Hanisch 1998.

Methods	Double‐blind randomised controlled trial
Participants	Baseline characteristics Number randomised: 827 participants Number analysed: 158 participants Ranitidine Age (years; mean (range)): 55 (22 ‐ 88) Number of participants (n): 57 Gender (male/female; n): ‐ Pirenzipine Age (years; mean (range)): 53 (18 ‐ 86) Number of participants (n): 44 Gender (male/female; n): ‐ Placebo Age (years; mean (range)): 58 (22 ‐ 88) Number of participants (n): 57 Gender (male/female; n): ‐ Notes: Age not given for all randomised participants, but only for those who were in mechanical ventilation for longer than 48 hours Inclusion criteria All adult patients referred to ICU of the surgical department of John Wolfgang Goethe University, Frankfurt Exclusion criteria Patients with active peptic ulcer disease and concomitant ulcer medications Existing upper GI bleeding Age < 18 years 4.transplanted patients (kidney, liver, heart) Pre‐existing pneumonia and gastric resection Baseline imbalances: Groups were similar with respect to age and APACHE ll score
Interventions	Ranitidine Dose (total/d): 150 mg Duration of treatment (days): ‐ Route: IV Intervention: sostril: 3 × 50 mg IV Concomitant medications Pirenzipine Dose (total/d): 30 mg Duration of treatment (days): ‐ Route: IV Intervention: gastrozepin: 3 × 10 mg IV Concomitant medications Placebo Dose (total/d): ‐ Duration of treatment (days): ‐ Route: IV Intervention: placebo Concomitant medications: ‐ Adherence to regimen: All 827 randomised patients completed the trial. However, only 158 participants who were on mechanical ventilation for ≥ 48 hours were part of the analysis, as the primary outcome was pneumonia rate Duration of trial: December 1991 to December 1992 Duration of follow‐up: not clearly mentioned in the study report. Probably until death or discharge
Outcomes	Outcomes sought in review and reported in trial Primary outcome Incidence of pneumonia in patients under mechanical ventilation ≥ 48 hours (defined according to Daschner as "radiological signs of pneumonia and purulent tracheal secretion or positive microbiological findings in tracheal aspiration and temperature > 38°C and leucocytosis > 10,000 mm³ Secondary outcomes Incidence of clinically relevant stress bleeding: defined as bright red blood via gastric tube or melena combined with haemodynamic changes (systolic blood pressure < 100 mmHg, tachycardia > 100 beats per minute) and requirement of blood transfusion (fall ni haemoglobin > 2 g/dL within 24 hours) and endoscopic identification of bleeding site and activity All‐cause mortality in ICU Duration of ICU stay (standard deviation not reported) Duration of mechanical ventilation(standard deviation not reported) Participnats requiring blood transfusion Units of blood transfused (mean and SD not reported) Outcomes sought but not reported in trial report All‐cause mortality in hospital Adverse events of interventions Outcomes reported in report but not used in review Duration of Intubation (standard deviation not reported) Duration of ICU stay (standard deviation not reported)
Notes	Setting: Department of Surgery, Division of General and Trauma Surgery, Johann Wolfgang Goethe University, Frankfurt am Main, Germany Source of funding: ‐ Conflicts of interest: ‐ Ethics approval: approved by the Ethics Committee of Johann Wolfgang Goethe University, Frankfurt/Main Informed consent: ‐ Clinical trials registration: ‐ Sample size calculation: Quote: "Assuming a pneumonia rate of 25% in ranitidine treated patients and a pneumonia rate of 15% in placebo treated patients, the complete sample size was calculated to be at least 100 patients (alpha = 0.05 and beta = 0.20)"
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "A complete and balanced randomisation schedule was generated by the institute of biomathematics of the university of Frankfurt" Comment: method adopted to obtain random sequence generation clearly mentioned in the study report
Allocation concealment (selection bias)	Low risk	Quote: "At the time of entering the ICU patients were assigned to a consecutive study number, the application of a blinded drug regimen was started" "...the drugs were prepared in advance by a staff who were not involved in the treatment of patients and identified by the above mentioned consecutive study number i.e. the code was located exclusively with this group during the trial'' Comment: Randomisation code was used exclusively with staff who were not involved in the treatment of patients, and these staff were responsible for preparing the 3 interventions through a similar mechanism (dissolving each in 100 mL of 5% glucose) to avoid detection during treatment
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "Blinding of drugs (placebo, ranitidine, pirenzipine) was achieved by dissolving them in glucose (100 mL; 5% Braun, Melsungen, Germany) resulting in an equal infusion volume for each patient. Drugs were prepared by staff who were not involved in the treatment of patients and identified by the above mentioned consecutive study number"; "All blinded drugs (only identifiable by their consecutive study number) were given to the patients by a staff nurse in the ICU" Comment: This was a placebo‐controlled nature of the study design in which the 3 interventions were prepared in a similar manner (dissolving each in 100 mL of 5% glucose) to ensure adequate blinding because of which the details of interventions received were not known. Participants and personnel were blinded, ensuring no performance bias
Blinding (detection bias) Clinically important upper GI bleeding	Low risk	Quote: "Data documentation for each patient was performed prospectively and daily by a different staff not involved in the treatment of patients in the randomised assignment of the drugs" Comment: not clear whether they were involved in outcome assessment. Moreover, GI bleeding was detected as per the definition in the study protocol and was an objective outcome
Blinding (detection bias) Nosocomial pneumonia	Low risk	Quote: "Data documentation for each patient was performed prospectively and daily by a different staff not involved in the treatment of patients in the randomised assignment of the drugs" Comment: not clear whether they were involved in outcome assessment. Moreover, pneumonia was detected as per the definition in the study protocol and was an objective outcome
Blinding of outcome assessment (detection bias) Adverse reactions of interventions	Low risk	Quote: "Data documentation for each patient was performed prospectively and daily by a different staff not involved in the treatment of patients in the randomised assignment of the drugs" Comment: not clear whether they were involved in outcome assessment. However, outcomes of interest were objective in nature
Incomplete outcome data (attrition bias) All outcomes	High risk	Comment: 741 patients randomised, but only 158 completed 48 hours of mechanical ventilation and were reported in the trial
Selective reporting (reporting bias)	Low risk	Comment: Data on all randomised participants were not included in the results. Only outcomes for participants who were on mechanical ventilation for longer than 48 hours are reported. Of 827 randomised patients, a total of 158 were mechanically ventilated for ≥ 48 hours. Data on the remaining 669 patients were not available. However, this does not account for reporting bias, as the study intended to report its primary outcome of pneumonia only for participants who completed ≥ 48 hours on mechanical ventilation. All intended outcomes were reported only for participants who spent ≥ 48 hours in the ICU
Other bias	Low risk	Comment: unclear on the source of funding. No other sources of bias suspected