Importance Whether selective decontamination of the digestive tract (SDD) reduces mortality in critically ill patients remains uncertain.

Objective To determine whether SDD reduces in-hospital mortality in critically ill adults.

Design, Setting, and Participants A cluster, crossover, randomized clinical trial that recruited 5982 mechanically ventilated adults from 19 intensive care units (ICUs) in Australia between April 2018 and May 2021 (final follow-up, August 2021). A contemporaneous ecological assessment recruited 8599 patients from participating ICUs between May 2017 and August 2021.

Interventions ICUs were randomly assigned to adopt or not adopt a SDD strategy for 2 alternating 12-month periods, separated by a 3-month interperiod gap. Patients in the SDD group (n = 2791) received a 6-hourly application of an oral paste and administration of a gastric suspension containing colistin, tobramycin, and nystatin for the duration of mechanical ventilation, plus a 4-day course of an intravenous antibiotic with a suitable antimicrobial spectrum. Patients in the control group (n = 3191) received standard care.

Main Outcomes and Measures The primary outcome was in-hospital mortality within 90 days. There were 8 secondary outcomes, including the proportion of patients with new positive blood cultures, antibiotic-resistant organisms (AROs), and Clostridioides difficile infections. For the ecological assessment, a noninferiority margin of 2% was prespecified for 3 outcomes including new cultures of AROs.

Results Of 5982 patients (mean age, 58.3 years; 36.8% women) enrolled from 19 ICUs, all patients completed the trial. There were 753/2791 (27.0%) and 928/3191 (29.1%) in-hospital deaths in the SDD and standard care groups, respectively (mean difference, −1.7% [95% CI, −4.8% to 1.3%]; odds ratio, 0.91 [95% CI, 0.82-1.02]; P = .12). Of 8 prespecified secondary outcomes, 6 showed no significant differences. In the SDD vs standard care groups, 23.1% vs 34.6% had new ARO cultures (absolute difference, −11.0%; 95% CI, −14.7% to −7.3%), 5.6% vs 8.1% had new positive blood cultures (absolute difference, −1.95%; 95% CI, −3.5% to −0.4%), and 0.5% vs 0.9% had new C difficile infections (absolute difference, −0.24%; 95% CI, −0.6% to 0.1%). In 8599 patients enrolled in the ecological assessment, use of SDD was not shown to be noninferior with regard to the change in the proportion of patients who developed new AROs (−3.3% vs −1.59%; mean difference, −1.71% [1-sided 97.5% CI, −∞ to 4.31%] and 0.88% vs 0.55%; mean difference, −0.32% [1-sided 97.5% CI, −∞ to 5.47%]) in the first and second periods, respectively.

Conclusions and Relevance Among critically ill patients receiving mechanical ventilation, SDD, compared with standard care without SDD, did not significantly reduce in-hospital mortality. However, the confidence interval around the effect estimate includes a clinically important benefit.

Trial Registration ClinicalTrials.gov Identifier: NCT02389036