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Effect of Probiotics on Incident Ventilator-Associated Pneumonia in Critically Ill Patients: A Randomized Clinical Trial
Abstract
Importance
Growing interest in microbial dysbiosis during critical illness has raised questions about the therapeutic potential of microbiome modification with probiotics. Prior randomized trials in this population suggest that probiotics reduce infection, particularly ventilator-associated pneumonia (VAP), although probiotic-associated infections have also been reported.
Objective
To evaluate the effect of Lactobacillus rhamnosus GG on preventing VAP, additional infections, and other clinically important outcomes in the intensive care unit (ICU).
Design, Setting, and Participants
Randomized placebo-controlled trial in 44 ICUs in Canada, the United States, and Saudi Arabia enrolling adults predicted to require mechanical ventilation for at least 72 hours. A total of 2653 patients were enrolled from October 2013 to March 2019 (final follow-up, October 2020).
Interventions
Enteral L rhamnosus GG (1 × 10¹⁰ colony-forming units) (n = 1321) or placebo (n = 1332) twice daily in the ICU.
Main Outcomes and Measures
The primary outcome was VAP determined by duplicate blinded central adjudication. Secondary outcomes were other ICU-acquired infections including Clostridioides difficile infection, diarrhea, antimicrobial use, ICU and hospital length of stay, and mortality.
Results
Among 2653 randomized patients (mean age, 59.8 years [SD], 16.5 years), 2650 (99.9%) completed the trial (mean age, 59.8 years [SD], 16.5 years; 1063 women [40.1%.] with a mean Acute Physiology and Chronic Health Evaluation II score of 22.0 (SD, 7.8) and received the study product for a median of 9 days (IQR, 5-15 days). VAP developed among 289 of 1318 patients (21.9%) receiving probiotics vs 284 of 1332 controls (21.3%; hazard ratio [HR], 1.03 (95% CI, 0.87-1.22; P = .73, absolute difference, 0.6%, 95% CI, –2.5% to 3.7%). None of the 20 prespecified secondary outcomes, including other ICU-acquired infections, diarrhea, antimicrobial use, mortality, or length of stay showed a significant difference. Fifteen patients (1.1%) receiving probiotics vs 1 (0.1%) in the control group experienced the adverse event of L rhamnosus in a sterile site or the sole or predominant organism in a nonsterile site (odds ratio, 14.02; 95% CI, 1.79-109.58; P < .001).
Conclusions and Relevance
Among critically ill patients requiring mechanical ventilation, administration of the probiotic L rhamnosus GG compared with placebo, resulted in no significant difference in the development of ventilator-associated pneumonia. These findings do not support the use of L rhamnosus GG in critically ill patients.
Trial Registration
ClinicalTrials.gov Identifier: NCT02462590
... A recent large multicenter randomized controlled trial (RCT; n ¼ 2650) by Johnstone et al. [3] reported that probiotics (Lactobacillus rhamnosus GG) did not reduce the risk of ventilatorassociated pneumonia (VAP) (hazard ratio 1.03, 95% confidence interval [CI] 0.87e1.22, p ¼ 0.73) and increased the odds of adverse events (14.02, 95% CI 1.79e109.58, ...
... We found 6196 records from databases and other sources, and after removing duplicates and screening the title and abstract, 169 articles were accessed for eligibility. Of these, 75 articles with 71 unique studies were included ( Fig. 1), with a total sample size of 8551 patients [3], [21e41], [42e63], [64e94]. One study was not meta-analyzed because the outcomes were not reported by groups [39]. ...
... Diversity adjusted required information size (DARIS) is the calculated optimum sample size for statistical inference. The most reported AE associated with probiotic administration is the isolation of probiotic species from a sterile site culture or as the sole or predominant organism from a nonsterile site culture (n ¼ 13) [3], followed by bowel ischemia or intestinal ischemia and necrosis (n ¼ 11), reported in two trials conducted in patients with acute pancreatitis and delivered probiotics postpylorically [36,65]. Four SAEs that resulted in death or significant disability were reported in two studies [3,36] (eTable 7 and 18). ...
Background & aims:
Several systematic reviews and meta-analyses of randomized controlled trials concluded that probiotics administration in critically ill patients was safe and associated with reduced rates of ventilator-associated pneumonia and diarrhea. However, a recent large multicenter trial found probiotics administration, compared to placebo, was not efficacious and increased adverse events. An updated meta-analysis that controls for type-1 and -2 errors using trial sequential analysis, with a detailed account of adverse events associated with probiotic administration, is warranted to confirm the safety and efficacy of probiotic use in critically ill patients.
Methods:
RCTs that compared probiotics or synbiotics to usual care or placebo and reported clinical and diarrheal outcomes were searched in 4 electronic databases from inception to March 8, 2022 without language restriction. Four reviewers independently extracted data and assessed the study qualities using the Critical Care Nutrition (CCN) Methodological Quality Scoring System. Random-effect meta-analysis and trial sequential analysis (TSA) were used to synthesize the results. The primary outcome was ventilator-associated pneumonia (VAP). The main subgroup analysis compared the effects of higher versus lower quality studies (based on median CCN score).
Results:
Seventy-five studies with 71 unique trials (n = 8551) were included. In the overall analysis, probiotics significantly reduced VAP incidence (risk ratio [RR] 0.70, 95% confidence interval [CI] 0.56-0.88; I2 = 65%; 16 studies). However, such benefits were demonstrated only in lower (RR 0.47, 95% CI 0.32, 0.69; I2 = 44%; 7 studies) but not higher quality studies (RR 0.89, 95% CI 0.73, 1.08; I2 = 43%; 9 studies), with significant test for subgroup differences (p = 0.004). Additionally, TSA showed that the VAP benefits of probiotics in the overall and subgroup analyses were type-1 errors. In higher quality trials, TSA found that future trials are unlikely to demonstrate any benefits of probiotics on infectious complications and diarrhea. Probiotics had higher adverse events than control (pooled risk difference: 0.01, 95% CI 0.01, 0.02; I2 = 0%; 22 studies).
Conclusion:
High-quality RCTs did not support a beneficial effect of probiotics on clinical or diarrheal outcomes in critically ill patients. Given the lack of benefits and the increased incidence of adverse events, probiotics should not be routinely administered to critically ill patients.
Prospero registration:
CRD42022302278.
... Various studies have shown the positive effect of probiotics in preventing VAP (8)(9)(10)(11). However, some studies reported that the administration enteral of probiotics, compared with placebo among critically ill patients requiring mechanical ventilation, has no statistically significant impact on the development of VAP (9,(12)(13)(14)(15). ...
... It should be noted that probiotics are live microorganisms, so the risk of iatrogenic infections increases with their administration (15,16). A recent meta-analysis showed a positive effect of probiotics in mechanically ventilated patients. ...
... The effectiveness of Limosilactobacillus reuteri DSM 17938 in preventing VAP was first examined in our study. Other studies have used Lactobacillus rhamnosus GG or a combination of several probiotics (7,15,19). The present study is distinctive because it confirmed the microbiologic diagnosis of VAP using lower respiratory tract sampling and quantitative cultures (mini-BAL). ...
PurposeVentilator-Associated Pneumonia (VAP) is one of the most common nosocomial infections in the Pediatric Intensive Care Unit (PICU). Using new strategies to prevent nosocomial infections is crucial to avoid antibiotic resistance. One of these strategies is the utilization of probiotics. This study aims to investigate the efficacy of probiotic prophylaxis in preventing VAP in mechanically ventilated children.Method
This study was a randomized, double-blind clinical trial. The study included 72 children under 12 years of age under mechanical ventilation for more than 48 h in the Mofid Children's Hospital. Patients were randomly divided into Limosilactobacillus reuteri DSM 17938 probiotic recipients (n = 38) and placebo groups (n = 34). In addition to the standard treatment, both groups received a sachet containing probiotics or a placebo twice a day. Children were screened for VAP based on clinical and laboratory evidence.ResultsThe mean age of children in the intervention and placebo groups was 4.60 ± 4.84 and 3.38 ± 3.49 years, respectively. After adjusting the other variables, it was observed that chance of VAP among probiotics compared to the placebo group was significantly decreased (OR adjusted = 0.29; 95% CI: 0.09–0.95). Also, probiotic was associated with a significantly lower chance of diarrhea than the placebo group (OR adjusted = 0.09; 95% CI: 0.01–0.96).Conclusion
Probiotic utilization is effective in preventing the incidence of VAP and diarrhea in children under mechanical ventilation in the PICU.
... However, evidence needs to be considered when evaluating the benefits of probiotics for VAP prevention. Large multicenter RCTs (including 2653 critically ill patients requiring invasive MV) evaluated the effects of probiotics and showed no significant reduction in the incidence of VAP (43). In addition, probiotic or prebiotic supplements do not seem to be associated with a reduction in VAP in patients with trauma (44)(45)(46) or other critically illness (47)(48)(49)(50)(51)(52)(53)(54). ...
... Notably, the primary finding was inconsistent with the results of previous meta-analysis (59,95,96) and RCTs (43,44,46,49,50,52,54,97), which showed that probiotics cannot alleviate VAP in invasive mechanically ventilated patients. The reasons that probiotic supplementation did not improve VAP were complex, and we believe that the following reasons can be discussed: First, the principal limitation of these studies stems from small sample size. ...
... Second, some large clinical trials used a single probiotic strain. Only Lactobacillus rhamnosus was used by Johnstone et al. (43) and Anandaraji et al. (54). Accumulating evidence shows that different strains of probiotics exert beneficial effects through multiple mechanisms and have synergistic effects when supplemented as combinations of strains (99). ...
Background
Ventilator-associated pneumonia (VAP) is one of the common critical complications of nosocomial infection (NI) in invasive mechanically ventilated intensive care unit (ICU) patients. The efficacy of total parenteral nutrition (TPN), enteral nutrition and/or adjuvant peripheral parenteral nutrition (EPN) supplemented with or without probiotic, prebiotic, and synbiotic therapies in preventing VAP among these patients has been questioned. We aimed to systematically and comprehensively summarize all available studies to generate the best evidence of VAP prevention for invasive mechanically ventilated ICU patients.
Methods
Randomized controlled trials (RCTs) for the administration of TPN, EPN, probiotics-supplemented EPN, prebiotics-supplemented EPN, and synbiotics-supplemented EPN for VAP prevention in invasive mechanically ventilated ICU patients were systematically retrieved from four electronic databases. The incidence of VAP was the primary outcome and was determined by the random-effects model of a Bayesian framework. The secondary outcomes were NI, ICU and hospital mortality, ICU and hospital length of stay, and mechanical ventilation duration. The registration number of Prospero is CRD42020195773.
Results
A total of 8339 patients from 31 RCTs were finally included in network meta-analysis. The primary outcome showed that probiotic-supplemented EPN had a higher correlation with the alleviation of VAP than EPN in critically invasive mechanically ventilated patients (odds ratio [OR] 0.75; 95% credible intervals [CrI] 0.58–0.95). Subgroup analyses showed that probiotic-supplemented EPN prevented VAP in trauma patients (OR 0.30; 95% CrI 0.13–0.83), mixed probiotic strain therapy was more effective in preventing VAP than EPN therapy (OR 0.55; 95% CrI 0.31–0.97), and low-dose probiotic therapy (less than 10 ¹⁰ CFU per day) was more associated with lowered incidence of VAP than EPN therapy (OR 0.16; 95% CrI 0.04–0.64). Secondary outcomes indicated that synbiotic-supplemented EPN therapy was more significantly related to decreased incidence of NI than EPN therapy (OR 0.34; 95% CrI 0.11–0.85). Prebiotic-supplemented EPN administration was the most effective in preventing diarrhea (OR 0.05; 95% CrI 0.00–0.71).
Conclusion
Probiotic supplementation shows promise in reducing the incidence of VAP in critically invasive mechanically ventilated patients. Currently, low quality of evidence reduces strong clinical recommendations. Further high-quality RCTs are needed to conclusively prove these findings.
Systamatic Review Registration
[ https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020195773 ], identifier [CRD42020195773].
... While oral probiotics have been trialed as therapeutic interventions in CF (37) and ventilatorassociated pneumonia (VAP) (38), these have deliberately targeted lower intestinal microbiota rather than respiratory communities, and therefore effects on respiratory microbiota remain undetermined. No human studies to date have assessed "respiratory probiotics" (i.e., viable microbiota instilled or aerosolized into the lower respiratory tract). ...
... However, their biologic potency and potential for harm should not be dismissed. In a prominent recent study of enteric probiotics to prevent VAP (38), patients randomized to probiotics (enteral Lactobacillus rhamnosus) derived no benefit with regard to VAP, yet had a significantly increased number of sterile-site Lactobacillus infections (confirmed via sequencing to be the probiotic strain). This important finding should serve as a cautionary warning: if we believe in the therapeutic potency of microbiome interventions, we should not dismiss their comparably potent capacity to cause harm. ...
... Similarly, oral probiotics have negligible effects on lower gut bacterial community composition (60). Finally, the risks of treating patients with viable microbiota are far from zero; recent examples include transmission of virulent pathogens via FMT (61) and sterile site infections caused by probiotic strains in mechanically ventilated patients(38). ...
The last decade of research has revolutionized our understanding of respiratory microbiology, revealing that the lungs and airways contain diverse and dynamic microbial communities in health and disease. This "respiratory ecosystem"-a densely interconnected environment of microbial and host interactions-represents a tremendous and under-appreciated source of biological and clinical heterogeneity across patients with acute and chronic lung disease. Unlike other major sources of heterogeneity, such as comorbidities and host genetics, the respiratory microbiome is readily modifiable by clinical interventions, and therefore represents an untapped opportunity for therapeutic manipulation. As a potential "treatable trait" in efforts to subphenotype patients and deliver precision medicine, the respiratory microbiome is a promising therapeutic target. In this Pulmonary Perspective, we identify and discuss multiple challenges, both conceptual and practical, that must be overcome before the respiratory microbiome can be effectively modulated as a therapeutic target. Barriers include: 1) the need to identify specific microbiologic and ecologic "targets" for therapeutic modulation; 2) the need for an improved understanding of the efficacy and persistence of response to respiratory microbiome-modulating interventions; 3) the need for clinicians to be able to access, understand and utilize microbiome data for sub-phenotyping patients, and 4) specific concerns in special populations (including children, patients with chronic lung disease, and critically ill patients). By delineating these barriers, we identify opportunities for prospective research to advance our understanding of the respiratory microbiome, its role in human respiratory disease, and its genuine potential as a therapeutic target.
... 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][16][17][18]; nonetheless, other studies [19,20] reported promising results, which were further confirmed by several meta-analyses [21][22][23][24][25][26][27][28]. ...
... 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. ...
... 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. ...
Abstract 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
... Moreover, safety outcomes were not assessed. Recently, the results of a large, multicenter RCT, Probiotics to prevent Severe Pneumonia and Endotracheal Colonisation Trial (PROSPECT), were published which did not find a reduced incidence of VAP with the use of probiotics [15]. ...
... The detailed screening process is depicted in Figure 1. After deduplication and screening, a total of 19 reports were included in our review [10,11,15,[26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41]. These 19 reports provided data on 18 RCTs comprising a total of 4893 participants (2409 in the probiotic/synbiotic group and 2484 in the control group) from 13 countries. ...
... Only two studies reported any adverse effects of treatment [15,31]. Johnstone and colleagues reported that the risk of adverse events was significantly higher in the probiotic group (15/1318) than in the placebo group (1/1332) with an OR of 14.02 (95% CI 1.79-109.58) ...
Background:
Presently, there is conflicting evidence regarding the efficacy of probiotics in the prevention of ventilator-associated pneumonia (VAP). This meta-analysis was conducted to update current clinical evidence and evaluate the efficacy and safety of probiotics for the prevention of VAP.
Methods:
We searched three databases and two trial registers to retrieve randomised controlled trials (RCTs) comparing probiotics or synbiotics with placebo or standard treatment for the prevention of VAP in adult patients receiving mechanical ventilation in the intensive care unit (ICU).
Results:
Our meta-analysis included 18 RCTs involving 4893 patients. Our results showed that probiotics may reduce the incidence of VAP (RR 0.68, 95% CI: 0.55-0.84; low certainty). However, in our subgroup and sensitivity analyses, the effect was not significant in double-blind studies, and in studies with a low risk of bias in the randomisation process. Probiotics reduced the length of ICU stay (MD -2.22 days, 95% CI: -4.17 to -0.28; moderate certainty) and the duration of antibiotic use (MD -1.25 days, 95% CI -1.86 to -0.64; moderate certainty).
Conclusions:
Probiotics may reduce the incidence of VAP but due to the low quality of pooled evidence, the use of probiotics warrants caution. Further, large-scale, high-quality RCTs need to be conducted to provide conclusive evidence.
... Some studies have shown that probiotics or synbiotics are more effective than placebo treatments in reducing mortality and the incidence of ventilator-associated pneumonia (VAP) [14,15]. However, other studies find probiotics useless or even engendering adverse effects [16][17][18][19]. Clinicians are puzzled by the conflicting nature of the evidence. ...
... The incidence of VAP Fourteen studies [14,15,18,19,26,27,30,32,36,37,41,42,44,45] reported data on the incidence of VAP. Quantitative pooling of data revealed a significant reduction in the incidence of VAP in patients receiving probiotics or synbiotics (Figure 3). ...
... RCTs [14,18,26,27,33,[37][38][39][40][43][44][45] reported data on the incidence of ICU-acquired infections. Pooling data from RCTs demonstrated that there was no significant difference in the incidence of ICU-acquired infections between the treatment and control groups (RR = 0.92; 95% CI: 0.84-1.01, ...
Background:
Microbial dysbiosis in critically ill patients is a leading cause of mortality and septic complications. Probiotics and synbiotics have emerged as novel therapy on gut microbiota to prevent septic complications. However, current evidence on their effects is conflicting. This work aims to systematically review the impact of probiotics or synbiotics in critically ill adult patients.
Methods:
A comprehensive search of the PubMed, CBM, Embase, CENTRAL, ISI, and CNKI databases was performed to identify randomized controlled trials that evaluate probiotics or synbiotics in critically ill patients. The quality assessment was based on the modified Jadad's score scale and the Cochrane Handbook for Systematic Reviews of Interventions Version 5.0.1. The major outcome measure was mortality. Secondary outcomes included incidence of septic complications, sepsis incidence, length of intensive care unit (ICU) stay, incidence of non-septic complication, and ventilator day. Data synthesis was conduct by Review Manager 5.4.
Results:
A total of 25 randomized controlled trials reporting on 5049 critically ill patients were included. In the intervention group, 2520 participants received probiotics or synbiotics, whereas 2529 participants received standard care or placebo. Pooling data from randomized controlled trials demonstrated a significant reduction in the incidence of ventilator-associated pneumonia (VAP) in the treatment group [(risk ratio (RR) 0.86; 95% confidence interval (CI): 0.78-0.95; p < 0.003, I2 = 85%)]. However, in the subgroup analysis, the reduction of incidence of VAP was only significant in patients receiving synbiotics (RR = 0.61, 95% CI: 0.47-0.80, p = 0.0004, I2 = 40%) and not significant in those receiving only probiotics (RR = 0.91, 95% CI: 0.82-1.01, p = 0.07, I2 = 65%). Moreover, sepsis incidence of critically ill patients was only significantly reduced by the addition of synbiotics (RR = 0.41; 95% CI: 0.22-0.72, p = 0.005, I2 = 0%). The incidence of ICU-acquired infections was significantly reduced by the synbiotics therapy (RR = 0.72; 95% CI: 0.58-0.89, p = 0.0007, I2 = 79%). There was no significant difference in mortality, diarrhea, or length of ICU stay between the treatment and control groups.
Conclusions:
Synbiotics is an effective and safe nutrition therapy in reducing septic complications in critically ill patients. However, in such patients, administration of probiotics alone compared with placebo resulted in no difference in the septic complications.
... In the randomized, placebo-controlled PROSPECT trial in 44 hospitals across three countries, Johnstone et al. investigated whether probiotic administration could lower the incidence of VAP [57]. The study included 2653 patients in the ICU-expected to be on mechanical ventilation for at least 72 h-split evenly between 1 × 10 10 colony forming units of L. rhamnosus GG or placebo twice daily, for a period of sixty days or until discharge. ...
... Several subgroup analyses, including the evaluation of antibiotic treatment, the presence of sepsis and type of ICU admission, did not reveal significant differences either. This is in line with the recent findings by Johnstone et al. that found no differences in ICU and hospital length of stay, or mortality [57]. Moreover, while a meta-analysis of 14 trials reporting on a total of 1233 critically ill patients found a reduction in infections following probiotic treatment (risk ratio 0.80, confidence interval 0.68-0.95) ...
... Moreover, while a meta-analysis of 14 trials reporting on a total of 1233 critically ill patients found a reduction in infections following probiotic treatment (risk ratio 0.80, confidence interval 0.68-0.95) [55], the incidence of infections was not different between groups in the two recent trials (by Johnstone et al. and Litton et al.) [57,59]. The incidence of any infection was 31.4% in both the placebo and the probiotic group (hazard ratio 0.97, confidence interval 0.84-1.11) ...
The understanding of the gut microbiome in health and disease has shown tremendous progress in the last decade. Shaped and balanced throughout life, the gut microbiome is intricately related to the local and systemic immune system and a multitude of mechanisms through which the gut microbiome contributes to the host’s defense against pathogens have been revealed. Similarly, a plethora of negative consequences, such as superinfections and an increased rate of hospital re-admissions, have been identified when the gut microbiome is disturbed by disease or by the iatrogenic effects of antibiotic treatment and other interventions. In this review, we describe the role that probiotics may play in the intensive care unit (ICU). We discuss what is known about the gut microbiome of the critically ill, and the concept of probiotic intervention to positively modulate the gut microbiome. We summarize the evidence derived from randomized clinical trials in this context, with a focus on the prevention of ventilator-associated pneumonia. Finally, we consider what lessons we can learn in terms of the current challenges, efficacy and safety of probiotics in the ICU and what we may expect from the future. Throughout the review, we highlight studies that have provided conceptual advances to the field or have revealed a specific mechanism; this narrative review is not intended as a comprehensive summary of the literature.
... Nosocomial infections remain a leading cause of adverse outcomes in critical illness including mortality, prolonged hospitalization and resource utilization 1,2,43 . The association between microbiota dysbiosis and nosocomial infections has led to clinical trials of microbiota-modifying therapies in critically ill patients, but studies have been hindered by a limited understanding of the mechanisms linking dysbiosis with infections, resulting in untargeted approaches such as probiotics and digestive tract decontamination that have yielded modest or negligible benefits 44,45,46 , as well as possible harm in this vulnerable patient population [47][48][49] . Our findings reveal that pathological microbiota alterations in critical illness may render the host more susceptible to infections via induction of immune dysfunction, suggesting that microbiota therapeutics in the ICU should be targeted at correcting the drivers of microbiota-immune metasystem dysbiosis. ...
... Clinical outcomes of nosocomial infection and death were recorded up to 30 d following ICU admission. Nosocomial infections were identified as newly diagnosed infections occurring at least 48 h after admission, diagnosed by the treating specialist physician, resulting in administration of new antimicrobial treatments and were independently confirmed by a physician member of the study team based on the following definitions: diagnosis of VAP and HAP required the presence of new or progressive radiographic infiltrate on chest radiograph plus two of fever, purulent sputum, white blood cell count >10 × 10 6 l −1 or <3.0 × 10 6 l −1 , as previously described 44 and all cases of VAP met the Center for Disease Control and Prevention National Healthcare Safety Network (CDC NHSN) case definition of probable or definite VAP 59 . Nosocomial BSIs met the CDC NHSN definition of BSI/central-line-associated BSI, UTIs were identified based on Infectious Disease Society of America clinical practice guideline criteria for the diagnosis of catheter-associated urinary tract infections and Clostridium difficile infection was based on the presence of new diarrhea and positive stool testing for C. difficile toxin 60,61 . ...
Critically ill patients in intensive care units experience profound alterations of their gut microbiota that have been linked to a high risk of hospital-acquired (nosocomial) infections and adverse outcomes through unclear mechanisms. Abundant mouse and limited human data suggest that the gut microbiota can contribute to maintenance of systemic immune homeostasis, and that intestinal dysbiosis may lead to defects in immune defense against infections. Here we use integrated systems-level analyses of fecal microbiota dynamics in rectal swabs and single-cell profiling of systemic immune and inflammatory responses in a prospective longitudinal cohort study of critically ill patients to show that the gut microbiota and systemic immunity function as an integrated metasystem, where intestinal dysbiosis is coupled to impaired host defense and increased frequency of nosocomial infections. Longitudinal microbiota analysis by 16s rRNA gene sequencing of rectal swabs and single-cell profiling of blood using mass cytometry revealed that microbiota and immune dynamics during acute critical illness were highly interconnected and dominated by Enterobacteriaceae enrichment, dysregulated myeloid cell responses and amplified systemic inflammation, with a lesser impact on adaptive mechanisms of host defense. Intestinal Enterobacteriaceae enrichment was coupled with impaired innate antimicrobial effector responses, including hypofunctional and immature neutrophils and was associated with an increased risk of infections by various bacterial and fungal pathogens. Collectively, our findings suggest that dysbiosis of an interconnected metasystem between the gut microbiota and systemic immune response may drive impaired host defense and susceptibility to nosocomial infections in critical illness.
... Despite the proposed advantages of probiotics, randomized controlled trials evaluating their impact on sepsis or sepsis related complications in critically ill patients are inconclusive (57)(58)(59). In a meta-analysis evaluating 2972 critically ill patients, probiotics reduced the rate of infections by 20% (risk ratio 0.80, CI 0.68-0.95) ...
... However, in more recent randomized controlled trials, these effects were not demonstrated and, further, some immunocompromised patients developed lactobacillus bacteremia. While the risk of bacteremia has been associated with the probiotic strain containing Lactobacillus rhamnous GG, the potential for other probiotic strains to induce a similar effect cannot be dismissed (57,60). Additional evidence from a systematic review and meta-analysis evaluating the safety of probiotics suggests an association between probiotics and the risk of sepsis, fungemia, and gastric ischemia, with critically ill patients at the highest risk (61). ...
Brain injury resulting from sepsis, or sepsis-associated encephalopathy (SAE), occurs due to impaired end-organ perfusion, dysregulated inflammation affecting the central nervous system (CNS), blood-brain barrier (BBB) disruption, mitochondrial dysfunction, oxidative stress, accumulation of toxic neuropeptides and impaired toxin clearance secondary to sepsis-induced hepatic and renal dysfunction. The gut microbiome becomes pathologically altered in sepsis, which likely contributes to the pathogenesis of SAE. Herein, we review the literature detailing dysregulation of microbiota-gut-brain axis (MGBA) in SAE and highlight potential therapeutic strategies to modulate the gut microbiome to mitigate sepsis-induced brain injury.
... Ventilator-associated pneumonia (VAP) is one of the most common causes of morbidity and mortality in mechanically ventilated patients. 1 It usually develops after 48 hours or longer after mechanical ventilation (MV). The pathogenesis of VAP is complex and usually requires bacterial colonization of the upper digestive tract and aspiration of contaminated secretions into the lower airway. ...
... Johnstone et al in their meta-analysis found that probiotics do not show any beneficial effect on VAP. 1 Probiotics may be ineffective before persisting in the lower digestive tract. 2 Probiotics cannot be general effects and their viability in gut environment is different. Probiotics are nothing but a form of dietary fiber that cannot be digested and good bacteria present in any individual's gut. ...
Context Ventilator-associated pneumonia (VAP) is one of the most common causes of morbidity and mortality in mechanically ventilated patients. Curing and preventing effects of probiotics in promoting the growth of Bifidobacterium in the digestive system and the central role of bacteria colonization in the pathogenesis of VAP are evident.
Aims The purpose of this study was to evaluate the effects of administration of commercially available probiotics, that is, orodispersible probiotic sachets on VAP prevention and clinical outcomes in critically ill patients.
Settings and Design Randomized control trials.
Methods and Materials In this study, 120 mechanically ventilated patients were randomly divided into two groups ( n = 60 per group). Group 1 was given orodispersible probiotic sachets by gavage, twice a day in addition to routine care, while group 2 received only routine care. Demographic and clinical data were analyzed and clinical outcomes to the primary component (prevalence of VAP) and secondary component (other clinical factors) were interpreted.
Statistical Analysis Used In this study, data were analyzed via SAS statistical software version 9.4, using Student's t -test, chi-squared test, repeated measure analysis of variance, and Wilcoxon test.
Results There was a significant reduction in VAP diagnosed patients, as well as Clostridiumdifficile -associated diarrhea and some complications of mechanical ventilation, in group 1 in comparison to group 2. The improvement in VAP was significantly greater for group 1 as compared with group 2. However, the mortality rate was similar between two groups.
Conclusions This study demonstrated that a daily diet with orodispersible probiotic sachets can be used as add-on therapy with other medications in the prevention of VAP. As a result, the use of orodispersible probiotic sachets in the treatment plan of patients undergoing long-term intubation is recommended.
... Previous studies have shown a possible effect of probiotics in reducing the incidence of ventilator-associated pneumonia (VAP) [104,105]. However, subsequent randomized controlled trials (RCTs) yielded conflicting results [106,107]. The results of these studies cannot be generalized because the probiotics used and their dosage varied from study to study, which is a recurrent problem in studies comparing probiotics. ...
... The results of these studies cannot be generalized because the probiotics used and their dosage varied from study to study, which is a recurrent problem in studies comparing probiotics. Other studies using other genera, species, strains or doses are expected to clarify this issue [107]. Although the use of probiotics is an attractive microbiota-targeted therapy, they are not without risk, particularly in ICU patients, where Lactobacillus bacteraemia has been described following probiotic administration [108]. ...
Gut microbiota plays an essential role in health and disease. It is constantly evolving and in permanent communication with its host. The gut microbiota is increasingly seen as an organ, and its failure, reflected by dysbiosis, is seen as an organ failure associated with poor outcomes. Critically ill patients may have an altered gut microbiota, namely dysbiosis, with a severe reduction in "health-promoting" commensal intestinal bacteria (such as Firmicutes or Bacte-roidetes) and an increase in potentially pathogenic bacteria (e.g. Proteobacteria). Many factors that occur in critically ill patients favour dysbiosis, such as medications or changes in nutrition patterns. Dysbiosis leads to several important effects, including changes in gut integrity and in the production of metabolites such as short-chain fatty acids and trimethylamine N-oxide. There is increasing evidence that gut microbiota and its alteration interact with other organs, highlighting the concept of the gut-organ axis. Thus, dysbiosis will affect other organs and could have an impact on the progression of critical diseases. Current knowledge is only a small part of what remains to be discovered. The precise role and contribution of the gut microbiota and its interactions with various organs is an intense and challenging research area that offers exciting opportunities for disease prevention, management and therapy, particularly in critical care where multi-organ failure is often the focus. This narrative review provides an overview of the normal composition of the gut microbiota, its functions, the mechanisms leading to dysbiosis, its consequences in an intensive care setting, and highlights the concept of the gut-organ axis.
... 155 This finding was mirrored in a large, rigorous, multicenter, randomized trial conducted after the most recent meta-analysis. 157 Neither this trial nor the meta-analyses found a significant impact on ICU length of stay, hospital length of stay, or mortality. b. ...
... 3. Prophylactic probiotics (Quality of Evidence: LOW) a. Probiotics should be considered with caution due to sparse data on impact in children, lack of clear benefit in adults, and case reports of Lactobacillus bacteremia associated with probiotic therapy in pediatric patients, including those not known to be immunocompromised. 157,163,[230][231][232][275][276][277][278] No impact on VAP rates for pediatric patients These interventions may be indicated for reasons other than VAP prophylaxis. ...
The purpose of this document is to highlight practical recommendations to assist acute care hospitals to prioritize and implement strategies to prevent ventilator-associated pneumonia (VAP), ventilator-associated events (VAE), and non-ventilator hospital-acquired pneumonia (NV-HAP) in adults, children, and neonates. This document updates the Strategies to Prevent Ventilator-Associated Pneumonia in Acute Care Hospitals published in 2014. This expert guidance document is sponsored by the Society for Healthcare Epidemiology (SHEA), and is the product of a collaborative effort led by SHEA, the Infectious Diseases Society of America, the American Hospital Association, the Association for Professionals in Infection Control and Epidemiology, and The Joint Commission, with major contributions from representatives of a number of organizations and societies with content expertise.
... Other definitions of the infectious component in sepsis research include the International Classification of Disease codes, expert judgment, and algorithms that take into account blood culture sampling and initiation of antibiotic therapy (1,11,(12)(13)(14)(15). These assessment methods demonstrate poor and variable precision in clinical sepsis, rendering comparisons between studies difficult (5,16,17). ...
... Despite the lack of a gold standard, there is a need for validated definitions of infection. Therefore, we have included the three references that are most often used as gold standards in the field: the Calandra and Cohen definitions, the diagnosis at hospital discharge, and adjudications by an expert panel (15,27,34). All three standards have advantages and disadvantages. ...
OBJECTIVES:. The Sepsis-3 definition states the clinical criteria for sepsis but lacks clear definitions of the underlying infection. To address the lack of applicable definitions of infection for sepsis research, we propose new criteria, termed the Linder-Mellhammar criteria of infection (LMCI). The aim of this study was to validate these new infection criteria.
DESIGN:. A multicenter cohort study of patients with suspected infection who were admitted to emergency departments or ICUs. Data were collected from medical records and from study investigators.
SETTING:. Four academic hospitals in Sweden, Switzerland, the Netherlands, and Germany.
PATIENTS:. A total of 934 adult patients with suspected infection or suspected sepsis.
INTERVENTIONS:. None.
MEASUREMENTS AND MAIN RESULTS:. Agreement of infection site classification was measured using the LMCI with Cohen κ coefficient, compared with the Calandra and Cohen definitions of infection and diagnosis on hospital discharge as references. In one of the cohorts, comparisons were also made to adjudications by an expert panel. A subset of patients was assessed for interobserver agreement.
MEASUREMENTS AND MAIN RESULTS:. The precision of the LMCI varied according to the applied reference. LMCI performed better than the Calandra and Cohen definitions (κ = 0.62 [95% CI, 0.59–0.65] vs κ = 0.43 [95% CI, 0.39–0.47], respectively) and the diagnosis on hospital discharge (κ = 0.57 [95% CI, 0.53–0.61] vs κ = 0.43 [95% CI, 0.39–0.47], respectively). The interobserver agreement for the LMCI was evaluated in 91 patients, with agreement in 77%, κ = 0.72 (95% CI, 0.60–0.85). When tested with adjudication as the gold standard, the LMCI still outperformed the Calandra and Cohen definitions (κ = 0.65 [95% CI, 0.60–0.70] vs κ = 0.29 [95% CI, 0.24–0.33], respectively).
CONCLUSIONS:. The LMCI is useful criterion of infection that is intended for sepsis research, in and outside of the ICU. Useful criteria for infection have the potential to facilitate more comparable sepsis research and exclude sepsis mimics from clinical studies, thus improving and simplifying sepsis research.
... In the PROSPECT study, probiotics were not superior to placebo in terms of the incidence of antibiotic-associated diarrhea (52.4% vs. 50.0%, p = 0.57) or C. difficile infections (2.4% vs. 2.1%, respectively, p = 0.60) among 2653 critically ill patients in the largest multicenter international placebo-controlled trial [69]. The variety of strains investigated, dosages, timing, length of therapy, and contradictory findings preclude a clear conclusion regarding the effectiveness of probiotics in critically ill patients, and more well-planned multicenter trials are necessary. ...
Optimizing the entire therapeutic regimen in septic critically ill patients should be based not only on improving antibiotic use but also on optimizing the entire therapeutic regimen by considering possible drug-drug or drug-nutrient interactions. The aim of this narrative review is to provide a comprehensive overview on recent advances to optimize the therapeutic regimen in septic critically ill patients based on a pharmacokinetics and pharmacodynamic approach. Studies on recent advances on TDM-guided drug therapy optimization based on PK and/or PD results were included. Studies on patients <18 years old or with classical TDM-guided therapy were excluded. New approaches in TDM-guided therapy in septic critically ill patients based on PK and/or PD parameters are presented for cefiderocol, carbapenems, combinations beta-lactams/beta-lactamase inhibitors (piperacillin/tazobactam, ceftolozane/tazobactam, ceftazidime/avibactam), plazomicin, oxazolidinones and polymyxins. Increased midazolam toxicity in combination with fluconazole, nephrotoxic synergism between furosemide and aminoglycosides, life-threatening hypoglycemia after fluoroquinolone and insulin, prolonged muscle weakness and/or paralysis after neuromuscular blocking agents and high-dose corticosteroids combinations are of interest in critically ill patients. In the real-world practice, the use of probiotics with antibiotics is common; even data about the risk and benefits of probiotics are currently spares and inconclusive. According to current legislation, probiotic use does not require safety monitoring, but there are reports of endocarditis, meningitis, peritonitis, or pneumonia associated with probiotics in critically ill patients. In addition, probiotics are associated with risk of the spread of antimicrobial resistance. The TDM-guided method ensures a true optimization of antibiotic therapy, and particular efforts should be applied globally. In addition, multidrug and drug-nutrient interactions in critically ill patients may increase the likelihood of adverse events and risk of death; therefore, the PK and PD particularities of the critically ill patient require a multidisciplinary approach in which knowledge of clinical pharmacology is essential. Citation: Onofrei, M.I.; Ghiciuc, C.M.; Luca, C.M.; Postolache, P.; Sapaniuc, C.; Enache Leonte, G.; Rosu, F.M.
... are associated with a reduction in infections, particularly in patients with ventilator-associated pneumonia (VAP) and treated with antibiotics, but not to increased survival [118]. Conversely, a more recent study did not confirm the beneficial role of Lactobacillus rhamnosus GG in reducing VAP incidence in ICU patients [156]. Another meta-analysis, which analyzed 4893 patients, has shown that probiotics reduce VAP, ICU length of stay, and duration of antibiotic therapy; however, the high variability in treatments and type of patients prevents the introduction of the use of probiotics as VAP prophylaxis [116]. ...
Critically ill patients undergo early impairment of their gut microbiota (GM) due to routine antibiotic therapies and other environmental factors leading to intestinal dysbiosis. The GM establishes connections with the rest of the human body along several axes representing critical inter-organ crosstalks that, once disrupted, play a major role in the pathophysiology of numerous diseases and their complications. Key players in this communication are GM metabolites such as short-chain fatty acids and bile acids, neurotransmitters, hormones, interleukins, and toxins. Inten-sivists juggle at the crossroad of multiple connections between the intestine and the rest of the body. Harnessing the GM in ICU could improve the management of several challenges, such as infections, traumatic brain injury, heart failure, kidney injury, and liver dysfunction. The study of molecular pathways affected by the GM in different clinical conditions is still at an early stage, and evidence in critically ill patients is lacking. This review aims to describe dysbio-sis in critical illness and provide intensivists with a perspective on the potential as adjuvant strategies (e.g., nutrition, probiotics, prebiotics and synbiotics supplementation, adsorbent charcoal, beta-lactamase, and fecal microbiota transplantation) to modulate the GM in ICU patients and attempt to restore eubiosis.
... that SH intervention restored the dominant species and increased the proportion of beneficial flora, and the three SH treatment groups increased the number of Lactobacillus, Rikenellaceae_RC9_gut_group and Alistipes to different degrees. Lactobacillus can improve ventilator-associated pneumonia (Johnstone et al., 2021), and Rikenellaceae_RC9_gut_group are positively correlated with Butyric and valeric acids (Qing et al., 2019), and Alistipes may have a protective effect against certain diseases (Parker et al., 2020). Although the exact mechanism of their rise in numbers is not clear, it is possible that SH increases intestinal flora by stimulating intestinal protective mechanisms, the mechanism of which needs further investigation. ...
Introduction
Pseudomonas aeruginosa is a major nosocomial pathogen that frequently causes ventilator-associated pneumonia in specific populations. Sodium houttuyfonate (SH) has shown mild antibacterial activity against P. aeruginosa in vitro , but the mechanism of potent antimicrobial activity of SH against P. aeruginosa infection in vivo remains unclear.
Methods
Here, using the mouse pneumonia model induced by P. aeruginosa nasal drip to explore the therapeutic effects of SH.
Results
We found that SH exhibits dose-dependent therapeutic effects of reducing P. aeruginosa burden and systemic inflammation in pneumonia mice. SH ameliorates inflammatory gene expression and production of inflammatory proteins, such as interleukin-6 (IL-6), nuclear factor kappa-B (NF-κB) and toll-like receptor 4 (TLR4), associated with the TLR4/NF-κB pathway in mice with P. aeruginosa pneumonia. Furthermore, we analyzed the intestinal flora of mice and found that compared with the model group, the abundance and diversity of beneficial bacterial flora of SH treatment groups increased significantly, suggesting that SH can improve the intestinal flora disorder caused by inflammation. In addition, SH improves alpha and beta diversity index and reduces species abundance differences of intestinal flora in pneumonia mice.
Discussion
Taken together, our presented results indicate that SH may effectively alleviate the acute pulmonary infection induced by P. aeruginosa by reducing the disturbance of regulating immunity and intestinal flora in mice.
... Beyond corticosteroids and cystic fibrosis transmembrane conductance regulator modulators, several other interventions have been trialled to modulate the lung microbiota with varied success. For example, oral probiotics have been studied in the context of both cystic fibrosis and ventilator-associated pneumonia, although these likely target shifts in the gut microbiome and their effects on the respiratory microbiome remain unknown 93 exercise and a healthy diet may contribute towards eubiosis in the lower airway, whereas obesity, an unhealthy diet and frequent antibiotic use could disrupt the lower airway microbiome in an unfavourable manner. Finally, we surmise that lower airway immune resilience and the diversity of the lung microbiome (a symbol of health in its own right) follows a quasi-sinusoidal path, peaking in adulthood. ...
New methods and technologies within the field of lung biology are beginning to shed new light into the microbial world of the respiratory tract. Long considered to be a sterile environment, it is now clear that the human lungs are frequently exposed to live microbes and their by-products. The nature of the lung microbiome is quite distinct from other microbial communities inhabiting our bodies such as those in the gut. Notably, the microbiome of the lung exhibits a low biomass and is dominated by dynamic fluxes of microbial immigration and clearance, resulting in a bacterial burden and microbiome composition that is fluid in nature rather than fixed. As our understanding of the microbial ecology of the lung improves, it is becoming increasingly apparent that certain disease states can disrupt the microbial–host interface and ultimately affect disease pathogenesis. In this Review, we provide an overview of lower airway microbial dynamics in health and disease and discuss future work that is required to uncover novel therapeutic targets to improve lung health. Like the gut, the lung harbours a diverse, interacting assortment of microbiota. In this review, Natalini, Singh and Segal examine the role of the lung microbiome in health and disease and discuss future work that is needed to produce novel diagnostic and therapeutic tools aimed at improving lung health.
... Critical care research articles recently published in two high-quality medical journals were searched to find 20 illustrative examples of Blindness to Marginal Utility. [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27] This does not intend to be a systematic review or comprehensive list but rather to provide different instances of the interpretation of marginality. Results are displayed in Table 1. ...
BACKGROUND: Randomized clinical trials (RCT) in critical care mostly return negative results. The research community discusses strategies to improve RCTs design. METHODS: This paper presents a theoretical framework based on marginal utility to treat the problems of hypothesis generation and treatment effects valuation and presents recently published high-quality studies as instances where such a framework predicts irrelevant findings. RESULTS: Blindness to marginal utility, i.e., inobservance of the marginal utility of the proposed intervention, is common in critical care RCTs. CONCLUSION: Critical care RCTs are usually blind to marginal utility and are, therefore, prone to produce irrelevant findings.
... 10 Existing studies that leverage an adjudication committee for pneumonia do not describe the process or the reliability of the method in detail. [11][12][13] For example, recurrent pneumonia was utilized as an endpoint in a study of microbiological treatment failure in bacterial pneumonia, but the adjudication process used to ascertain the endpoint was not outlined. 14 A large randomized controlled trial (RCT) of community-acquired pneumonia (CAP) employed an endpoint adjudication committee to determine the primary outcome, clinically indicated treatment with antibiotics, but did not detail the validity of the adjudication process. ...
Rationale
Clinical endpoints that constitute successful treatment in severe pneumonia are difficult to ascertain and vulnerable to bias. Utility of a protocolized adjudication procedure to determine meaningful endpoints in severe pneumonia is not well described.
Objectives
To develop and validate a protocol for classification and adjudication of clinical endpoints in severe bacterial and viral pneumonia in a prospective cohort of critically ill, mechanically ventilated patients.
Methods
Each episode of pneumonia was independently reviewed by two of six pulmonary and critical care physician adjudicators. If a discrepancy in at least one critical answer occurred between the two adjudicators, a third adjudicator reviewed the case and answered the specific question(s) for which there was a lack of agreement. If discrepancy remained after all three adjudications, consensus was achieved through committee review.
Results
Evaluation of 784 pneumonia episodes during 593 hospitalizations achieved a 79% crude rate of interobserver agreement defined as agreement between 2 of 3 reviewers. Culture-negative pneumonia was associated with increased interobserver agreement. Multiple episodes of pneumonia and bacterial and viral co-infection in the initial episode of pneumonia were associated with decreased interobserver agreement. For bacterial pneumonia, patients with an adjudicated day 7-8 clinical impression of cure for the initial episode of pneumonia were more likely to be discharged alive compared to patients with a day 7-8 clinical impression of indeterminate (p < 0.01), superinfection (p = 0.03), or a combined impression of persistence and superinfection (p = 0.04). In viral pneumonia, patients with an adjudicated clinical impression of cure for an initial episode of viral pneumonia were more likely to be discharged alive compared to patients with an adjudicated clinical impression of persistence (p < 0.01), indeterminate (p < 0.01), or bacterial superinfection (p < 0.01).
Conclusions
We developed and validated a protocol for classification and adjudication of clinical endpoints in severe pneumonia. This protocol can be applied to cohorts of patients with severe pneumonia to provide uniform assessment of patient-centered endpoints.
... 17 However, a contrary report has been published wherein the use of Lactobacillus rhamnosus GG for lowering VAP in critically ill patients was shown to be ineffective in reducing VAP. 18 Further research is needed to determine whether the use of Lactobacillus rhamnosus GG really helps in lowering the incidence of VAP. ...
Context
The safety and efficacy of probiotics during severe illness has been a subject of ongoing interest. The impact of probiotics can worsen nutritional status, which could potentially result in a deterioration of the patient’s overall life-threatening status.
Objective
This systematic review and meta-analysis evaluated the safety and efficacy of probiotics in reducing intensive care unit (ICU)–acquired infections in adult critically ill patients.
Data Sources
PubMed and Cochrane library databases for the period 2011–2020 were searched.
Data Extraction
Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement (PRISMA) methodology was used to search for randomized controlled trials that evaluated the use of probiotics among critically ill patients.
Data Analysis
No significant difference was observed between probiotics and control groups in terms of the mortality rate (risk ratio 1.13, 95% confidence interval .82 to 1.55, P = .46). Probiotics, however, provided a significant reduction in ICU-acquired infections (risk ratio .73, 95% confidence interval .58 to .93, P = .01).
Conclusion
The use of probiotics seems to play a role in decreasing the incidence of ICU-acquired infections. Also, a potential reduction in terms of the incidence of diarrhea has been reported, with no examples of adverse incidents, suggesting probiotics are safe.
... Lactobacillus rhamnosus GG prevented high-risk ICU populations from VAP (Morrow et al., 2010). However, there were no significant differences between the probiotic group (patients who received Lactobacillus rhamnosus GG) and the placebo group in the prevention of VAP among critically ill patients, as confirmed by a randomized controlled trial (Johnstone et al., 2021). An unanticipated finding was that the use of probiotics might even increase the risk of bacteremia in ICU patients (Yelin et al., 2019). ...
The coronavirus disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). According to the World Health Organization statistics, more than 500 million individuals have been infected and more than 6 million deaths have resulted worldwide. Although COVID-19 mainly affects the respiratory system, considerable evidence shows that the digestive, cardiovascular, nervous, and reproductive systems can all be involved. Angiotensin-converting enzyme 2 (AEC2), the target of SARS-CoV-2 invasion of the host is mainly distributed in the respiratory and gastrointestinal tract. Studies found that microbiota contributes to the onset and progression of many diseases, including COVID-19. Here, we firstly conclude the characterization of respiratory, gut, and oral microbial dysbiosis, including bacteria, fungi, and viruses. Then we explore the potential mechanisms of microbial involvement in COVID-19. Microbial dysbiosis could influence COVID-19 by complex interactions with SARS-CoV-2 and host immunity. Moreover, microbiota may have an impact on COVID-19 through their metabolites or modulation of ACE2 expression. Subsequently, we generalize the potential of microbiota as diagnostic markers for COVID-19 patients and its possible association with post-acute COVID-19 syndrome (PACS) and relapse after recovery. Finally, we proposed directed microbiota-targeted treatments from the perspective of gut microecology such as probiotics and prebiotics, fecal transplantation and antibiotics, and other interventions such as traditional Chinese medicine, COVID-19 vaccines, and ACE2-based treatments.
... As a corollary, a myriad of RCTs have been performed evaluating the effect of interventions directed at changing microbial composition in efforts to improve disease. [34][35][36][37] However, RCTs are often exclusive and not a reflection of real-world situations where a patient's daily activities are not in controlled conditions. 38,39 For instance, a controlled diet among participants would be desired in an RCT in order to avoid confounding effects of diet on the microbiome. ...
Pharmacomicrobiomic studies investigate drug‐microbiome interactions, such as the effect of microbial variation on drug response and disposition. Studying and understanding the interactions between the gut microbiome and drugs is becoming increasingly relevant to clinical practice due to its potential for avoiding adverse drug reactions or predicting variability in drug response. The highly variable nature of the human microbiome presents significant challenges to assessing microbes' influence. Studies aiming to explore drug‐microbiome interactions should be well designed to account for variation in the microbiome over time and collect data on confounders such as diet, disease, concomitant drugs, and other environmental factors. Here, we assemble a set of important considerations and recommendations for the methodological features required for performing a pharmacomicrobiomic study in humans with a focus on the gut microbiome. Consideration of these factors enable discovery, reproducibility, and more accurate characterization of the relationships between a given drug and the microbiome. Furthermore, appropriate interpretation and dissemination of results from well‐designed studies will push the field closer to clinical relevance and implementation.
... As described above, widespread multi-taxa dysbiosis has been observed in septic humans, and the optimal approach to microbiota modulation has not been defined. Preliminary clinical trials of probiotics in adult patients with critical illness showed promising signals towards a reduction in systemic hospital-acquired infections 139 , but a recent large randomized controlled trial of a Lactobacillus rhamnosus GG probiotic in this patient population failed to impact rates of secondary (hospital-acquired) infections or survival 140 . Case reports of FMT therapy in septic patients have been published, but limited data is available on the safety and efficacy of this approach 141 . ...
Despite compartmentalization within the lumen of the gastrointestinal tract, the gut microbiota has a far-reaching influence on immune cell development and function throughout the body. This long-distance relationship is crucial for immune homeostasis, including effective host defense against invading pathogens that cause systemic infections. Herein, we review new insights into how commensal microbes that are spatially restricted to the gut lumen can engage in long-distance relationships with innate and adaptive immune cells at systemic sites to fortify host defenses against infections. In addition, we explore the consequences of intestinal dysbiosis on impaired host defense and immune-mediated pathology during infections, including emerging evidence linking dysbiosis with aberrant systemic inflammation and immune-mediated organ damage in sepsis. As such, therapeutic modification of the gut microbiota is an emerging target for interventions to prevent and/or treat systemic infections and sepsis by harnessing the long-distance relationships between gut microbes and systemic immunity.
... New data affirm the long-held fear that selective oral and digestive decontamination may not be effective in ICUs with high baseline rates of antibiotic resistance. Subglottic secretion drainage may not shorten the duration of mechanical ventilation or ICU length-of-stay as is once thought [45][46][47][48][49]. Furthermore, two recent RCTs showed no significant difference in VAP development among ventilated ICU patients receiving probiotic or monoclonal antibody administration than placebo [50,51]. ...
Background
Ventilator-associated pneumonia is a challenge in critical care and is associated with high mortality and morbidity. Although some consensuses on preventing ventilator-associated pneumonia are reached, it is still somewhat controversial. Meta-analysis has shown that postpyloric tube feeding may reduce the incidences of ventilator-associated pneumonia, which still desires high-quality evidence. This trial aims to evaluate the efficacy and safety profiles of postpyloric tube feeding versus gastric tube feeding.
Methods/design
In this multicenter, open-label, randomized controlled trial, we will recruit 924 subjects expected to receive mechanical ventilation for no less than 48 h. Subjects on mechanical ventilation will be randomized (1:1) to receive postpyloric or gastric tube feeding and routine preventive measures simultaneously. The primary outcome is the proportion of patients with at least one ventilator-associated pneumonia episode. Adverse events and serious adverse events will be observed closely.
Discussion
The VIP study is a large-sample-sized, multicenter, open-label, randomized, parallel-group, controlled trial of postpyloric tube feeding in China and is well-designed based on previous studies. The results of this trial may help to provide evidence-based recommendations for the prevention of ventilator-associated pneumonia.
Trial registration
Chictr.org.cn ChiCTR2100051593 . Registered on 28 September 2021
... 105 A recent large-scale multicenter trial did not show any benefit in using probiotics as a measure for decreasing ventilator-associated pneumonia or other infections among patients in ICU. 106 However, probiotics were beneficial in selected patient populations, requiring an individualized approach for sepsis. 107 Prebiotics are nutrients degraded by the gut microbiota that alter the function and composition of the microbiome. ...
Sepsis is a leading cause of death in critically ill patients, primarily due to multiple organ failures. It is associated with a systemic inflammatory response that plays a role in the pathogenesis of the disease. Intestinal barrier dysfunction and bacterial translocation (BT) play pivotal roles in the pathogenesis of sepsis and associated organ failure. In this review, we describe recent advances in understanding the mechanisms by which the gut microbiome and BT contribute to the pathogenesis of sepsis. We also discuss several potential treatment modalities that target the microbiome as therapeutic tools for patients with sepsis.
... Contrary to the conclusion of this umbrella review and others, the largest multicenter study on the use of probiotics, which was published after the study period, failed to show any benefit for all outcomes-including VAP-in a broad critically ill patient population. 8 Moreover, the study found lactobacillus bacteremia in patients with serious underlying comorbidities, raising concerns of harm. This is the largest study enrolling 2,653 randomized adult critically ill patients across 44 ICUs in different parts of the world. ...
Soni KD. Probiotics: Should We Use Them Proactively in Critical Illness? Indian J Crit Care Med 2022;26(3):266-267.
Background:
According to reports, ventilator-associated pneumonia affects critically ill patients more frequently than any other nosocomial infection. Probiotic usage as a prophylactic intervention has shown promising results in numerous studies.
Objectives:
We performed a meta-analysis to evaluate the effect of probiotics on different parameters in critically ill ventilated subjects.
Material and methods:
A systematic literature search up to June 2022 was performed and 5893 critically ill ventilated subjects at the baseline of the studies were identified; 2912 of them were using the probiotics, and there were 2981 controls. Odds ratio (OR) and mean difference (MD) with 95% confidence interval (95% CI) were calculated to assess the effect of probiotics on different parameters in critically ill ventilated subjects using the dichotomous and contentious methods with a random or fixed effects model.
Results:
The probiotics caused a significantly lower incidence of ventilator-associated pneumonia (OR = 0.52; 95% CI: 0.40-0.68, p < 0.001), shorter duration of mechanical ventilation (MD = -2.22; 95% CI: -3.33--1.11, p < 0.001), shorter intensive care unit (ICU) stay (MD = -2.09; 95% CI: -3.41--0.77, p = 0.002), shorter hospital stay (MD = -2.36; 95% CI: -4.54--0.19, p = 0.03), and lower oropharyngeal colonization (OR = 0.59; 95% CI: 0.36-0.96, p = 0.03) in critically ill ventilated subjects compared with controls. However, probiotic use had no significant difference in terms of diarrhea incidence (OR = 0.74; 95% CI: 0.52-1.07, p = 0.11) and in-hospital mortality (OR = 0.90; 95% CI: 0.79-1.03, p = 0.14) in critically ill ventilated subjects compared with controls.
Conclusion:
Probiotics caused a significantly lower ventilator-associated pneumonia incidence, shorter duration of mechanical ventilation, shorter ICU and hospital stay, and lower oropharyngeal colonization. However, there was no significant difference in terms of diarrhea incidence and in-hospital mortality in subjects who used probiotics compared with controls. The low sample size of 9 out of 27 researches and the small number of studies in several comparisons requires attention when analyzing the results.
Introduction:
We aimed to analyze intensive care unit (ICU)-acquired pneumonia according to 7 definitions, estimating associated hospital mortality.
Methods:
This cohort study was nested within an international randomized trial, evaluating the effect of probiotics on ICU-acquired pneumonia in 2650 mechanically ventilated adults. Each clinically suspected pneumonia was adjudicated by two physicians blinded to allocation and center. The primary outcome was ventilator-associated pneumonia (VAP) informed by ventilation for ≥2 days, new, progressive or persistent infiltrate plus 2 of: temperature > 38 °C or < 36 °C; leukopenia (<3 × 10(Fernando et al., 20206)/L) or leukocytosis (>10 × 10(Fernando et al., 20206)/L); and purulent sputum. We also used 6 other definitions estimating the risk of hospital mortality.
Results:
The frequency of ICU-acquired pneumonia varied by definition: the trial primary outcome VAP (21.6%), Clinical Pulmonary Infection Score (CPIS) (24.9%), American College Chest Physicians (ACCP) (25.0%), International Sepsis Forum (ISF) (24.4%), Reducing Oxidative Stress Study (REDOXS) (17.6%), Centers for Disease Control (CDC) (7.8%), and invasively microbiologically confirmed (1.9%). The trial primary outcome VAP (HR 1.31 [1.08, 1.60]), ISF (HR 1.32 [1.09,1.60]), CPIS (HR 1.30 [1.08,1.58]) and ACCP definitions (HR 1.22 [1.00,1.47]) were associated with hospital mortality.
Conclusions:
Rates of ICU-acquired pneumonia vary by definition and are associated with differential increased risk of death.
The bipartite relationship between nutrition and the intestinal microbiome represents an exciting frontier in critical care medicine. In this review, the authors first address these topics independently, leading with a summary of recent clinical studies assessing intensive care unit nutritional strategies, followed by an exploration of the microbiome in the context of perioperative and intensive care, including recent clinical data implicating microbial dysbiosis as a key driver of clinical outcomes. Finally, the authors address the intersection of nutrition and the microbiome, exploring the use of supplemental pre-, pro-, and synbiotics to influence microbial composition and improve outcomes in critically ill and postsurgical patients.
Dieses Kapitel beschäftigt sich mit besonderen hygienischen Aspekten in speziellen Bereichen. Dabei geht es in erster Linie um bereichsspezifische organisatorische Belange, Gerätschaften oder Anwendungen. Die sichere Anwendung der Basishygiene wird vorausgesetzt, ebenso wie die Aufbereitung von Medizinprodukten oder bauliche Aspekte, die bereits in den Vorkapiteln behandelt wurden.
Purpose of review:
In this paper, we review the current evidence with respect to definitions, risk factors, and outcomes of diarrhea in the critically ill and highlight research gaps in the literature.
Recent findings:
Definitions of diarrhea in the intensive care unit (ICU) include the World Health Organization quantified as >3 liquid bowel movements per day and the Bristol Stool Chart score of 7. Diarrhea incidence is 37.7-73.8% and varies based on definition applied. Clostridioides difficile associated diarrhea (CDAD) is uncommon with an incidence of 2.2%. Risk factors for diarrhea include total number of antibiotics, enteral nutrition, and suppository use. The composition of enteral nutrition including high osmolarity and high fiber feeds contributed to diarrhea occurrence. Opiates decrease diarrhea incidence whereas probiotics have no effect on the incidence or duration of diarrhea. Outcomes of diarrhea include increased length of stay in the ICU and hospital, however its impact on mortality is unclear.
Summary:
Diarrhea remains a common problem in clinical practice and attention must be paid to modifiable risk factors. Further research is needed on interventions to decrease its burden.
The incidence of postoperative gastrointestinal dysfunction among neurosurgical patients is as high as 80%. Probiotics help to maintain gastrointestinal barrier defense, provide competitive adherence to mucus and epithelial cells, and regulate gastrointestinal motility. Therefore, the purpose of this study was to investigate whether probiotics enhance gastrointestinal health after craniotomy in patients with brain tumors. This study was a 15-day, prospective, randomized, double-blind, placebo-controlled trial for patients being treated with elective craniotomy for brain tumors. Participants were randomly divided into the probiotics group (4 g probiotics, twice daily) and placebo group. The primary outcome was the time of first stool after surgery. The secondary outcomes included assessments of the gastrointestinal function, changes in gastrointestinal permeability and clinical outcomes. We enrolled a total of 200 participants (probiotics: 100; placebo: 100) and followed the principles of intention-to-treat analysis. The time of first stool and flatus were significantly shorter in the probiotics group compared to the placebo group (P < 0.001, respectively). No significant trends were observed for any other of the secondary outcome variables. Our findings suggest that probiotics can improve the gastrointestinal mobility of patients received craniotomy, and this improvement cannot be explained by changes in gastrointestinal permeability.
Zusammenfassung
Kritisch kranke Patienten leiden häufig unter einer komplexen und schwerwiegenden immunologischen Dysfunktion. Die Differenzierung und Funktion von Immunzellen werden maßgeblich durch metabolische Prozesse gesteuert. Neue immunonutritive Konzepte versuchen daher, die Immunfunktionen intensivmedizinischer Patienten über enterale und parenterale Ernährung positiv zu beeinflussen. Die vorliegende Übersichtsarbeit präsentiert kondensiert die verfügbare Evidenz zu den gängigen isolierten Supplementen (antioxidative Substanzen, Aminosäuren, essenzielle Fettsäuren) und die damit verbundenen Problematiken. Im zweiten Teil werden sich daraus ergebende neuartige und umfassendere Konzepte der Immunonutrition zur Beeinflussung des intestinalen Mikrobioms und zur Modulation der Makronährstoffkomposition vorgestellt. Die Immunonutrition des kritisch kranken Patienten hat enormes Potenzial und kann sich zukünftig zu einem wertvollen klinischen Tool zur Modulation des Immunmetabolismus intensivmedizinischer Patienten entwickeln.
Die Pneumonieprophylaxe bei beatmeten Patienten zur Vermeidung einer Ventilator-assoziierten Pneumonie (VAP) ist auf Grund einer deutlich erhöhten Morbidität und Letalität von elementarer Bedeutung. Eine Auswertung der Medical Information Mart for Intensive Care III (MIMIC III) Datenbank ergab nach entsprechender Adjustierung eine Erhöhung des Risikos bzgl. der 90d und 180d Mortalität bei Patienten mit einer VAP gegenüber Patienten ohne eine VAP entsprechend bei dem 1,465fachen (OR = 1,465, 95 % Konfidenz Intervall (KI) 1,188–1,807, p < 0,001) und dem 1,635fachen (OR = 1,635, 95 % KI: 1,333–2,005, p < 0,001) (Luo et al. 2021).
Purpose of review:
This review aims to provide an overview of the current knowledge about microbiota-targeted therapies in sepsis, and calls out - despite recent negative studies - not to halt our efforts of translating these tools into regular medical practice.
Recent findings:
The intestinal microbiome has an important role in shaping our immune system, and microbiota-derived metabolites prime innate and adaptive inflammatory responses to infectious pathogens. Microbiota composition is severely disrupted during sepsis, which has been linked to increased risk of mortality and secondary infections. However, efforts of using these microbes as a tool for prognostic or therapeutic purposes have been unsuccessful so far, and recent trials studying the impact of probiotics in critical illness did not improve patient outcomes. Despite these negative results, researchers must continue their attempts of harnessing the microbiome to improve sepsis survival in patients with a high risk of clinical deterioration. Promising research avenues that could potentially benefit sepsis patients include the development of next-generation probiotics, use of the microbiome as a theranostic tool to direct therapy, and addressing the restoration of microbial communities following ICU discharge.
Summary:
Although research focused on microbiome-mediated therapy in critically ill patients has not yielded the results that were anticipated, we should not abandon our efforts to translate promising preclinical findings into clinical practice.
Surgical science has driven innovation and inquiry across adult and pediatric disciplines that provide critical care regardless of location. Surgically originated but broadly applicable knowledge has been globally shared within the pages Critical Care Medicine over the last 50 years.
Introduction:
Clostridioides difficile infection (CDI) is a serious complication of critical illness. The objective of the study was to determine its incidence, prevalence, timing, severity, predictors, and outcomes.
Methods:
We performed a prospective nested cohort study of CDI within a randomized trial comparing Lactobacillus rhamnosus GG to placebo. We adjudicated cases of CDI using standardized definitions, assessed timing (pre-ICU, in ICU, post-ICU) and severity. We analyzed risk factors and outcomes.
Results:
Of 2650 patients, 86 were diagnosed with CDI during 90,833 hospital-days (0.95/1000 hospital-days); CDI prevalence was 3.2%. CDI incidence varied in timing; 0.3% patients had CDI pre-ICU, 2.2% in the ICU; an 0.8% developed CDI post-ICU. Relapse or recurrence of CDI was documented in 9.3% patients. Infections were mild/moderate in severity. Complications included septic shock (26.7%), organ failure (16.3%), and toxic megacolon requiring colectomy (1.2%). No risk factors for CDI were identified. CDI was not associated with hospital mortality. The duration of hospital stay was longer for those who had CDI compared those who did not, CONCLUSION: CDI was uncommon, severity was mild to moderate and not associated with mortality however CDI was associated with a longer hospital stay.
Background:
Patient and public involvement in randomised clinical trials has received increased focus, including in intensive care trials, but the frequency, method and extent is unknown. This meta-epidemiological study investigated patient and public involvement in contemporary, large ICU trials.
Methods:
We systematically searched PubMed for large (≥225 randomised patients), contemporary trials (published between 1 January 2019 and 31 January 2022) assessing interventions in adult patients in ICU settings. Abstracts and full-text articles were assessed independently and in duplicate. Data were extracted using a pre-defined, pilot-tested data extraction form with details on trials, patient and public involvement including categories and numbers of individuals involved, methods of involvement, and trial stage(s) with involvement. Trials authors were contacted as necessary.
Results:
We included 100 trials, with 18 using patients and public involvement; these were larger and conducted in more centres than trials without patients and public involvement. Among trials with patient and public involvement, patients (in 14/18 trials), clinicians (13 trials), and family members (12 trials) were primarily involved, mainly in the development of research design (15 trials) and development of research focus (13 trials) stages and mostly by discussion (12 trials) and solo interviews (10 trials). A median of 65 individuals (range 1 to 6894) were involved.
Conclusions:
We found patient and public involvement in a fifth of large, contemporary ICU trials. Primarily patients, families, and clinicians were included, particularly in the trial planning stages and mostly through interviews and discussions. Increased patient and public involvement in ICU trials is warranted. This article is protected by copyright. All rights reserved.
Unlabelled:
Clinical research in Canada is conducted primarily in "academic" hospitals, whereas most clinical care is provided in "community" hospitals. The objective of this nested observational study was to compare patient characteristics, outcomes, process-of-care variables, and trial metrics for patients enrolled in a large randomized controlled trial who were admitted to academic and community hospitals in Canada.
Design:
We conducted a preplanned observational study nested within the Probiotics: Prevention of Severe Pneumonia and Endotracheal Colonization Trial (PROSPECT, a randomized controlled trial comparing probiotics to placebo in mechanically ventilated patients) Research Program.
Setting:
ICUs.
Patients:
Mechanically ventilated patients.
Measurements:
We compared patient characteristics, interventions, outcomes, and trial metrics between patients enrolled in PROSPECT from academic and community hospitals.
Main results:
Participating centers included 34 (82.9%) academic and seven (17.1%) community hospitals, which enrolled 2,203 (86.2%) and 352 (13.8%) patients, respectively. Compared with academic hospitals, patients enrolled in community hospitals were older (mean [sd] 62.7 yr [14.9 yr] vs 59.5 yr [16.4 yr]; p = 0.044), had longer ICU stays (median [interquartile range {IQR}], 13 d [8-23 d] vs 11 d [7-8 d]; p = 0.012) and higher mortality (percentage, [95% CI] in the ICU, 30.4% [25.8-35.4%]vs 20.5% [18.9-11.3%]; p = 0.002) and hospital (40.6% [35.6-45.8%] vs 26.1% [24.3-27.9%]; p < 0.001). Trial metrics, including informed consent rate (85.9% vs 76.3%; p = 0.149), mean (sd) monthly enrolment rate (2.1 [1.4] vs 1.1 [0.7]; p = 0.119), and protocol adherence (90.6% vs 91.6%; p = 0.207), were similar between community and academic ICUs.
Conclusions:
Community hospitals can conduct high-quality research, with similar trial metrics to academic hospitals. Patient characteristics differed between community and academic hospitals, highlighting the need for broader engagement of community hospitals in clinical research to ensure generalizability of study results.
Abstract
Purpose
We sought to compare the cost-effectiveness of probiotics and usual care with usual care without probiotics in mechanically ventilated, intensive care unit patients alongside the Probiotics to Prevent Severe Pneumonia and Endotracheal Colonization Trial (PROSPECT).
Methods
We conducted a health economic evaluation alongside the PROSPECT randomized control trial (October 2013–March 2019). We adopted a public healthcare payer’s perspective. Forty-four intensive care units in three countries (Canada/USA/Saudi Arabia) with adult critically ill, mechanically ventilated patients (N = 2,650) were included. Interventions were probiotics (Lactobacillus rhamnosus GG) vs placebo administered enterally twice daily. We collected healthcare resource use and estimated unit costs in 2019 United States dollars (USD) over a time horizon from randomization to hospital discharge/death. We calculated incremental cost-effectiveness ratios (ICERs) comparing probiotics vs usual care. The primary outcome was incremental cost per ventilator-associated pneumonia (VAP) event averted; secondary outcomes were costs per Clostridioides difficile-associated diarrhea (CDAD), antibiotic-associated diarrhea (AAD), and mortality averted. Uncertainty was investigated using nonparametric bootstrapping and sensitivity analyses.
Results
Mean (standard deviation [SD]) cost per patient was USD 66,914 (91,098) for patients randomized to probiotics, with a median [interquartile range (IQR)] of USD 42,947 [22,239 to 76,205]. By comparison, for those not receiving probiotics, mean (SD) cost per patient was USD 62,701 (78,676) (median [IQR], USD 41,102 [23,170 to 75,140]; incremental cost, USD 4,213; 95% confidence interval [CI], −2,269 to 10,708). Incremental cost-effectiveness ratios for VAP or AAD events averted, probiotics were dominated by usual care (more expensive, with similar effectiveness). The ICERs were USD 1,473,400 per CDAD event averted (95% CI, undefined) and USD 396,764 per death averted (95% CI, undefined). Cost-effectiveness acceptability curves reveal that probiotics were not cost-effective across wide ranges of plausible willingness-to-pay thresholds. Sensitivity analyses did not change the conclusions.
Conclusions
Probiotics for VAP prevention among critically ill patients were not cost-effective.
Study registration data www.ClinicalTrials.gov (NCT01782755); registered 4 February 2013.
Coronavirus 2, universally known as SARS‐CoV‐2 (severe acute respiratory syndrome coronavirus 2), was identified only a year ago as the causative agent of a new acute respiratory disease: the “coronavirus disease 2019” (COVID‐19). The pathognomonic symptoms of COVID‐19 are cough, fever, and dyspnea. To date, only two studies have been published to assess whether there are differences between the respiratory microbiota of healthy people and those with COVID‐19, and in both cases the sample size was small. This chapter details these two studies. In any case, COVID‐19 contains numerous aspects that constitute clear targets for the application of probiotics: the presence of diarrhea and other digestive symptoms in a high percentage of cases; modulation of the immune and inflammatory response to the virus; and so on.
Objectives:
Nosocomial pneumonia is a common complication in critically ill patients. The goal of this study was to examine the efficacy of the toll-like receptor 4 (TLR4) agonist 3-deacyl phosphorylated hexacyl disaccharide (3D PHAD), in a clinically relevant murine model of pneumonia and assess the cellular mechanisms that mediate the protective response.
Design:
Mice received intrapulmonary 3D PHAD (20 μg) or vehicle for 2 consecutive days prior to challenge with intrapulmonary Klebsiella pneumoniae (2.3x103 colony forming units (CFU)). Mice were followed for 14-day survival, pulmonary K. pneumoniae burden, lung leukocyte profile, leukocyte phagocytic capacity and cytokine production. Pneumonia severity and leukocyte recruitment were further assessed by histological evaluation.
Setting:
Research laboratory.
Subjects:
Wild type, male C57BL/6 J mice.
Interventions:
Intrapulmonary treatment with 20 μg 3D PHAD for 2 consecutive days.
Measurements and main results:
Intrapulmonary treatment with 3D PHAD decreased lung K. pneumoniae CFU and pneumonia severity with an associated improvement in survival compared to mice treated with vehicle. The numbers of neutrophils, monocytes and macrophages in the lungs of 3D PHAD-treated mice were higher than in vehicle-treated mice prior to infection, but were not significantly different from vehicle-treated mice at 48 hours after K. pneumoniae challenge. Lung innate leukocytes from 3D PHAD-treated mice had increased phagocytic capacity. Treatment with 3D PHAD alone increased cytokines in the lungs, but decreased cytokines in plasma during K. pneumoniae pneumonia as compared to control.
Conclusions:
Intrapulmonary treatment with 3D PHAD augments innate immunity in the lung and facilitates resistance to K. pneumoniae pneumonia.
Purpose
To categorize, quantify and interpret findings documented in feedback letters of monitoring or auditing visits for an investigator-initiated, peer-review funded multicenter randomized trial testing probiotics for critically ill patients.
Materials & methods
In 37 Canadian centers, monitoring and auditing visits were performed by 3 trained individuals; findings were reported in feedback letters. At trial termination, we performed duplicate content analysis on letters, categorizing observations first into unique findings, followed by 10 pre-determined trial quality management domains. We further classified each observation into a) missing operational records, b) errors in process, and potential threats to c) data integrity, d) patient privacy or e) safety.
Results
Across 37 monitoring or auditing visits, 75 unique findings were categorized into 10 domains. Most frequently, observations were in domains of training documentation (180/566 [32%]) and the informed consent process (133/566 [23%]). Most observations were missing operational records (438/566 [77%]) rather than errors in process (128/566 [23%]). Of 75 findings, 13 (62/566 observations [11%]) posed a potential threat to data integrity, 1 (1/566 observation [0.18%]) to patient privacy, and 9 (49/566 observations [8.7%]) to patient safety.
Conclusions
Monitoring and auditing findings predominantly concerned missing documentation with minimal threats to data integrity, patient privacy or safety.
Trial Registration: PROSPECT (Probiotics: Prevention of Severe Pneumonia and Endotracheal Colonization Trial): NCT02462590.
Purpose of review:
The COVID-19 pandemic has altered the profile of critical care services internationally, as professionals around the globe have struggled to rise to the unprecedented challenge faced, both in terms of individual patient management and the sheer volume of patients that require treatment and management in intensive care. This review article sets out key priorities in nutritional interventions during the patient journey, both in the acute and recovery phases.
Recent findings:
The current review covers the care of the acutely unwell patient, and the evidence base for nutritional interventions in the COVID-19 population. One of the biggest differences in caring for critically ill patients with acute respiratory failure from COVID-19 is often the time prior to intubation. This represents specific nutritional challenges, as does nursing patients in the prone position or in the setting of limited resources. This article goes on to discuss nutritional support for COVID-19 sufferers as they transition through hospital wards and into the community.
Summary:
Nutritional support of patients with severe COVID-19 is essential. Given the longer duration of their critical illness, combined with hypermetabolism and energy expenditure, patients with COVID-19 are at increased risk for malnutrition during and after their hospital stay.
Objectives:
This study investigated the preventive effects of pro-, pre- and synbiotics on ventilator-associated pneumonia (VAP) among critically ill patients.
Methods:
The PubMed, Web of Science, Ovid MEDLINE, Embase, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov databases were searched for relevant articles written before February 19, 2022. Only randomized controlled trials (RCTs) comparing the clinical efficacy of pro-, pre- and synbiotics with placebos or standard treatments for the prevention of incidental VAP were included.
Results:
A total of 15 RCTs were included. Patients receiving pro-, pre- and synbiotics had a lower risk than the control group of contracting VAP (risk ratio [RR], 0.70; 95% CI, 0.57-0.85; I2 = 67%). The duration of mechanical ventilation was significantly shorter in the study group than in the control group (mean difference [MD], -1.61 days; 95% CI, -2.72 to -0.50; I2 = 86%), and the study group had a shorter duration of stay in the intensive care unit than the control group did (MD, -1.72 days; 95% CI, -3.22 to -0.23; I2 = 87%).
Conclusions:
Pro-, pre- and synbiotics can prevent VAP and the use of probiotics for patients who are critically ill should be supported.
Objectives:
To determine the safety and efficacy of probiotics or synbiotics on morbidity and mortality in critically ill adults and children.
Data sources:
We searched MEDLINE, EMBASE, CENTRAL, and unpublished sources from inception to May 4, 2021.
Study selection:
We performed a systematic search for randomized controlled trials (RCTs) that compared enteral probiotics or synbiotics to placebo or no treatment in critically ill patients. We screened studies independently and in duplicate.
Data extraction:
Independent reviewers extracted data in duplicate. A random-effects model was used to pool data. We assessed the overall certainty of evidence for each outcome using the Grading Recommendations Assessment, Development, and Evaluation approach.
Data synthesis:
Sixty-five RCTs enrolled 8,483 patients. Probiotics may reduce ventilator-associated pneumonia (VAP) (relative risk [RR], 0.72; 95% CI, 0.59 to 0.89 and risk difference [RD], 6.9% reduction; 95% CI, 2.7-10.2% fewer; low certainty), healthcare-associated pneumonia (HAP) (RR, 0.70; 95% CI, 0.55-0.89; RD, 5.5% reduction; 95% CI, 8.2-2.0% fewer; low certainty), ICU length of stay (LOS) (mean difference [MD], 1.38 days fewer; 95% CI, 0.57-2.19 d fewer; low certainty), hospital LOS (MD, 2.21 d fewer; 95% CI, 1.18-3.24 d fewer; low certainty), and duration of invasive mechanical ventilation (MD, 2.53 d fewer; 95% CI, 1.31-3.74 d fewer; low certainty). Probiotics probably have no effect on mortality (RR, 0.95; 95% CI, 0.87-1.04 and RD, 1.1% reduction; 95% CI, 2.8% reduction to 0.8% increase; moderate certainty). Post hoc sensitivity analyses without high risk of bias studies negated the effect of probiotics on VAP, HAP, and hospital LOS.
Conclusions:
Low certainty RCT evidence suggests that probiotics or synbiotics during critical illness may reduce VAP, HAP, ICU and hospital LOS but probably have no effect on mortality.
Introduction:
Ventilator-associated pneumonia (VAP) is reported as the second most common nosocomial infection among critically ill patients with the incidence ranging from 2 to 16 episodes per 1000 ventilator days. The use of probiotics has been shown to have a promising effect in many RCTs. Our systematic review and meta-analysis were thus planned to determine the effect of probiotic use in critically ill ventilated adult patients on the incidence of VAP, length of hospital stay, length of ICU stay, duration of mechanical ventilation, the incidence of diarrhea, and the incidence of oropharyngeal colonization and in-hospital mortality.
Methodology:
Systematic search of various databases (such as Embase, Cochrane, and Pubmed), published journals, clinical trials, and abstracts of the various major conferences were made to obtain the RCTs which compare probiotics with placebo for VAP prevention. The results were expressed as risk ratios or mean differences. Data synthesis was done using statistical software - Review Manager (RevMan) Version 5.4 (The Cochrane Collaboration, 2020).
Results:
Nine studies met our inclusion criterion and were included in the meta-analysis. The incidence of VAP (risk ratio: 0.70, CI 0.56, 0.88; P = 0.002; I2 = 37%), duration of mechanical ventilation (mean difference -3.75, CI -6.93, -0.58; P 0.02; I2 = 96%), length of ICU stay (mean difference -4.20, CI -6.73, -1.66; P = 0.001; I2 = 84%) and in-hospital mortality (OR 0.73, CI 0.54, 0.98; P = 0.04; I2 = 0%) in the probiotic group was significantly lower than that in the control group. Probiotic administration was not associated with a statistically significant reduction in length of hospital stay (MD -1.94, CI -7.17, 3.28; P = 0.47; I2 = 88%), incidence of oro-pharyngeal colonization (OR 0.59, CI 0.33, 1.04; P = 0.07; I2 = 69%), and incidence of diarrhea (OR 0.59, CI 0.34, 1.03; P = 0.06; I2 = 38%).
Discussion:
Our meta-analysis shows that probiotic administration has a promising role in lowering the incidence of VAP, the duration of mechanical ventilation, length of ICU stay, and in-hospital mortality.
Background:
Most randomized controlled trials (RCTs) and meta-analyses of RCTs examine effect modification (also called a subgroup effect or interaction), in which the effect of an intervention varies by another variable (e.g., age or disease severity). Assessing the credibility of an apparent effect modification presents challenges; therefore, we developed the Instrument for assessing the Credibility of Effect Modification Analyses (ICEMAN).
Methods:
To develop ICEMAN, we established a detailed concept; identified candidate credibility considerations in a systematic survey of the literature; together with experts, performed a consensus study to identify key considerations and develop them into instrument items; and refined the instrument based on feedback from trial investigators, systematic review authors and journal editors, who applied drafts of ICEMAN to published claims of effect modification.
Results:
The final instrument consists of a set of preliminary considerations, core questions (5 for RCTs, 8 for meta-analyses) with 4 response options, 1 optional item for additional considerations and a rating of credibility on a visual analogue scale ranging from very low to high. An accompanying manual provides rationales, detailed instructions and examples from the literature. Seventeen potential users tested ICEMAN; their suggestions improved the user-friendliness of the instrument.
Interpretation:
The Instrument for assessing the Credibility of Effect Modification Analyses offers explicit guidance for investigators, systematic reviewers, journal editors and others considering making a claim of effect modification or interpreting a claim made by others.
This article is one of ten reviews selected from the Annual Update in Intensive Care and Emergency Medicine 2020. Other selected articles can be found online at https://www.biomedcentral.com/collections/annualupdate2020. Further information about the Annual Update in Intensive Care and Emergency Medicine is available from http://www.springer.com/series/8901.
Probiotics are routinely administered to hospitalized patients for many potential indications1 but have been associated with adverse effects that may outweigh their potential benefits2–7. It is particularly alarming that probiotic strains can cause bacteremia8,9, yet direct evidence for an ancestral link between blood isolates and administered probiotics is lacking. Here we report a markedly higher risk of Lactobacillus bacteremia for intensive care unit (ICU) patients treated with probiotics compared to those not treated, and provide genomics data that support the idea of direct clonal transmission of probiotics to the bloodstream. Whole-genome-based phylogeny showed that Lactobacilli isolated from treated patients’ blood were phylogenetically inseparable from Lactobacilli isolated from the associated probiotic product. Indeed, the minute genetic diversity among the blood isolates mostly mirrored pre-existing genetic heterogeneity found in the probiotic product. Some blood isolates also contained de novo mutations, including a non-synonymous SNP conferring antibiotic resistance in one patient. Our findings support that probiotic strains can directly cause bacteremia and adaptively evolve within ICU patients. Patients in intensive care units administered a bacterial probiotic had an elevated risk of bloodstream infection due to the probiotic strain.
Introduction
Ventilator-associated pneumonia (VAP) is the most common healthcare-associated infection in critically ill patients. Prior studies suggest that probiotics may reduce VAP and other infections in critically ill patients; however, most previous randomised trials were small, single centre studies. The Probiotics: Prevention of Severe Pneumonia and Endotracheal Colonization Trial (PROSPECT) aims to determine the impact of the probiotic Lactobacillus rhamnosus GG on VAP and other clinically important outcomes in critically ill adults.
Methods
PROSPECT is a multicentre, concealed, randomised, stratified, blinded, controlled trial in patients ≥18 years old, anticipated to be mechanically ventilated ≥72 hours, in intensive care units (ICUs) in Canada, the USA and Saudi Arabia. Patients receive either 1×10 ¹⁰ colony forming units of L. rhamnosus GG twice daily or an identical appearing placebo. Those at increased risk of probiotic infection are excluded. The primary outcome is VAP. Secondary outcomes are other ICU-acquired infections including Clostridioides difficile infection, diarrhoea (including antibiotic-associated diarrhoea), antimicrobial use, ICU and hospital length of stay and mortality. The planned sample size of 2650 patients is based on an estimated 15% VAP rate and will provide 80% power to detect a 25% relative risk reduction.
Ethics and dissemination
This protocol and statistical analysis plan outlines the methodology, primary and secondary analyses, sensitivity analyses and subgroup analyses. PROSPECT is approved by Health Canada (#9427-M1133-45C), the research ethics boards of all participating hospitals and Public Health Ontario. Results will be disseminated via academic channels (peer reviewed journal publications, professional healthcare fora including international conferences) and conventional and social media. The results of PROSPECT will inform practice guidelines worldwide.
Trialregistration number
NCT02462590 ; Pre-results.
Background
Host-associated microbial communities have important roles in tissue homeostasis and overall health. Severe perturbations can occur within these microbial communities during critical illness due to underlying diseases and clinical interventions, potentially influencing patient outcomes. We sought to profile the microbial composition of critically ill mechanically ventilated patients, and to determine whether microbial diversity is associated with illness severity and mortality.
Methods
We conducted a prospective, observational study of mechanically ventilated critically ill patients with a high incidence of pneumonia in 2 intensive care units (ICUs) in Hamilton, Canada, nested within a randomized trial for the prevention of healthcare-associated infections. The microbial profiles of specimens from 3 anatomical sites (respiratory, and upper and lower gastrointestinal tracts) were characterized using 16S ribosomal RNA gene sequencing.
Results
We collected 65 specimens from 34 ICU patients enrolled in the trial (29 endotracheal aspirates, 26 gastric aspirates and 10 stool specimens). Specimens were collected at a median time of 3 days (lower respiratory tract and gastric aspirates; interquartile range [IQR] 2–4) and 6 days (stool; IQR 4.25–6.75) following ICU admission. We observed a loss of biogeographical distinction between the lower respiratory tract and gastrointestinal tract microbiota during critical illness. Moreover, microbial diversity in the respiratory tract was inversely correlated with APACHE II score (r = − 0.46, p = 0.013) and was associated with hospital mortality (Median Shannon index: Discharged alive; 1.964 vs. Deceased; 1.348, p = 0.045).
Conclusions
The composition of the host-associated microbial communities is severely perturbed during critical illness. Reduced microbial diversity reflects high illness severity and is associated with mortality. Microbial diversity may be a biomarker of prognostic value in mechanically ventilated patients.
Trial registration
ClinicalTrials.gov ID NCT01782755. Registered February 4 2013.
Electronic supplementary material
The online version of this article (10.1186/s12931-018-0950-5) contains supplementary material, which is available to authorized users.
Sepsis in early infancy results in one million annual deaths worldwide, most of them in developing countries. No efficient means of prevention is currently available. Here we report on a randomized, double-blind, placebo-controlled trial of an oral synbiotic preparation (Lactobacillus plantarum plus fructooligosaccharide) in rural Indian newborns. We enrolled 4,556 infants that were at least 2,000 g at birth, at least 35 weeks of gestation, and with no signs of sepsis or other morbidity, and monitored them for 60 days. We show a significant reduction in the primary outcome (combination of sepsis and death) in the treatment arm (risk ratio 0.60, 95% confidence interval 0.48-0.74), with few deaths (4 placebo, 6 synbiotic). Significant reductions were also observed for culture-positive and culture-negative sepsis and lower respiratory tract infections. These findings suggest that a large proportion of neonatal sepsis in developing countries could be effectively prevented using a synbiotic containing L. plantarum ATCC-202195.
In clinical trials it is not uncommon to face a multiple testing problem which can have an impact on both type I and type II error rates, leading to inappropriate interpretation of trial results. Multiplicity issues may need to be considered at the design, analysis and interpretation stages of a trial. The proportion of trial reports not adequately correcting for multiple testing remains substantial. The purpose of this article is to provide an introduction to multiple testing issues in clinical trials, and to reduce confusion around the need for multiplicity adjustments. We use a tutorial, question-and-answer approach to address the key issues of why, when and how to consider multiplicity adjustments in trials. We summarize the relevant circumstances under which multiplicity adjustments ought to be considered, as well as options for carrying out multiplicity adjustments in terms of trial design factors including Population, Intervention/Comparison, Outcome, Time frame and Analysis (PICOTA). Results are presented in an easy-to-use table and flow diagrams. Confusion about multiplicity issues can be reduced or avoided by considering the potential impact of multiplicity on type I and II errors and, if necessary pre-specifying statistical approaches to either avoid or adjust for multiplicity in the trial protocol or analysis plan.
Critical illness may be associated with the loss of normal, “health promoting” bacteria, allowing overgrowth of disease-promoting pathogenic bacteria (dysbiosis), which, in turn, makes patients susceptible to hospital-acquired infections, sepsis, and organ failure. This has significant world health implications, because sepsis is becoming a leading cause of death worldwide, and hospital-acquired infections contribute to significant illness and increased costs. Thus, a trial that monitors the ICU patient microbiome to confirm and characterize this hypothesis is urgently needed. Our study analyzed the microbiomes of 115 critically ill subjects and demonstrated rapid dysbiosis from unexpected environmental sources after ICU admission. These data may provide the first steps toward defining targeted therapies that correct potentially “illness-promoting” dysbiosis with probiotics or with targeted, multimicrobe synthetic “stool pills” that restore a healthy microbiome in the ICU setting to improve patient outcomes.
Background
Critical illness is characterized by a loss of commensal flora and an overgrowth of potentially pathogenic bacteria, leading to a high susceptibility to nosocomial infections. Probiotics are living non-pathogenic microorganisms, which may protect the gut barrier, attenuate pathogen overgrowth, decrease bacterial translocation and prevent infection. The purpose of this updated systematic review is to evaluate the overall efficacy of probiotics and synbiotic mixtures on clinical outcomes in critical illness. Methods
Computerized databases from 1980 to 2016 were searched. Randomized controlled trials (RCT) evaluating clinical outcomes associated with probiotic therapy as a single strategy or in combination with prebiotic fiber (synbiotics). Overall number of new infections was the primary outcome; secondary outcomes included mortality, ICU and hospital length of stay (LOS), and diarrhea. Subgroup analyses were performed to elucidate the role of other key factors such as probiotic type and patient mortality risk on the effect of probiotics on outcomes. ResultsThirty trials that enrolled 2972 patients were identified for analysis. Probiotics were associated with a significant reduction in infections (risk ratio 0.80, 95 % confidence interval (CI) 0.68, 0.95, P = 0.009; heterogeneity I2 = 36 %, P = 0.09). Further, a significant reduction in the incidence of ventilator-associated pneumonia (VAP) was found (risk ratio 0.74, 95 % CI 0.61, 0. 90, P = 0.002; I2 = 19 %). No effect on mortality, LOS or diarrhea was observed. Subgroup analysis indicated that the greatest improvement in the outcome of infections was in critically ill patients receiving probiotics alone versus synbiotic mixtures, although limited synbiotic trial data currently exists. Conclusion
Probiotics show promise in reducing infections, including VAP in critical illness. Currently, clinical heterogeneity and potential publication bias reduce strong clinical recommendations and indicate further high quality clinical trials are needed to conclusively prove these benefits.
Background:
Probiotics are live microorganisms that may confer health benefits when ingested. Randomized trials suggest that probiotics significantly decrease the incidence of ventilator-associated pneumonia (VAP) and the overall incidence of infection in critically ill patients. However, these studies are small, largely single-center, and at risk of bias. The aim of the PROSPECT pilot trial was to determine the feasibility of conducting a larger trial of probiotics to prevent VAP in mechanically ventilated patients in the intensive care unit (ICU).
Methods:
In a randomized blinded trial, patients expected to be mechanically ventilated for ≥72 hours were allocated to receive either 1 × 10(10) colony-forming units of Lactobacillus rhamnosus GG or placebo, twice daily. Patients were excluded if they were at increased risk of L. rhamnosus GG infection or had contraindications to enteral medication. Feasibility objectives were: (1) timely recruitment; (2) maximal protocol adherence; (3) minimal contamination; and (4) estimated VAP rate ≥10 %. We also measured other infections, diarrhea, ICU and hospital length of stay, and mortality.
Results:
Overall, in 14 centers in Canada and the USA, all feasibility goals were met: (1) 150 patients were randomized in 1 year; (2) protocol adherence was 97 %; (3) no patients received open-label probiotics; and (4) the VAP rate was 19 %. Other infections included: bloodstream infection (19.3 %), urinary tract infections (12.7 %), and skin and soft tissue infections (4.0 %). Diarrhea, defined as Bristol type 6 or 7 stools, occurred in 133 (88.7 %) of patients, the median length of stay in ICU was 12 days (quartile 1 to quartile 3, 7-18 days), and in hospital was 26 days (quartile 1 to quartile 3, 14-44 days); 23 patients (15.3 %) died in the ICU.
Conclusions:
The PROSPECT pilot trial supports the feasibility of a larger trial to investigate the effect of L. rhamnosus GG on VAP and other nosocomial infections in critically ill patients.
Trial registration:
Clinicaltrials.gov NCT01782755 . Registered on 29 January 2013.
Background:
To inform clinical guidance, public health efforts, and research directions, probiotic use in U.S. health care needs to be better understood. This work aimed to assess the prevalence of inpatient probiotic use in a sample of U.S. hospitals.
Methods:
Probiotic use among patients discharged in 2012 was estimated using the MarketScan Hospital Drug Database. In addition, the annual trend in probiotic use (2006-2012) was assessed among a subset of hospitals.
Results:
Among 145 hospitals with 1,976,167 discharges in 2012, probiotics were used in 51,723 (2.6%) of hospitalizations occurring in 139 (96%) hospitals. Patients receiving probiotics were 9 times more likely to receive antimicrobials (P < .0001) and 21 times more likely to have a Clostridium difficile infection diagnosis (P < .0001). The most common probiotic formulations were Saccharomyces boulardii (32% of patients receiving probiotics), Lactobacillus acidophilus and Lactobacillus bulgaricus (30%), L acidophilus (28%), and Lactobacillus rhamnosus (11%). Probiotic use increased from 1.0% of 1,090,373 discharges in 2006 to 2.9% of 1,006,051 discharges in 2012 (P < .0001).
Conclusions:
In this sample of U.S. hospitals, a sizable and growing number of inpatients received probiotics as part of their care despite inadequate evidence to support their use in this population. Additional research is needed to guide probiotic use in the hospital setting.
This Viewpoint describes early observations about the human microbiota and what research might tell us about the benefits and vulnerabilities of an individual’s microbial ecosystem.All animals coexist in intimate, dependent relationships with microbes. Humans are no exception. Host-associated microbes, like nearly all others on this planet, form communities in which the overall composition, structure, and function are explained by ecological processes and environmental factors. Evidence of coadaptation and mutual benefit are key features of these symbioses between hosts and their microbial communities, or microbiotas.1 The human microbiota is a fundamental component of what it means to be human.
Background:
Probiotics are defined as live microorganisms that may confer health benefits when ingested. Meta-analysis of probiotic trials suggests a 25 % lower ventilator-associated pneumonia (VAP) and 18 % lower infection rates overall when administered to patients in the intensive care unit (ICU). However, prior trials are small, largely single center, and at high risk of bias. Before a large rigorous trial is launched, testing whether probiotics confer benefit, harm, or have no impact, a pilot trial is needed. The aim of the PROSPECT Pilot Trial is to determine the feasibility of performing a larger trial in mechanically ventilated critically ill patients investigating Lactobacillus rhamnosus GG. A priori, we determined that the feasibility of the larger trial would be based on timely recruitment, high protocol adherence, minimal contamination, and an acceptable VAP rate.
Methods/design:
Patients ≥18 years old in the ICU who are anticipated to receive mechanical ventilation for ≥72 hours will be included. Patients are excluded if they are at increased risk of probiotic-associated infection, have strict enteral medication contraindications, are pregnant, previously enrolled in a related trial, or are receiving palliative care. Following informed consent, patients are randomized in variable unspecified block sizes in a fixed 1:1 ratio, stratified by ICU, and medical, surgical, or trauma admitting diagnosis. Patients receive 1 × 10(10) colony forming units of L. rhamnosus GG (Culturelle, Locin Industries Ltd) or an identical placebo suspended in tap water administered twice daily via nasogastric tube in the ICU. Clinical and research staff, patients, and families are blinded.
Discussion:
The primary outcomes for this pilot trial are the following: (1) recruitment success, (2) ≥90 % protocol adherence, (3) ≤5 % contamination, and (4) ~10 % VAP rate. Additional clinical outcomes are VAP, other infections, diarrhea (total, antibiotic associated, and Clostridium difficile), ICU and hospital length of stay, and mortality. The morbidity, mortality, and cost of VAP underscore the need for cost-effective prophylactic interventions. The PROSPECT Pilot Trial is the initial step toward rigorously evaluating whether probiotics decrease nosocomial infections, have no effect, or actually cause infections in critically ill patients.
Trial registration:
ClinicalTrials.gov. NCT01782755.
Background:
Antibiotic-associated diarrhoea (AAD) occurs most frequently in older (≥65 years) inpatients exposed to broad-spectrum antibiotics. When caused by Clostridium difficile, AAD can result in life-threatening illness. Although underlying disease mechanisms are not well understood, microbial preparations have been assessed in the prevention of AAD. However, studies have been mostly small single-centre trials with varying quality, providing insufficient data to reliably assess effectiveness. We aimed to do a pragmatic efficacy trial in older inpatients who would be representative of those admitted to National Health Service (NHS) and similar secondary care institutions and to recruit a sufficient number of patients to generate a definitive result.
Methods:
We did a multicentre, randomised, double-blind, placebo-controlled, pragmatic, efficacy trial of inpatients aged 65 years and older and exposed to one or more oral or parenteral antibiotics. A computer-generated randomisation scheme was used to allocate participants (in a 1:1 ratio) to receive either a multistrain preparation of lactobacilli and bifidobacteria, with a total of 6 × 10(10) organisms, one per day for 21 days, or an identical placebo. Patients, study staff, and specimen and data analysts were masked to assignment. The primary outcomes were occurrence of AAD within 8 weeks and C difficile diarrhoea (CDD) within 12 weeks of recruitment. Analysis was by modified intention-to-treat. This trial is registered, number ISRCTN70017204.
Findings:
Of 17,420 patients screened, 1493 were randomly assigned to the microbial preparation group and 1488 to the placebo group. 1470 and 1471, respectively, were included in the analyses of the primary endpoints. AAD (including CDD) occurred in 159 (10·8%) participants in the microbial preparation group and 153 (10·4%) participants in the placebo group (relative risk [RR] 1·04; 95% CI 0·84-1·28; p=0·71). CDD was an uncommon cause of AAD and occurred in 12 (0·8%) participants in the microbial preparation group and 17 (1·2%) participants in the placebo group (RR 0·71; 95% CI 0·34-1·47; p=0·35). 578 (19·7%) participants had one or more serious adverse event; the frequency of serious adverse events was much the same in the two study groups and none was attributed to participation in the trial.
Interpretation:
We identified no evidence that a multistrain preparation of lactobacilli and bifidobacteria was effective in prevention of AAD or CDD. An improved understanding of the pathophysiology of AAD is needed to guide future studies.
Funding:
Health Technology Assessment programme; National Institute for Health Research, UK.
Diarrhoea is frequently reported in the intensive care unit (ICU). Little is known about diarrhoea incidence and the role of the different risk factors alone or in combination. This prospective observational study aims at determining diarrhoea incidence and risk factors in the two first weeks of ICU, focusing on the respective contribution of feeding, antibiotics, and antifungal drugs.
Out of 422 patients consecutively admitted into a mixed medical-surgical ICU during a 2-month period, 278 patients were included according to the following criteria: ICU stay > 24 h, no admission diagnosis of gastrointestinal bleeding, and absence of enterostomy or colostomy. Diarrhoea was defined as at least three liquid stools per day. Diarrhoea episodes occurring during the first day in the ICU, related to the use of laxative drugs or Clostridium difficile infection were not analysed. Multivariate and stratified analyses were performed to determine diarrhoea risk factors, and the impact of the combination of enteral nutrition (EN) with antibiotics or antifungal drugs.
1595 patient-days were analysed. Diarrhoea was observed in 38 patients (14%) and 83 patient-days (incidence rate: 5.2 per 100 patient-days). The median day of diarrhoea onset was the 6th day, and 89% of patients had <=4 diarrhoea days. The incidence of Clostridium difficile infection was 0.7%. Diarrhoea risk factors were EN covering >60% of energy target (relative risk (RR), 1.75 [1.02--3.01]), antibiotics (RR, 3.64 [1.26--10.51]) and antifungal drugs (RR, 2.79 [1.16--6.70]). EN delivery per se was not a diarrhoea risk factor. In patients receiving >60% of energy target by EN, diarrhoea risk was increased by the presence of antibiotics (RR, 4.8 [2.1--13.7]) or antifungal drugs (RR, 5.0 [2.8--8.7]).
Diarrhoea incidence during the first two weeks in a mixed population of patients in a tertiary ICU is 14%. Diarrhoea risk factors are EN covering >60% of energy target, use of antibiotics and antifungal drugs. The combination of EN covering >60% of energy target with antibiotics or antifungal drugs increases the incidence of diarrhoea.
Background
Critically ill patients have considerable oxidative stress. Glutamine and antioxidant supplementation may offer therapeutic benefit, although current data are conflicting.
Methods
In this blinded 2-by-2 factorial trial, we randomly assigned 1223 critically ill adults in 40 intensive care units (ICUs) in Canada, the United States, and Europe who had multiorgan failure and were receiving mechanical ventilation to receive supple- ments of glutamine, antioxidants, both, or placebo. Supplements were started within 24 hours after admission to the ICU and were provided both intravenously and en- terally. The primary outcome was 28-day mortality. Because of the interim-analysis plan, a P value of less than 0.044 at the final analysis was considered to indicate statistical significance.
Results
There was a trend toward increased mortality at 28 days among patients who re- ceived glutamine as compared with those who did not receive glutamine (32.4% vs. 27.2%;adjustedoddsratio,1.28;95%confidenceinterval[CI],1.00to1.64;P=0.05). In-hospital mortality and mortality at 6 months were significantly higher among those who received glutamine than among those who did not. Glutamine had no effect on rates of organ failure or infectious complications. Antioxidants had no ef- fect on 28-day mortality (30.8%, vs. 28.8% with no antioxidants; adjusted odds ratio, 1.09; 95% CI, 0.86 to 1.40; P=0.48) or any other secondary end point. There were no differences among the groups with respect to serious adverse events (P=0.83).
Conclusions
Early provision of glutamine or antioxidants did not improve clinical outcomes, and glutamine was associated with an increase in mortality among critically ill patients with multiorgan failure. (Funded by the Canadian Institutes of Health Research; ClinicalTrials.gov number, NCT00133978.)
To catalog what is known about the safety of interventions containing Lactobacillus, Bifidobacterium, Saccharomyces, Streptococcus, Enterococcus, and/or Bacillus strains used as probiotic agents in research to reduce the risk of, prevent, or treat disease.
We searched 12 electronic databases, references of included studies, and pertinent reviews for studies addressing the safety of probiotics from database inception to August 2010 without language restriction.
We identified intervention studies on probiotics that reported the presence or absence of adverse health outcomes in human participants, without restriction by study design, participant type, or clinical field. We investigated the quantity, quality, and nature of adverse events.
The search identified 11,977 publications, of which 622 studies were included in the review. In 235 studies, only nonspecific safety statements were made ("well tolerated"); the remaining 387 studies reported the presence or absence of specific adverse events. Interventions and adverse events were poorly documented. A number of case studies described fungemia and some bacteremia potentially associated with administered probiotic organisms. Controlled trials did not monitor routinely for such infections and primarily reported on gastrointestinal adverse events. Based on reported adverse events, randomized controlled trials (RCTs) showed no statistically significantly increased relative risk (RR) of the overall number of experienced adverse events (RR 1.00; 95% confidence interval [CI]: 0.93, 1.07, p=0.999); gastrointestinal; infections; or other adverse events, including serious adverse events (RR 1.06; 95% CI: 0.97, 1.16; p=0.201), associated with short-term probiotic use compared to control group participants; long-term effects are largely unknown. Existing studies primarily examined Lactobacillus alone or in combination with other genera, often Bifidobacterium. Few studies directly compared the safety among different intervention or participant characteristics. Indirect comparisons indicated that effects of delivery vehicles (e.g., yogurt, dairy) should be investigated further. Case studies suggested that participants with compromised health are most likely to experience adverse events associated with probiotics. However, RCTs in medium-risk and critically ill participants did not report a statistically significantly increased risk of adverse events compared to control group participants.
There is a lack of assessment and systematic reporting of adverse events in probiotic intervention studies, and interventions are poorly documented. The available evidence in RCTs does not indicate an increased risk; however, rare adverse events are difficult to assess, and despite the substantial number of publications, the current literature is not well equipped to answer questions on the safety of probiotic interventions with confidence.
Probiotics are live microorganisms intended to confer a health benefit when consumed. One condition for which probiotics have been advocated is the diarrhea that is a common adverse effect of antibiotic use.
To evaluate the evidence for probiotic use in the prevention and treatment of antibiotic-associated diarrhea (AAD).
Twelve electronic databases were searched (DARE, Cochrane Library of Systematic Reviews, CENTRAL, PubMed, EMBASE, CINAHL, AMED, MANTIS, TOXLINE, ToxFILE, NTIS, and AGRICOLA) and references of included studies and reviews were screened from database inception to February 2012, without language restriction.
Two independent reviewers identified parallel randomized controlled trials (RCTs) of probiotics (Lactobacillus, Bifidobacterium, Saccharomyces, Streptococcus, Enterococcus, and/or Bacillus) for the prevention or treatment of AAD.
Two independent reviewers extracted the data and assessed trial quality.
A total of 82 RCTs met inclusion criteria. The majority used Lactobacillus-based interventions alone or in combination with other genera; strains were poorly documented. The pooled relative risk in a DerSimonian-Laird random-effects meta-analysis of 63 RCTs, which included 11 811 participants, indicated a statistically significant association of probiotic administration with reduction in AAD (relative risk, 0.58; 95% CI, 0.50 to 0.68; P < .001; I(2), 54%; [risk difference, -0.07; 95% CI, -0.10 to -0.05], [number needed to treat, 13; 95% CI, 10.3 to 19.1]) in trials reporting on the number of patients with AAD. This result was relatively insensitive to numerous subgroup analyses. However, there exists significant heterogeneity in pooled results and the evidence is insufficient to determine whether this association varies systematically by population, antibiotic characteristic, or probiotic preparation.
The pooled evidence suggests that probiotics are associated with a reduction in AAD. More research is needed to determine which probiotics are associated with the greatest efficacy and for which patients receiving which specific antibiotics.
Enteral administration of probiotics may modify the gastrointestinal environment in a manner that preferentially favors the growth of minimally virulent species. It is unknown whether probiotic modification of the upper aerodigestive flora can reduce nosocomial infections.
To determine whether oropharyngeal and gastric administration of Lactobacillus rhamnosus GG can reduce the incidence of ventilator-associated pneumonia (VAP).
We performed a prospective, randomized, double-blind, placebo-controlled trial of 146 mechanically ventilated patients at high risk of developing VAP. Patients were randomly assigned to receive enteral probiotics (n = 68) or an inert inulin-based placebo (n = 70) twice a day in addition to routine care.
Patients treated with Lactobacillus were significantly less likely to develop microbiologically confirmed VAP compared with patients treated with placebo (40.0 vs. 19.1%; P = 0.007). Although patients treated with probiotics had significantly less Clostridium difficile-associated diarrhea than patients treated with placebo (18.6 vs. 5.8%; P = 0.02), the duration of diarrhea per episode was not different between groups (13.2 ± 7.4 vs. 9.8 ± 4.9 d; P = 0.39). Patients treated with probiotics had fewer days of antibiotics prescribed for VAP (8.6 ± 10.3 vs. 5.6 ± 7.8 d; P = 0.05) and for C. difficile-associated diarrhea (2.1 ± 4.8 SD d vs. 0.5 ± 2.3 d; P = 0.02). No adverse events related to probiotic administration were identified.
These pilot data suggest that L. rhamnosus GG is safe and efficacious in preventing VAP in a select, high-risk ICU population. Clinical trial registered with www.clinicaltrials.gov (NCT00613795).
The Medical Research Council has for some years encouraged collaborative clinical trials in leukaemia and other cancers, reporting the results in the medical literature. One unreported result which deserves such publication is the development of the expertise to design and analyse such trials. This report was prepared by a group of British and American statisticians, but it is intended for people without any statistical expertise. Part I, which appears in this issue, discusses the design of such trials; Part II, which will appear separately in the January 1977 issue of the Journal, gives full instructions for the statistical analysis of such trials by means of life tables and the logrank test, including a worked example, and discusses the interpretation of trial results, including brief reports of 2 particular trials. Both parts of this report are relevant to all clinical trials which study time to death, and wound be equally relevant to clinical trials which study time to other particular classes of untoward event: first stroke, perhaps, or first relapse, metastasis, disease recurrence, thrombosis, transplant rejection, or death from a particular cause. Part I, in this issue, collects together ideas that have mostly already appeared in the medical literature, but Part II, next month, is the first simple account yet published for non-statistical physicians of how to analyse efficiently data from clinical trials of survival duration. Such trials include the majority of all clinical trials of cancer therapy; in cancer trials,however, it may be preferable to use these statistical methods to study time to local recurrence of tumour, or to study time to detectable metastatic spread, in addition to studying total survival. Solid tumours can be staged at diagnosis; if this, or any other available information in some other disease is an important determinant of outcome, it can be used to make the overall logrank test for the whole heterogeneous trial population more sensitive, and more intuitively satisfactory, for it will then only be necessary to compare like with like, and not, by chance, Stage I with Stage III.
There is no single generally accepted clinical definition of frailty. Previously developed tools to assess frailty that have been shown to be predictive of death or need for entry into an institutional facility have not gained acceptance among practising clinicians. We aimed to develop a tool that would be both predictive and easy to use.
We developed the 7-point Clinical Frailty Scale and applied it and other established tools that measure frailty to 2305 elderly patients who participated in the second stage of the Canadian Study of Health and Aging (CSHA). We followed this cohort prospectively; after 5 years, we determined the ability of the Clinical Frailty Scale to predict death or need for institutional care, and correlated the results with those obtained from other established tools.
The CSHA Clinical Frailty Scale was highly correlated (r = 0.80) with the Frailty Index. Each 1-category increment of our scale significantly increased the medium-term risks of death (21.2% within about 70 mo, 95% confidence interval [CI] 12.5%-30.6%) and entry into an institution (23.9%, 95% CI 8.8%-41.2%) in multivariable models that adjusted for age, sex and education. Analyses of receiver operating characteristic curves showed that our Clinical Frailty Scale performed better than measures of cognition, function or comorbidity in assessing risk for death (area under the curve 0.77 for 18-month and 0.70 for 70-month mortality).
Frailty is a valid and clinically important construct that is recognizable by physicians. Clinical judgments about frailty can yield useful predictive information.
Background:
Probiotics, prebiotics, and synbiotics are used increasingly, although the safety and potential harms of these interventions are poorly understood.
Purpose:
To examine how harms-related information is reported in publications of randomized controlled trials (RCTs) of probiotics, prebiotics, and synbiotics.
Data sources:
Cochrane Central Register of Controlled Trials, PubMed, EMBASE, and Web of Science (without language restrictions) from 1 January 2015 to 20 March 2018.
Study selection:
RCTs assessing the safety or efficacy of at least 1 intervention involving probiotics, prebiotics, or synbiotics alone or in combination with another intervention compared with any control (such as a placebo or an antibiotic) for any clinical condition.
Data extraction:
4 reviewers independently assessed study characteristics, the reporting of harms, and the presentation of safety results.
Data synthesis:
Of 384 trials conducted in healthy volunteers (n = 136) or patients with any of several medical conditions (n = 248), 339 (88%) were published in specialty journals. Trials most often evaluated probiotics (n = 265 [69%]). Studies in persons with medical conditions enrolled outpatients (n = 195) and high-risk patients (n = 53). No harms-related data were reported for 106 trials (28%), safety results were not reported for 142 (37%), and the number of serious adverse events (SAEs) per study group was not given for 309 (80%). Of 242 studies mentioning harms-related results, 37% (n = 89) used only generic statements to describe AEs and 16% (n = 38) used inadequate metrics. Overall, 375 trials (98%) did not give a definition for AEs or SAEs, the number of participant withdrawals due to harms, or the number of AEs and SAEs per study group with denominators.
Limitation:
Journal publication processes may have affected the completeness of reporting; only English-language publications were examined.
Conclusion:
Harms reporting in published reports of RCTs assessing probiotics, prebiotics, and synbiotics often is lacking or inadequate. We cannot broadly conclude that these interventions are safe without reporting safety data.
Primary funding source:
No specific funding.
OBJECTIVE
To determine whether probiotic prophylaxes reduce the odds of Clostridium difficile infection (CDI) in adults and children.DESIGNIndividual participant data (IPD) meta-analysis of randomized controlled trials (RCTs), adjusting for risk factors.METHODS
We searched 6 databases and 11 grey literature sources from inception to April 2016. We identified 32 RCTs (n=8,713); among them, 18 RCTs provided IPD (n=6,851 participants) comparing probiotic prophylaxis to placebo or no treatment (standard care). One reviewer prepared the IPD, and 2 reviewers extracted data, rated study quality, and graded evidence quality.RESULTSProbiotics reduced CDI odds in the unadjusted model (n=6,645; odds ratio [OR] 0.37; 95% confidence interval [CI], 0.25-0.55) and the adjusted model (n=5,074; OR, 0.35; 95% CI, 0.23-0.55). Using 2 or more antibiotics increased the odds of CDI (OR, 2.20; 95% CI, 1.11-4.37), whereas age, sex, hospitalization status, and high-risk antibiotic exposure did not. Adjusted subgroup analyses suggested that, compared to no probiotics, multispecies probiotics were more beneficial than single-species probiotics, as was using probiotics in clinical settings where the CDI risk is ≥5%. Of 18 studies, 14 reported adverse events. In 11 of these 14 studies, the adverse events were retained in the adjusted model. Odds for serious adverse events were similar for both groups in the unadjusted analyses (n=4,990; OR, 1.06; 95% CI, 0.89-1.26) and adjusted analyses (n=4,718; OR, 1.06; 95% CI, 0.89-1.28). Missing outcome data for CDI ranged from 0% to 25.8%. Our analyses were robust to a sensitivity analysis for missingness.CONCLUSIONS
Moderate quality (ie, certainty) evidence suggests that probiotic prophylaxis may be a useful and safe CDI prevention strategy, particularly among participants taking 2 or more antibiotics and in hospital settings where the risk of CDI is ≥5%.TRIAL REGISTRATIONPROSPERO 2015 identifier: CRD42015015701Infect Control Hosp Epidemiol 2018;1-11.
Background:
Antibiotics can disturb gastrointestinal microbiota which may lead to reduced resistance to pathogens such as Clostridium difficile (C. difficile). Probiotics are live microbial preparations that, when administered in adequate amounts, may confer a health benefit to the host, and are a potential C. difficile prevention strategy. Recent clinical practice guidelines do not recommend probiotic prophylaxis, even though probiotics have the highest quality evidence among cited prophylactic therapies.
Objectives:
To assess the efficacy and safety of probiotics for preventing C.difficile-associated diarrhea (CDAD) in adults and children.
Search methods:
We searched PubMed, EMBASE, CENTRAL, and the Cochrane IBD Group Specialized Register from inception to 21 March 2017. Additionally, we conducted an extensive grey literature search.
Selection criteria:
Randomized controlled (placebo, alternative prophylaxis, or no treatment control) trials investigating probiotics (any strain, any dose) for prevention of CDAD, or C. difficile infection were considered for inclusion.
Data collection and analysis:
Two authors (independently and in duplicate) extracted data and assessed risk of bias. The primary outcome was the incidence of CDAD. Secondary outcomes included detection of C. difficile infection in stool, adverse events, antibiotic-associated diarrhea (AAD) and length of hospital stay. Dichotomous outcomes (e.g. incidence of CDAD) were pooled using a random-effects model to calculate the risk ratio (RR) and corresponding 95% confidence interval (95% CI). We calculated the number needed to treat for an additional beneficial outcome (NNTB) where appropriate. Continuous outcomes (e.g. length of hospital stay) were pooled using a random-effects model to calculate the mean difference and corresponding 95% CI. Sensitivity analyses were conducted to explore the impact of missing data on efficacy and safety outcomes. For the sensitivity analyses, we assumed that the event rate for those participants in the control group who had missing data was the same as the event rate for those participants in the control group who were successfully followed. For the probiotic group, we calculated effects using the following assumed ratios of event rates in those with missing data in comparison to those successfully followed: 1.5:1, 2:1, 3:1, and 5:1. To explore possible explanations for heterogeneity, a priori subgroup analyses were conducted on probiotic species, dose, adult versus pediatric population, and risk of bias as well as a post hoc subgroup analysis on baseline risk of CDAD (low 0% to 2%; moderate 3% to 5%; high > 5%). The overall quality of the evidence supporting each outcome was independently assessed using the GRADE criteria.
Main results:
Thirty-nine studies (9955 participants) met the eligibility requirements for our review. Overall, 27 studies were rated as either high or unclear risk of bias. A complete case analysis (i.e. participants who completed the study) among trials investigating CDAD (31 trials, 8672 participants) suggests that probiotics reduce the risk of CDAD by 60%. The incidence of CDAD was 1.5% (70/4525) in the probiotic group compared to 4.0% (164/4147) in the placebo or no treatment control group (RR 0.40, 95% CI 0.30 to 0.52; GRADE = moderate). Twenty-two of 31 trials had missing CDAD data ranging from 2% to 45%. Our complete case CDAD results proved robust to sensitivity analyses of plausible and worst-plausible assumptions regarding missing outcome data and results were similar whether considering subgroups of trials in adults versus children, inpatients versus outpatients, different probiotic species, lower versus higher doses of probiotics, or studies at high versus low risk of bias. However, in a post hoc analysis, we did observe a subgroup effect with respect to baseline risk of developing CDAD. Trials with a baseline CDAD risk of 0% to 2% and 3% to 5% did not show any difference in risk but trials enrolling participants with a baseline risk of > 5% for developing CDAD demonstrated a large 70% risk reduction (interaction P value = 0.01). Among studies with a baseline risk > 5%, the incidence of CDAD in the probiotic group was 3.1% (43/1370) compared to 11.6% (126/1084) in the control group (13 trials, 2454 participants; RR 0.30, 95% CI 0.21 to 0.42; GRADE = moderate). With respect to detection of C. difficile in the stool pooled complete case results from 15 trials (1214 participants) did not show a reduction in infection rates. C. difficile infection was 15.5% (98/633) in the probiotics group compared to 17.0% (99/581) in the placebo or no treatment control group (RR 0.86, 95% CI 0.67 to 1.10; GRADE = moderate). Adverse events were assessed in 32 studies (8305 participants) and our pooled complete case analysis indicates probiotics reduce the risk of adverse events by 17% (RR 0.83, 95% CI 0.71 to 0.97; GRADE = very low). In both treatment and control groups the most common adverse events included abdominal cramping, nausea, fever, soft stools, flatulence, and taste disturbance.
Authors' conclusions:
Based on this systematic review and meta-analysis of 31 randomized controlled trials including 8672 patients, moderate certainty evidence suggests that probiotics are effective for preventing CDAD (NNTB = 42 patients, 95% CI 32 to 58). Our post hoc subgroup analyses to explore heterogeneity indicated that probiotics are effective among trials with a CDAD baseline risk >5% (NNTB = 12; moderate certainty evidence), but not among trials with a baseline risk ≤5% (low to moderate certainty evidence). Although adverse effects were reported among 32 included trials, there were more adverse events among patients in the control groups. The short-term use of probiotics appears to be safe and effective when used along with antibiotics in patients who are not immunocompromised or severely debilitated. Despite the need for further research, hospitalized patients, particularly those at high risk of CDAD, should be informed of the potential benefits and harms of probiotics.
Complex microbial communities within the human body, constituting the microbiome, have a broad impact on human health and disease. A growing body of research now examines the role of the microbiome in patients with critical illness, such as sepsis and acute respiratory failure. In this article, we provide an introduction to microbiome concepts and terminology and we systematically review the current evidence base of the critical-illness microbiome, including 51 studies in animal models and pediatric and adult critically-ill patients. We further examine how this emerging scientific discipline may transform the way we manage infectious and inflammatory diseases in intensive care units. The evolving molecular, culture-independent techniques offer the ability to study microbial communities in unprecedented depth and detail, and in the short-term, may enable us to diagnose and treat infections in critical care more precisely and effectively. Longer-term, these tools may also give us insights in the underlying pathophysiology of critical illness and reveal previously unsuspected targets for innovative, microbiome-targeted therapeutics. We finally propose a roadmap for future studies in the field for transforming critical care from its current isolated focus on the host to a more personalized paradigm addressing both human and microbial contributions to critical illness.
Antibiotics are widely prescribed; however they can cause disturbances in gastrointestinal flora which may lead to reduced resistance to pathogens such as Clostridium difficile (C. difficile). Probiotics are live organisms thought to balance the gastrointestinal flora. The 45%. These results proved robust to sensitivity analyses of plausible and worst-plausible assumptions regarding missing outcome data and were similar whether considering trials in adults versus children, lower versus higher doses, different probiotic species, or higher versus lower risk of bias. Our ju