Efficacy of Repeated Courses of Ibuprofen in the Closure of Patent Ductus Arteriosus in Premature Infants

Patent ductus arteriosus (PDA) is a common condition in premature infants and is associated with various prematurity-related morbidities if left untreated. A hemodynamically significant PDA (hsPDA) can decrease systemic flow with left to right shunting, which is attributable to intraventricular hemorrhage, necrotizing enterocolitis, retinopathy of prematurity, and bronchopulmonary dysplasia. Ibuprofen, a propionic acid derivative and a nonselective cyclo-oxygenase (COX) inhibitor, has been reported to be as effective to close a PDA as indomethacin with fewer adverse effects, including gastrointestinal, cerebral, and renal hemodynamic effects. Orogastric administration of ibuprofen, compared to intravenous ibuprofen, was demonstrated to have the same efficacy with fewer adverse effects. In addition to pharmacological management, surgical ligation or percutaneous transcatheter devices are other treatment choices for PDA closure.

In most clinical practices, surgical ligation is the alternative treatment following failure of PDA closure after repeated courses of COX inhibitors. Nevertheless, surgical ligation is associated with an increased risk of neurodevelopment impairment, chronic lung disease, and severe retinopathy of prematurity. Therefore, the purpose of the present study was to research the efficacy and safety of repeated courses of COX inhibitor. The most recent studies with large study populations have demonstrated the efficacy of repeated courses of ibuprofen.^{,  ,}  In the study of Richards et al, authors investigated the rate of PDA closure in a population of infants with < 1 kg birth weight following repeated doses of ibuprofen. Although the study did not specify the route of ibuprofen administration, the overall rate of PDA closure after a single and second course of ibuprofen was 45% and 40%, respectively. With 83% responding to either one or two courses of treatment, the above study suggests that a second course of ibuprofen may be effective in closing a PDA in even the most premature infants. However, the risk of a failed closure by ibuprofen that required surgical ligation was higher among infants with < 26 weeks' gestational age and those weighing < 750 g.

Another retrospective study in 2012, consisting of 164 preterm infants (< 32 weeks' gestational age), investigated the efficacy of repeated courses of intravenous ibuprofen in closure of an hsPDA. Unlike the study by Richards et al, this study demonstrated that the closure rate of PDA after a second (44%) or third (55%) course of ibuprofen was similar to the closure rate after the first course (66%), with no additional side effects following multiple courses. In addition, the study confirmed the higher closure rate after the first course of ibuprofen, if started prior to Postnatal Day 5. In another study by Olgun et al, the authors aimed to describe the efficacy and safety of repeated courses of oral ibuprofen in premature infants with hsPDA. The overall closure rates following the first, second, and third courses of oral ibuprofen were 71%, 40%, and 35%, respectively. Although there is an increasing closure rate following repeated oral ibuprofen administration, a third course did not increase the closure rate significantly. Hence, the study suggested surgical ligation following the second course of treatment if a patient still has PDA with concomitant signs of severe heart failure.

In general, either oral or intravenous ibuprofen have been proven to be as effective as indomethacin in closure of PDA with less risk of all-cause mortality, necrotizing enterocolitis, and decreased urine output. However, oral ibuprofen, compared to intravenous ibuprofen, seems to be more effective in PDA closure with a significantly decreased risk of “failure to close PDA after three doses.” Furthermore, evidence has demonstrated that a second course of oral/intravenous ibuprofen may also be helpful after treatment failure of the initial course. To date, no study has demonstrated the outcome of pharmacological management of PDA with multiple courses of ibuprofen is better or worse than surgical closure. Therefore, a large prospective study may be required to determine whether pharmacological management of PDA with multiple courses of ibuprofen is better or worse than surgical closure.