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IMPORTANCESepsis is a common syndrome with substantial morbidity and mortality. A combination of vitamin C, thiamine, and corticosteroids has been proposed as a potential treatment for patients with sepsis.OBJECTIVE To determine whether a combination of vitamin C, thiamine, and hydrocortisone every 6 hours increases ventilator-and vasopressor-free days compared with placebo in patients with sepsis.DESIGN, SETTING, AND PARTICIPANTS Multicenter, randomized, double-blind, adaptive-sample-size, placebo-controlled trial conducted in adult patients with sepsis-induced respiratory and/or cardiovascular dysfunction. Participants were enrolled in the emergency departments or intensive care units at 43 hospitals in the United States between August 2018 and July 2019. After enrollment of 501 participants, funding was withheld, leading to an administrative termination of the trial. All study-related follow-up was completed by January 2020. INTERVENTIONS Participants were randomized to receive intravenous vitamin C (1.5 g), thiamine (100 mg), and hydrocortisone (50 mg) every 6 hours (n = 252) or matching placebo (n = 249) for 96 hours or until discharge from the intensive care unit or death. Participants could be treated with open-label corticosteroids by the clinical team, with study hydrocortisone or matching placebo withheld if the total daily dose was greater or equal to the equivalent of 200 mg of hydrocortisone. MAIN OUTCOMES AND MEASURESThe primary outcome was the number of consecutive ventilator-and vasopressor-free days in the first 30 days following the day of randomization. The key secondary outcome was 30-day mortality. RESULTS Among 501 participants randomized (median age, 62 [interquartile range {IQR}, 50-70] years; 46% female; 30% Black; median Acute Physiology and Chronic Health Evaluation II score, 27 [IQR, 20.8-33.0]; median Sequential Organ Failure Assessment score, 9 [IQR, 7-12]), all completed the trial. Open-label corticosteroids were prescribed to 33% and 32% of the intervention and control groups, respectively. Ventilator-and vasopressor-free days were a median of 25 days (IQR, 0-29 days) in the intervention group and 26 days (IQR, 0-28 days) in the placebo group, with a median difference of −1 day (95% CI, −4 to 2 days; P = .85). Thirty-day mortality was 22% in the intervention group and 24% in the placebo group.CONCLUSIONS AND RELEVANCE Among critically ill patients with sepsis, treatment with vitamin C, thiamine, and hydrocortisone, compared with placebo, did not significantly increase ventilator-and vasopressor-free days within 30 days. However, the trial was terminated early for administrative reasons and may have been underpowered to detect a clinically important difference.

Objective To determine whether automated identification with physician notification of the systemic inflammatory response syndrome in medical intensive care unit (MICU) patients expedites early administration of new antibiotics or improvement of other patient outcomes in patients with sepsis. Design A prospective, randomized, controlled, single-center study. Setting MICU of an academic, tertiary-care medical center. Patients 442 consecutive patients admitted over a 4 month period who met modified SIRS criteria in a MICU. Intervention Patients were randomized to monitoring by an electronic “Listening Application” to detect modified (SIRS) criteria vs. usual care. The Listening Application notified physicians in real-time when modified SIRS criteria were detected, but did not provide management recommendations. Measurements and Main Results The median time to new antibiotics was similar between the intervention and usual care groups whether comparing among all patients (6.0h vs 6.1h, p=0.95), patients with sepsis (5.3h vs. 5.1h; p=0.90), patients on antibiotics at enrollment (5.2h vs. 7.0h, p= 0.27), or patients not on antibiotics at enrollment (5.2h vs. 5.1h, p= 0.85). The amount of fluid administered following detection of modified SIRS criteria was similar between groups whether comparing all patients or only patients hypotensive at enrollment. Other clinical outcomes including ICU length of stay, hospital length of stay, and mortality were not shown to be different between patients in the intervention and control groups. Conclusions Real-time alerts of modified SIRS criteria to physicians in one tertiary care MICU were feasible and safe but did not influence measured therapeutic interventions for sepsis or significantly alter clinical outcomes.