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Objective  The purpose of this study was to estimate the time to recovery of command‐following and associations between hypoxemia with time to recovery of command‐following.    Methods  In this multicenter, retrospective, cohort study during the initial surge of the United Statesʼ pandemic (March–July 2020) we estimate the time from intubation to recovery of command‐following, using Kaplan Meier cumulative‐incidence curves and Cox proportional hazard models. Patients were included if they were admitted to 1 of 3 hospitals because of severe coronavirus disease 2019 (COVID‐19), required endotracheal intubation for at least 7 days, and experienced impairment of consciousness (Glasgow Coma Scale motor score <6).    Results  Five hundred seventy‐one patients of the 795 patients recovered command‐following. The median time to recovery of command‐following was 30 days (95% confidence interval [CI] = 27–32 days). Median time to recovery of command‐following increased by 16 days for patients with at least one episode of an arterial partial pressure of oxygen (PaO 2 ) value ≤55 mmHg ( p  < 0.001), and 25% recovered ≥10 days after cessation of mechanical ventilation. The time to recovery of command‐following  was associated with hypoxemia (PaO 2  ≤55 mmHg hazard ratio [HR] = 0.56, 95% CI = 0.46–0.68; PaO 2  ≤70 HR = 0.88, 95% CI = 0.85–0.91), and each additional day of hypoxemia decreased the likelihood of recovery, accounting for confounders including sedation. These findings were confirmed among patients without any imagining evidence of structural brain injury (n = 199), and in a non‐overlapping second surge cohort (N = 427, October 2020 to April 2021).    Interpretation  Survivors of severe COVID‐19 commonly recover consciousness weeks after cessation of mechanical ventilation. Long recovery periods are associated with more severe hypoxemia. This relationship is not explained by sedation or brain injury identified on clinical imaging and should inform decisions about life‐sustaining therapies. ANN NEUROL 2022;91:740–755

Prolonged Unconsciousness is Common in COVID‐19 and Associated with Hypoxemia