Effects of prolonged versus acute indomethacin therapy in very low birth-weight infants with patent ductus arteriosus

Abstract

Indomethacin has proven effective in closing the patent ductus arteriosus (PDA) in most low birth weight (LBW) neonates with this disorder. Early reopening of the ductus is a problem and often leads to the need for surgery. Prolonged use of indomethacin for several days has been suggested as a means to alleviate this problem. The present study was designed to determine if prolonged therapy over 5 days is more effective than a two-dose regimen in preventing reopening of the PDA. Seventy neonates were randomized for either prolonged therapy over 1 week or to receive two doses of indomethacin. All infants were given two doses of indomethacin 0.15 mg per kg, 12h apart. The maintenance group received an additional 0.1 mg per kg daily for 5 days. Ten days after the infants' initial dose of indomethacin, 6 of 22 in the nonmaintenance group as compared to 0 of 22 in the maintenance group had reopening of their ductus arteriosus. Ten infants in the maintenance group eventually had the ductus reopen at a median of 29, range 11-66 days compared to a median of 3, range 2-44 days in the nonmaintenance group. Significantly fewer babies in the maintenance group had a grade II-IV intraventricular hemorrhage compared to the nonmaintenance group. There was no other significant difference in the two groups in the incidence of necrotizing enterocolitis, retrolental fibroplasia or death. Indomethacin given over 5 days is effective for closure of the ductus arteriosus and will prevent reopening until after the acute clinical course in babies under 1500 g; however, the overall incidence of reopening was not different.

Treatment of persistent patent ductus arteriosus in preterm infants: time to accept the null hypothesis?

“…Search results and citation lists for prior publications identified 75 randomized-controlled trials of interventions that close a PDA in preterm infants. In 26 trials (five comparing long and short courses of indomethacin, [37][38][39][40][41] 19 comparing indomethacin and ibuprofen, [42][43][44][45][46][47][48][49][50][51][52][53][54][55][56][57][58][59][60] and two that included very early crossover to treatment of nonresponders 29,61 ), rates of ductal closure did not differ between treatment assignments, precluding evaluation of effects of ductal closure on other outcomes, so these were excluded. The remaining 49 trials, 36, including 4728 subjects, were deemed potentially informative, as all but one documented substantial reduction in ductal patency after treatment.…”

Indomethacin Use for the Management of Patent Ductus Arteriosus in Preterms: A Web-Based Survey of Practice Attitudes Among Neonatal Fellowship Program Directors in the United States

“…In addition, randomized trials conducted to date have varied in their definition of ductal closure based on echocardiographic findings. These variations in echocardiographic definitions of ductal closure have relevance for the interpretation of response rates in the literature and the need for further treatment [10,13,14,20,26,28,32,33,35,37].Although an initial indomethacin course will produce PDA closure in 60-80% of premature infants, the PDA reopens later in 6-53% of infants who initially respond to indomethacin [14,17,22,30]. There also appears to be no consensus regarding the best approach for the management of reopened PDA in premature infants, specifically for a PDA that reopens after the first 2 weeks of postnatal life [25,29].…”

“…Therefore, the use of indomethacin is contraindicated if there is oliguria, thrombocytopenia, or renal insufficiency. However, there appears to be no uniform criteria for the magnitude of oliguria, the degree of elevated creatinine levels, and the magnitude of thrombocytopenia [10,13,14,20,26,28,32,33,35,37].Institutional practice is expected to be based on existing evidence. If there is strong evidence for a particular treatment plan, one would expect it to be used by most academic medical institutions.…”

“…Indomethacin is often used as a first line of treatment for PDA, with reported response rates greater than 60% in premature infants. However, studies have failed to provide conclusive results regarding the optimum duration, specifically short course (three dose) versus prolonged course (more than three doses) of indomethacin therapy [9,20,21,26,32,33,37]. Evidence is insufficient to support or refute the use of multiple courses (two or more courses) of indomethacin for the management of persistent PDA [23].…”

“…In addition, randomized trials conducted to date have varied in their definition of ductal closure based on echocardiographic findings. These variations in echocardiographic definitions of ductal closure have relevance for the interpretation of response rates in the literature and the need for further treatment [10,13,14,20,26,28,32,33,35,37].…”