Kuusela 1997.

Methods	Single‐blind randomised controlled trial
Participants	Baseline characteristics Number randomised: 53 participants Number analysed: 53 participants Ranitidine Age (months; mean (range)): 31 (29 ‐ 33) Number of participants (n): 26 Gender (male/female; n): No prophylaxis Age (months; mean (range)): 32 (29 ‐ 32) Number of participants (n): 27 Gender (male/female; n): Inclusion criteria Start of mechanical ventilation during first 2 hours of life Exclusion criteria Other infants treated in the neonatal ICU No informed consent given by parents Baseline imbalances: The 2 groups were comparable with respect to gestational age, birth weight, Apgar score, cord blood pH, and gender. Participants were preterm and full‐term infants
Interventions	Ranitidine Dose (total/d): ‐ Duration of treatment (days): 4 Route: ‐ Intervention: 5 mg/kg body weight/d divided into 3 doses Concomitant medications: Enteral feeding was administered to 17 infants. Morphine only to 4 patients who received gastroscopy. 40 participants received either morphine or phenobarbital for reasons not related to endoscopy No prophylaxis Dose (total/d): ‐ Duration of treatment (days): ‐ Route: Intervention: no prophylaxis Concomitant medications: Enteral feeding was administered to 17 infants. Morphine only to 4 patients who received gastroscopy. 40 participants received either morphine or phenobarbital for reasons not related to endoscopy Adherence to regimen: Of 53 participants who were randomised, only 48 were analysed as there were 5 dropouts due to early death (2 participants at gestational age < 33 weeks and 1 participant at gestational age ≥ 33 weeks) and oesophageal atresia (n = 2). 3 infants belonged to the ranitidine group and 2 belonged to the control group Duration of trial: 10‐Month period Duration of treatment : 4 days; study was discontinued when significant results of the first block of 20 preterm infants randomised were available for interpretation Duration of follow‐up: Routine follow‐ups were made at 7 days, then afterwards weekly up to 4 weeks
Outcomes	Outcomes sought in review and reported in trial Clinically important upper GI bleeding, detected through endoscopic findings (not extractable) Note: The intervention was given for 4 days only, whereas endoscopic findings were done at 3 and 6 days (even after treatment), the results of which could not be extracted separately All‐cause mortality in ICU Duration of intubation (mean and range provided, but the range exceeds the study period of 4 days) Outcomes sought but not reported in trial VAP All‐cause mortality in ICU All‐cause mortality in hospital Duration of ICU stay Participants requiring blood transfusions Number of units of blood transfused Adverse events of interventions Outcomes reported but not used in review Gastric colonisation Intragastric pH
Notes	Setting: Department of Neonatal Intensive Care, University Hospital, Tampere, Finland Source of funding: Quote: "Supported in part by the Finnish Foundation of Pediatric Research" Conflicts of interest: ‐ Ethics approval: Quote: "The study protocol was approved by the Ethics Committee of the Tampere University Hospital" Informed consent: Quote: "The parents received both oral and written information on the study; their informed consent was obtained" Clinical trials registration: ‐ Sample size calculation: ‐ Additional notes: Randomisation of participants was performed after infants were stratified into 2 groups (infants at less than and more than 33 weeks' gestational age) because infants usually less than 33 weeks are ventilated more often. Thus balance was achieved with respect to gestational age for both groups. Study was discontinued after significant results for the first 20 preterm infants (the first block) were available.When the study was stopped, results for a second block of 10 preterm infants and a third block of 7 preterm infants were available, along with results for a block of 16 and 20 mature infants
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "The first randomisation block included 20 envelopes in random order for both groups (gestational age < 33 weeks and gestational age ≥ 33 weeks). Followed by two randomisation blocks of 10 envelops for more preterm infants. Babies closer to term were randomised in one block with 20 envelops" Comment: Method adopted to obtain random sequence generation is clearly mentioned in the study report
Allocation concealment (selection bias)	Low risk	Quote: "The first randomisation block included 20 envelopes in random order for both groups (gestational age < 33 weeks and gestational age ≥ 33 weeks). Followed by two randomisation blocks of 10 envelops for more preterm infants. Babies closer to term were randomised in one block with 20 envelops" Comment: Method adopted to conceal allocation is clearly mentioned in the study report
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "Only the sequence number of the patient were written in the patients records by the nurse responsible for medication; thus the attending physicians the endoscopist and the pathologist remained blinded as to the treatment group" Comment: Study personnel were blinded to treatments. Moreover outcomes of interest were objective in nature
Blinding (detection bias) Clinically important upper GI bleeding	Low risk	Quote: "Only the sequence number of the patient [was] written in the patient records by the nurse responsible for medication; thus the attending physicians, the endoscopist, and the pathologist remained blinded as to the treatment group" Comment: The endoscopist was blinded to whether or not the participant received prophylaxis. Moreover the outcome measured was objective in nature
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: "Only the sequence number of the patient [was] written in the patient records by the nurse responsible for medication; thus the attending physicians, the endoscopist, and the pathologist remained blinded as to the treatment group" Comment: Outcome assessors were blinded. Moreover owing to the objective nature of the outcomes of interest, the likelihood of detection bias is low
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: 5 babies were not part of the analysis (3 in treatment and 2 in control groups). A sensitivity analysis was done in which it was assumed that the 3 dropout neonates randomised to the treatment group had mucosal abnormalities, and the 2 dropout neonates randomised to the control group had no mucosal abnormalities. Results of this assumption still indicate that ranitidine was effective in preventing gastric mucosal lesions in infants under stress
Selective reporting (reporting bias)	Low risk	Comment: All intended outcomes were reported and analysed
Other bias	Low risk	Comment: The Finnish Foundation of Pediatric Research funded the study. The role of the sponsor in the conduct and reporting of the trial is unclear. No other sources of bias are suspected