Association of Sedation, Coma, and In-Hospital Mortality in Mechanically Ventilated Patients With Coronavirus Disease 2019–Related Acute Respiratory Distress Syndrome

A Retrospective Cohort Study

Karuna Wongtangman, MD; Peter Santer, MD, DPhil; Luca J. Wachtendorf; Omid Azimaraghi, MD; Elias Baedorf Kassis, MD; Bijan Teja, MD, MBA; Kadhiresan R. Murugappan, MD; Shahla Siddiqui, MD; Matthias Eikermann, MD, PhD


Crit Care Med. 2021;49(9):1524-1534. 

In This Article

Abstract and Introduction


Objectives: In patients with coronavirus disease 2019–associated acute respiratory distress syndrome, sedatives and opioids are commonly administered which may lead to increased vulnerability to neurologic dysfunction. We tested the hypothesis that patients with coronavirus disease 2019–associated acute respiratory distress syndrome are at higher risk of in-hospital mortality due to prolonged coma compared with other patients with acute respiratory distress syndrome matched for disease severity.

Design: Propensity-matched cohort study.

Setting: Seven ICUs in an academic hospital network, Beth Israel Deaconess Medical Center (Boston, MA).

Patients: All mechanically ventilated coronavirus disease 2019 patients between March and May 2020 were identified and matched with patients with acute respiratory distress syndrome of other etiology.

Interventions: None.

Measurements and Main Results: Using clinical data obtained from a hospital registry, we matched 114 coronavirus disease 2019 patients to 228 noncoronavirus disease 2019–related acute respiratory distress syndrome patients based on baseline disease severity. Coma was identified using the Richmond Agitation Sedation Scale less than or equal to −3. Multivariable logistic regression and mediation analyses were used to assess the percentage of comatose days, sedative medications used, and the association between coronavirus disease 2019 and in-hospital mortality. In-hospital mortality (48.3% vs 31.6%, adjusted odds ratio, 2.15; 95% CI, 1.34–3.44; p = 0.002), the percentage of comatose days (66.0% ± 31.3% vs 36.0% ± 36.9%, adjusted difference, 29.35; 95% CI, 21.45–37.24; p < 0.001), and the hypnotic agent dose (51.3% vs 17.1% of maximum hypnotic agent dose given in the cohort; p < 0.001) were higher among patients with coronavirus disease 2019. Brain imaging did not show a higher frequency of structural brain lesions in patients with coronavirus disease 2019 (6.1% vs 7.0%; p = 0.76). Hypnotic agent dose was associated with coma (adjusted coefficient, 0.61; 95% CI, 0.45–0.78; p < 0.001) and mediated (p = 0.001) coma. Coma was associated with in-hospital mortality (adjusted odds ratio, 5.84; 95% CI, 3.58–9.58; p < 0.001) and mediated 59% of in-hospital mortality (p < 0.001).

Conclusions: Compared with matched patients with acute respiratory distress syndrome of other etiology, patients with coronavirus disease 2019 received higher doses of hypnotics, which was associated with prolonged coma and higher mortality.


Patients with coronavirus disease 2019 (COVID-19) can have neurologic manifestations, including acute cerebrovascular events and coma.[1–6] In patients with severe COVID-19 requiring admission to the ICU, coma occurs in approximately 15% of patients and is typically diagnosed during the second week of hospital admission.[2,5] Little is known about the etiology and the effect of coma in patients with COVID-19 presenting to an ICU for treatment of acute respiratory distress syndrome (ARDS).

During the COVID-19 pandemic, unprecedented numbers of patients have required sedation in the ICUs and other hospital locations due to prolonged ventilator dependence.[7] Although sedation is typically required to facilitate mechanical ventilation, deeper sedation levels may be favored by ICU staff to reduce the possibility of a patient's self-extubation, which carries an increased risk of exposing staff and other patients to COVID-19. Long-acting sedatives were also used more frequently due to impending national shortages of commonly used short-acting sedatives. Finally, clinicians might have favored deep sedation to allow tolerance of lung-protective ventilation strategies.

We tested the hypothesis that patients with COVID-19–associated ARDS compared with patients with ARDS due to other etiologies are at higher risk of increased in-hospital mortality. Contingent on this hypothesis, we also hypothesized that the association of COVID-19 and in-hospital mortality was mediated by a high percentage of comatose days as a consequence of deep sedation during mechanical ventilation.