Probiotic in the Prevention of Ventilator-Associated Pneumonia in Critically Ill Patients

Evidence From Meta-Analysis and Trial Sequential Analysis of Randomized Clinical Trials

Yue-chen Sun; Chen-yi Wang; Hai-li Wang; Yao Yuan; Jian-hong Lu; Lei Zhong


BMC Pulm Med. 2022;22(168) 

In This Article

Abstract and Introduction


Background: Probiotic might have a role in the prevention of ventilator-associated pneumonia (VAP) among mechanically ventilated patients, but the efficacy and safety remained inconsistent. The aim of this systematic review and meta-analysis was to evaluate the efficacy and safety of probiotic (prebiotic, synbiotic) versus placebo in preventing VAP in critically ill patients undergoing mechanical ventilation.

Methods: PubMed, Embase and the Cochrane library databases were searched to 10 October 2021 without language restriction for randomized or semi-randomized controlled trials evaluating probiotic (prebiotic, synbiotic) vs. placebo in prevention of VAP in critically ill mechanically ventilated patients. The pooled relative risk (RR) along with 95% confidence intervals (CI) were combined using a random-effects model. Furthermore, the trial sequential analysis (TSA) and subgroup analyses were performed. Statistical significance was regarded as P < 0.05.

Results: Twenty-three trials involving 5543 patients were eligible for this meta-analysis. The combined RR of decreasing the risk of VAP by probiotic was 0.67 (0.56, 0.81) for all eligible studies, 0.69 (n = 5136; 95% CI = 0.57 to 0.84; P < 0.01) for adults studies and 0.55 (n = 407; 95%CI = 0.31 to 0.99; P = 0.046) for neonates/children studies. Additionally, the above-mentioned positive finding in 20 adults studies was verified by the results of TSA, subgroup analyses and cumulative meta-analysis. Ample evidences demonstrated a 31% decrease in RR of incidence of VAP was noted when prophylactic probiotic therapy was administrated among adult patients. Finally, there were no effects on the ICU/hospital/28-/90-day mortality, bacteremia, CRBSI, diarrhea, ICU-acquired infections, infectious complications, pneumonia, UTI and wound infection between two groups (P > 0.05 for all).

Conclusions: Based on the results of our study, the current evidences suggested that prophylactic administration of probiotic might be utilized as a preventive method for VAP in neonates/children and adults patients who required mechanical ventilation. However, further large, high-quality RCTs are warranted to assess the efficacy and safety of probiotic treatment in critically ill patients, especially for the neonates/children studies and the long-term consequences of this therapy.


Ventilator-associated pneumonia (VAP), characterized as a type of nosocomial pneumonia that occurs at least 48 h after the initiation of mechanical ventilation (MV) in intensive care unit (ICU), leaded to prolonged the duration of MV, stay in ICU and hospital, as well as increased mortality and healthcare burden.[1–3] The latest data, conducted in 538,600 patients from 14 countries, revealed that the pooled incidence of VAP is 15.1 per 1000 ventilator-days (VD), and high-income countries (9.0 per 1000 VD) is lower than lower- and upper-middle-income countries (18.5 and 15.2, per 1000 VD, respectively).[4] Ferrer et al., in a review of the epidemiology of ICU-acquired pneumonia,[5] have estimated that the all-cause mortality attributable to VAP ranged from 20 to 50% and the overall attributable mortality associated with VAP was approximately 13%. Furthermore, a lately data from Japan indicated that the average hospitalization costs for patients with VAP was $67,080, significantly higher than that those without VAP ($32,196).[6]

On account of the high incidence, severity and enormous burdens of VAP, ample studies have assessed various kinds of prevention strategies, including pharmacological and non-pharmacological interventions, to prevent VAP over the years.[7] Fortunately, the incidence of VAP has been steadily decreasing in recent years possibly due to the application of the ventilator bundles, such as hand hygiene, oral care, semi-recumbent position, and subglottic secretion drainage system, daily sedation vacations as well as deep vein thrombosis prophylaxis, etc..[5,7] For quite a long time, antibiotic use has been the cornerstone of preventing and treating various infections, especially in ICU, but equally, inappropriate antimicrobial therapy was linked to potential risks such as affecting the microbiota composition, bringing the problem of superinfections and increasing the occurrence of drug-resistance bacteria.[8–10]

Therefore, an emerging number of studies has assessed the non-antibiotic approaches for the prevention of VAP in the last few years. The term "probiotics", defined as live nonpathogenic microorganisms that exert a health benefit to the host later,[11] first appeared in 1974[12] and it might represent a novel non-antibiotic intervention.[13] The beneficial effects of probiotics in the prevention of VAP were not yet entirely elucidated, perhaps via modulating intestinal microbiota, adjusting immune response, improving gut barrier function and suppressing pathogenic bacteria overgrowth, etc..[12,14]

There were several studies in this area over the last few years since the first study of probiotic (prebiotic and synbiotic) in preventing VAP in mechanically ventilated critically ill patients was published. A series of studies showed unfavorable results with regard to the prevention of VAP by probiotics;[15–18] nonetheless, other studies[19,20] reported promising results, which were further confirmed by several meta-analyses.[21–28]

Considering these controversial results, we therefore undertook a systematic review and meta-analysis to compare the efficacy and safety of administering probiotic (prebiotic, synbiotic) versus placebo on the prevention of VAP in critically ill ventilated patients.