Effect of Probiotics on Incident Ventilator-Associated Pneumonia in Critically Ill Patients: A Randomized Clinical Trial
Open accessAbstract
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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Others have reported a lack of efficacy of "probiotics" when they studied only a specific strain that was not included in the title, creating misperceptions in physicians who only read the titles or "news summaries."
“Others have reported a lack of efficacy of “probiotics” when they studied only a specific strain that was not included in the title, creating misperceptions in physicians who only read the titles or “news summaries” [74].”
From Lactobacillus Bacteremia and Probiotics: A Review (2023) · cites this paper as [74]
The Primary Outcome and Discussion report no significant reduction in ventilator-associated pneumonia with L rhamnosus GG, and the Limitations specify that this was the strain evaluated. The paper’s title says “Probiotics” without naming the strain. Our copy does not address whether the title or news summaries created misperceptions among physicians. (LLM, conf=0.88)
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- Affiliations
- King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
- McMaster University, Hamilton, Canada
- McMaster University (CA)
- Canadian Critical Care Trials Group (CA)
- University of Toronto (CA)
- University of Calgary (CA)
- Université de Sherbrooke, Sherbrooke, Canada
- University of Toronto, Toronto, Canada
- McGill University, Montréal, Canada
- University of Alberta, Edmonton, Canada
- Université de Montréal, Montréal, Canada
- Dalhousie University (CA)
- for the Prevention of Severe Pneumonia and Endotracheal Colonization Trial (PROSPECT) Investigators and the Canadian Critical Care Trials Group
- ORCID
- Thabane, Lehana
- Karachi, Tim
- Wilcox, M. Elizabeth
- Stelfox, Henry T.
- Hall, Richard
- Oczkowski, Simon
- Bowdish, Dawn
- Sekhon, Tina
- Ayas, Najib
- Sekhon, Mypinder
- Foster, Denise
- Couillard, Philippe
- Doig, Christopher
- Parhar, Ken
- Booth, Joshua
- Martin, Anne
- Berthiaume, Luc
- Johnston, Richard
- Bagshaw, Sean
- Blouw, Marcus
- Olafson, Kendiss
- Davis, Megan
- Dechert, William
- Tran, Lara
- Smith, Candice
- Tung, Jennifer
- Savija, Nevena
- Skitch, Steven
- Campbell, Tracy
- Khaled, Alia
- Erb, Jason
- Maslove, David
- Sibley, Stephanie
- Hunt, Miranda
- Bosma, Karen J
- Lapinsky, Stephen
- Munshi, Laveena
- Grewal, Gagan
- Kyeremanteng, Kwadwo
- Meggison, Hilary
- Neilipovitz, David
- Patel, Rakesh
- Porteous, Rebecca
- Watpool, Irene
- Macleod, Rob
- Cardinal, Pierre
- Kim, John
- Seely, Andrew
- Clarke, France
- Phillips, Kaitlyn
- Young, Crystal
- Carter, Jeff
- Lee, Yoon
- Amaral, Andre
- Cuthbertson, Brian H
- Scales, Damon
- Kaur, Navjot
- Wang, Jane
- Chen, Daniel
- Fraser, Brooke
- Suen, Matthew
- McCredie, Victoria
- Wilcox, Elizabeth
- Lui, Jane
- Pham, Tam
- Heslegrave, Ronald
- Carrier, François-Martin
- Chassé, Michaël
- Denault, André
- Hébert, Paul
- Mancebo, Jordi
- Robillard, Nicholas
- Boudreau, Nathalie
- Marchand, Louis-Étienne
- Masse, Marie-Hélène
- Lamarche, Yoan
- Serri, Karim
- Verdant, Colin
- Turgeon, Alexis
- Grushka, Jeremy
- Jayaraman, Dev
- Razek, Tarek
- Alam, Norine
- Hatzakorzian, Roupen
- Magder, Sheldon
- Shahin, Jason
- Oeckler, Richard
- Bridges, Shaun
- Moore, Kaitlin MS
- Tlayjeh, Haytham
- Hegazy, Mohamed
- Gramish, Jawaher
- Venue
- JAMA
- Publisher
- American Medical Association (AMA)
- Published
- 2021-09-21
- Volume
- 326
- Issue
- 11
- Pages
- 1024
- ISSN
- 0002-9955 (ISSN-L)
- 0098-7484
- PMC
- PMC8456390
- OpenAlex
- W3199054172
- Cited by
- 226
- References
- 43
- Citations by year
- 2026: 42 · 2025: 49 · 2024: 31 · 2023: 50 · 2022: 51 · 2021: 2 · 2015: 1
- FWCI
- 24.10
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- JAMA (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- McMaster University
- Academic Medical Organization of Southwestern Ontario
- Canadian Frailty Network
- Topics
- Health Sciences › Medicine › Critical Care and Intensive Care Medicine › Nosocomial Infections in ICU
- Life Sciences › Agricultural and Biological Sciences › Food Science › Probiotics and Fermented Foods
- Health Sciences › Nursing › Nutrition and Dietetics › Clinical Nutrition and Gastroenterology
- Keywords
- probiotics, Lactobacillus rhamnosus GG, ventilator-associated pneumonia, critically ill patients, mechanical ventilation, intensive care unit infections, Clostridium difficile infection, diarrhea, antimicrobial use, length of hospital stay, mortality, microbiome, nosocomial infection prevention, dysbiosis, intensive care unit patients
- MeSH terms
- Aged, Anti-Bacterial Agents, Bacterial Infections, Diarrhea, Female, Humans, Intensive Care Units, Male, Middle Aged, Respiration, Artificial, Treatment Failure, Probiotics, Lacticaseibacillus rhamnosus, Pneumonia, Ventilator-Associated
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