TY - JOUR
T1 - Benefits and harm of probiotics and synbiotics in adult critically ill patients. A systematic review and meta-analysis of randomized controlled trials with trial sequential analysis
AU - Lee, Zheng Yii
AU - Lew, Charles Chin Han
AU - Ortiz-Reyes, Alfonso
AU - Patel, Jayshil J.
AU - Wong, Yu Jun
AU - Loh, Carolyn Tze Ing
AU - Martindale, Robert G.
AU - Heyland, Daren K.
N1 - Publisher Copyright:
© 2023 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism
PY - 2023/4
Y1 - 2023/4
N2 - Background & aims: Several systematic reviews and meta-analyses of randomized controlled trials concluded that probiotics administration in critically ill patients was safe and associated with reduced rates of ventilator-associated pneumonia and diarrhea. However, a recent large multicenter trial found probiotics administration, compared to placebo, was not efficacious and increased adverse events. An updated meta-analysis that controls for type-1 and -2 errors using trial sequential analysis, with a detailed account of adverse events associated with probiotic administration, is warranted to confirm the safety and efficacy of probiotic use in critically ill patients. Methods: RCTs that compared probiotics or synbiotics to usual care or placebo and reported clinical and diarrheal outcomes were searched in 4 electronic databases from inception to March 8, 2022 without language restriction. Four reviewers independently extracted data and assessed the study qualities using the Critical Care Nutrition (CCN) Methodological Quality Scoring System. Random-effect meta-analysis and trial sequential analysis (TSA) were used to synthesize the results. The primary outcome was ventilator-associated pneumonia (VAP). The main subgroup analysis compared the effects of higher versus lower quality studies (based on median CCN score). Results: Seventy-five studies with 71 unique trials (n = 8551) were included. In the overall analysis, probiotics significantly reduced VAP incidence (risk ratio [RR] 0.70, 95% confidence interval [CI] 0.56–0.88; I2 = 65%; 16 studies). However, such benefits were demonstrated only in lower (RR 0.47, 95% CI 0.32, 0.69; I2 = 44%; 7 studies) but not higher quality studies (RR 0.89, 95% CI 0.73, 1.08; I2 = 43%; 9 studies), with significant test for subgroup differences (p = 0.004). Additionally, TSA showed that the VAP benefits of probiotics in the overall and subgroup analyses were type-1 errors. In higher quality trials, TSA found that future trials are unlikely to demonstrate any benefits of probiotics on infectious complications and diarrhea. Probiotics had higher adverse events than control (pooled risk difference: 0.01, 95% CI 0.01, 0.02; I2 = 0%; 22 studies). Conclusion: High-quality RCTs did not support a beneficial effect of probiotics on clinical or diarrheal outcomes in critically ill patients. Given the lack of benefits and the increased incidence of adverse events, probiotics should not be routinely administered to critically ill patients. Prospero registration: CRD42022302278.
AB - Background & aims: Several systematic reviews and meta-analyses of randomized controlled trials concluded that probiotics administration in critically ill patients was safe and associated with reduced rates of ventilator-associated pneumonia and diarrhea. However, a recent large multicenter trial found probiotics administration, compared to placebo, was not efficacious and increased adverse events. An updated meta-analysis that controls for type-1 and -2 errors using trial sequential analysis, with a detailed account of adverse events associated with probiotic administration, is warranted to confirm the safety and efficacy of probiotic use in critically ill patients. Methods: RCTs that compared probiotics or synbiotics to usual care or placebo and reported clinical and diarrheal outcomes were searched in 4 electronic databases from inception to March 8, 2022 without language restriction. Four reviewers independently extracted data and assessed the study qualities using the Critical Care Nutrition (CCN) Methodological Quality Scoring System. Random-effect meta-analysis and trial sequential analysis (TSA) were used to synthesize the results. The primary outcome was ventilator-associated pneumonia (VAP). The main subgroup analysis compared the effects of higher versus lower quality studies (based on median CCN score). Results: Seventy-five studies with 71 unique trials (n = 8551) were included. In the overall analysis, probiotics significantly reduced VAP incidence (risk ratio [RR] 0.70, 95% confidence interval [CI] 0.56–0.88; I2 = 65%; 16 studies). However, such benefits were demonstrated only in lower (RR 0.47, 95% CI 0.32, 0.69; I2 = 44%; 7 studies) but not higher quality studies (RR 0.89, 95% CI 0.73, 1.08; I2 = 43%; 9 studies), with significant test for subgroup differences (p = 0.004). Additionally, TSA showed that the VAP benefits of probiotics in the overall and subgroup analyses were type-1 errors. In higher quality trials, TSA found that future trials are unlikely to demonstrate any benefits of probiotics on infectious complications and diarrhea. Probiotics had higher adverse events than control (pooled risk difference: 0.01, 95% CI 0.01, 0.02; I2 = 0%; 22 studies). Conclusion: High-quality RCTs did not support a beneficial effect of probiotics on clinical or diarrheal outcomes in critically ill patients. Given the lack of benefits and the increased incidence of adverse events, probiotics should not be routinely administered to critically ill patients. Prospero registration: CRD42022302278.
KW - Critical illness
KW - Meta-analysis
KW - Probiotics
KW - Synbiotics
KW - Systematic review
KW - Trial sequential analysis
UR - http://www.scopus.com/inward/record.url?scp=85149367847&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85149367847&partnerID=8YFLogxK
U2 - 10.1016/j.clnu.2023.01.019
DO - 10.1016/j.clnu.2023.01.019
M3 - Article
C2 - 36857961
AN - SCOPUS:85149367847
SN - 0261-5614
VL - 42
SP - 519
EP - 531
JO - Clinical Nutrition
JF - Clinical Nutrition
IS - 4
ER -