7. Ibuprofen.

RCT ID	Population	Intervention	Comparison	Outcomes	Notes
Dani 2005	155 preterm infants (< 28 wks of GA), < 6 h of postnatal age, without 2 to 4 grade GMH‐IVH, ≥ 50,000 platelets/mm3, serum creatinine concentration ≤ 1.5 mg/dL Mean BW ± SD (in grams): 832 ± 215 in ibuprofen group; and 812 ± 209 in PLA group Mean GA ± SD (wks): 25.3 ± 1.2 in ibuprofen group; and 25.9 ± 1.1 in PLA group MV: SIMV/SIPPV: 57/77 (74%) in ibuprofen group; 53/78 (68%) in PLA group HFOV: 26/77 (34%) in ibuprofen group, 17/78 (22%) in PLA group	3 doses of ibuprofen (Arfen, Lisapharma, Erba, Italy; 10 mg/kg within 6 h after birth, followed by 5 mg/kg after 24 and 48 h) N = 77	Indistinguishable non‐specified placebo N = 78	Incidence of germinal matrix hemorrhage‐intraventricular hemorrhage (GMH‐IVH) at 7 days of life with grading (no or 1 – success; 2 to4 – failure; serial ECG was performed at days 7, 15, 30 and at 40 wks' of postconceptional age); the rates of ductal closure on day 3; adverse events and complications (i.e. bronchopulmonary dysplasia, NEC, retinopathy of prematurity, sepsis). Length of stay in hospital, death; severity of infant respiratory distress syndrome; serum creatinine level (at 1, 3 and 5 d of life), urine output (first 5 d of life), fluid intake (during first week of life), hematuria, gastric bleeding, blood in the endotracheal aspirate or stools, oozing from puncture sites – to evaluate bleeding.	Both, ibuprofen and placebo were infused continuously in period of 15 min. In patients with ductus arteriosus still patent, ibuprofen was administered as a nonrandomized rescue treatment. If this therapy also failed to promote ductal closure or if there was a contraindication to repeated pharmacologic treatment, then surgical ligation of the ductus arteriosus was performed. Additional treatment: dopamine and/or dobutamine for hypotension Postnatal dexamethasone for severe respiratory failure
De Carolis 2000	50 preterm neonates (< 31 wks of GA), at 2 h of life; BW ≥ 500 g, platelet count ≥ 50 x 109/l), without neonatal indomethacin administration. All children were mechanically ventilated. Mean GA with SD (wks): 28.1 ± 1.1 in ibuprofen group 28.0 ± 1.9 in control group Mean BW ± SD (g): 934 ± 288 in ibuprofen group; 993 ± 308 in control group	Ibuprofen lysine salt (Arfen, Lysafarma, Erba‐Como, Italy; 10 mg/kg infused over 20 min via peripheral vein and within 2 h after birth, followed by 2 doses of 5 mg/kg after 24 and 48 h using the same modality; intravenously) N = 25 (23 analyzed)	Control group: no intervention, i.e. no placebo administration N = 25 (23 analyzed)	PDA (assessed with ECG evaluation, after birth, at day 3 of life, and whenever suspicion occurred). Adverse events. Hemoglobin, hematocrit, platelet count, serum electrolytes, blood urea nitrogen, and serum creatine were monitored. Coagulation tests: at birth and then following the clinical indications. Renal function evaluated daily (urine output, blood urea nitrogen, serum creatinine concentrations, creatinine clearance, fractional excretion of sodium on second and third day after birth. Clinical bleeding tendency and occurrence of sepsis assessed the first 3 day of life. Abdominal distension, food tolerance and NEC were also monitored. GMH‐IVH, PVL, cerebral flow patterns were measured with Doppler ultrasound on days 1, 3, 7 and weekly until discharge. Pulmonary parameters (FiO2, mean arterial pressure, bronchopulmonary dysplasia, days of mechanical ventilation, days of oxygen therapy). Need for treatment with indomethacin after 72 hs, surgical ligation, mortality at 28 days of age.	In the presence of significant PDA at the completion of ibuprofen cycle, treatment with indomethacin (3 x 0.2 mg/kg at 12 h intervals, by intravenous infusion over 20 min) was carried out; the same in control group with significant PDA at day 3. Failure to respond was indication for surgical ligation. Additional treatment: 200 mg/kg of Curosurf.
Gournay 2004	131 preterms (< 28 wks of GA, i.e. up to 27 wks and 6 d), within 6 h of birth; whose mother did not use nephrotoxic medications within 3d before delivery); without GMH‐IVH grade 3 or 4. Mean GA with SD (wks): 26.3 ± 0.9 in ibuprofen group; 26.0 ± 0.9 in PLA group. Mean BW ± SD (g): 844 ± 181 in ibuprofen group; 851 ± 164 in PLA group. Majority of infants were mechanically ventilated (88% in ibuprofen and 94% in PLA groups).	Ibuprofen (Orphan, Paris, France) 3 doses, within 6 h of birth; loading dose of 10 mg/kg, followed by two maintenance doses of 5 mg/kg at 24 h intervals N = 65 After day 3, symptomatic PDA was treated by open curative ibuprofen, then back‐up indomethacin, surgery, or both.	Placebo (saline, equivalent volumes) N = 66	Primary outcome: need for surgical ligation, based on presence of significant PDA on the echocardiogram, resulting in clinical manifestation of increased pulmonary blood flow, steal flow to peripheral organs, or a combination of these criteria. Secondary criteria: frequency of PDA at day 3; rate of curative treatment with ibuprofen; frequency of backup treatment with indomethacin; rate of cystic PVL; frequency of GMH‐IVH grade 3 or 4 (Volpe classification); rate of NEC, intestinal perforation, or both; duration of MV; frequency of bronchopulmonary dysplasia (defined as the need for supplementary oxygen at 36 wks after conception; effects on renal function; the actuarial curve of survival during the study period.	Analysis per protocol. Both ibuprofen and PLA were supplied by Orphan Europe (Paris, France).
Sangtawesin 2008	62 VLBW (≤ 1500 g) premature neonates (26 to 32 wks of GA), admitted to the neonatal unit, with open ductus arteriosus; without maternal non‐steroid anti‐inflammatory drug use; with serum creatinine < 1.5 mg/dl and/or blood urinary nitrogen < 30 mg/dl, and platelet count > 75000 cells/mm3 Mean age of drug administration ± SD (h): 18.14 ± 6.03 in ibuprofen group; and 20.09 ± 5.67 in PLA group. Mean GA ± SD (wks): 29.32 ± 1.94 (range: 26 to32) in ibuprofen group; 29.29 ± 2.16 (range: 26 to32) in PLA group Mean BW ± SD (g): 1156.90 ± 263.6 (range: 765 to 1500) in ibuprofen group; 1162.90 ± 261.0 (range: 690 to 1500) in PLA group Majority of infants had ventilator assistant (93.55% in ibuprofen group; 87.1% in PLA group).	Oral ibuprofen suspension (Junifen, Boots Company, Thailand; 3 doses; at a dosage of 10 mg/kg for first dose within 24 h of life and 5 mg/kg for the second and third doses after 24 and 48 h; given via orogastric tube, followed by 0.5 ml of distilled water). N = 31 Patients with any significant adverse drug reactions which required treatment were excluded.	Oral placebo (3 doses of orange starch suspension, administered with the same method and time schedule as oral ibuprofen). N = 31	Primary outcome: PDA: incidence of symptomatic (defined as echocardiographic and clinical evidence of hemodynamically significant PDA); size in mm, close on day 3, weight in grams (≤ 1200 or 1201 to 1500). Secondary outcomes: Respiratory system (persistent pulmonary hypertension, bronchopulmonary dysplasia, ventilatory days, days of oxygen therapy); renal function (serum blood urea nitrogen, serum creatinine); gastrointestinal system (days of start and full feeding, local gastrointestinal bleeding), NEC ≥ stage II); GMH‐IVH (total, grade 1 and 2 to 3; retinopathy of prematurity (total, stage 1 and 2); length of hospital stay; death. Complete blood count, blood urinary nitrogen, creatinine, electrolyte, coagulogram were evaluated 24 h after the fully course of drug administration. ECG was performed each dose, of ibuprofen administration and on days 7, 14 and 28 of life.	Additional treatment: if during the course of the study, symptomatic PDA did occur, standard treatment with intravenous indomethacin was given. Surgical ligation was performed in cases of medication failure.
Van Overmeire 2004	415 low‐birthweight preterm infants (24 to 30 wks of GA), within 6 h after birth, admitted to NICU; without GMH‐IVH higher than grade 1 and contradiction for ibuprofen administration (i.e. serum creatinine level > 115 µmol/L or serum bilirubin > 85 µmol/L, platelet count < 60 x 109/L, tendency to bleed). Mean GA with SD (wks): 28.1 ± 1.7 in ibuprofen group; and, 28.1 ± 1.6 in PLA group. Mean BW with SD (g): 1048 ± 215 in ibuprofen group; and, 1065 ± 315 in PLA group. Majority of infants were mechanically ventilated from birth: 85% in ibuprofen group and 84% in PLA group.	Ibuprofen lysine (an initial dose of 10 mg/kg within the first 6 h of life, followed by 2 doses of 5 mg/kg after 24 h and 48 h). N = 205 Vials contained 20 mg of ibuprofen with 14 mg of lysine in water or normal saline.	Placebo (intravenously; 3 doses of saline as an initial dose of 1 ml/kg, followed by 0.5 ml/kg after 24 and 48 h). N = 210	Primary outcome: occurrence of sIVH (cranial ultrasonography was done at baseline, and then repeated on days 2, 3 7, 14, and 28 of life, or before discharge; GMH‐IVH was graded from 1 to 4, according to standard classification systems). The presence of cystic PVL after age of 2 wks was also reported. Secondary outcomes: the presence of confirmed with ECG open PDA after 3 d of life, and the need for its pharmacological rescue treatment or surgical ligation; occurrence of renal dysfunction (measured by urine production); NEC; and death. Adverse effect.	Both ibuprofen and placebo were infused over 15 minutes. Fluids were given following the standard guidelines. ITT analysis. Additional treatment: a non‐randomized intravenous pharmacological rescue treatment was given with either indomethacin (3 doses of 0·2 mg/kg with 12‐h intervals) or ibuprofen‐lysine (first dose of 10 mg/kg followed by 2 doses of 5 mg/kg at 24 h and 48 h). If the infant was still on mechanical ventilation without decrease of the ductal shunt after rescue intervention, the ductus was surgically ligated. Half of patients received surfactant treatment (60% in PLA and 55% in ibuprofen group).

BW = body weight; d = days; ECG = echocardiography; GA = gestational age; GMH‐IVH = germinal matrix hemorrhage‐intraventricular hemorrhage; h = hour; HFOV = high‐frequency oscillatory ventilation; ITT= intention to treat; iv = intravenous; min = minute; MV = mechanical ventilation; NEC = necrotizing enterocolitis; NICU = neonatal intensive care unit; PDA = patent ductus arteriosus; PLA = placebo; PVL = periventricular leukomalacia; SD = standard deviation; SIMV = synchronized intermittent mandatory ventilation; SIPPV = Synchronized intermittent positive pressure ventilation; sIVH = severe intraventricular hemorrhage; VLBW: very low birth weight; wks = week