Lago 2014.

Methods	Single centre double‐blind randomised controlled trial conducted at the NICU of the Padua University Hospital, Padua, Italy Study period: February 2008 to June 2010
Participants	112 preterm infants < 32 weeks' PMA with haemodynamically significant PDA on ECHO. Informed consent was withdrawn from 1 infant in the continuous ibuprofen group
Interventions	Ibuprofen (standard treatment): 56 infants, bolus of IV ibuprofen of 10 mg 5 mg and 5 mg administered over 15 minutes, 24 hours apart Ibuprofen (infusion): 55 infants, continuous infusion of ibuprofen of 10 mg, 5 mg and 5 mg given over 24 hours, and boluses of equal volumes of 5% dextrose administered over 15 minutes, 24 hours apart
Outcomes	PDA closure rate after 2 standard‐dose ibuprofen courses, PDA closure after first ibuprofen course, reopening of PDA, need for surgical ligation, oliguria (urine output ≤ 1 mL/kg/hour, creatinine after treatment, gastrointestinal haemorrhage, intestinal perforation during ibuprofen treatment, NEC during ibuprofen treatment, BPD (at 36 weeks' PMA), ROP (all stages and stage ≥ 3, IVH (all grades and grades III‐IV), cystic PVL, NEC, isolated bowel perforation, mortality, and duration of hospital stay
Notes	No information on funding provided
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated
Allocation concealment (selection bias)	Low risk	Eligible infants were randomised by the hospital pharmacist to receive in a 1 : 1 ratio either standard treatment (bolus) or continuous infusion of ibuprofen. Throughout the study, the hospital pharmacist kept the randomisation list inaccessible to the clinical investigators and NICU personnel
Blinding of participants and personnel (performance bias) All outcomes	High risk	Ibuprofen was given as continuous infusion or as intermittent boluses, which must have been known to the caregivers
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	It was not stated whether the cardiologist performing the ECHOs was blinded to the treatments
Incomplete outcome data (attrition bias) All outcomes	Low risk	Outcome data were presented for all randomised infants, except for 1 infant in the continuous ibuprofen group, for whom the parents withdrew informed consent
Selective reporting (reporting bias)	Unclear risk	The protocol for this study was not available to us and we could not ascertain whether there were deviations from the protocol
Other bias	Low risk	Appeared free of other bias