Efficacy of probiotics or synbiotics in critically ill patients: A systematic review and meta- analysis

doi:10.21203/rs.3.rs-3123743/v1

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Efficacy of probiotics or synbiotics in critically ill patients: A systematic review and meta- analysis

https://doi.org/10.21203/rs.3.rs-3123743/v1

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Background

This latest systematic review and meta-analysis aim to examine the effects of probiotic and synbiotic supplementation in critically ill patients.

Methods

Relevant articles were retrieved from PubMed, Embase, the Cochrane Database, and the Web of Science. The primary output measure was the incident of vendor associated pneumonia, and the secondary outputs were diarra, Clostridium diffusion infection (CDI), incident of sepsis, incident of hospital acquired pneumonia, incident of any infection, duration of mechanical exploitation, in hospital morality, length of hospital stay, ICU morality rate, And length of ICU stay. Data were pooled and expressed as relative risk (RR) and standardized mean difference (SMD) with a 95% confidence interval (CI).

Results

Third three studies were included in this systematic review and meta-analysis, with 4065 patients who received probiotics or synbiotics (treatment group) and 3821 patients who received standard care or placebo (control group). The pooled data from all included studies demonstrated that the treatment group has significantly reduced incidence of vessel associated pneumonia (VAP) (RR = 0.80; 95% CI: 0.67–0.96; p = 0.021, I2 = 52.5%) and sepsis (RR = 0.97; 95% CI: 0.66–1.42; p = 0.032, I2 = 54.4%), As well as significantly increased duration of mechanical exploitation (SMD=-0.47; 95% CI: -0.74–0.20, p = 0.012, I2 = 63.4%), length of hospital stay (SMD=-0.33; 95% CI: -0.57–0.08, p = 0.000, I2 = 74.2%), ICU mobility (RR = 0.95; 95% CI: 0.71–1.27; p = 0.004, I2 = 62.8%), And length of ICU stay [SMD=-0.29; 95% CI: -0.58-0.01; p = 0.000, I2 = 82.3%)] than the control group There were no significant differences in diarra, CDI, incidence of hospital acquired pneumonia, and in hospital morality between the two groups.

Conclusion

Our meta-analysis showed that probiotic and synbiotic supplements are beneficial for critically ill patients as they significantly reduce the incidence of vendor associated pneumonia and sepsis, as well as the duration of mechanical exploitation, length of hospital stay, length of ICU stay, and ICU morality How, this intervention has minimal impact on diarra, CDI, incidence of hospital acquired pneumonia, and in hospital morality in critically ill patients.

Critically ill patients

Probiotics

Synbiotics

Meta-analysis

Ventilator-associated pneumonia

Mortality

Mechanical ventilation is the most important life support in the intensive care unit (ICU)[1] and has saved countless lives. Ventilator-associated pneumonia (VAP) is a common nosocomial infection in patients under mechanical ventilation in the ICU, and its development is associated with prolonged duration of mechanical ventilation, length of stay in hospital, hospitalization costs, and increased mortality[2]. Recent studies have demonstrated that the main infection route of VAP[3] includes oropharyngeal secretions entering the lower respiratory tract of patients along the tracheal cannula, and regurgitation of bacteria from the stomach into the lower respiratory tract due to the relaxation of the esophageal sphincter caused by prolonged nasal feeding. Due to injuries (infection and trauma), weakened gastrointestinal motility, and disturbed hormone levels, ICU patients have a disrupted intestinal microbiota characterized by an overgrowth of pathogens, which can consequently lead to VAP. Studies have shown that VAP can be prevented by eliminating the pathogen itself or blocking the bacterial infection route using antibiotics, selective intestinal disinfection, semi-reclining position breathing, tracheal intubation, chlorhexidine mouthwash, or drainage of subglottic secretions. The prevention of VAP is critical for improving the success rate of rescue in patients requiring chronic mechanical ventilation.

The gastrointestinal tract is the largest immune organ in the body, and the integrity of the intestinal barrier is key to the functional homeostasis of the intestinal mucosa and resistance to various diseases. It was reported that probiotic strains can protect intestinal barrier integrity[4] and treat or prevent certain diseases in the host[5]. In addition, probiotics can induce the release of antimicrobial factors from host cells, inhibit immune cell proliferation, stimulate IgA production, and promote antioxidant activity[6]. Synbiotics are inactive oligosaccharides that serve as nourishment for probiotics and have been shown to promote the growth and reproduction of probiotics. Probiotics and synbiotics are increasingly being used in the clinical setting. A growing body of work has reported that the addition of exogenous probiotics or synbiotics can lower the incidence of VAP and improve the prognosis of patients in ICU. However, whether oral probiotics or synbiotics can help prevent VAP is still controversial, and studies on the clinical efficacy of probiotics in VAP prevention have been inconsistent[7]. Therefore, this systematic review is aimed to assess the efficacy and safety of probiotics or synbiotics in preventing VAP in critically ill patients in the ICU.

The research protocol, outcomes, and relevant items in this systematic review were reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) Statement[8]. The protocol for this meta-analysis has been registered with PROSPERO (CRD42023398511).

2.1 Data source and search strategy

Relevant articles were searched in PubMed, Embase, the Cochrane Library, and the Web of Science using subject headings and keywords containing “critical ill”, “critically ill”, “Critically illnesses”, “Illness*, Critical”, “Critically Ill”, “probiotic”, “probiotics”, “synbiotic” and “synbiotics”. In addition, the references of the included studies and relevant review articles were screened to identify eligible clinical trials that were not found through the database searches. The identified articles were imported, stored, and managed by EndNote 20. Each search result was independently reviewed for eligibility by two authors (Shengyong Cui, Jiaqi Lou), and any disagreement was resolved by the corresponding author (Jiliang Li).

2.2 Eligibility criteria

Inclusion criteria: (1) Type of study: Randomized controlled trial (RCT) or retrospective cohort studies; (2) Participants: Critically ill patients of all ages; (3) Intervention: Probiotics alone or in combination with prebiotics (synbiotics) compared with placebo; and (4) Outcomes: Incidences of ventilator-associated pneumonia, diarrhea, Clostridium difficile infection (CDI), sepsis, hospital-acquired pneumonia, and any infection; Duration of mechanical ventilation, in-hospital mortality, length of hospital stay, ICU mortality, and length of ICU stay.

Exclusion criteria: (1) Studies that did not meet the inclusion criteria, which included but were not limited to case reports, conference abstracts, letters, responses, short comments, clinical guidelines, animal experiments, cell experiments, research protocols, reviews, systematic reviews or meta-analysis; (2) Studies without clear inclusion and exclusion criteria; (3) Outcomes that had not been clearly stated; (4) Uncontrolled studies; (5) Preclinical studies in animal models. If multiple articles reported the same or overlapping data, the article with the longer duration of the intervention or larger sample size was included in this study.

2.3 Data extraction and quality assessment

Articles were independently selected by two authors by screening the titles and/or abstracts, and full-text articles were then evaluated for eligibility and adequacy in information. For each study that fulfilled the eligibility criteria, study sources (author, publication year, and country), characteristics of study population (sample size, study design, type of subjects, male to female ratio, baseline mean age, sequential organ failure assessment score and acute physiology Ⅱ score), characteristics of prebiotic, probiotic, and synbiotic species (type, dosage, duration of intervention), and outcomes (including at least one of the following: Incidence of ventilator-associated pneumonia, diarrhea, CDI, sepsis, hospital-acquired pneumonia, duration of mechanical ventilation, in-hospital mortality, length of hospital stay, ICU mortality and length of ICU stay) were extracted using a standard data extraction template.

The methodological quality of each included RCT was assessed using the Cochrane Collaboration’s risk of bias tool[9] based on the Cochrane Handbook for Systematic Reviews of Interventions Version 5.0.1. The risk of bias for each item was judged as low, high, or unclear based on the criteria of the Cochrane Handbook for Systematic Reviews. Data extraction and quality assessment were performed independently by two authors (Shengyong Cui, Jiaqi Lou), and any discrepancy was settled by discussion and consensus. When a consensus was not reached, a third researcher (Jiliang Li) acted as an arbitrator. Data synthesis was performed using Review Manager (RevMan) 5.4. The quality of case-control studies and cohort studies was assessed by the Newcastle-Ottawa Scale (NOS)[10].

2.4 Statistical analysis

Data were extracted independently by two authors (Jiaqi Lou and Guoying Jin) from the full texts of the studies and compiled into shared sheets. The following information was collected from the included studies: first author, year of publication, duration of treatment, study design, inclusion and exclusion criteria, intervention and number of subjects, and primary and secondary outcomes. Data were validated by a third author (Cui Chen) using a standardized method. The methodological quality assessment shown in Table S1 was based on the Cochrane Reviewers’ Handbook[11]. Discrete numerical variables were reported in risk ratio (RR) and 95% confidence intervals (CIs). Continuous variables are expressed as mean difference (MD). The standardized mean difference (SMD) was used as a summary statistic in this meta-analysis due to the application of different methods to assess the same outcome. When the standard deviations (SDs) of mean differences were not provided in the study, SDs for the changes from baseline were calculated by: SD² change = SD² baseline + SD² final − (2 × correlation coefficient × SD baseline × SD final, assuming that the correlation coefficient (R) was 0.5[9]. The I² statistic was used to quantify heterogeneity, and forest plots were generated and double-checked by two authors (Jiaqi Lou and Jiliang Li). If I² < 50%, the pooled outcomes were considered to have low statistical heterogeneity, and if I² > 50%, the pooled outcomes were considered to have high statistical heterogeneity[12]. Each low heterogeneity analysis was estimated using a fixed-effects model, otherwise, the random-effects model was applied. The possible sources of heterogeneity were analyzed using one or more of the following methods: (i) Subgroup analyses based on the characteristics of age, type of intervention, research design, follow-up duration, and type of intervention; and (ii) leave-one-out sensitivity analysis by omitting the studies one by one to identify which RCT(s) caused the heterogeneity and how each contributed to the overall analysis. The potential publication bias in each analysis was assessed using funnel plots, Egger’s regression test and sensitivity analysis, in which p < 0.05 was considered statistically significant. When there was evidence of funnel plot asymmetry or the Egger’s regression test result was statistically different, potentially missing studies were substituted using the “trim and fill” method to estimate the effect of publication bias on the observed pooled effect size[13]. In case of a significant result, the number of potentially missing studies required to make the p-value non-significant was estimated using the “fail-safe N” method. All statistical analyses were performed using StataSE 15.1. A P < 0.05 was considered statistically significant for all tests except for the heterogeneity test, in which case a P < 0.10 was used.

3.1 Characteristics of included studies

The PRISMA statement flowchart illustrated in Fig. 1 shows the process of study selection. Of the 922 records initially identified from the database search, 271 were duplicates filtered by software and 30 were duplicates filtered by manual screening. Of the 621 remaining articles, 548 were excluded based on the articles’ title/abstract, and 103 were reviewed. The detailed full-article review resulted in 33 trials that met our inclusion criteria and were thus included in the present systematic review and meta-analysis. The summarized characteristics of the 29 RCTs and 4 retrospective cohort studies are shown in Table S1[3, 5, 14–44]. A total of 7,886 patients were grouped into the probiotics or synbiotics group (n = 4065) and control group (n = 3821).

The majority of the studies were randomized, parallel-group, placebo-controlled trials. All clinical trials were double-blinded except for the studies conducted by reference[3, 27, 28, 33]. Four studies were retrospective cohort studies[15, 20, 22, 26], and 8 were multi-center studies[5, 18, 19, 24, 32, 33, 39, 42]. These trials were published between 2004 and 2022, with sample sizes in individual trials ranging from 19 to 2650. A total of 32 trials were published in English and 1 trial was published in Spanish. Eight trials were carried out in the United States, four trials each were in Iran and China, three trials each in the United Kingdom and India, two each were in Australia, Canada and Greece, and one each in Saudi Arabia, Malaysia, Spain, Thailand, and Netherlands. The participants’ ages at the time of intervention ranged in all-age. The detailed information of the included studies is summarized in Table S1.

Interventions in the included trials consisted of different forms of probiotics, synbiotics, or prebiotics. Twenty-five trials investigated the efficacy of probiotics and eight assessed the efficacy of synbiotics. All drugs were given orally or through tube feeding, and the composition of probiotics and synbiotics administered in each group varied among studies. Furthermore, probiotics and synbiotics were administered in different dosage forms, and the duration of the intervention durations also varied among trials.

3.2 Risk of bias and quality assessment of individual studies

Four cohort studies were assessed by the NOS and 29 RCTs were assessed by the Cochrane Collaboration risk of bias tool. The characteristics of the included studies and their designs are shown in Fig. 2, and Table 1, which summarizes the risk of bias of the included trials based on different quality domains of the risk of bias tool. Among the 4 cohort studies, the study acomplished by Sato[15] was scored 8 points, the study by Fleming et al. 2019 was scored 8 points, (2) the study by Shimizu et al. 2018 was scored 7 points, the study by Kenna et al. 2016 was scored 5 points. The NOS scores of the four cohort studies all exceeded 5 points, and thus all of these studies were included for subsequent meta-analysis. In the 29 RCTs, the outcome assessors were double-blinded in 86% (25/29) of the trials, and adequate randomized sequence generation was reported in 79% (23/29) of the trials but was unclear in the remaining six RCTs. For the remaining 3 RCTs, 1 was single-blinded[27], 1 was non-blinded[28], and 1 was an open-label crossover trial[33]. All of the 29 RCTs, except 9 RCTs, had a low risk of bias in allocation concealment. While most of the RCTs had a low risk of bias in the blinding of participants and key study personnel, r RCTs had high risks of bias, and 4 RCTs had unclear risks of bias. In addition, all of the RCTs showed a low risk of bias for incomplete outcome data and selective outcome reporting.

Table 1

Quality assessment of 4 retrospective cohort studies using the Newcastle-Ottawa Scale (NOS).
Study, year	Selection				Comparability	Outcome			NOS Score
Study, year	Adequate definition of cases	Representativeness of the cases	Selection of controls	Definition of controls	Control for important factor	Ascertainment of exposure	Same method of ascertainment for cases and controls	Nonresponse rate
Sato et al. 2022	1	1	1	1	2	1	0	1	8
Fleming et al. 2019	1	1	1	1	2	1	0	1	8
(2)Shimizu et al. 2018	1	1	1	1	1	1	0	1	7
Kenna et al. 2016	1	1	1	0	1	0	1	0	5
The Newcastle-Ottawa Scale (NOS) evaluates cohort studies and case-control studies through three sections (eight items in total), including selection, comparability, exposure or outcome. The full score is 9 points. Our research team evaluated each selected cohort study.

3.3 Meta-analysis findings

3.3.1 Incidence of VAP

Eleven studies[5, 19, 21, 22, 24, 28, 33, 36–39] reported data on the incidence of VAP. Quantitative pooling of data revealed a significantly lower incidence of VAP in patients receiving probiotics or synbiotics compared with controls (RR = 0.80; 95% CI: 0.67–0.96; p = 0.021, I² = 52.5%) (Fig. 2B). The Egger’s regression test result indicated no significant difference between the two groups (p = 0.310). However, subgroup analysis showed a significantly lower incidence of VAP only in patients receiving probiotics (RR = 0.79, 95% CI: 0.64–0.98, p = 0.008, I² = 61.3%) and not in those receiving only synbiotics (RR = 0.85, 95% CI: 0.55–1.33, p = 0.531, I² = 0.0%). Subgroup analysis of 11 research designs of the included studies also ascertained that the use of probiotics or synbiotics in 10 RCTs reduced the incidence of VAP (RR = 0.82, 95% CI: 0.68–0.98; p = 0.023, I² = 53.4%), but the same conclusion could not be drawn in the cohort studies (Fig. 3, Figures S1 and S2).

Considering that the patient populations included adults, children, and infants, we decided to conduct a subgroup analysis of VAP stratified by age. Only one study included in the subgroup analysis of VAP indicators was targeted at children[28]. The subgroup analysis showed that probiotics or synbiotics treatment reduced VAP incidence, regardless of adults or children. In addition, we performed a subgroup analysis of VAP stratified by trial designs in which only one study was a retrospective cohort study[22], and obtained the same results as the age-stratified subgroup analysis. In the sensitivity analysis, the removal of individual study did not lead to a significant change in the OR values (Fig. 4). Table 2 summarizes the results of different subgroup analyses of VAP.

Table 2

Subgroup analysis of VAP by outcome
Subgroup	No. of trials	No. of participants	RR	95% CI	I² (%)	p for heterogeneity	p for heterogeneity among groups
Probiotics or Synbiotics
Probiotics	9	4019	0.79	0.64–0.98	61.3	0.008	0.021
Synbiotics	2	331	0.85	0.55–1.33	0.0	0.531	0.021
Adult or Children
Adult	10	4200	0.82	0.68-1.00	52.0	0.027	0.021
Children	1	150	0.59	0.35–0.97	0.0	0.000	0.021
Trial design
RCT	10	4171	0.82	0.68–0.98	53.4	0.023	0.021
Retrospective cohort study	1	179	0.49	0.22–1.13	0.0	0.000	0.021

3.3.2 Diarrhea

Complete data on diarrhea were available in 4 studies. Pooled data from these trials demonstrated that there was no significant difference in the incidence of diarrhea between the treatment and control groups (RR = 1.03; 95% CI: 0.98–1.09, p = 0.174, I² = 39.6%). The funnel plot showed no evidence of publication bias, and Egger’s regression test result was not statistically different (p = 0.310) (Fig. 5, Figure S3 and S4). Sensitivity analysis showed no significant change in the result after excluding each study.

3.3.3 Incidences of CDI, sepsis, and hospital-acquired pneumonia

The risk of CDI was not significantly different between the treatment and control groups in four trials (RR = 1.11; 95% CI: 0.73–1.70, p = 0.384, I² = 1.7%), but the incidence of sepsis was significantly lower in the treatment group than in the control group in eight trials (RR = 0.97; 95% CI: 0.66–1.42, p = 0.032, I² = 54.4%). Subgroup analysis of sepsis incidence by trial design showed that probiotics or synbiotics had no effect on the incidence of sepsis in two cohort studies (RR = 1.34; 95% CI: 0.82–2.19, p = 0.396, I² = 0.00%)[20, 22], but lowered the incidence of sepsis in six RCTs (RR = 0.85; 95% CI: 0.51–1.40, p = 0.023, I² = 61.8%). There was no difference in the incidence of hospital-acquired pneumonia between patients receiving probiotics or synbiotics and those receiving placebo (p > 0.05 for all). Both the funnel plot and Egger's test showed no publication bias in these analyses (p for Egger's test was 0.861, 0.588, 0.628). There was no significant change in the pooled 95% CI upon removal of each study (Figs. 6–9 and Figures S5-S10).

3.3.4 Duration of mechanical ventilation

Meta-analysis of seven trials showed that the duration of mechanical ventilation was significantly shorter in the treatment group than in the control group (SMD = -0.47; 95% CI: -0.74 – -0.20, p = 0.012, I² = 63.4%) (Figure S5). The I² statistic indicated a high heterogeneity among the studies. However, funnel plot symmetry and the lack of significant difference in the Egger’s regression test (p = 0.361) indicated that there was no detectable publication bias. We then conducted a subgroup analysis and found that both probiotics and synbiotics can reduce mechanical ventilation time in critically ill patients (Figs. 10–11 and Figures S11-S12).

3.3.5 ICU mortality and length of ICU stay

ICU mortality data was reported in ten studies. There was a significant difference in ICU mortality between the treatment and control groups (RR = 0.95; 95% CI: 0.71–1.27, p = 0.004, I² = 62.8%). There was no significant publication bias in the selected studies, as indicated by funnel plot symmetry and the lack of significant difference in the Egger’s regression test (p = 0.361). Subgroup analysis also revealed that probiotics or synbiotics could reduce ICU mortality (Figs. 12–13, Figure S13-S14).

Probiotics and synbiotics were associated with a significant improvement in the length of ICU stay in eleven studies (SMD = -0.29; 95% CI: -0.58–0.01, p = 0.000, I² = 82.3%). Neither the funnel plot nor the Egger’s regression test indicated the presence of publication bias (p = 0.241). In addition, subgroup analysis showed that both probiotics and synbiotics alone could reduce the length of ICU stay in critically ill patients. Sensitive analysis showed that no single study qualitatively altered the pooled mortality and length of ICU stay, providing evidence for the stability of the meta-analysis (Figs. 14–15 and Figures S15-S16).

3.3.6 In-hospital mortality and the length of hospital stay

In-hospital mortality was significantly different between the treatment and control groups (RR = 0.94; 95% CI: 0.66–1.03, p = 0.947, I² = 0.0%). The funnel plot was partially symmetrical, and Egger’s regression for funnel plot asymmetry revealed no risk of publication bias (p = 0.302). Subgroup analysis by intervention type showed that neither synbiotics nor probiotics were effective in reducing in-hospital mortality (Figs. 16–17 and Figures S17-S18).

Both the meta-analysis and subgroup analysis by intervention type demonstrated that probiotics or synbiotics can reduce the hospitalization time of critically ill patients (SMD = -0.33; 95% CI: -0.57 – -0.08, p = 0.000, I² = 74.2%). Visual inspection of the funnel plot and further evaluation by Egger’s test indicated no publication bias (p = 0.307). Sensitivity analysis revealed no substantial change in hospitalization time after omitting each of the sixteen studies, confirming the stability of the results (Figs. 18–19 and Figures S19-20).

The intestinal microbiota is a complex microbial community that plays an irreplaceable role in human life. Intestinal dysbiosis is very common in patients with critical illnesses[45, 46]. Since the gut microbiome is critical for maintaining host immunity, disruption of the gut microbiome may result in life-threatening host responses to injuries such as trauma, burns, and infections, which can lead to tissue and organ damage and even death[47]. It was recently reported that ecological dysregulation in ICU patients may affect survival and contribute to organ failure, kidney failure, heart failure, or respiratory failure[48].

Microbe-modulating therapies, in the forms of prebiotics, probiotics, and synbiotics, offer a promising approach for healthcare professionals to manage the progression of serious diseases and associated complications due to their low cost and potentially harmless nature. A study investigating the modulation of microbiota in the treatment of acute respiratory distress syndrome[49] found that selective decontamination of the digestive tract can effectively control the incidence of aspiration pneumonia. Furthermore, probiotics have been shown as a potential approach for restoring the gut microbiome in chronic kidney disease[50]. There is increasing evidence demonstrating that probiotics therapy can reduce systemic inflammation, postoperative infection, and even mortality by modulating the gut microbiome[51–53]. Although some studies have explored the relationships between probiotics or synbiotics supplements and gut barrier function, changes in gut microbiota, and some clinical outcomes in critically ill patients, the results have been inconsistent. A meta-analysis of the pooled data from 25 RCTs affirmed that symbiotic therapy significantly reduced the risk of sepsis complications[54]. However, to the best of our knowledge, there is no meta-analysis that simultaneously assessed the effects of probiotics and synbiotics administration on ventilator-associated pneumonia and included cohort studies and patient populations of all ages. Therefore, in this systematic review and meta-analysis, we examined the efficacy of probiotics and synbiotics on several clinical outcomes including VAP from 33 clinical trials (RCTs and cohort studies) to provide support for the clinical application of these supplementations.

Our finding that probiotics or synbiotics can lower the incidence of VAP is consistent with those from a previous meta-analysis by Batra[55], which included nine trials of probiotic intervention in critically ill patients and found a similarly pronounced reduction in the duration of mechanical ventilation, length of ICU stay, and in-hospital mortality in the intervention group. This conclusion may have been influenced by other factors in the included studies such as study quality, population characteristics, and microbial classification, all of which can lead to varying estimates of the therapeutic efficacy of probiotics or synbiotics. In order to account for these confounding factors, we conducted further subgroup analyses and took into account the presence of outcome bias. Ten RCTs suggested the same result, and only one cohort study did not support the efficacy of enteric microbiotherapy in reducing the incidence of VAP. However, the reduction in the incidence of VAP was only significant in patients receiving probiotics, accompanied by high heterogeneity, but not in those receiving synbiotics. Although the latter group had low heterogeneity, we still believed that there was some clinical heterogeneity since there were only two trials that had a synbiotics group. Similar heterogeneity was observed in subgroup analyses of patients of different ages, with probiotics or synbiotics reducing the incidence of VAP in critically ill adult patients, but no associated benefit in critically ill pediatric patients. Our meta-analysis of seven studies suggested a significant reduction in the number of days of mechanical ventilation between the treatment and control groups, and both probiotics and synbiotics were found to reduce the duration of mechanical ventilation in critically ill patients in the subgroup analyses. Moreover, we found that neither probiotics nor synbiotics reduced the incidence of hospital-acquired pneumonia, which may be attributed to the small number of relevant studies.

Some meta-analysis studies have shown that probiotics are beneficial for treating acute diarrhea in pediatric patients[56, 57], but the patient population of these studies did not include pediatric patients in ICU. Other studies[58, 59] also showed that probiotics play a role in preventing antibiotic-associated diarrhea in adults, but they did not examine ICU patients. Our study reported no significant difference in the incidence of diarrhea between the treatment and control groups. We could not perform a subgroup analysis of the effect of age on probiotics in reducing diarrhea due to few trials.

According to a review[60], some strains of probiotics and/or prebiotics could be effective in supporting the growth and metabolism of anaerobic bacteria. The Infectious Diseases Society of America also does not recommend the use of probiotics for the prevention of CDI[61]. In our study, there was no significant change in the risk of CDI with probiotics or synbiotics use compared with placebo among critically ill patients, indicating no benefit from gut microbial agents.

Sepsis is a strong host response to infection, and its management remains a major challenge. In recent years, the use of gut microbiomes in the treatment of sepsis has attracted some attention. The maintenance or restoration of the microbiota and its metabolites may be a therapeutic or prophylactic approach for treating sepsis[62]. Samara et al.[63] found that supplementation with a probiotic mixture enhanced gut microbiome maturation and reduced intestinal tract inflammation in extremely preterm infants. Another double-blinded placebo-controlled randomized clinical trial[64] also concluded that supplementation with probiotics reduced IL-1β and LPS levels in patients. These findings suggest that probiotics have the potential function of attenuating host inflammatory responses. Our meta-analysis ascertained that probiotics or synbiotics can reduce the incidence of sepsis in critically ill patients, even after the removal of studies with a high risk of bias.

We also evaluated the effects of probiotics or synbiotics on the length of hospital and ICU stay and in-hospital and ICU mortality. Except for in-hospital mortality, the other three clinical outcomes were improved with either probiotic or synbiotics treatment. Our results were similar to those from the systematic review and meta-analysis conducted by Manzanares et al.[65] and Alsuwaylihi et al.[66], which were focused on probiotics alone. Interestingly, the benefits of synbiotics in reducing the length of ICU stay, ICU mortality and length of hospital stay were also found in our subgroup analyses, providing new evidence for the clinical application of probiotics or synbiotics in the future. However, limitations of this study include small sample size, personal equation in the process of data extraction, and different composition and dosage of the intervention. Therefore, our findings should be interpreted with caution. Future high-quality studies of other diseases and various populations in the ICU are warranted to determine whether probiotics or synbiotics can significantly reduce the overall risk of the described clinical outcomes in order to provide more insights into the form, composition, and frequency of this supplementation for optimal outcomes.

Probiotics or synbiotics supplementation plays a beneficial role in critically ill patients and presents a novel approach to the management of critical diseases. This systematic review and meta-analysis supports the potential role of probiotics or synbiotics in reducing the incidence of VAP and sepsis, as well as the duration of mechanical ventilation, length of hospital stay, length of ICU stay, and ICU mortality in critically ill patients.

VAP: Ventilator-Associated Pneumonia; HAP: Hospital Acquired Pneumonia; ICU: Intensive Care Unit; IL-1β: Interleukin-1β; LPS: Lipopolysaccharide.

Ethics approval and consent to participate

Not applicable

Consent for publication

Not applicable

Availability of data and materials

Data sharing not applicable to this article as no datasets were generated or analysed during the current study

Conflicts of Interest

The authors declare that they have no competing interests

Funding

This work was supported by the Zhejiang Provincial Medical and Health Science and Technology Program Project [grant number 2023RC081]; and the Project of NINGBO Leading Medical & Health Discipline [grant number 2022-F17]. Funders played no role in the study design, execution or manuscript writing.

Authors’ contributions

JQ Land SY C contributed equally to this work. JQ L, YF F and JL L designed and conceptualized the study. JQ L, SY C, N H and GY J completed the record retrieval and data extraction. Mathematical modeling and meta-analysis were conducted with the help of C C and C Z. The original draft was written by JQ L. All authors have read and agreed to the published version of the manuscript.

Acknowledgements

Not applicable

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No competing interests reported.

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Efficacy of probiotics or synbiotics in critically ill patients: A systematic review and meta- analysis

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Abstract

Background

Methods

Results

Conclusion

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1. Background

2. Methods

2.1 Data source and search strategy

2.2 Eligibility criteria

2.3 Data extraction and quality assessment

2.4 Statistical analysis

3. Results

3.1 Characteristics of included studies

3.2 Risk of bias and quality assessment of individual studies

3.3 Meta-analysis findings

3.3.1 Incidence of VAP

3.3.2 Diarrhea

3.3.3 Incidences of CDI, sepsis, and hospital-acquired pneumonia

3.3.4 Duration of mechanical ventilation

3.3.5 ICU mortality and length of ICU stay

3.3.6 In-hospital mortality and the length of hospital stay

4. Discussion

5. Conclusions

Abbreviations

Declarations

References

Additional Declarations

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