Effect of Selective Decontamination of the Digestive Tract on Hospital Mortality in Critically Ill Patients Receiving Mechanical Ventilation: A Randomized Clinical Trial

Abstract

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.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Myburgh reported receipt of grants from the National Health and Medical Research Council of Australia outside the submitted work. Dr Seppelt reported receipt of grants from the National Health and Medical Research Council of Australia outside the submitted work. Dr Gordon reported receipt of grants from the National Institute for Health and Care Research (NIHR) outside the submitted work. Dr Hammond reported receipt of grants from Baxter Healthcare, the National Health and Medical Research Council of Australia, and CSL Bioplasma and consulting fees paid to her employer from RevImmune Inc. Dr Taylor reported paid consultancy work for various pharmaceutical and medical device companies as well as the Australian government. Dr Young reported receipt of personal fees from AM Pharma and nonfinancial support from Baxter Healthcare. Dr Finfer reported receipt of nonfinancial support from Baxter Healthcare, grants from CSL Pty Ltd to his institution, and grants from Baxter Healthcare to his institution. No other disclosures were reported. The George Institute for Global Health holds intellectual property arising out of the development and manufacturing of the SuDDICU study drugs. None of the SuDDICU investigators have any direct or indirect financial or commercial interests relating to the development of the SuDDICU study drugs

Figures

Figure 1.. Participant Flow in the SuDDICU Trial

ICU indicates intensive care unit; SDD, selective decontamination of the digestive tract.

Figure 2.. In-Hospital Mortality in the Selective Decontamination of the Digestive Tract and Standard Care Groups

SDD indicates selective decontamination of the digestive tract. Severity of illness was determined by the Acute Physiology and Chronic Health Evaluation (APACHE) scores, ranging from 0 to 71 (APACHE II) or 0 to 299 (APACHE III), with higher scores indicating an increased risk of death. The median APACHE II and APACHE III scores were 20 and 70, respectively. P values are from the likelihood ratio test of the interaction term between the subgroup variable and the intervention.

Figure 3.. Ecological Assessment Outcomes

The change in mean proportions of microbiological outcomes between selective decontamination of the digestive tract (SDD) and standard care are presented from the pretrial period vs intervention period 1 and the interperiod gap combined (first intervention) and from the interperiod gap vs intervention period 2 and the posttrial period combined (second intervention). The predefined noninferiority margin of 2% is presented as the red line. The noninferiority margin was rejected for new organisms isolated and Clostridioides difficile infection, but not for cultures of antibiotic-resistant organisms, presented by the noninferiority P value.