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


Search Results and Study Characteristics

The chart of the study-selection procedure was presented in Figure 1. Up to 10 October, 2021, 222 citations through the initial search of electronic databases were identified, and only 23 remnant trials, including 20 adult and 3 neonate/child populations studies, were ultimately included in our study. The 23 literatures, including 22 full-text articles and 1 abstract, on probiotics prophylaxis were reported between 2007 and 2021 and enrolled 52 to 2650 patients with a total of 5574 participants. The ages of the patients in adult populations ranged from 39.48 to 74.00 years. In studies eligible for inclusion in our meta-analysis, the follow-up times varied, ranging from 14 to 180 days with the proportion of female patients from 18.46 to 59.28%. Of them, the number of studies on patients treated with placebo/control compared to those treated with prebiotic, synbiotic and probiotic is 1, 4 and 18, respectively. Table 1 depicted the main characteristics of the 23 eligible trials.

Figure 1.

Flow diagram of study selection process

Assessment of Study Quality

As listed in Figure 2, a high risk of both performance and detection bias was presented in three studies[34–36] as a result of lacking of blinding or blind inadequacy. Because of a prematurely termination of schedule,[35,37] an imbalance in several significant baseline variables,[20] an unreached of predetermined sample size[17,19] and the funding provided by third parties,[17,20,38–40] we rated these studies as having high risk of other bias. The quality of the evidence of probiotics in reducing VAP incidence in adult population was "high" (GRADE). Moreover, the quality of the evidence for secondary endpoints ranged from "very low" to "moderate" (Additional file 3: Appendix 3).

Figure 2.

Risk of bias assessment. a Risks of bias summary. b Risks of bias graph

Sensitivity Analysis and Assessment of Reporting Bias

The sensitivity analysis across studies for the primary outcome indicated the influence of each study set to the imputed RR is nonsignificant, demonstrating the stability of pooled estimate.

The publication bias existed by inspection of the funnel plot (Figure 3), which was further confirmed through the Egger's test (P < 0.01). However, the Begg's test (P = 0.81) revealed no significant publication bias for our study. Then, a trim and fill method was used to identify potential publication bias, and the results showed that the impact of this bias is insignificant (Additional file 3: Appendix 3).

Figure 3.

Funnel plot for publication bias. The blue dots and dotted line represent one single studies and 95% confidence intervals, respectively.

Synthesis of Primary Outcome

All 23 studies reported the main outcome of interest and the synthesized RR was 0.67 (n = 5543; 95% CI = 0.56 to 0.81; P < 0.01), with a moderate heterogeneity among these studies (X2 = 53.60, P < 0.01; I2 = 59.00%, Figure 4). Meanwhile, the combined RR was 0.69 (n = 5136; 95% CI = 0.57 to 0.84; P < 0.05) for adults studies and 0.55 (n = 407; 95% CI = 0.31 to 0.99; P = 0.046) for neonates/children studies.

Figure 4.

Forest plot of pooled data demonstrating the reduction in risk of ventilator-associated pneumonia incidence. RR relative risk, CI confidence interval

As shown in Figure 5, although the accrued number of patients did not reach the required information size (RIS, 84.52%, 5136/6077), the cumulative Z-curve crossed the conventional boundary line and RIS-adjusted boundary value, thus indicating that a favorable effect of probiotic in preventing VAP is observed in adult patients. As revealed in Additional file 3: Appendix 3, however, the TSA of neonates/children patients showed that the cumulative Z-curve did not reach the adjusted boundary line and the optimal information size despite this line surpass the conventional boundary line slightly, indicating that the current evidence is inconclusive.

Figure 5.

Trial sequential analysis for effects of probiotics on VAP incidence in adult patients. The required information size of 6077 was calculated based on the VAP incidence of 20.69, 25.27% in the probiotic and placebo group, respectively (α = 5%, β = 20%, I2 = 56.40%)

Synthesis of Secondary Outcomes

Compared with the control (placebo) group, the probiotic (prebiotic, synbiotic) group had no significant effect on the ICU/hospital/28-/90-day mortality, bacteremia, CRBSI, diarrhea, ICU-acquired infections, infectious complications, pneumonia, UTI and wound infection (P > 0.05 for all, Additional file 3: Appendix 3).

The Results of Subgroup Analyses and Cumulative Meta-analysis in Adult Patients

From the prebiotic (n = 60; RR, 0.47; 95% CI = 0.22 to 0.98; P = 0.04), synbiotic (n = 516; RR, 0.57; 95% CI = 0.33 to 0.98; P = 0.04) and probiotic (n = 4560; RR, 0.74; 95% CI = 0.59 to 0.91; P = 0.01) analysis, the incidences of VAP in MV critically ill patients were proven to be significantly reduced by the use of this treatment. In subgroup analysis based on the risk of bias, a positive result was observed both in trials reporting low risk of bias (n = 3610; RR, 0.62; 95% CI = 0.45 to 0.85; P < 0.01) and in those reporting high risk of bias (n = 1526; RR, 0.76; 95% CI = 0.59 to 0.97; P = 0.03). This was also confirmed by another subgroup analysis of multi-center trials (n = 3729; RR, 0.64; 95% CI = 0.46 to 0.89; P = 0.01) versus single-center trials (n = 1407; RR, 0.73; 95% CI = 0.58 to 0.91; P = 0.01; Additional file 3: Appendix 3). Details of the results of this meta-analysis were shown in Table 2.

Although no statistical significance that prophylactic probiotic among adult patients could result in a reduction of VAP incidence could be achieved before 2016 Zarinfar[41] studies showed a consistently positive result thereafter (Figure 6).

Figure 6.

Cumulative meta-analysis showing the cumulative evidence of the efficacy of probiotic in preventing VAP in adult critically ill patients undergoing MV. VAP ventilator-associated pneumonia, MV mechanical ventilation, RR relative risk, CI confidence interval