Burgess 1995.

Methods	Double‐blind parallel‐group randomised placebo‐controlled trial
Participants	Baseline characteristics Number randomised: 34 participants Number analysed: 34 participants Ranitidine Age (years; mean (SD)): 38.4 (4.5) Number of participants (n): 16 Gender (male/female; n): 11/5 Placebo Age (years; mean (SD)): 34.5 (3.7) Number of participants (n): 8 Gender (male/female; n): 4/4 Inclusion criteria Severe head injury and Glasgow Coma Scale score < 10 Admitted to the University of Louisville surgical intensive care unit Exclusion criteria Concomitant peptic ulcer disease Other gastrointestinal injury Receiving anti‐ulcer therapy Having any oral intake Baseline imbalances: Quote: "All 34 patients were comatose on admission and required ventilatory support"; "No significant differences in demographic characteristics were present between the two treatment groups" Comment: The 2 groups were comparable with respect to mean Glasgow Coma Scale score (mean 8, range 4 to 10; and mean 6.7 range 3 to 10), mean Injury Severity Score (mean 32, range 25 to 41; and mean 30, range 25 to 57), and time from injury to study drug administration
Interventions	Ranitidine Dose (total/d): 150 mg Duration of treatment (days; mean (SD)): Treatment period was complete when participant was withdrawn from the trial or had received study drug for 72 hours Route: IV Intervention: 6.25 mg/h continuous IV ranitidine infusion, prepared by diluting 11 mg parenteral ranitidine to a volume of 240 mL with 0.9% sodium chloride and delivered at a rate of 10 mL/h Concomitant medications: Antacid therapy, steroids and tube feedings were not allowed Placebo Dose (total/day): ‐ Duration of treatment (days; mean (SD)): The treatment period was complete when the patient was withdrawn from the trial or had received 72 hours of study drug Route: IV Intervention: 1.9% sodium chloride administered at 10 mL/h Concomitant medications: Antacid therapy, steroids and tube feedings were not allowed Adherence to regimen: Quote: "All 34 patients were comatose on admission and required ventilatory support. Ten patients were withdrawn before completing 72‐hour study period. Five of these patients were in the placebo treatment group and were withdrawn from the trial because of protocol‐defined upper gastrointestinal tract bleeding. Of the remaining four patients,who were from the ranitidine group; one was withdrawn due to death secondary to severe head injury, two were withdrawn because they became combative and removed their NG tubes and pH probes, and the final patient was withdrawn from the trial when steroids were prescribed for an optic nerve injury by the attending physicians. One patient from the placebo group was removed due to withdrawal of NG tube" Comment: 24 participants completed the prescribed 72 hours of the trial, and reasons for the remaining 10 not completing the 72‐hour period are well documented Duration of trial: February 1988 to November 1988 Duration of follow‐up: 48 hours after study withdrawal
Outcomes	Outcomes sought in review and reported in trial Clinically important upper GI bleeding defined by haematemesis, haematochezia, bright red blood per NG tube, or 'coffee ground' NG tube aspirates. Participants with any of these signs plus a 5% decrease from baseline in haematocrit occurring at least 8 hours after study drug initiation were given diagnosis of upper gastrointestinal tract bleeding Note: The 5 participants who bled belonged to the placebo group; bleeding occurred before 72 hours into the trial All‐cause mortality in ICU Participants requiring blood transfusion Adverse events of interventions (no adverse reactions reported) Outcomes sought but not reported in trial VAP Duration of ICU stay Duration of intubation Number of units of blood transfused (mean and SD not provided) Outcomes reported in trial but not used in review Intragastric pH values
Notes	Setting: Department of Surgery, University of Louisville, School of Medicine, Louisville, Kentucky, USA Source of funding: Quote: "The study was supported by a grant from Glaxo Inc. Research Institute" Conflicts of interest: ‐ Ethics approval: Quote: "The study was approved by the Human Studies Committee" Informed consent: Quote: "...informed consent was obtained from each patient's legal representative" Clinical trials registration: ‐ Sample size calculation: ‐
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Within 24 hr of injury, each patient was randomly assigned to receive either 6.25 mg/hr continuous intravenous ranitidine infusion or a saline placebo infusion in accordance with a computer‐generated randomisation scheme" Comment: Method adopted to obtain random sequence generation is clearly mentioned in the trial report
Allocation concealment (selection bias)	Unclear risk	Comment: No information on allocation concealment reported
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "To maintain the integrity of the study blinding and to avoid potential bias, the principal investigator did not have access to the pH data" Comment: This is a double‐blind, placebo‐controlled, parallel‐group study design in which study personnel were blinded
Blinding (detection bias) Clinically important upper GI bleeding	Low risk	Quote: "To maintain the integrity of the study blinding and to avoid potential bias, the principal investigator did not have access to the pH data" Comment: The trial did investigate the relationship between intragastric pH values and the incidence of bleeding. Moreover, we are unclear whether it was the principal investigator who was also involved in outcome assessment. However, GI bleed was detected as per the study definition, and owing to the objective nature of the outcome, the likelihood of performance and detection bias is low
Blinding (detection bias) Nosocomial pneumonia	Unclear risk	Comment: Trial did not address this outcome
Blinding of outcome assessment (detection bias) Adverse reactions of interventions	Unclear risk	Comment: Blinding for other outcome assessments is unclear. Criteria for diagnosis of other outcomes are not fully described
Incomplete outcome data (attrition bias) All outcomes	Low risk	Quote: "All patients completed at least 8 hours of investigational therapy and were included in the analysis" Comment: All randomised participants were part of the final analysis
Selective reporting (reporting bias)	Low risk	Comment: All intended outcomes were analysed and included in the report
Other bias	Low risk	Comment: Trial was supported by a grant from Glaxo Inc. Research Institute; trial authors (number not sure) had affiliation with this company. No other sources of bias are suspected