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


The present systematic review and meta-analysis of 23 studies examined the effects of probiotic versus placebo in preventing VAP among critically ill patients and concluded that prophylactic probiotic therapy impacts positively on the incidence of VAP, with a 31%, 45% reduced risk in adults and neonates/children, respectively. Furthermore, the above mentioned positive result in adults patients was lately confirmed by the result of TSA, subgroup analyses and cumulative meta-analysis. There was no statistical difference of ICU/hospital/28-/90-day mortality, bacteremia, CRBSI, diarrhea, ICU-acquired infections, infectious complications, pneumonia, UTI and wound infection between two groups.

Diminishing the occurrence of VAP remains a challenge. Unlike previous recognition that lung is a sterile organ,[42] there exists a "lung microbiota" in our lung. In healthy lungs, a dynamic balance between immigration of microorganism from the upper respiratory tract and elimination of bacteria by host defense mechanisms is existed.[8] Unfortunately, this balance is being disrupted when people suffer from several certain respiratory diseases, such as asthma, cystic fibrosis and lung infections, etc..[43] Of note, the disruption of microbial homeostasis might be associated with the occurrence of VAP. Indeed, orotracheal intubation, which might impair the natural lung defense mechanisms, is a promoter of microbiome dysbiosis.[44] Furthermore, the gut–lung–microbiome axis is one of current researching hotspots in basic research in recent years. Significantly, this axis is bidirectional—gut dysbiosis is related to lung disorders and infections, whereas, the changes in lung microbial composition can affect the intestinal flora—mainly through the circulation of soluble microbial components and metabolites (ie, peptidoglycans, lipopolysaccharide).[8] The source of bacterial dysbiosis in the lung might be derived from the gut, thus resulting in the occurrence of VAP.[45] Hence, we suspect that as a potential benefit of inhaled antibiotics in preventing VAP, "aerosolized probiotics"[46] might emerge in the near future, which may play a role in regulation of lung microbiome directly.

For quite a long time, probiotics are generally recognized as safe, and probiotic products are now ubiquitous in our lives, such as yogurts, cheeses, snacks and cosmetic products, etc..[12] Moreover, probiotics are increasingly given as accessory or therapeutic method to hospitalized patients, especially for the critically ill patients (eg. VAP, sepsis and antibiotic-associated diarrhea, etc.).[47] Despite probiotic products and probiotics are being used widely in life and clinical practice, their safety has not been fully assessed. Recently, some of scholars have expressed their concern as regards the probiotic safety[11,48] and Nieuwboer, et al.[47] suggested that a solid evidence for the proper and safe use of probiotics is still needed to be established, in particular for high-risk population (eg. prematurity, immunocompromised and critically ill patients, etc.). Conversely, Cabana and colleagues[49] reported that some of probiotic strains were subject to stringent safety evaluation followed by notification of the US Food and Drug Administration for comment, and the data from many high-quality studies have tracked adverse complications and provided evidences in favor of probiotics. In our meta-analysis, 8.70% (2/23) of the eligible studies expressed a degree of uncertainty about the safety, 17.39% (4/23) of the studies were silent about the safety issues, and 69.57% (16/23) of the studies have indicated that no obvious adverse events attributed to the probiotic (prebiotic, synbiotic) were noted in these study populations. Nonetheless, a large multicenter, randomized, concealed, blinded trial of 2650 critically ill patients (4.35%, 1/23),[18] found that compared with the placebo therapy, administration of the probiotic (lactobacillus rhamnosus GG) did not decrease the occurrence of VAP, and an increased risk of adverse events was noted among patients receiving this treatment.

There have been several relevant meta-analyses in this area to date, producing several conflicting outcomes.[15,16,21–28] Gu et al.[15] in 2012 published a meta-analysis of seven trials and failed to demonstrate a beneficial effect in reducing VAP in adult patients undergoing MV, and the result was further reinforced by a 2013 meta-analysis[16] with five trials. By contrast, an earlier meta-analysis[21] in 2010 concurred with our findings and revealed that the administration of probiotics is associated with a reduction in VAP incidence in adult patients who are mechanically ventilated, which was further proved by a subsequent 2014 Cochrane review with eight trials,[22] two meta-analyses for adult and children patients[23,24] and several meta-analyses for adult or (and) children patients.[25–28] Previous meta-analyses on this issue have focused on only adult patients or the combination analysis of both adult patients and non-adult patients.

The current meta-analysis has several strengths compared to earlier works. First, this study, to our knowledge, might be the first cumulative meta-analysis which conducted the TSA from the view of adult and neonates/children populations, resulting in a more robust, reliable and precise pooled estimate. Second, in contrast to prior meta-analyses, we analyzed the influences of probiotic on VAP from the viewpoint of neonates/children and adults populations, respectively, which was partly reflected a true effect of probiotic in the prevention of VAP in mechanically ventilated patients. Third, as the evidence accumulates and sample size increases, especially with the addition of a large new study (n = 2650),[18] our study had enhanced the statistical power to examine the efficacy of protective effects of probiotics in reducing VAP incidence.

Our meta-analysis has several potential shortcomings as well. First, since the possibility of false positive result in TSA, as well as the limited numbers of the eligible articles and samples, the positive result for neonates/children patients should be interpreted with caution. Consequently, further study on the beneficial effects of probiotics on VAP for these patients is needed. Second, the diagnosis of VAP might be complex due to the lack of uniformly accepted diagnostic standard, which might lead to increased the heterogeneity among these included studies. Finally, another limitation of the study is that it has not pre-registered a PROSPERO registration number. Thus, further large studies, especially for the neonates/children and an objective accepted diagnostic criteria of VAP, are necessary to verify our findings in this area.