Indomethacin Therapy for Patent Ductus Arteriosus in Premature Infants

Abstract

Patent ductus arteriosus (PDA) occurs in 18–77% of very low-birth-weight (VLBW) infants [10]. This wide variation in incidence of PDA is mainly attributable to a difference in gestational age distribution in the studied VLBW population; the lower the gestational age, the higher the risk for symptomatic PDA in these infants, and they are also less likely to respond to medical therapy. Since the reports of the first successful treatment of PDA with indomethacin in 1976 [3, 5, 9], a large number of studies have attempted to seek the best strategy for indomethacin use. Prophylactic use of indomethacin has been shown to reduce the incidence of symptomatic PDA and grade III and IV intraventricular hemorrhage (IVH), but it has not shown any significant difference in mortality or long-term neurodevelopmental outcomes compared to a control group [4]. Prophylactic use of indomethacin has not been widely used primarily because of spontaneous closure of ductus in a significant proportion of VLBW infants and potential adverse effects of indomethacin. Rather than prophylactically treating all VLBW infants, indomethacin treatment could be limited to VLBW infants with asymptomatic PDA. Cooke et al. [3] conducted a meta-analysis on three randomized controlled trials in which asymptomatic PDA was treated with indomethacin, placebo, or no intervention. Indomethacin significantly reduced the incidence of symptomatic PDA and duration of supplemental oxygen. However, there was no effect on mortality, chronic lung disease, IVH, or length of ventilation. Long-term neurodevelopmental outcomes were not reported in these studies. Again, asymptomatic PDA may close in time, and one may question the justification for indomethacin treatment for all asymptomatic PDA. For symptomatic PDA, there is agreement regarding the need for treatment, and indomethacin has been the drug of choice. However, the optimal treatment strategy for indomethacin has not been clearly established with regard to appropriate dose, duration, and when to subject patients to surgical ligation, particularly for extremely low-birth-weight infants [2]. Ductal closure would certainly be dependent on indomethacin blood level. It would also be influenced by gestational age, postnatal age, and ductal size and flow. Pharmacokinetic data for indomethacin indicate that preterm infants less than 1000 g have lower indomethacin plasma levels compared to larger premature infants, possibly due to their relatively large extracellular fluid space and lower serum protein concentration [16]. It has been noted that prostaglandin levels rise 24–72 hours after the last dose of indomethacin [13], coinciding with the time for a risk of PDA reopening. In most trials, short courses of indomethacin have been studied. It thus appears that to achieve and maintain ductal closure, a prolonged course of indomethacin exposure may be more successful than a short course. Sangem et al. [12] examined neonatal outcomes in premature infants with multiple courses of indomethacin. Of 259 infants with persistent PDA, the ductus closed in 224 (84%) with either the first or the second course of indomethacin. Among the remaining 35 infants, 11 had a surgical ligation and 23 received the third course of indomethacin with a closure rate of 43%. Overall closure rate for PDA by indomethacin was 234 of 258 (91%). This result is similar to that of a study by Sperandio et al. [14], in which incremental doses of indomethacin were given to 129 infants of gestational age \33 weeks and with symptomatic PDA. In this study, following the initial three doses K.-S. Lee (&) University of Chicago Comer Children’s Hospital, 5841 South Maryland Avenue, Chicago, IL 60637, USA e-mail: klee@uchicago.edu