Continuous infusion versus intermittent bolus doses of indomethacin for patent ductus arteriosus closure in symptomatic preterm infants

Patent ductus arteriosus (PDA) occurs when an artery near the heart and lungs stays open and does not close off after birth. Babies born early (preterm) have an increased risk of complications and death due to PDA. Indomethacin has been used to close the PDA; however, it can reduce blood flow in organs such as brain, kidneys and intestine. There is no agreement on the ideal dose and duration of treatment with indomethacin. In order to reduce the adverse effects of indomethacin on blood flow, some investigators have recommended administering the same total dose as a continuous infusion over 36 hours. In this review, the analysis of the two eligible trials found that the data was insufficient to reach a conclusion regarding the effectiveness of the 36-hr continuous infusion method. The blood flow lowering side-effects of indomethacin were reduced by the continuous infusion method, but there was insufficient data to recommend this administration method versus the traditional method.

Authors' conclusions: 

The available data is insufficient to draw conclusions regarding the efficacy of continuous indomethacin infusion vs. bolus injections for the treatment of PDA. Although continuous indomethacin seems to cause less alterations in cerebral, renal and mesenteric circulations, the clinical meaning of this effect is unclear. Definitive recommendations about the preferred method of indomethacin administration in premature infants cannot be made based on the current findings of this review.

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Background: 

Indomethacin is a prostaglandin inhibitor used for the prevention and the treatment of patent ductus arteriosus (PDA). Potential adverse effects of indomethacin use in premature infants include reduction in cerebral, mesenteric and renal blood flow and platelet dysfunction. Administering indomethacin continuously over 36-hours has been suggested as a safer and more effective option to prevent such adverse effects compared to bolus administration.

Objectives: 

To compare the efficacy and safety of continuous infusion vs. bolus administration of indomethacin in closing a symptomatic PDA in preterm infants.

Search strategy: 

We searched MEDLINE (via PubMed), CINAHL, EMBASE and CENTRAL (The Cochrane Library) through 2009.

Selection criteria: 

Randomized and quasi-randomized controlled trials comparing continuous indomethacin infusion to bolus doses for closure of a symptomatic PDA in preterm infants with a symptomatic PDA diagnosed clinically and/or by echocardiography.

Data collection and analysis: 

Data collection and analysis were done in accordance with the recommendations of the CNRG.

Main results: 

Only two small trials comparing continuous vs. bolus indomethacin were eligible. Analysis of these studies showed that there were no statistically significant differences in PDA closure at day 2 (RR 1.57, 95% CI 0.54, 4.60) and at day 5 (RR 2.77, 95% CI 0.33, 23.14). There was no statistical difference between the bolus and continuous groups for the secondary outcomes of reopening of PDA, neonatal mortality, intraventricular hemorrhage and necrotizing enterocolitis. None of the trials reported on outcomes such as requirement for retreatment with indomethacin or surgical ligation, mortality, bronchopulmonary dysplasia, retinopathy of prematurity, neurodevelopmental outcome and isolated intestinal perforation.

The review demonstrated that there was a decrease in cerebral blood flow velocity after bolus injections and that the difference between the bolus and continuous infusion groups remained significant for 12 - 24 hours. Similar decrease in blood flow to the renal and mesenteric circulations following bolus administration was reported in one study (Christmann 2002). None of the trials detected predefined levels of decreased urine output and increased levels of BUN and creatinine.

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