Metz 1993.

Methods	Multi‐centre double‐blind randomised controlled trial
Participants	Baseline characteristics Number randomised: 167 participants Number analysed: 167 participants Ranitidine Age (years; mean (SE)): 35.4 (1.91) Number of participants (n): 86 Gender (male/female; n): 67/19 Placebo Age (years; mean (SE)): 32.5 (1.86) Number of participants (n): 81 Gender (male/female; n): 56/25 Inclusion criteria Severe head injury, defined as Glasgow Coma Score (12) of ≥ 10 Age ≥ 18 years Participants who had NG tube in place Expected ICU stay longer than 72 hours Exclusion criteria Active GI bleeding at baseline Severe burns (more than 20% of body surface area) Renal insufficiency (serum creatinine concentration > 3 mg/dL [265.2 μmol/L]) Documented peptic ulcer diseases within last 6 months Baseline count of < 50,000 thrombocytes/μL History of usage of antacids within last 4 hours or histamine 2 receptor antagonist within last 24 hours of study entry Baseline imbalances: Quote: "No statistically significant difference was present between treatment groups with regard to any demographic variables" Comment: The imbalance between the 2 groups was only with respect to number of people on mechanical ventilation at study entry. 65 in placebo group and 80 in the ranitidine group. The other baseline characteristics were comparable. Nosocomial pneumonia was present on entry in 2 participants in both groups, respectively. Prothrombin time > upper limit was present in 31/77 and 28/83 participants, respectively
Interventions	Ranitidine Dose (total/d): 150 mg Duration of treatment (days): Investigational therapy was administered for a maximum of 5 days Route: IV Intervention: 6.25 mg/h continuous ranitidine infusions Concomitant medications: Concurrent enteral nutrition and treatment with H2 receptor antagonists (other than the study drug), antacids, prostaglandins, somatostatin analogues, propranolol, digitalis, and salicylates were not allowed Placebo Dose (total/d): 150 mg Duration of treatment (days): Investigational therapy was administered for a maximum of 5 days Route: IV Intervention: placebo 6.25 mg/h continuous infusion Concomitant medications: Concurrent enteral nutrition and treatment with H2 receptor antagonists (other than the study drug), antacids, prostaglandins, somotostatin analogues, propranolol, digitalis ,and salicylates were not allowed Adherence to regimen: If upper GI bleeding was detected according to the definition, then participant was withdrawn from the study. All participants adhered to the prescribed study regimen Duration of trial: January 1990 to September 1991 Duration of follow‐up: probably until discharge or untimely death
Outcomes	Outcomes sought in review and reported in trial Primary outcomes Incidence of upper GI bleed: Bleeding assessments were performed at 8‐hour intervals and were recorded throughout the study monitoring period and consisted of evaluation of the following: Presence of Gastrooccult Positive nasogastric tube drainage Presence of bright red blood per nasogastric tube Haematemesis Haemoccult positive stool Melena and haematochezia If any of the preceding variables were present, the following 4 questions were addressed to establish the diagnosis of stress ulcer GI bleeding: Was the gastric drainage occult blood positive and were 'coffee grounds'  present for previous 8 hours? Was there minimum 50 mL bright red blood aspirated per NG tube? Did the patient experience haematemesis in the last 8 hours? Was there endoscopic or surgical confirmation of an upper GI source of bleeding? If the answer to any of the preceding 4 questions was "yes", the participant was considered to have GI bleeding Secondary outcomes Incidence of nosocomial pneumonia diagnosed on the basis of chest radiograph indicating pulmonary infiltrates and 1 of the following groupings of clinical findings established by Centers for Diseases Control and Prevention Adequate sputum (< 10 epithelial cells per lower‐power field) cultures revelling a respiratory pathogen consistent with the sputum gram stain Positive culture from thoracentesis, transtracheal aspirate, or bronchoscopic brush consistent with sputum gram stain Adequate sputum as discussed above Positive blood culture No other source of infection except pulmonary Sputum positive by DNA probe for Legionella, e.g. diagnostic single antibody titre (immunoglobulin [IgG] IgM) or 4‐fold increase in paired serum samples (IgG) for pathogen  Histopathologic evidence of pneumonia Outcomes sought but not reported in trial All‐cause mortality in ICU All‐cause mortality in hospital Duration of ICU stay Duration of intubation Participants requiring blood transfusions Units of blood transfused Adverse events of interventions Outcomes reported in report but not used in review Incidence of upper GI bleeding with respect to risk factors
Notes	Setting: 10 ICUs from across the United States of America Source of funding: Quote: "This study was supported in part by a research grant from Glaxo Pharmaceuticals" Ethics approval: Quote: "The study was approved by the institutional review boards of all participating sites." Comment: ethics approval obtained from all 10 participating sites Informed consent: Quote: "Informed consent was obtained from patient or a legally authorized representative" Clinical trials registration: ‐ Sample size calculation: ‐ Additional notes: Two participants who were diagnosed with pneumonia at baseline were excluded from the denominator of participants who subsequently developed nosocomial pneumonia during the study
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Patients were then randomised to treatment with 6.25 mg/hour continuous ranitidine or placebo infusion according to a computer generated randomisation scheme" Comment: Method adopted to obtain random sequence generation is 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	Comment: This is a placebo‐controlled trial in which both the intervention and the control were administered at the same rate as per a computer‐generated randomisation scheme, which suggests that participants and study personnel were blinded. Therefore the likelihood of performance bias is low
Blinding (detection bias) Clinically important upper GI bleeding	Low risk	Comment: This was a placebo‐controlled trial, and GI bleeding was an objective outcome that was detected as per the definition in the study report
Blinding (detection bias) Nosocomial pneumonia	Low risk	Comment: This is a placebo‐controlled trial, and nosocomial pneumonia was an objective outcome detected as per the definition in the study report
Blinding of outcome assessment (detection bias) Adverse reactions of interventions	Low risk	Comment: This is a placebo‐controlled trial, and all other outcomes of interest were objective in nature. Therefore the likelihood of performance or detection bias is low
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: All randomised participants completed the trial and were included in the final analysis. There are no treatment withdrawals and no trial group changes. Therefore the likelihood of attrition bias is low
Selective reporting (reporting bias)	Low risk	Comment: All intended outcomes were analysed and reported
Other bias	Low risk	Comment: This study was supported in part by a research grant from Glaxo Pharmaceuticals, and some of the equipment used was provided by this organisation. The role of the sponsor in the conduct and reporting of the trial is unclear. No other form of bias was detected