Cook 1998.

Methods	Multi‐centre blinded randomised placebo‐controlled trial
Participants	Baseline characteristics Number randomised: 1200 participants Number analysed: 1200 participants Ranitidine Age (years; mean (SD)): 58.8 (18.1) Number of participants (n): 596 Gender (male/female; n): 369/227 Sucralfate Age (years; mean (SD)): 58.7 (18.7) Number of participants (n): 604 Gender (male/female; n): 354/250 Inclusion criteria Consecutive participants who were screened and admitted to 16 participating intensive care units (ICUs) Projected to require mechanical ventilation for ≥ 48 hours Exclusion criteria Diagnosis of gastrointestinal bleeding or pneumonia on admission Gastrectomy Prognosis considered to be hopeless Previous randomisation in this or another trial Receipt of ≥ 2 previous doses of open‐label prophylactic therapy Baseline imbalance: Quote: "Demographic and baseline physiologic characteristics were similar in the two groups" Comment: Mean and SD for APACHE II scores were 24.7 +/‐ 7.1 and 24.6 +/‐ 7.3 in the ranitidine and sucralfate groups. The main reasons for admission were medical: elective surgery or emergency surgery
Interventions	Ranitidine Dose (total/d): 150 mg Duration of treatment (days; mean (SE)): ‐ Route: IV Intervention: administered in intravenous bolus form, with the dose adjusted for renal failure as follows: standard dose, 50 mg every 8 hours; dose for patients with an estimated creatinine clearance rate of 25 to 50 mL per minute, 50 mg every 12 hours; dose for patients with an estimated creatinine clearance rate below 25 mL per minute, 50 mg every 24 hours; and dose for patients dependent on dialysis, 50 mg every 12 hours. 70.3% received enteral feeding + sucralfate placebo Concomitant medications: "Fourteen patients in the ranitidine group (2.3%) and 16 in the sucralfate group (2.6%) received an additional drug as prophylaxis against stress ulcers outside of the study protocol" "Most patients received enteral nutrition (70.3% and 71.8%, respectively; P = 0.55). Enteral feeding was started a median of 3 days (interquartile range, 2 to 4) after admission to the ICU" Sucralfate Dose (total/d): 2400 mg Duration of treatment (days; mean (SE)): ‐ Route: NG tube Intervention: Sucralfate suspension was given through a nasogastric tube or orally. 71.8% received Enteral feeding + Ranitidine placebo Concomitant medications: "Fourteen patients in the ranitidine group (2.3%) and 16 in the sucralfate group (2.6%) received an additional drug as prophylaxis against stress ulcers outside of the study protocol" "Most patients received enteral nutrition (70.3% and 71.8%, respectively; P = 0.55). Enteral feeding was started a median of 3 days (interquartile range, 2 to 4) after admission to the ICU" Adherence to regimen: Quote: "No patient received active drug instead of the assigned placebo, or vice versa. Of the scheduled doses of ranitidine and sucralfate, 94.2% and 91.7%, respectively, were administered. Among patients who missed doses, the mean number of doses missed was 2.3 (median, 3; interquartile range, 2 to 3) for ranitidine and 2.9 (median, 4; interquartile range, 1 to 4) for sucralfate" Duration of trial: October 1992 to May 1996 Duration of follow‐up: probably until death or discharge
Outcomes	Outcomes sought in review and reported in trial: Clinically important GI bleeding defined as overt bleeding plus 1 of the following 4 features, in the absence of other causes: Spontaneous drop of ≥ 20 mmHg in systolic or diastolic blood pressure within 24 hours after upper gastrointestinal bleeding Increase in pulse rate of 20 beats per minute and decrease in systolic blood pressure of 10 mmHg on the patient’s assuming an upright position Decrease in haemoglobin concentration ≥ 2 g/dL in 24 hours and transfusion of 2 units of packed red cells within 24 hours after bleeding Failure of haemoglobin concentration (in g/dL) to increase after transfusion by at least the number of units transfused minus 2 (i.e. if 4 units of packed cells were transfused, bleeding would be considered clinically important if the haemoglobin concentration did not rise by ≥ 2 g/dL) VAP defined according to the modified version of the criteria of the Centers for Disease Control and Prevention New radiographic infiltrate that had persisted for ≥ 48 hours (as interpreted by designated study radiologists blinded to participants' treatment assignments) plus ≥ 2 of the following: temperature > 38.5°C or < 35.0°C, a leucocyte count > 10,000/mm³ or < 3000/mm³, purulent sputum, or isolation of pathogenic bacteria from an endotracheal aspirate   Clinical Pulmonary Infection Score revised by Pugin et al (range, 0 to 12, with pneumonia defined by a score ≥ 7) Criteria of the Memphis Ventilator‐Associated Pneumonia Consensus Conference for Definite Ventilator‐Associated Pneumonia (if there was radiographic evidence of abscess and a positive needle aspirate, or if there was histologic proof of pneumonia at biopsy or autopsy) and probable ventilator‐associated pneumonia (if bronchoalveolar lavage or protected brush‐catheter sampling yielded positive quantitative or semi‐quantitative cultures, if there was a positive blood culture of an organism found within 48 hours of isolation in the sputum, if there was a positive pleural‐fluid culture of an organism found within 48 hours of isolation in the sputum, or if histologic examination showed formation of an abscess or consolidation with polymorphonuclear cell infiltration) Summary judgement based on all available information; disagreement was resolved through discussion All‐cause mortality in ICU Duration of ICU stay (median and interquartile ranges) Duration of intubation (median and interquartile ranges) Outcomes sought but not reported in trial All‐cause mortality in hospital Number of participants requiring blood transfusion Number of units of blood transfused Adverse events of interventions Outcomes reported in trial but not used in review Intragastric pH status (with and without enteral nutrition) Gastric colonisation
Notes	Setting: 16 ICUs: McMaster University, Hamilton, The University of Toronto, Toronto, The University of Western Ontario, London, Dalhousie University, Halifax, Memorial University, St. John’s, Newf , Queen’s University, Kingston. University of British Columbia, University of Ottawa, Ottawa, University of Alberta, Edmonton Vancouver General Hospital, Vancouver, Royal Alexandra Hospital, Edmonton, Grey Nun’s Hospital, Edmonton, Winnipeg Health Sciences Center, Winnipeg, Man., Toronto Hospital, General Division, Toronto; Wellesley Hospital, Toronto London Health Sciences Center (Victoria Campus), London, Ont., London Health Sciences Center (University Campus), London, Ont., St. Joseph’s Health Center, London, Ont., St. Joseph’s Hospital, Hamilton, Ont., Henderson Hospital, Hamilton, Ont., Kingston General Hospital, Kingston,Ont., Ottawa Civic Hospital, Ottawa, Ont., Health Sciences Center, St. John’s, Newf, Victoria General Hospital, Halifax, N.S. Source of funding: Quote: "Supported by the Medical Research Council of Canada and Hoechst Marion Roussel. Drugs were supplied by Glaxo Wellcome, Baxter, and Hoechst Marion Roussel. Dr. Cook is a Career Scientist of the Ontario Ministry of Health" Conflicts of interest: ‐ Ethics approval: Quote: "The protocol was approved by the institutional review board of all participating enters ..." Informed consent: Quote: "...and the patients or their proxies gave informed consent" Clinical trials registration: ‐ Sample size calculation: Quote: "On the basis of data published through 1991, when our study was designed, we anticipated a 25 percent incidence of pneumonia and identified a 25 percent reduction in the risk of pneumonia associated with sucralfate as being plausible and clinically important. This led to the calculation of a sample size of 1200 patients as necessary to give the study 75 percent power to detect such a difference, assuming a two‐sided significance test at the 0.05 level. We analysed all patients in the groups to which they were randomly assigned, according to the intention‐to‐treat principle" Additional notes: Gram‐negative bacilli and gram‐positive cocci were the main isolates from endotracheal aspirates from patients with ventilator‐associated pneumonia
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Patients were randomly assigned to study groups in blocks of six, with stratification according to centre, by means of a computer generated random‐number table prepared at the McMaster University Methods Center and managed by the ICU study pharmacist at each site" Comment: Method adopted to obtain random sequence generation is clearly mentioned in the trial report
Allocation concealment (selection bias)	Low risk	Quote: "...managed by the ICU study pharmacist at each site who administered the coded drugs" Comment: Method to obtain allocation concealment is clearly mentioned in the trial report
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "The patients, research nurses, and all ICU care givers were unaware of the treatment assignments for the duration of the study. Therefore, clinicians did not monitor gastric pH" "The radiologists, outcome adjudicators, all investigators, and the study statistician were also blinded until all events had been adjudicated and the analyses completed" Comment: Blinding was done, so the likelihood of performance bias and detection bias is low
Blinding (detection bias) Clinically important upper GI bleeding	Low risk	Quote: "The patients, research nurses, and all ICU care givers were unaware of the treatment assignments for the duration of the study. Therefore, clinicians did not monitor gastric pH" "The radiologists, outcome adjudicators, all investigators, and the study statistician were also blinded until all events had been adjudicated and the analyses completed" Comment: Blinding was done. Moreover the outcome of interest was objective in nature, so the likelihood of performance bias and detection bias is low
Blinding (detection bias) Nosocomial pneumonia	Low risk	Quote: "The patients, research nurses, and all ICU care givers were unaware of the treatment assignments for the duration of the study. Therefore, clinicians did not monitor gastric pH" "The radiologists, outcome adjudicators, all investigators, and the study statistician were also blinded until all events had been adjudicated and the analyses completed" Comment: Blinding was done. Moreover the outcome of interest was objective in nature, so the likelihood of performance bias and detection bias is low
Blinding of outcome assessment (detection bias) Adverse reactions of interventions	Low risk	Quote: "The patients, research nurses, and all ICU care givers were unaware of the treatment assignments for the duration of the study..." Comment: Blinding was done. Moreover all other outcomes of interest were objective in nature
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: All participants who were randomised to the 2 groups were analysed
Selective reporting (reporting bias)	Low risk	Comment: All intended outcomes were reported
Other bias	Low risk	Comment: Hoechst Marion Roussel supported the trial and also sponsored sucralfate needed for administering to study participants. The role of the sponsor in the conduct and reporting of the trial is unclear. No other sources of bias are suspected