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


Study Cohort and Patients' Cognitive Status Over Time

Among 2,301 patients with a diagnosis of COVID-19 between March 1, and May 12, 2020, 270 patients (11.7 %) were admitted to the ICU. Among those, 141 patients (61.3%) were intubated and mechanically ventilated and therefore included in this study. One-hundred fourteen mechanically ventilated COVID-19 patients (80.9%) were matched with 228 non–COVID-19 ARDS patients (eFigure 1, Table 1 shows baseline characteristics at the time of initiation of mechanical ventilation and standardized difference after matching. Figure 1 shows the cumulative frequency of death or extubation in each study group over 28 days, as well as the cognitive status during mechanical ventilation for patients in each study group.

Figure 1.

Cumulative frequency of survival and extubation, and patients' cognitive function during mechanical ventilation in patients with coronavirus disease 2019 (COVID-19) and non–COVID-19-related acute respiratory distress syndrome (ARDS). The cumulative proportion of subjects who died (gray bars) and those who were successfully extubated (white bars) are shown over time. Death substantially differed between patients with and without COVID-19–related ARDS. The shaded areas between the gray and white bars represent the Richmond Agitation Sedation Score (RASS): coma (dark blue, RASS ≤ −3), arousable (blue, −3 < RASS ≤ −1), alert (light blue, −1 < RASS ≤ +1), and agitated (pink, RASS > +1) stage. Patients with COVID-19–related ARDS were more likely to be in a comatose state and had higher in-hospital mortality. + p < 0.05 for higher in-hospital mortality. # p < 0.05 for lower ventilator-free days. $ p < 0.05 for higher percentage of coma during the first 10 d of mechanical ventilation.

Primary and Secondary Outcomes

COVID-19 patients experienced a higher percentage of coma during the first 10 days of mechanical ventilation (66.0% ± 31.3%) compared with non–COVID-19 patients (36.0% ± 36.9%). This result was confirmed in an adjusted analysis (adjusted coefficient [aCoef], 29.34; 95% CI, 21.45–37.24; p < 0.001). Mediation analysis revealed that COVID-19 patients experienced a significantly higher percentage of coma, which in turn was significantly associated with in-hospital mortality (adjusted odds ratio [aOR], 5.84; 95% CI, 3.56–9.58; p < 0.001). 58.6% of the effect of COVID-19 on in-hospital mortality was mediated through the indirect effect of coma (aOR, 1.57; 95% CI, 1.22–2.00; p < 0.001). The direct effect of COVID-19 diagnosis on mortality was insignificant (aOR, 1.37; 95% CI, 0.87–2.15; p = 0.17) (eFigure 2,

Hypnotic Agent Dose and use of Sedative Medications. The hypnotic agent dose was higher in COVID-19 patients (51.3% ± 20.6% vs 17.1% ± 12.5%) (p < 0.001). The hypnotic agent dose was associated with the percentage of coma (aCoef, 0.61; 95% CI, 0.45–0.78; p < 0.001). Mediation analysis demonstrated that 52.0% of the effect of COVID-19 diagnosis on coma was mediated through the indirect effect of hypnotic agent dose (aOR, 3.08; 95% CI, 1.62–5.83; p = 0.001) (eFigure 3,

During mechanical ventilation, opioids were the most commonly used medications. There was no significant difference in the numbers of patients receiving opioids between COVID-19 and non–COVID-19 patients (112 [98.2%] vs 214 [93.9%]; p = 0.07). However, the duration of treatment was significantly longer in COVID-19 patients (10.1 ± 5.7 vs 5.6 ± 4.7 d; p < 0.001). COVID-19 patients received a higher proportion of sedative medications and higher doses for a longer time (Table 2) (eTable 3, The SBI was significantly higher during the first 10 days of mechanical ventilation in COVID-19 patients (p < 0.001) along with a higher percentage of patients who were comatose (Figure 2).

Figure 2.

Daily mean Pao2:FIO2 (P/F) ratio, percentage of patients in coma and the Sedation Burden Index (SBI). A, Daily mean P/F ratio. B, Daily percentage of patients in a comatose state. Daily percentage of patients in a comatose state defined as Richmond Agitation Sedation Score less than or equal to −3. C, Daily drug burden index. SBI was calculated for an individual by summing the burdens from every sedative medication used on that day, using the equation: ., where D is the drug dose taken, and d is the minimum recommended daily dose. *p < 0.05. COVID-19 = coronavirus disease 2019.

Neurologic Consultation and Brain Imaging. Brain imaging was performed in 36 patients (31.6%) with COVID-19 and 100 patients (43.9%) without COVID-19. Results from neuroimaging reports revealed that patients with and without COVID-19 were not significantly different in terms of pathologic brain lesions (p = 0.76). Seven COVID-19 patients (6.1%) suffered a stroke (3 ischemic and 4 hemorrhagic), and 16 non–COVID-19 patients (7.0%) had pathologic brain lesions (8 ischemic stroke, 4 hemorrhagic stroke, 4 severe cerebral edema). The proportional hazards ratio was not significantly different between sedation-related coma versus coma that was accompanied by an additional neurologic injury (adjusted hazard ratio, 1.34; 95% CI, 0.69–2.59; p = 0.38) (eFigure 4,

Sensitivity and Exploratory Analyses

The primary results were confirmed throughout all sensitivity analyses. In the complete, unselected cohort of all ARDS patients (n = 3,201) (eTable 1,, COVID-19 patients experienced a higher percentage of coma (aCoef, 35.00; 95% CI, 29.25–40.70; p < 0.001), which in turn was significantly associated with in-hospital mortality (aOR, 3.57; 95% CI, 2.97–4.30; p < 0.001). The effect of COVID-19 on in-hospital mortality was mediated through the indirect effect of coma (p < 0.001). Details of sensitivity analyses are provided in the supplementary document, section 4 (

Effect Modification and Subgroup Analysis in Patients who Received NMBAs and Prone Positioning

When considering the effect of adjunctive treatments on the use of sedative medications, an effect modification by prone positioning was observed (p for interaction = 0.04) but not with NMBA use (p for interaction = 0.12). However, a diagnosis of COVID-19 was associated with an increase of hypnotic agent dose in all subgroups of patients (eTable 5,

Trend in ARDS Treatment

When comparing the common adjunctive therapies used in the management of ARDS prior to and during the COVID-19 pandemic, we found that prone positioning and NMBA use increased during the COVID-19 period (March to May 2020) (48.2% vs 3.5% and 56.1% vs 23.2%, respectively; p < 0.001). Doses and number of sedative and analgesic medications also increased (Figure 3) (eTable 3,

Figure 3.

Trends in acute respiratory distress syndrome (ARDS) treatment prior to and during the coronavirus disease 2019 (COVID-19) pandemic. Our COVID-19 treatment period began in March 2020. The average daily sedative medication dose used per patient increased during the COVID-19 pandemic period (*p < 0.001). **p < 0.05 for high medication dose in a patient with COVID-19 compared with a non–COVID-19 ARDS patient.

Delirium-free Days

Within 28 days, COVID-19 patients had a significantly lower median number of days alive without delirium or coma (delirium-free days) compared with non–COVID-19 patients (median [IQR] = 11 [1–19] vs 21 d 5–25 d; absolute incidence rate ratio, 0.64; 95% CI, 0.49–0.83; adjusted difference, −6.5 d; p = 0.001).