From March 2 through July 30, 2020, we obtained behavioral assessments in 3203 of 10,797 patients admitted to the hospital who tested positive for SARS-CoV-2. Of those included, a total of 1623 (50.7%) were managed for part or all of their clinical course in an ICU and 1580 (49.3%) were treated in a non-ICU setting. The mean age of included patients was 63.2 (± 17.2) years old, 1,788 (55.8%) patients were men, and 948 (24.6%) patients had a BMI ≥ 30 (Table S1). Medical management included invasive mechanical ventilation in 336 (10.5%). Patients were excluded if they were not admitted or did not have at least one GCS assessment. Patients in the study cohort with behavioral assessments were more frequently admitted to the ICU and tended to be older compared with hospitalized patients with COVID-19 who were not enrolled (n = 7594) (Table S2. Our study found a low prevalence of bacterial sepsis (1.6%), a finding consistent with other reports .
We obtained a median number of 8 GCS assessments per patient (IQR 3–19) and found that 1090 (32%) patients were comatose (Table S1 and Fig. 1). Approximately 83% of all GCS assessments and 56% of GCS assessments greater than 8 were obtained in the ICU setting. Coma first developed on median hospital day 2 (IQR 1–9), and median time to event for noncomatose patients was 6 days (IQR 2–18). Nine hundred sixty-one (91.2%) of comatose patients, but only 619 (28.8%) of noncomatose patients, were admitted to the ICU. We obtained daily SIRS scores and found that 1538 (48.0%) had a score of 2 or above at least once during their hospital stay, which persisted for a median of 1 day (IQR 1–2).
Predictors of Coma
Patients who became comatose were more likely men. Preceding the onset of coma, they were more likely to have hypoxia and to have received sedatives, paralytics, or opiate medications (Table 1). Ninety-three patients had a GCS score of 9–12 (Table S3). Coma was more common in patients who were intubated (HR 1.68, 95% CI 1.42–1.99) and those who had an SIRS score of 2 or above at least once during the hospital stay (HR 5.92, 95% CI 5.03–6.97). Age, patients with a BMI of 30 or above, Black race, Hispanic ethnicity, or hypotension prior to the onset of coma were not associated. Accounting for each day that patients with COVID-19 had an SIRS score of 2 or more, a fivefold increased risk of coma was seen (HR 5.05, 95% CI 4.27–5.98; Fig. 2). The risk of coma increased with the number of days with an SIRS score of 2 or above for patients receiving neuromuscular blocking agents, those receiving sedative or opiate medications, and those receiving none of these medications (Table 2 and Fig. S1). The lag between SIRS first crossing a threshold of 2 and the onset of coma was 4 days (IQR 1–11). Serum measures of inflammation and disease severity were available, including IL-6, D-dimer, lactate dehydrogenase, ferritin, absolute lymphocyte count, creatinine, and creatinine kinase, which were elevated in patients with coma (Table S4 and Fig. S2). To account for the relationship between SIRS and medications and how this could relate to coma, we explored medications as a mediator between the relationship of SIRS and coma. We found paralytic medications to be a statistically significant mediator (p < 0.0001) and found that use of paralytic medications explained 60% of the effect between SIRS and coma (Table 3). Sedatives and opiates were also statistically significant mediators (p < 0.0001), but they had less of an effect on the relationship between SIRS and coma, explaining only 55% of the relationship between SIRS and coma. Serum markers of inflammation may turn out to define the inflammatory state preceding the onset of coma more precisely, and almost all were found to be elevated preceding coma compared with in patients who did not develop coma (Table S4).
One hundred thirty-seven patients did not receive any neuromuscular blocking agents, sedatives, or opiates prior to the onset of coma (Table 2). Only 3 patients of this cohort of 137 patients did not undergo at least one imaging study, lumbar puncture, or EEG as part of the workup of coma. The large majority of these patients underwent at least one imaging study (n = 133); this consisted of a brain computed tomography scan in 116 patient and a brain magnetic resonance imaging scan in 97 patients. As potential causes for coma, imaging studies revealed an ischemic stroke in 12% (n = 16); intracerebral, subarachnoid, or subdural hemorrhages in 6% (n = 8); and imaging findings consistent with posterior reversible leukoencephalopathy in 4% (n = 5) of those who underwent imaging. Importantly, 19% (n = 26) showed no abnormalities, and 59% (n = 78) revealed nonspecific findings, such as white matter hyperintensities, that would not likely explain coma. Additionally, lumbar punctures were obtained in 15% (n = 21), and none of them revealed abnormal findings. EEGs were obtained in three patients, all of whom had nonspecific abnormalities, such as moderate to severe diffuse background slowing (n = 3), triphasic waves (n = 1), and generalized periodic discharges at 0.5–1 Hz (n = 1), but none revealed seizures.
Coma was seen in 712 of 2742 (26%) patients with COVID-19 discharged alive, 329 of 441 (74.6%) patients who died, and 13 of 20 (65%) patients still hospitalized. Coma was an independent predictor of death (OR 7.77, 95% CI 6.29–9.65), after accounting for age, BMI, race/ethnicity, and sex. The median hospital length of stay was 31 days (IQR 13–59) for patients discharged alive, 16 days (IQR 7–32) for those who died, and 57 days (IQR 48–77) for those who were still hospitalized. The median length of stay was longer for comatose patients compared with those without coma (13 days [IQR 11.9–14.1] vs. 11 [IQR 9.6–12.4]), adjusting for age, BMI, race/ethnicity, and sex.