Rohde 1980.

Methods	Randomised controlled trial
Participants	Baseline characteristics Number randomised: ‐ Number analysed: ‐ Cimetidine Age (years; mean (SD)): ‐ Number of participants (n): 14 Gender (male/female; n): Placebo Age (years; mean (SD)): ‐ Number of participants (n): 14 Gender (male/female; n): Inclusion criteria Severe burns (at least 25% of the body surface area and second degree) severe cerebral injuries (unconscious for at least 72 hours) Severe polytrauma (at least 3 body regions) Respiratory insufficiency (controlled respiration for at least 8 hours) Exclusion criteria Bleeding abnormalities History of peptic ulcer, gastric carcinoma, atrophic gastritis, History of gastric operations Age < 18 years Not consenting for the trial or death before the start of interventions Severe renal or liver insufficiency, or bone marrow disease (decision was left to the executive group) Baseline imbalances: ‐
Interventions	Cimetidine Dose (total/d): 1.2 g Duration of treatment (days): 14 days Route: IV and later PO Intervention: 1.2 g/d IV for 5 days and thereafter PO for 9 days if their physical state was appropriate. Otherwise the drug was continuously applied IV until the end of treatment. The single IV dose of 200 mg (about 3 mg/kg) was given in 4‐hour intervals by a 2‐rain injection or infusion starting at 8 am. The oral dose was applied as 200‐ mg tablets at meals under surveillance of the nurses, 2 tablets at breakfast, 1 at lunch and dinner, and 2 at bedtime. In renal failure (creatinine more than 2.5 mg/dL corresponding to 221 nmol/L), the dose was reduced to 2 × 200 rag/d (8 am and 8 pm), which kept the blood level as high as 1.2 g/d in normal conditions Concomitant medications Placebo Dose (total/d): ‐ Duration of treatment (days): 14 days Route: ‐ Intervention: ‐ Concomitant medications: ‐ Adherence to regimen In May 1977, the subgroup (strata) 1 (participants with burns) were excluded from the trial as the consultant specialising in burns left the trial centre and participants with severe burn injuries were shifted too In September 1977, failure in trial design was detected in subgroup (strata) 2, and in February 1978, the subgroup was excluded from the trial sighting selection bias In March 1978, subgroup (strata) 4 (participants with respiratory insufficiency) was excluded owing to "imprecise entrance criteria" The third subgroup (strata) of polytrauma participants was included, but the trial was stopped on June 1978, much ahead of the actual date of termination for ethical reasons Duration of trial: March 1977 to June 1978 Duration of follow up: until death or discharge from hospital
Outcomes	Outcome sought in review and reported in trial Clinical manifestation of bleeding defined by detection of visible blood in the gastric aspirate (at least in 1, as diagnosed by the clinical surgeon of the executive group, on duty) or by recording haematemesis and/or melena following careful observation of participants All‐cause mortality in hospital or ICU (data given for survival) Outcomes sought but not reported in trial report Ventilator‐associated pneumonia (VAP) Duration of ICU stay Duration of intubation Participants requiring blood transfusion Units of blood transfused Adverse events of interventions Outcomes reported in report but not used in review Acute ulceration
Notes	Setting: Department of Surgery, Marburg, Germany Source of funding: ‐ Conflicts of interest: ‐ Ethics approval: Quote: "The definite protocol was submitted to the local ethical committee...". Comment: Approval from the ethics committee was sought. Moreover, the trial was constantly monitored by an executive group Informed consent: Informed consent was sought from participants, as it was a criterion for inclusion/exclusion from the trial Clinical trials registration: ‐ Sample size calculation: Although the trial was planned as a double‐blind trial with a fixed sample size (100 participants) of people admitted to ICU, it was executed as a sequential single‐blind study only in 1 subgroup of participants (polytrauma) and was ended before the planned termination date for ethical reasons
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Comment: Participants were randomised in blocks of 4. The 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	Unclear risk	Quote: "The study was executed as a single blind sequential trial (a deviation from the planned double blind method) due to ethical reasons" Comment: unclear on who was blinded and how it was executed
Blinding (detection bias) Clinically important upper GI bleeding	Low risk	Comment: GI bleeding was detected as per the definition in the study protocol, not blinding the outcome assessor to this objective outcome would not have caused detection or performance bias
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, so the likelihood of detection bias is low
Incomplete outcome data (attrition bias) All outcomes	High risk	Comment: Data for only 1 strata of participants (polytrauma) are available, as the strata were terminated as mentioned above in "Adherence to regimen". This appears to be an incomplete report
Selective reporting (reporting bias)	High risk	Comment: Data for only 1 strata of participants (polytrauma) are available, as the strata were terminated as mentioned above in "Adherence to regimen"
Other bias	Low risk	Comment: The source of funding is not clearly mentioned in the study report. No additional biases were detected