Should a prolonged or short course of indomethacin be used in preterm infants to treat patent ductus arteriosus?(Archimedes)

A 27 week gestation infant is diagnosed to have a significant patent ductus arteriosus (PDA) on echocardiography on day 2. The infant is ventilator dependent. You decide to treat with indomethacin. The resident suggests that it would be better if prolonged indomethacin therapy could be administered over 5-7 days to ensure that the PDA remains closed. What evidence did she have?

Structured clinical question

In preterm infants with patent ductus arteriosus [patient], is prolonged course indomethacin [intervention] better than shortcourse conventional therapy [comparator] in preventing recurrences and decreasing the need for surgical ligation [outcomes]?

Search strategy and outcome

Medline (1966-Dec 2002); "indomethacin" AND "patent ductus arteriosus" AND "infant, newborn"; LIMIT to "english language" and "human"--375 references. Other databases searched were Cochrane Controlled Trials Register (Issue 4, 2002), EMBASE (1980-Dec 2002), CINAHL (1982-Dec 2002), abstracts published in Pediatric Research (1990-2002). Five relevant trials were identified. See table 2.

Commentary

The five RCTs comparing prolonged versus short course indomethacin differ in the dosage regimes (for both prolonged and short course groups), diagnosis of PDA, and onset of treatment. Also there is a wide variation in the gestational age and birth weight.

In all but one study (Rennie et al), PDA was diagnosed by echocardiography. In two studies (Lee et al; Rhodes et al), PDA was detected on echocardiographic screening at predetermined intervals, while in two studies (Tammela et al; Hammerman et al), a clinically symptomatic PDA was confirmed on echocardiography.

There is significant "in between study heterogeneity" as far as outcomes like failure of PDA closure, need for surgical ligation, recurrence of PDA, and …