Effect of Probiotics on Incident Ventilator-Associated Pneumonia in Critically Ill Patients: A Randomized Clinical Trial

Abstract

Importance: Growing interest in microbial dysbiosis during critical illness has raised questions about the therapeutic potential of microbiome modification with probiotics. Prior randomized trials in this population suggest that probiotics reduce infection, particularly ventilator-associated pneumonia (VAP), although probiotic-associated infections have also been reported.

Objective: To evaluate the effect of Lactobacillus rhamnosus GG on preventing VAP, additional infections, and other clinically important outcomes in the intensive care unit (ICU).

Design, setting, and participants: Randomized placebo-controlled trial in 44 ICUs in Canada, the United States, and Saudi Arabia enrolling adults predicted to require mechanical ventilation for at least 72 hours. A total of 2653 patients were enrolled from October 2013 to March 2019 (final follow-up, October 2020).

Interventions: Enteral L rhamnosus GG (1 × 1010 colony-forming units) (n = 1321) or placebo (n = 1332) twice daily in the ICU.

Main outcomes and measures: The primary outcome was VAP determined by duplicate blinded central adjudication. Secondary outcomes were other ICU-acquired infections including Clostridioides difficile infection, diarrhea, antimicrobial use, ICU and hospital length of stay, and mortality.

Results: Among 2653 randomized patients (mean age, 59.8 years [SD], 16.5 years), 2650 (99.9%) completed the trial (mean age, 59.8 years [SD], 16.5 years; 1063 women [40.1%.] with a mean Acute Physiology and Chronic Health Evaluation II score of 22.0 (SD, 7.8) and received the study product for a median of 9 days (IQR, 5-15 days). VAP developed among 289 of 1318 patients (21.9%) receiving probiotics vs 284 of 1332 controls (21.3%; hazard ratio [HR], 1.03 (95% CI, 0.87-1.22; P = .73, absolute difference, 0.6%, 95% CI, -2.5% to 3.7%). None of the 20 prespecified secondary outcomes, including other ICU-acquired infections, diarrhea, antimicrobial use, mortality, or length of stay showed a significant difference. Fifteen patients (1.1%) receiving probiotics vs 1 (0.1%) in the control group experienced the adverse event of L rhamnosus in a sterile site or the sole or predominant organism in a nonsterile site (odds ratio, 14.02; 95% CI, 1.79-109.58; P < .001).

Conclusions and relevance: Among critically ill patients requiring mechanical ventilation, administration of the probiotic L rhamnosus GG compared with placebo, resulted in no significant difference in the development of ventilator-associated pneumonia. These findings do not support the use of L rhamnosus GG in critically ill patients.

Trial registration: ClinicalTrials.gov Identifier: NCT02462590.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Lauzier reported being the recipient of a Research Career Award from the Fonds de la Recherché du Québec-Santé. Dr Marshall reported receiving personal fees from AM Pharma, serving as a consultant to Gilead, being an associate editor for Critical Care Medicine, and holding the Unity Health Chair in Trauma Research. Dr Dionne reported being a recipient of a Career Award from Physician Services Incorporated of Ontario. Dr. Surette reported holding a Canada Research Chair in Interdisciplinary Microbiome Research. Dr Lamontagne reported being a recipient of a Research Career Award from the Fonds de la Recherché du Québec-Santé. Dr D’Aragon reported being a recipient of a Research Career Award from the Fonds de la Recherché du Québec-Santé. Dr Zarychanski reports holding the Lyonel G. Israels Research Chair in Hematology (University of Manitoba). Dr Lellouche reported cofounding and serving as a member of the board of directors of Oxynov and having a patent for automated oxygen. Dr Cook reported being a recipient of a Research Chair in Intensive Care Medicine from the Canadian Institutes for Health Research. No other disclosures were reported.

Figures

Figure 1.. Screening, Selection, and Flow of Patients in PROSPECTa

aNo data were collected on ineligible patients. Ten patients in the placebo group and 15 in the probiotics group had consent withdrawn for the study product but were followed up for outcomes and were included in the primary analysis. bMissed patients included those admitted to the ICU on weekends or holidays or other times when the research coordinators or pharmacists were unavailable. cEnrollment in an additional study. dOther reasons included nonresidents, incarcerated patients, or family members who were not approached due to extreme stress.

Figure 2.. Subgroup Analyses: Ventilator-Associated Pneumonia