van den Berg 1985.

Methods	Double‐blind randomised controlled trial
Participants	Baseline characteristics Number randomised: 34 participants Number analysed: 28 participants Cimetidine Age (years; median (SD)): 43.9 (‐) Number of participants (n): 14 Gender (male/female; n): 9/5 Placebo Age (years; median (SD)): 48.4 (‐) Number of participants (n): 14 Gender (male/female; n): 9/5 Inclusion criteria On assisted ventilation in either medical or surgical ICU Exclusion criteria Previous oesophageal or gastric operations Upper gastrointestinal bleeding on admission Period of assisted ventilation was expected to be less than 3 days  Baseline imbalances: Quote "All the factors including the distribution of patients according to sex, age, nature of intensive care unit were almost same within the two groups except for the mean risk factors (it was 2.6 per person in the cimetidine group and 1.9 in the placebo group)" Comment: More people in the cimetidine group had 3 or more risk factors when compared with the placebo group
Interventions	Cimetidine Dose (total/d): varies Duration of treatment (days, mean (SD)): Treatment was given for at least 3 days and ended on extubation of the patient after 14 days in case of assisted mechanical ventilation Route: IV Intervention: cimetidine 20 mg/kg weight per 24 hours by continuous infusion. In participants with renal insufficiency or anuria, no more than 400 mg of cimetidine per 24 hours was given Concomitant medications: Sour skimmed milk mixture (pH 6.5 at 600 mL per 24 hours) was used as supportive treatment in participants with a relatively good condition (6 participants in cimetidine and 11 participants in the placebo group) Placebo Dose (total/d): ‐ Duration of treatment (days, mean (SD)): Treatment was given for at least 3 days and ended on extubation of the patient after 14 days in case of assisted mechanical ventilation Route: IV Intervention: placebo normal saline by continuous infusion Concomitant medications: Sour skimmed milk mixture (pH 6.5 at 600 mL per 24 hours) was used as supportive treatment in participants with a relatively good condition (6 participants in the cimetidine and 11 participants in the placebo group) Adherence to regimen: 34 participants entered the study. While 28 completed the trial, 6 people dropped out for the following reasons: 1 participant died on the second day of the study from sepsis, 1 participant developed exanthema on the second day after which all medication was stopped, 1 participant was inadvertently given open cimetidine, 1 participant had bleeding duodenal ulcer proven endoscopically at the end of the study, 1 participant developed anuria, and 1 participant proved to have previous gastric surgery Duration of trial: ‐ 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 outcomes Stress induced upper gastrointestinal bleeding: blood loss from the upper GI tract was measured by labelling the erythrocytes in 10 mL of autologous blood with 25 µ Ci of chromium chloride. These labelled erythrocytes were re‐injected intravenously at the beginning of the treatment period. The gastric contents were aspirated either continuously or hourly, starting from the first day of treatment. Blood loss was calculated from the radioactivity of the gastric contents. Previous experience has shown that participants lost around 1 to 7 mL of blood every 25 hours. Blood loss more than double the higher figure of 15 mL per 24 hours was considered to be suggestive of mucosal damage Secondary outcomes All‐cause mortality in ICU (not clearly mentioned for each intervention) Outcomes sought but not reported in trial Incidence of ventilator‐associated pneumonia All‐cause mortality in hospital Duration of ICU stay Duration of intubation Number of participants requiring blood transfusions Units of blood transfused Adverse reactions due to interventions Outcomes reported in trial but not used in review Gastric pH values Blood loss (measured by Cr‐labelled erythrocytes)
Notes	Setting: Rotterdam University Hospital, Netherlands Source of funding: ‐ Conflicts of interest: ‐ Ethics approval: ‐ Informed consent: ‐ Clinical trials registration: ‐ Sample size calculation: ‐
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: not clearly mentioned in the study report
Allocation concealment (selection bias)	Unclear risk	Comment: not clearly mentioned in the study report
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "The study was performed double blind. The investigators were not involved in the treatment of the patients" Comment: This was a placebo‐controlled trial, and study personnel and investigators were blinded. Therefore, the likelihood of performance bias is low
Blinding (detection bias) Clinically important upper GI bleeding	Low risk	Quote: "The study was performed double blind. The investigators were not involved in the treatment of the patients" Comment: GI bleeding was detected as per the definition in the study protocol and the investigators were blinded. Therefore, the likelihood of detection or performance bias is low
Blinding (detection bias) Nosocomial pneumonia	Unclear risk	Comment: Study did not address this outcome
Blinding of outcome assessment (detection bias) Adverse reactions of interventions	Low risk	Quote: "The study was performed double blind. The investigators were not involved in the treatment of the patients" Comment: Study was performed as a double‐blinded randomised controlled trial, and the outcomes of interest were objective in nature. Therefore, the likelihood of detection bias is low
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: Not all randomised participants were part of the final analysed. 6 participants were excluded for reasons mentioned under "Adherence to the regimen". Moreover, it is unclear to which group these participants belonged, and an intention‐to‐treat analysis was not done. A per‐protocol analysis was performed for the outcomes of interest, and the number of participants available for analysis appears to be balanced between groups. Therefore, the likelihood of attrition bias is low
Selective reporting (reporting bias)	High risk	Comment: All intended outcomes were analysed and reported. All‐cause mortality in ICU was not specifically reported for each group
Other bias	Low risk	Comment: unclear on the source of funding. No additional biases were detected