Large study finds higher burden of acute brain dysfunction for COVID-19 ICU patients

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COVID-19 patients admitted to intensive care in the early months of the pandemic were subject to a significantly higher burden of delirium and coma than is typically found in patients with acute respiratory failure. Choice of sedative medications and curbs on family visitation played a role in increasing acute brain dysfunction for these patients. That's according to an international study led by researchers at Vanderbilt University Medical Centre in coordination with researchers in Spain.

The study, which is far the largest of its kind to date, tracks the incidence of delirium and coma in 2,088 COVID-19 patients admitted before 28 April, 2020, to 69 adult intensive care units across 14 countries.

ICU delirium is associated with higher medical costs and greater risk of death and long-term ICU-related dementia. Seminal studies at VUMC over the past two decades have spurred widespread interest in ICU delirium research, and the resulting body of evidence has come to inform critical care guidelines endorsed by medical societies in several countries. These guidelines include well calibrated pain management with prompt discontinuation of analgesics and sedatives, daily spontaneous awakening trials, daily spontaneous breathing trials, delirium assessments throughout the day, early mobility and exercise, and family engagement.

Some 82% of patients in this observational study were comatose for a median of 10 days, and 55% were delirious for a median of three days. Acute brain dysfunction (coma or delirium) lasted for a median of 12 days.

"This is double what is seen in non-COVID ICU patients," said VUMC's Brenda Pun, co-first author on the study with Dr Rafael Badenes, of the University of Valencia in Spain. The authors cite a previous large, multi-site ICU study, also led by VUMC, where acute brain dysfunction lasted a median of five days, including four days of coma and one day of delirium.

The authors note that COVID-19 disease processes could predispose patient to a higher burden of acute brain dysfunction. But they also note that a number of patient care factors, some of which are related to pressures posed on health care by the pandemic, also appear to have played a significant role.

The study appears to show a reversion to outmoded critical care practices, including deep sedation, widespread use of benzodiazepine infusions (benzodiazepine is a nervous system depressant), immobilisation, and isolation from families. The authors find that, where COVID-19 is concerned, there has been an apparent widespread abandonment of newer clinical protocols that are proven to help ward off the acute brain dysfunction that stalks many critically ill patients.

"It is clear in our findings that many ICUs reverted to sedation practices that are not in line with best practice guidelines," Pun said, "and we're left to speculate on the causes. Many of the hospitals in our sample reported shortages of ICU providers informed about best practices. There were concerns about sedative shortages, and early reports of COVID-19 suggested that the lung dysfunction seen required unique management techniques including deep sedation. In the process, key preventive measures against acute brain dysfunction went somewhat by the boards."

Using electronic health records, investigators were able to closely examine patient characteristics, care practices and findings from clinical assessments. Some 88% of patients tracked in the study were invasively mechanical ventilated at some point during hospitalization, 67% on the day of ICU admission. Patients receiving benzodiazepine sedative infusions were at 59% higher risk of developing delirium. Patients who received family visitation (in-person or virtual) were at 30% lower risk of delirium.

"There's no reason to think that, since the close of our study, the situation for these patients has changed," said one of the study's senior authors, Dr Pratik Pandharipande, professor of anaesthesiology.

"These prolonged periods of acute brain dysfunction are largely avoidable. Our study sounds an alarm: as we enter the second and third waves of COVID-19, ICU teams need above all to return to lighter levels of sedation for these patients, frequent awakening and breathing trials, mobilisation and safe in-person or virtual visitation."

Study details

Prevalence and risk factors for delirium in critically ill patients with COVID-19 (COVID-D): a multicentre cohort study

Brenda T Pun, Rafael Badenes, Gabriel Heras La Calle, Onur M Orun, Wencong Chen, Rameela Raman, Beata-Gabriela K Simpson, Stephanie Wilson-Linville, Borja Hinojal Olmedillo, Ana Vallejo de la Cueva, Mathieu van der Jagt, Rosalía Navarro Casado, Pilar Leal Sanz, Günseli Orhun, Carolina Ferrer Gómez, Karla Núñez Vázquez, Patricia Piñeiro Otero, Fabio Silvio Taccone, Elena Gallego Curto, Anselmo Caricato, Hilde Woien, Guillaume Lacave, Hollis R O'Neal Jr, Sarah J Peterson, Nathan E Brummel, Timothy D Girard, E Wesley Ely, Pratik P Pandharipande for the COVID-19 Intensive Care International Study Group

Published in The Lancet Respiratory Medicine on 8 January, 2021



To date, 750 000 patients with COVID-19 worldwide have required mechanical ventilation and thus are at high risk of acute brain dysfunction (coma and delirium). We aimed to investigate the prevalence of delirium and coma, and risk factors for delirium in critically ill patients with COVID-19, to aid the development of strategies to mitigate delirium and associated sequelae.

This multicentre cohort study included 69 adult intensive care units (ICUs), across 14 countries. We included all patients (aged ≥18 years) admitted to participating ICUs with severe acute respiratory syndrome coronavirus 2 infection before April 28, 2020. Patients who were moribund or had life-support measures withdrawn within 24 h of ICU admission, prisoners, patients with pre-existing mental illness, neurodegenerative disorders, congenital or acquired brain damage, hepatic coma, drug overdose, suicide attempt, or those who were blind or deaf were excluded. We collected de-identified data from electronic health records on patient demographics, delirium and coma assessments, and management strategies for a 21-day period. Additional data on ventilator support, ICU length of stay, and vital status was collected for a 28-day period. The primary outcome was to determine the prevalence of delirium and coma and to investigate any associated risk factors associated with development of delirium the next day. We also investigated predictors of number of days alive without delirium or coma. These outcomes were investigated using multivariable regression.

Between Jan 20 and April 28, 2020, 4530 patients with COVID-19 were admitted to 69 ICUs, of whom 2088 patients were included in the study cohort. The median age of patients was 64 years (IQR 54 to 71) with a median Simplified Acute Physiology Score (SAPS) II of 40·0 (30·0 to 53·0). 1397 (66·9%) of 2088 patients were invasively mechanically ventilated on the day of ICU admission and 1827 (87·5%) were invasively mechanical ventilated at some point during hospitalisation. Infusion with sedatives while on mechanical ventilation was common: 1337 (64·0%) of 2088 patients were given benzodiazepines for a median of 7·0 days (4·0 to 12·0) and 1481 (70·9%) were given propofol for a median of 7·0 days (4·0 to 11·0). Median Richmond Agitation–Sedation Scale score while on invasive mechanical ventilation was –4 (–5 to –3). 1704 (81·6%) of 2088 patients were comatose for a median of 10·0 days (6·0 to 15·0) and 1147 (54·9%) were delirious for a median of 3·0 days (2·0 to 6·0). Mechanical ventilation, use of restraints, and benzodiazepine, opioid, and vasopressor infusions, and antipsychotics were each associated with a higher risk of delirium the next day (all p≤0·04), whereas family visitation (in person or virtual) was associated with a lower risk of delirium (p<0·0001). During the 21-day study period, patients were alive without delirium or coma for a median of 5·0 days (0·0 to 14·0). At baseline, older age, higher SAPS II scores, male sex, smoking or alcohol abuse, use of vasopressors on day 1, and invasive mechanical ventilation on day 1 were independently associated with fewer days alive and free of delirium and coma (all p<0·01). 601 (28·8%) of 2088 patients died within 28 days of admission, with most of those deaths occurring in the ICU.

Acute brain dysfunction was highly prevalent and prolonged in critically ill patients with COVID-19. Benzodiazepine use and lack of family visitation were identified as modifiable risk factors for delirium, and thus these data present an opportunity to reduce acute brain dysfunction in patients with COVID-19.


Vanderbilt University Medical Centre material


The Lancet Respiratory Medicine study (Open access)

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