High-dose Ibuprofen for Patent Ductus Arteriosus in Extremely Preterm Infants: a Randomized Controlled Study

The patency of ductus arteriosus (PDA) is a frequent complication in preterm infants suffering from respiratory distress syndrome (RDS), and 60% to 70% of preterm infants of <28 weeks' gestation receive medical or surgical therapy for a PDA [1]. Neonates with a left-to-right shunt through the ductus complicating their RDS have higher respiratory failure, lower survival rate, and increased risk of intracranial haemorrhage (ICH), bronchopulmonary dysplasia (BPD) and necrotizing enterocolitis (NEC) [2]. Therefore, closure of PDA is indicated before a significant left-to-right shunting occurs.

Patent ductus arteriosus can be treated effectively with intravenous indomethacin and ibuprofen, leading to permanent ductal closure in 60% to 80% of infants [3-5]. However, preterm infants treated with ibuprofen experience lower serum creatinine values, higher urine output, and less undesirable decreased organ blood flow and vasoconstrictive adverse effects than indomethacin-treated patients [4].

Recently, Sperandio et al. reported that high-doses of indomethacin (1 mg/kg: fivefold the usual dose) were safe and effective in closing PDA in 98.5% of infants with gestational age < 33 weeks, and demonstrated that the closure rate of PDA was related to the cumulative dose of given indomethacin [6]. Moreover, Desfrere et al. demonstrated that the currently recommended dose regimen of ibuprofen (10-5-5 mg/kg/day) is associated with a low estimated probability (30.6%) of closing PDA in infants while a high-dose regimen (20-10-10 mg/kg/day) might be associated with a greater, although unsatisfactory, probability (54.8%) of closing PDA, without relevant side affects [7]. Furthermore, Hirt et al., based on pharmacokinetic findings, proposed increasing the dose regimen of ibuprofen during the postnatal period from 10-5-5 mg/kg/day in preterm infants <70 h of age to 14-7-7 mg/kg/day in infants 70-108 h of age and 18-9-9 mg/kg/day in infants 108-180 h of age [8].

These studies [6-8] suggest that the failure of pharmacologic PDA closure might be due to the inadequacy of the standard dose regimen because of large interindividual pharmacokinetics and pharmacodynamic variations in premature infants during treatment for PDA [9,10].

The investigators hypothesized that the early treatment of PDA with ibuprofen doses higher than those actually recommended might increase the closure rate in preterm infants with gestational age <29 weeks without increasing the occurrence of associated adverse effects. To assess this hypothesis the investigators planned a multicenter randomized controlled study to compare the effectiveness of the current ibuprofen regimen to that of a high-dose regimen in closing PDA.