredibly long time to recover consciousness after successful COVID-19 treatment. You have to be very, very cautious about withdrawing life support.”—DR. NICHOLAS D. SCHIFF

Dr. Varelas said he was impressed that Dr. Frontera's group had managed to conduct their study during the first wave of the COVID-19 pandemic.

“When we were all extremely busy and exhausted, they had the vision to create a study like this and follow these patients longitudinally,” he said. “That is astonishing, and at the same time very useful. Now we have data out to 12 months.”

While half of the patients at 12 months still had abnormal cognition based on the t-MoCA, Dr. Varelas pointed out that the telephone measure spans just 22 points, whereas the in-clinic tool has 30.

“The t-MoCA is not the most sensitive measure of cognitive status,” he said. “If other neuropsych tests had been performed, the numbers might have been even higher than 50 percent.”

Even so, Dr. Varelas said the study does reveal a light at the end of the tunnel. “The patient showed almost 50 percent less fatigue and sleep disturbance, 38 percent less depression, and 45 percent less anxiety at 12 months compared to six months,” he said. “Except for the Barthel and mRS, all these metrics were better at 12 months. That's something our patients and their families will be happy to hear.”

Link Up for More Information

• Waldrop G, Safavynia SA, Barra ME, et al. Prolonged unconsciousness is common in COVID-19 and associated with hypoxemia Ann Neurol 2022; Epub 2022 Mar 7.
    • Frontera JA, Yang D, Medicherla C, et al. Trajectories of neurologic recovery 12 months after hospitalization for COVID-19: A prospective longitudinal study Neurology 2022;Epub 2022 Mar 21.
      • Nersesjan V, Fonsmark L, Christensen RHB, et al. Neuropsychiatric and cognitive outcomes in patients 6 months after COVID-19 requiring hospitalization compared with matched control patients hospitalized for non-COVID-19 illness{DEFAULT_BOOST_FUNCTION}%22Neuropsychiatric%20and%20cognitive%20outcomes%20in%20patients%206%20months%20after%20COVID%20-19%20requiring%20hospitalization%20compared%20with%20matched%20control%20patients%20hospitalized%20for%20non-COVID%20-19%20illness%22&exPrm_hl.q=Neuropsychiatric%20and%20cognitive%20outcomes%20in%20patients%206%20months%20after%20COVID%20-19%20requiring%20hospitalization%20compared%20with%20matched%20control%20patients%20hospitalized%20for%20non-COVID%20-19%20illness. JAMA Psychiatry 2022; Epub Mar 23.