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Effect of Probiotics on Incident Ventilator-Associated Pneumonia in Critically Ill PatientsA Randomized Clinical Trial

Educational Objective
To understand the role of probiotic treatments for patients who are critically ill.
1 Credit CME
Key Points

Question  Does the probiotic Lactobacillus rhamnosus GG prevent ventilator-associated pneumonia (VAP) among critically ill patients?

Findings  In this randomized trial involving 2650 patients, no significant difference in VAP incidence was found among patients treated with probiotics compared with placebo (21.9% vs 21.3%, respectively; hazard ratio 1.03; 95% CI 0.87-1.22).

Meaning  These findings do not support the use of Lactobacillus rhamnosus GG for prevention of ventilator-associated pneumonia in critically ill patients requiring mechanical ventilation.

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

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Article Information

Corresponding Author: Deborah Cook, MD, MSc, Methods Center, St Joseph’s Healthcare, 50 Charlton Ave E, Room H327, Hamilton, ON, Canada L9H 4A6 (debcook@mcmaster.ca).

Accepted for Publication: July 23, 2021.

Author Contributions: Drs Cook and Heels-Ansdell had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Johnstone, Meade, Lauzier, Marshall, Duan, Dionne, Arabi, Thabane, Lamarche, Surrette, Zytaruk, Cook.

Acquisition, analysis, or interpretation of data: Johnstone, Meade, Lauzier, Marshall, Duan, Dionne, Arabi, Heels-Ansdell, Thabane, Lamarche, Surette, Zytaruk, Mehta, McIntyre, English, Rochwerg, Karachi, Henderson, Wood, Ovakim, Herridge, Granton, Wilcox, Goffi, Stelfox, Niven, Muscedere, Lamontagne, D'Aragon, St.-Arnaud, Ball, Nagpal, Girard, Aslanian, Charbonney, Williamson, Sligl, Friedrich, Adhikari, Marquis, Archambault, Khwaja, Kristof, Kutsogiannis, Zarychanski, Reeve, Lellouche, Hosek, Tsang, Binnie, Trop, Loubani, Hall, Cirone, Reynolds, Lysecki, Golan, Cartin-Ceba, Taylor, Cook.

Drafting of the manuscript: Johnstone, Meade, Lauzier, Marshall, Duan, Dionne, Lamarche, Zytaruk, Cook.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Dionne, Heels-Ansdell, Thabane, Zytaruk, Cook.

Obtained funding: Johnstone, Meade, Lauzier, Duan, Dionne, Zytaruk, Ball, Aslanian, Charbonney, Williamson, Kutsogiannis, Hall, Cook.

Administrative, technical, or material support: Lauzier, Duan, Dionne, Arabi, Lamarche, Surette, Zytaruk, Mehta, English, Rochwerg, Karachi, Henderson, Wood, Herridge, Granton, Wilcox, Stelfox, Niven, D'Aragon, St.-Arnaud, Ball, Nagpal, Aslanian, Williamson, Sligl, Marquis, Archambault, Kutsogiannis, Zarychanski, Reeve, Lellouche, Hosek, Tsang, Binnie, Reynolds, Lysecki, Golan, Cartin-Ceba, Cook.

Supervision: Lauzier, Duan, Arabi, Thabane, Zytaruk, Henderson, Lamontagne, D'Aragon, St-Arnaud, Girard, Aslanian, Sligl, Archambault, Khwaja, Lellouche, Trop, Hall, Cirone, Lysecki, Cook.

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.

Funding/Support: This trial was funded by the Canadian Institute for Health Research, Canadian Frailty Network, Physician Services Incorporated, Hamilton Academic Health Sciences Organization, Academic Medical Organization of Southwestern Ontario, St Joseph's Healthcare Hamilton, and McMaster University. I-Health donated active study product and placebo for the conduct of the trial.

Role of the Funders/Sponsors: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Writing Committee Members: Dr Johnstone (coprincipal investigator), Meade, Lauzier, Marshall, Heels-Ansdell, Thabane, Arabi, Dionne, and Duan, Zytaruk, Lamarche, Surette, and Cook (coprincipal investigator).

Data Monitoring Committee: Drs Andreas Laupacis (chair), Roberts, and Brun-Buisson.

Pneumonia and other Infection Adjudication Committee: Drs Johnstone, Francois Lauzier, and Cook (main) and Drs Duan, Dionne, Rochwerg, Centofanti, Oczkowski, and Cook (pilot).

C difficile Infection Adjudication Committee: Drs Dionne, Duan, and Johnstone.

Translational Science Committee: Drs Lamarche, Surette, and Bowdish

Group Information: The PROSPECT Investigators and the Canadian Critical Care Trials Group members are listed in Supplement 3.

Data Sharing Statement: See Supplement 4.

Additional Contributions: We thank the patients and families participating in this trial, as well as the collaborating research coordinators and investigators, and bedside clinicians who supported this work. The trial was designed by the PROSPECT steering committee, the PROSPECT investigators and research coordinators, and the Canadian Critical Care Trials Group. We thank the PROSPECT methods center staff for their expertise and data management, including Lois Saunders, Mary Copland, BA, Shelley Anderson-White, BA, Alyson Takaoka, MSc, France Clarke, RRT, Lori Hand, RRT, Megan Davis, BSc, Melissa Shears, MD, and Kristine Wachmann, RN. We thank Drs Kho, and Fowler, for their review of this manuscript for the Canadian Critical Care Trials Group. None mentioned herein were compensated.

Additional Information: Pharmacy Consultants: Christine Wallace, BSc, St Joseph’s Healthcare Hamilton, and Gita Sobi, BSc, Phm, Hamilton Health Sciences Center, Hamilton.

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