Our meta-analysis found that probiotics administration was associated with statistically significant reduction in the incidence of NP in critically ill patients. However, the pooled results showed that probiotics did not affect overall mortality, or length of stay in the hospital and the ICU, which were the secondary endpoints of the study.
The current meta-analysis is different from previous reviews in several aspects. Although three recent reviews addressed somewhat similar questions, our meta-analysis identified and included more eligible studies than the previous reviews [35
]. These previous reviews on probiotics administration included studies that recruited patients requiring MV only [35
] or studies of surgical patients only [36
]. Thus, those meta-analyses were limited to selected populations. Trials of any type of critically ill patients were eligible for our study, and therefore our results are applicable across a wide range of clinical situations that are encountered with critically ill patients. In order to diminish the number of confounding factors, we excluded two studies using chlorhexidine and antibiotic decontamination as control groups, because the use of chlorhexidine in oral care procedures and antibiotic decontamination of the digestive tract were considered to be effective in preventing NP [6
]. The review by Siempos et al
. used the data from one trial on the rate of respiratory tract infection as the rate of VAP [35
], which may have contributed to an overestimation of the VAP rate and a greater observed treatment effect. This trial has been recently published in a separate study [23
] and confirms that there are fewer patients with VAP than with respiratory tract infections. Accordingly, we included the latter study in our meta-analysis. Our results appear similar to the previous reviews by Siempos et al
] and Pitsouni et al
], but inconsistent with the results of the systematic review by Watkinson et al
]. Siempos et al
. found that administration of probiotics was beneficial in the incidence of both VAP and NP, length of stay in the ICU and colonization rates of Pseudomonas aeruginosa
in the respiratory tract [35
]. Similarly, the meta-analysis by Pitsouni et al
. demonstrated that probiotics significantly reduced the occurrence of postoperative pneumonia and any infectious complications, as well as the duration of postoperative hospital stay [36
]. While we restricted our subgroup analysis to patients in surgical populations, a pooled analysis showed a marginally non-significant reduction in NP in favor of probiotics. In contrast, Watkinson et al
. pooled eight trials and found that pre- pro- or synbiotics were not associated with any significant change in the outcomes studied, that is, length of ICU stay, hospital mortality and the incidence of nosocomial infection and more specifically incidence of pneumonia [37
]. Although there was no statistically significant effect on the incidence of NP in all subgroups, the risk reduction associated with probiotics use was substantial. The reasons for these inconsistent results may partly be due to differences in focus on clinical outcomes.
The results of this meta-analysis should be interpreted carefully based on other considerations. As the diagnosis of pneumonia is a more subjective outcome than mortality or length of stay in the ICU, it may be more subject to bias, and this may in part explain the marked reduction in pneumonia found in these studies. In addition, the definitions of pneumonia varied among different studies, which will affect the true nature of clinical outcomes. In addition, the absence of an effect on secondary outcomes may be from the small number of pooled RCTs and total patients. And lastly, the treatment durations in some studies were likely too short to demonstrate maximal benefits. Consequently, a lack of standard protocols and insufficient numbers of patients may make it difficult to derive conclusive results based on the current meta-analysis.
The potential harm due to probiotics therapy also warrants comment. The numbers of patients with diarrhea or abdominal cramps did not differ between those patients who received probiotics and those who did not in our current meta-analysis. However, a particular concern in critically ill patients is whether their exposure to probiotics places them at risk for developing an invasive infection. There were no reports of bacteremia or sepsis due to probiotics in the studies included in our meta-analysis. In addition, Besselink et al
. found an increased rate of bowel ischemia and mortality in those patients treated with probiotics [33
]. However, a meta-analysis of four RCTs that included severe acute pancreatitis, including the study by Besselink et al
] demonstrated that probiotics did not significantly influence mortality either favorably or adversely. Accordingly, we should monitor the safety of probiotics as our research efforts move forward.
Our analysis has several limitations. First, as already mentioned, there was heterogeneity in the inclusion criteria, the populations studied, the probiotic agents used, doses, time points when therapy was initiated, durations of therapy, the routes of administration, and the diagnostic criteria used for establishing NP or VAP. These factors were not comparable in most of the trials and might have affected the clinical outcomes. These differences may explain the statistical heterogeneity in some of the secondary outcomes investigated. Second, even though we were able to pool results across all trials, the number of patients included in this meta-analysis may not be sufficient to exclude significant clinical benefit. Third, most trials were done in single centers and may have had inherent bias related to local practice habits and the populations served. Although we extensively searched for relevant studies using multiple databases and multiple search items, and no language restriction was placed on the search, a funnel plot suggested the possibility of publication bias. Finally, the quality of the included studies was not consistent. Some RCTs included in our analysis had major methodological flaws [24
]. The quality of trials can affect the direction and magnitude of treatment effects when performing a meta-analysis.
Although the results have been encouraging, there is insufficient evidence to suggest to clinicians that administration of probiotics is associated with significant clinical benefit in critically ill patients. In addition, there is a lack of head-to-head comparative trials with different probiotics to investigate and clarify which probiotic bacterial strains were of most benefit to critically ill patients. Data regarding the superiority of different doses of probiotics and routes of administration are also lacking. The questions that remain to be evaluated in large-scale, randomized controlled trials of probiotics use in NP include the optimal type of probiotic preparation, administration route, dose intensity, timing and duration of administration, safety, patient eligibility, and contraindications.