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Meta-Analysis
. 2008 Jan 23;2008(1):CD006071.
doi: 10.1002/14651858.CD006071.pub2.

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

A S Görk  1 , R A Ehrenkranz, M B Bracken
Affiliations
Meta-Analysis

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

A S Görk et al. Cochrane Database Syst Rev. .

Abstract

Background: Indomethacin is a prostaglandin inhibitor used for the prevention and the treatment of patent ductus arteriosus (PDA). Although a 3-dose schedule has been commonly used, there is no consensus on optimal dosage and duration of indomethacin therapy for PDA closure. There are potential adverse effects of indomethacin use in premature infants such as a 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.

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

Search strategy: The standard search strategy of Cochrane Neonatal Review was used: MEDLINE and EMBASE (1966 - March 2007), Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 1, 2007), bibliographies of reviews and trials were examined for references to other trials, previous symposia proceedings published in Pediatric Research (Pediatric Academic Societies Annual Meeting Abstract Book, 1972 - 2006). No language restrictions were applied.

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: The methodological quality of each study was assessed. Authors were contacted regarding missing data as well as to inquire about the outcomes that were not reported. Meta-analysis was performed to calculate relative risk (RR), risk difference (RD) and 95% confidence intervals (CI).

Main results: Only two small trials comparing continuous versus bolus indomethacin were eligible. Analysis of these studies showed that, although the primary outcome of PDA closure on days two and five slightly favored bolus administration, there was no statistical difference between the two groups. The estimates for PDA closure were RR 1.57 (95% CI 0.54, 4.60), RD 0.10 (95% CI -0.13, 0.33) for day 2 and RR 2.77 (95% CI 0.33, 23.14), RD 0.15 (95% CI -0.13, 0.42) for day five. There was no statistical difference between the bolus and continuous groups for the secondary outcomes of reopening of PDA, neonatal mortality, intraventricular hemorrhage (IVH) and necrotizing enterocolitis (NEC). These analyses were based on a very small number of events reported by these trials. None of the trials reported on outcomes such as requirement for retreatment with indomethacin or surgical ligation, mortality, bronchopulmonary dysplasia (BPD), retinopathy of prematurity (ROP), 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 hour. In one study (Christmann 2002), the decrease in blood flow was maximum at 10 minutes [MD -46.40 (95% CI -75.41, -17.39)], while the other study (Hammerman 1995) reported a maximum drop at 30 minutes [MD -55.60 (95% CI -62.92, -48.28)]. Similar decrease in blood flow to the renal and mesenteric circulations following bolus administration was reported in one study (Christmann 2002). In both of these circulations, the decrease was maximum 30 minutes after the bolus injection [typical estimates for renal and mesenteric circulations, respectively: MD -42.00 (95% CI -76.59, -7.41) and MD -26.50 (95% CI -45.34, -7.66)] and lasted about two hours. None of the trials detected predefined levels of decreased urine output and increased levels of BUN and creatinine.

Authors' conclusions: Due to a paucity of events and lack of precision, the available data was found to be insufficient to draw conclusions regarding the efficacy of continuous indomethacin infusion versus 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 i.e. continuous versus bolus infusions for the treatment of PDA in premature infants cannot be made based on the current findings of this review.

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Conflict of interest statement

None

Figures

1.1
1.1. Analysis
Comparison 1 Continuous versus Bolus Indomethacin, Outcome 1 Failure of PDA to close.
1.2
1.2. Analysis
Comparison 1 Continuous versus Bolus Indomethacin, Outcome 2 Reopening of PDA after initial closure.
1.3
1.3. Analysis
Comparison 1 Continuous versus Bolus Indomethacin, Outcome 3 Neonatal mortality (death during the first 28 days of life).
1.4
1.4. Analysis
Comparison 1 Continuous versus Bolus Indomethacin, Outcome 4 Change in cerebral blood flow (Internal Carotid Artery; percent of baseline).
1.5
1.5. Analysis
Comparison 1 Continuous versus Bolus Indomethacin, Outcome 5 Change in cerebral blood flow (Middle Cerebral Artery; percent of baseline).
1.6
1.6. Analysis
Comparison 1 Continuous versus Bolus Indomethacin, Outcome 6 IVH (all grades).
1.7
1.7. Analysis
Comparison 1 Continuous versus Bolus Indomethacin, Outcome 7 Change in renal blood flow (Renal Artery; percent of baseline).
1.8
1.8. Analysis
Comparison 1 Continuous versus Bolus Indomethacin, Outcome 8 Changes in urine output (oliguria defined as urine output <1 cc/kg/hr) during therapy.
1.9
1.9. Analysis
Comparison 1 Continuous versus Bolus Indomethacin, Outcome 9 Change in BUN (>20 mg/dl) levels.
1.10
1.10. Analysis
Comparison 1 Continuous versus Bolus Indomethacin, Outcome 10 Change in creatinine (>1.8 mg/dl) levels.
1.11
1.11. Analysis
Comparison 1 Continuous versus Bolus Indomethacin, Outcome 11 Change in mesenteric blood flow (Superior Mesenteric Artery, percent of baseline).
1.12
1.12. Analysis
Comparison 1 Continuous versus Bolus Indomethacin, Outcome 12 NEC (Bell's stage 2 or greater).
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Update of

  • doi: 10.1002/14651858.CD006071

References

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References to other published versions of this review

Görk 2008
    1. Görk AS, Ehrenkranz RA, Bracken MB. Continuous infusion versus intermittent bolus doses of indomethacin for patent ductus arteriosus closure in symptomatic preterm infants. Cochrane Database of Systematic Reviews 2008, Issue 1. [DOI: 10.1002/14651858.CD006071.pub2] - DOI - PMC - PubMed

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