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


Patients with COVID-19 had a higher risk of in-hospital mortality and experienced a higher percentage of coma during mechanical ventilation compared with patients with ARDS from other etiologies—even after controlling for markers of comorbidities (including markers of heart, renal and liver failure) and ARDS severity (P/F ratio, A-a gradient, PaCO 2, pH, and minute ventilation). Coma was identified as a mediator of in-hospital mortality in patients with COVID-19.

COVID-19 is associated with neurologic disturbances and complications including impaired consciousness and stroke.[22,23] In our COVID-19 cohort, clinicians were concerned about a possible nonpharmacologic mechanism of coma in approximately one third of patients to the extent that they requested formal neurologic consultation and brain imaging. Neurologic workup revealed a frequency of stroke confirmed by neuroimaging of 6.1%, which was not different from the 7.0% observed in non–COVID-19 patients.

In our study, patients with COVID-19–associated ARDS received substantially higher doses of hypnotics than patients with ARDS of other etiology, which explained the higher occurrence rate of coma based on our association analysis. Higher utilization of analgesics and hypnotics in mechanically ventilated patients with ARDS due to COVID-19 compared with other etiologies has been reported previously.[24,25] The reasons for the higher requirements are multifactorial: First, based on early treatment suggestions for COVID-19 patients, clinicians opted for prone position therapy more often compared with patients with ARDS of other etiology (48.2 vs 3.5%; p < 0.001). NMBAs were used in most proned patients, which was accompanied by deep sedation targets according to a recommendation.[26] NMBA infusions and deep sedation may have been maintained unnecessarily during the periods when the patients were returned to the supine position. We have previously shown that a long duration of deep sedation after termination of neuromuscular blockade is associated with increased mortality.[27]

Second, more long-acting sedatives, such as benzodiazepines, were used in COVID-19 patients, which was likely related to national drug shortage reports. On April 10, 2020, propofol and dexmedetomidine were included in the U.S. Food and Drug Administration list of drug shortages.[28] In response, our institute issued a document to recommend alternative sedative agents, including benzodiazepines, to be considered during the pandemic drug shortage period. With differences in pharmacokinetic properties such as longer context-sensitive half-life than propofol, benzodiazepines and their metabolites can persist long after infusions are stopped and therefore may cause oversedation.[29]

Third, previous publications suggested that patients with COVID-19 can present with different phenotypes, one of which is high ventilatory drive (high dead space and shunt) despite good compliance.[25,30,31] It is possible that clinicians used higher doses of hypnotic agents to protect their patients with COVID-19 from self-inflicted lung injury. This hypothesis is supported by our finding that patients with COVID-19 received higher hypnotic agent doses and paralytics more frequently, resulting in lower minute ventilation compared with patients with ARDS of other etiology. Finally, in order to mitigate the risk of viral spreading across healthcare providers and patients, strict infection control protocols, including isolation of patients, personal protective equipment, and respiratory protection, were recommended.[32] Deep and prolonged sedation may have been unintended consequences. Maintaining deep sedation may also be anxiety driven; ICU staff may have been focused on the prevention of patients' self-extubation more for patients who tested positive for COVID-19.

Mediation analysis demonstrated a strong relationship between coma and increased in-hospital mortality. Expectedly, we found that a longer period of sedation was associated with a higher occurrence rate of delirium, which could have contributed to the effects of sedation on mortality. Our findings are supported by previous studies demonstrating that deep sedation or coma lead to immobilization, delirium, delays in extubation, and delays in ICU discharge.[33–35] Such delays increase the risk of nosocomial infections and other complications that can contribute to mortality.[36] Current sedation guidelines and sedation bundles should be considered and applied when possible.[37,38]

Our study is the largest cohort study investigating sedative drug usage and cognitive function in mechanically ventilated COVID-19 patients. We also have a highly detailed and granular database of non-COVID ARDS patients, with which we were able to compare characteristics, clinical practice, and outcomes.

However, several limitations arise from the retrospective design of our study. First, although we matched patients based on most relevant factors such as heart, liver, and renal failure at admission, as well as severity of ARDS, we cannot exclude the relevance of unmeasured confounders. Second, to the best of our knowledge, there is no robust way to combine the effects of different drug compounds. We adapted the drug burden index as a SBI to compare the effect of summative analgesic and sedative doses in critically ill patients.[39–41] We cannot identify the cause of high sedative medication needs, even though we controlled for all available variables that affect respiratory drive (P/F ratio, A-a gradient, PaCO2, pH, and minute ventilation). Finally, it is possible that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may have had direct effects on the brain which could not be identified by CT imaging. Leukoencephalopathy is a rare CNS complication in SARS-CoV-2 which cannot be diagnosed with a CT,[42] and it is possible that patients who were identified as not having a structural neurologic disease had an unidentified leukoencephalopathy.