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Evaluating probiotics for the prevention of ventilator-associated pneumonia: a randomised placebo-controlled multicentre trial protocol and statistical analysis plan for PROSPECT.

ABSTRACT: 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 1×1010?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.

SUBMITTER: Johnstone J

PROVIDER: S-EPMC6596980 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Evaluating probiotics for the prevention of ventilator-associated pneumonia: a randomised placebo-controlled multicentre trial protocol and statistical analysis plan for PROSPECT.

Johnstone Jennie J Heels-Ansdell Diane D Thabane Lehana L Meade Maureen M Marshall John J Lauzier Francois F Duan Erick Huaileigh EH Zytaruk Nicole N Lamarche Daphnee D Surette Michael M Cook Deborah J DJ

BMJ open 20190620 6

<h4>Introduction</h4>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 <i>Lactobacillus rhamnosus</i> GG on VAP and ...[more]

PMID: 31227528

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Project description: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.

Project description: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?×?1010 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.

Project description:IntroductionVentilator-associated pneumonia (VAP) is a common healthcare-associated infection in the intensive care unit (ICU). Probiotics are defined as live microorganisms that may confer health benefits when ingested. Prior randomised trials suggest that probiotics may prevent infections such as VAP and Clostridioides difficile-associated diarrhoea (CDAD). PROSPECT (Probiotics to Prevent Severe Pneumonia and Endotracheal Colonization Trial) is a multicentre, double-blinded, randomised controlled trial comparing the efficacy of the probiotic Lactobacillus rhamnosus GG with usual care versus usual care without probiotics in preventing VAP and other clinically important outcomes in critically ill patients admitted to the ICU.Methods and analysisThe objective of E-PROSPECT is to determine the incremental cost-effectiveness of L. rhamnosus GG plus usual care versus usual care without probiotics in critically ill patients. E-PROSPECT will be performed from the public healthcare payer's perspective over a time horizon from ICU admission to hospital discharge.We will determine probabilities of in-ICU and in-hospital events from all patients alongside PROSPECT. We will retrieve unit costs for each resource use item using jurisdiction-specific public databases, supplemented by individual site unit costs if such databases are unavailable. Direct costs will include medications, personnel costs, radiology/laboratory testing, operative/non-operative procedures and per-day hospital 'hoteling' costs not otherwise encompassed. The primary outcome is the incremental cost per VAP prevented between the two treatment groups. Other clinical events such as CDAD, antibiotic-associated diarrhoea and in-hospital mortality will be included as secondary outcomes. We will perform pre-specified subgroup analyses (medical/surgical/trauma; age; frailty status; antibiotic use; prevalent vs no prevalent pneumonia) and probabilistic sensitivity analyses for VAP, then generate confidence intervals using the non-parametric bootstrapping approach.Ethics and disseminationStudy approval for E-PROSPECT was granted by the Hamilton Integrated Research Ethics Board of McMaster University on 29 July 2019. Informed consent was obtained from the patient or substitute decision-maker in PROSPECT. The findings of this study will be published in peer-reviewed journals.Trial registration numberNCT01782755; Pre-results.

Project description:IntroductionVentilator-associated pneumonias (VAPs) are a complication of mechanical ventilation in the intensive care unit (ICU) that increase length of stay, morbidity, and mortality. While identifying and treating infections early is paramount to improving patient outcomes, more and more data demonstrate limited courses of antibiotics improve outcomes. Prolonged (10-14 day) courses of antibiotics have remained the standard of care for pneumonia due to gram-negative bacilli (GNR). We aimed to review our GNR VAPs to assess risk factors for recurrent GNR infections.MethodsWe reviewed trauma patients who developed VAP from 02/2019 through 05/2022. Demographics, injury characteristics, and outcomes were reviewed with a focus on pneumonia details including the cultured pathogen(s), antibiotic(s) used, treatment duration, and presence of recurrent infections. We then compared single episode VAPs to multiple episode VAPs among patients infected by GNRs.ResultsEleven of the fifty trauma patients admitted to the ICU suffered a VAP caused by a GNR. Of these eleven patients, six experienced a recurrent infection, four of which were caused by Pseudomonas aeruginosa and two of which were caused by Enterobacter aerogenes. Among the patients who received ten days of antibiotic treatment, half suffered a recurrence. Although, there was no difference in the microbiology or antibiotic duration between the recurrences and single episodes.ConclusionDespite prolonged use of antibiotics, we found that the risk of recurrent or persistent infections was high among patients with VAP due to GNB. Further study is needed to determine optimal treatment to minimize the risk of these recurrences.Key messageVentilator-associated pneumonia due to gram-negative bacilli is a rare but high morbidity complication in intensive care units. Despite prolonged duration of therapy, these infections still appear to account for many recurrent infections and further study into optimal therapy is warranted.

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Evaluating probiotics for the prevention of ventilator-associated pneumonia: a randomised placebo-controlled multicentre trial protocol and statistical analysis plan for PROSPECT.

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Evaluating probiotics for the prevention of ventilator-associated pneumonia: a randomised placebo-controlled multicentre trial protocol and statistical analysis plan for PROSPECT.

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