Probiotics: Prevention of Severe Pneumonia and Endotracheal Colonization Trial
Background: Probiotics are live microorganisms thought to have health benefits when ingested. Randomized controlled trials (RCTs) have documented their favourable impact on a range of problems, including prevention of upper respiratory tract infections, antibiotic-associated diarrhea, and Clostridium difficile-associated diarrhea in non-critically ill populations. Our recent meta-analysis of probiotic RCTs in the intensive care unit (ICU) also suggests 25-30% lower rates of ventilator-associated pneumonia (VAP) and 18% lower infection rates overall when administered to mechanically ventilated patients. However, these estimates arise from small, modest quality single-center RCTs yielding imprecise estimates of effect and uncertain generalizability, and require confirmation in a large rigorous RCT. Before such a trial is launched testing whether probiotics confer benefit, harm, or have no impact on infectious and non-infectious outcomes, a pilot trial was needed and completed.
Objective of the PROSPECT Pilot Trial: To determine the feasibility of performing a large RCT of enteral L. rhamnosus GG versus placebo in mechanically ventilated critically ill patients, based on: 1) recruitment success in 1 year; 2) >90% adherence to the probiotic protocol; 3) <5% contamination; 4) an estimated VAP rate.
Results of the Completed PROSPECT Pilot Trial: Patients were randomized in 14 centers in Canada and the US. The informed consent rate was 84%. Feasibility goals were met. 1) Recruitment was achieved in 1 year; 2) Protocol adherence was 96%; 3) There was no contamination; 4) The VAP rate was 15-40%, depending on the definition used.
Objective of the PROSPECT Main Trial: To determine, in mechanically ventilated critically ill patients, whether enteral L. rhamnosus GG prevents VAP and other infections.
Methods for PROSPECT Main Trial: Patients age 18 years or older, admitted to the ICU, with an anticipated duration of ventilation of ≥72 hours are included. Patients are excluded if they have increased risk of iatrogenic probiotic infection, strict contraindication or inability to receive enteral medications, are known or suspected to be pregnant, have hopeless prognosis, withholding or withdrawal of advanced life support is planned, or if previously enrolled in this or a related trial. Following informed consent, patients are randomized in variable unspecified block sizes in a fixed allocation ratio of 1:1, stratified by ICU and medical/surgical/trauma status. Twice daily, patients receive either 1x1010 colony forming units (CFU) of L. rhamnosus GG in 1 capsule or an identical placebo capsule. Both are suspended in water administered via nasogastric tube or by capsule. Research Nurses notify local Study Pharmacists after obtaining informed consent. Study Pharmacists obtain the allocation from the PROSPECT website. Only the Database Manager and Study Pharmacists will have access to the randomization schedule; everyone else remains blinded. Patients receive the intervention until:1) ICU discharge; 2) death; or 3) isolation of Lactobacillus spp. in a sterile site, or if cultured as the sole or dominant organism from a non-sterile site. The primary outcome is VAP; secondary outcomes include ICU-acquired respiratory and other infections, diarrhea (total, antibiotic-associated and Clostridium difficile-associated), antimicrobial use, length of stay and mortality (ICU and hospital), and acquired L. rhamnosus GG infections.
Relevance: Despite clinical uptake of some existing VAP prevention strategies, including probiotics, the morbidity, mortality and cost of VAP underscore the need for further cost-effective interventions to reduce its impact. Whether probiotics impact on VAP, other infections such as Clostridium difficile-associated diarrhea, or have an impact on antimicrobial stewardship is unclear, and will be addressed by the PROSPECT Trial.