Probiotics to Prevent Severe Pneumonia and Endotracheal Colonization Trial

Background:Probiotics are live microorganisms thought to have health benefits when ingested.
Randomized controlled trials (RCTs) have documented favourable impact on a range of clinical
problems, including prevention of upper respiratory tract infections, antibiotic-associated
diarrhea, Clostridium difficile-associated diarrhea, and irritable bowel syndrome. Our recent
meta-analysis of probiotic RCTs in the intensive care unit (ICU) also suggests 25% lower
rates of ventilator-associated pneumonia (VAP) and 18% lower infection rates overall when
administered to critically ill 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 methodologically
rigourous RCT. Before launching a complex costly RCT testing whether probiotics confer
benefit, harm, or have no impact on infectious and non-infectious outcomes, a pilot trial was
needed. The investigators completed a multicenter pilot RCT for which the primary outcomes
relate to feasibility: 1) recruitment success in 1 year; 2) >90% adherence to the probiotic
protocol; 3) <5% contamination; 4) an estimated VAP rate. Patients have been randomized in 14
centers in Canada and the US, with an informed consent rate of 84%. Feasibility goals were
met. 1) Recruitment for the Pilot was achieved in 1 year; 2) Adherence to the protocol was
96%; 3) There were no cases of contamination; 4) The VAP rate was 15%. This will be an
internal Pilot which will be incorporated into the main trial.

Setting: 13 ICUs in Canada, 2 ICUs in United States

Methods: 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 or endovascular infection, primary diagnosis of severe acute
pancreatitis, percutaneous gastric or jejunal feeding tubes already in situe, strict
contraindication or inability to receive enteral medications, have hopeless prognosis,
withholding or withdrawal of advanced life support is planned, or if previous enrolment 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 (Culturelle, Locin Industries Ltd) 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 predominant organism
from a non-sterile site.

RCT Trial Outcomes: The primary outcome is VAP; secondary outcomes include ICU-acquired
infections, diarrhea (total, antibiotic-associated and CDAD), antibiotic use, length of stay
and mortality in the ICU and hospital, and acquired L. rhamnosus GG infections.

Relevance: Despite clinical uptake of some existing VAP prevention strategies, 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 CDAD,
antibiotic-associated diarrhea or antibiotic use is unclear. When rigorously evaluated,
probiotics may have salutary effects decreasing nosocomial infections as prior RCTs suggest;
alternatively, probiotics may have no demonstrable effect, or actually cause infections in
critically ill patients with impaired immune function.

Inclusion Criteria:

1. Adults ≥ 18 years of age

2. Admitted to any ICU and receiving invasive mechanical ventilation

3. Anticipated ventilation of ≥72 hours at the time of screening, as per the ICU
physician.

Exclusion Criteria:

1. Invasively mechanically ventilated >72 hours at the time of screening;

2. Patients at potential increased risk of iatrogenic probiotic infection (see Section
2.6 for detailed explanation) including specific immunocompromised populations (HIV
<200 CD4 cells/μL, those receiving chronic immunosuppressive medications (e.g.,
azathioprine, cyclosporine, cyclophosphamide, tacrolimus, methotrexate, mycofenolate,
Anti-IL2), previous transplantation (including stem cell) at any time, malignancy
requiring chemotherapy in the last 3 months, neutropenia [absolute neutrophil count <
500]). However, patients receiving corticosteroids previously or presently or
projected to receive corticosteroids are not excluded;

3. Patients at risk for endovascular infection (previously documented rheumatic heart
disease, congenital valve disease, surgically repaired congenital heart disease,
unrepaired cyanotic congenital heart disease, any intracardiac repair with prosthetic
material [mechanical or bio-prosthetic cardiac valves], previous or current
endocarditis, permanent endovascular devices (e.g., endovascular grafts [e.g., aortic
aneurysm repair, stents involving large arteries such as aorta, femorals and
carotids], inferior vena cava filters, dialysis vascular grafts), tunnelled (not
short-term) hemodialysis catheters, pacemakers or defibrillators. Patients with
temporary central venous catheters, central venous dialysis catheters or peripherally
inserted central catheters (PICCs) are not excluded and patients with coronary artery
stents, coronary artery bypass grafts (CABG) or neurovascular coils are not excluded;
patients with mitral valve prolapse or bicuspid aortic valve are not excluded
providing they have no other exclusion criteria;

4. Patients with a primary diagnosis of severe acute pancreatitis, without reference to a
Ranson score [Ranson 1974]). However, patients with mild or moderate pancreatitis are
not excluded;

5. Patients with percutaneous gastric or jejunal feeding tubes already in situ as per
Health Canada guidance;

6. Strict contraindication or inability to receive enteral medications;

7. Intent to withdraw advanced life support as per the ICU physician;

8. Previous enrolment in this or current enrolment in a potentially confounding tria