Reusser 1990.

Methods	Open label, randomised controlled trial
Participants	Baseline characteristics Number randomised: 97 participants Number analysed: 40 participants Ranitidine Age (years; mean (range)): 40 (19 to 63) Number of participants (n): 19 Gender (male/female; n): 13/6 No prophylaxis Age (years; mean (range)): 33 (15 to 76) Number of participants (n): 21 Gender (male/female; n): 17/4 Inclusion criteria Critically ill patients Admitted to the surgical ICU of the Basel University Hospital Having the following risk factors: Severe acute intracranial lesion caused by trauma or spontaneous haemorrhage and requiring neurosurgery Respiratory failure due to impaired neurological condition and needing > 48 hours  of endotracheal intubation and mechanical ventilation Exclusion criteria Age < 15 years History of upper GI tract surgery Peptic ulcer disease, with current anti ulcer treatment Overt upper GI bleeding Intubated for less than 48 hours Initial endoscopy revealed gastric or duodenal ulcers Repeat endoscopy not possible Baseline imbalances: Quote: "No significant differences between treatment and control groups were detected in any of the clinical and therapeutic characteristics among both the groups. However, hypotension was more frequent in the control group (12 vs. 5)" Comment: Both groups were comparable with respect to age and gender distribution, and risk factors such as disseminated intravascular coagulation in addition to severe intracranial lesion and respiratory failure. Severe head injury was the main primary diagnosis in both groups
Interventions	Ranitidine Dose (total/d): 150 mg Duration of treatment (days): 7 days Route: IV Intervention: 50 mg IV every 8 hours, if more than 2 gastric pH values were < 4 within the second or subsequent dosing intervals, the ranitidine dosage was increased to 50 mg every 6 hours. If thereafter still more than 1 gastric pH was < 4 within a dosing interval, an antacid was added at a dosage required to maintain gastric pH at ≥ 4 Concomitant medications: steroids, pentobarbital, neuromuscular blockers, vasopressive drugs. Every participant had an NG tube in place. The pH was determined in aspirates of gastric fluid by indicator paper every 2 hours for the first 3 days, and thereafter every 6 hours in the control group and 3 hours after each ranitidine dose in the treatment group, because a representative ranitidine‐related pH could be expected at that time No prophylaxis Dose (total/d): ‐ Duration of treatment (days): 7 days Route: ‐ Intervention: ‐ Concomitant medications: steroids, pentobarbital, neuromuscular blockers, vasopressive drugs. Every participant had an NG tube in place. The pH was determined in aspirates of gastric fluid by indicator paper every 2 hours for the first 3 days, and thereafter every 6 hours in the control group and 3 hours after each ranitidine dose in the treatment group, because a representative ranitidine‐related pH could be expected at that time Adherence to regimen: For treatment of the 97 eligible participants, only 40 completed the trial and were available for analysis (19 in the treatment arm and 21 in the control arm) The remainder were excluded for the following reasons: Early consent was unobtainable in 12 participants Overlooked by house staff (n = 14) Not endoscoped (n = 19) Initial endoscopy revealed duodenal ulcer (n = 1) Intolerance to repeat endoscopy on day 5 (n = 1) Extubated within 48 hours (n = 7) Died within 48 hours due to neurologic deterioration (n = 3) In the treatment group, 5 (26%) participants remained on the original ranitidine dosage of 50 mg every 8 hours throughout the study, 5 (26%) required a dosage increase to 50 mg every 6 hours, and 9 (47%) needed additional antacids Duration of trial: August 1984 to September 1986 Duration of follow up: up to 7 days after study completion
Outcomes	Outcomes sought in review and reported in trial Primary outcome Incidence of GI bleeding. Endoscopic bleeding signs were classified as follows: petechiae, or submucosal haematoma, traces of fresh blood or 'coffee ground' material and frank bleeding. Occult bleeding was defined as positive slide test on 3 consecutive aspirates. Overt bleeding was defined as: bright red bleeding via NG tube, melena, or decrease in Hgb level  > 2 g/dL within 24 hours, associated with positive stool guaiac test or with gastric drainage of > 100 mL of 'coffee ground' material Secondary outcomes All‐cause mortality in hospital Duration of intubation Duration of ICU stay Participants requiring blood transfusion (no participant required blood transfusions) Units of blood transfused (no participant required blood transfusions) Outcomes sought but not reported in trial Incidence of ventilator‐associated pneumonia Adverse reactions of interventions Outcomes reported but not used in review Intragastric pH values Risk factors for development of GI bleeding  Incidence of stress lesions All‐cause mortality during the study
Notes	Setting: Department of Internal Medicine and Surgical Intensive Care Unit, University Hospital Basel, Switzerland Source of funding: ‐ Conflicts of interest: ‐ Ethics approval: Quote: "The study was approved by the ethical committee of the Basel University Hospital" Informed consent: Quote: "Informed consent was obtained from each patient's legal guardian" Clinical trials registration: ‐ Sample size calculation: ‐ Additional notes: Data are provided on number of deaths during the study (n = 1 in the ranitidine group), which is not similar to all‐cause mortality in ICU
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	High risk	Quote: "The need to monitor gastric pH to determine intensification of stress lesion prophylaxis in the treatment group prevented double‐blind study design” Comment: This was not a placebo‐controlled trial, and the different modes of administering study interventions would not have made it possible to blind study personnel and participants
Blinding (detection bias) Clinically important upper GI bleeding	Low risk	Quote: “The need to monitor gastric pH to determine intensification of stress lesion prophylaxis in the treatment group prevented double‐blind study design” Comment: Outcome assessors were not blinded. However, GI bleeding was an objective outcome that was detected as per the definition in the study protocol
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	Comment: All other outcomes of interest were objective in nature
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: It is mentioned that of the 97 eligible participants, only 40 completed the trial and were available for analysis. The remaining 43 participants were excluded for reasons mentioned under "Adherence to the regimen". Therefore, a protocol analysis was done to measure the outcomes of interest, and the number of participants appears to be balanced between groups. Therefore, the likelihood of this affecting the outcomes of interest is minimal
Selective reporting (reporting bias)	Low risk	Comment: All intended outcomes were analysed and reported
Other bias	Low risk	Comment: The source of funding is not clearly mentioned in the study report. No additional biases were detected