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Probiotics: Prevention of Severe Pneumonia and Endotracheal Colonization Trial-PROSPECT: protocol for a feasibility randomized pilot trial.

ABSTRACT: 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.

SUBMITTER: Johnstone J

PROVIDER: S-EPMC5154039 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Probiotics: Prevention of Severe Pneumonia and Endotracheal Colonization Trial-PROSPECT: protocol for a feasibility randomized pilot trial.

Johnstone Jennie J Meade Maureen M Marshall John J Heyland Daren K DK Surette Michael G MG Bowdish Dawn Me DM Lauzier Francois F Thebane Lehana L Cook Deborah J DJ

Pilot and feasibility studies 20150524

<h4>Background</h4>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 ...[more]

PMID: 27965798

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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: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 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.MethodsPROSPECT 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 disseminationThis 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 numberNCT02462590; Pre-results.

Project description:Ventilator-associated pneumonia (VAP) is a prevalent and costly nosocomial infection related to instrumentation of the airway with an endotracheal tube (ETT), enabling microaspiration of contaminated secretions. Modification of the ETT design to reduce microaspiration and/or biofilm formation may play an important role in VAP prevention. However, there is insufficient evidence to provide strong recommendations regarding the use of modified ETT and unaddressed safety concerns.We performed a pilot randomized controlled trial comparing two modified ETTs designed specifically to prevent VAP, with the standard ETT, to test the feasibility of and inform planning for a large, pivotal, randomized trial.This study was conducted with institutional review board approval under exception from informed consent. We randomized in a blinded fashion patients undergoing emergency endotracheal intubation both out of and in hospital to receive one of three different ETT types: (1) a polyurethane-cuffed tube (PUC-ETT), (2) a polyurethane-cuffed tube equipped with a port for continuous aspiration of subglottic secretions (PUC-CASS-ETT), or a (3) standard polyvinylchloride-cuffed tube (PVC-ETT). In addition to investigating feasibility and safety, the study coprimary end points were tracheal bacterial colonization reaching a cfu count >10(6) cfu per milliliter and the incidence of invasively diagnosed VAP.A total of 102 subjects were randomized and met the eligibility criteria. Randomization procedures performed well and integrity of blinding at randomization was maintained. The majority of intubations occurred in the hospital setting (n?=?77), and the remainder occurred out of hospital (n?=?25). Compared with the PVC-ETT, there were no significant differences in tracheal colonization for PUC-ETT (odds ratio [OR], 0.98; 95% confidence interval [CI], 0.31-3.09) or for PUC-CASS-ETT (OR, 1.26; 95% CI, 0.42-3.76). There were no differences in the risk of invasively diagnosed VAP (OR, 1.14; 95% CI, 0.21-6.08 for PUC-ETT; OR, 1.47; 95% CI, 0.30-7.10 for PUC-CASS-ETT), or of clinically diagnosed VAP by either clinical signs or chest radiograph criteria. We did not observe unexpected or serious adverse events related to the devices.A randomized trial of ETTs inserted during emergency intubation for the prevention of VAP is feasible and did not appear to carry heightened safety concerns. These preliminary data did not suggest different patterns of tracheal colonization or occurrence of VAP among the study groups. Clinical trial registered with www.clinicaltrials.gov (NCT01744483).

Project description:BackgroundDespite the continuing effort in investigating the preventive therapies for stroke-associated pneumonia (SAP), which is closely associated with unfavorable outcomes, conclusively effective therapy for the prevention of SAP is still lacking. Remote ischemic conditioning (RIC) has been proven to improve the survival in the sepsis model and inflammatory responses have been indicated as important mechanisms involved in the multi-organ protection effect of RIC. This study aimed to assess the safety and the preliminary efficacy of RIC in the prevention of SAP in patients with acute ischemic stroke.MethodsWe performed a proof-of-concept, pilot open-label randomized controlled trial. Eligible patients (age > 18 years) within 48 h after stroke onset between March 2019 and October 2019 with acute ischemic stroke were randomly allocated (1:1) to the RIC group and the control group. All participants received standard medical therapy. Patients in the RIC group underwent RIC twice daily for 6 consecutive days. The safety outcome included any adverse events associated with RIC procedures. The efficacy outcome included the incidence of SAP, changes of immunological profiles including mHLA-DR, TLR-2, and TLR-4 as well as other plasma parameters from routine blood tests.ResultsIn total, 46 patients aged 63.1 ± 12.5 years, were recruited (23 in each group). Overall, 19 patients in the RIC group and 22 patients in the control group completed this study. No severe adverse event was attributed to RIC procedures. The incidence of SAP was lower in the remote ischemic conditioning group (2 patients [10.5%]) than that in the control group (6 patients [27.3%]), but no significant difference was detected in both univariate and multivariate analysis (p = 0.249 and adjusted p = 0.666). No significance has been found in this pilot trial in the level of immunological profiles HLA-DR, TLR4 and TLR2 expressed on monocytes as well as blood parameters tested through routine blood tests between the two groups (p > 0.05). The IL-6 and IL-1β levels at day 5 after admission in the RIC group were lower than those in the control group (p < 0.05).InterpretationThis proof-of-concept pilot randomized controlled trial was to investigate RIC as a prevention method for SAP. Remote ischemic conditioning is safe in the prevention of SAP in patients with acute ischemic stroke. The preventive effect of RIC on SAP should be further validated in future studies.

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Probiotics: Prevention of Severe Pneumonia and Endotracheal Colonization Trial-PROSPECT: protocol for a feasibility randomized pilot trial.

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<i>Pro</i>biotics: Prevention of <i>S</i>evere <i>P</i>neumonia and <i>E</i>ndotracheal <i>C</i>olonization <i>T</i>rial-PROSPECT: protocol for a feasibility randomized pilot trial.

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