The Journal of Pediatrics
Volume 153, Issue 2 , Pages 183-189, August 2008

Increased Indomethacin Dosing for Persistent Patent Ductus Arteriosus in Preterm Infants: A Multicenter, Randomized, Controlled Trial

  • Priya Jegatheesan, MD

      Affiliations

    • Cardiovascular Research Institute and Department of Pediatrics, University of California, San Francisco, California
    • P.J. and V.I. contributed equally to the design and execution of this study.
    • ,
  • Vlad Ianus, MD

      Affiliations

    • Department of Pediatrics, Brown University, Providence, RI
    • P.J. and V.I. contributed equally to the design and execution of this study.
    • ,
  • Basharat Buchh, MD

      Affiliations

    • Department of Pediatrics, University of Chicago, Chicago, IL.
    • ,
  • Grace Yoon, BA

      Affiliations

    • Department of Pediatrics, University of Chicago, Chicago, IL.
    • ,
  • Nancy Chorne, MD

      Affiliations

    • Cardiovascular Research Institute and Department of Pediatrics, University of California, San Francisco, California
    • ,
  • Audrey Ewig, MD

      Affiliations

    • Department of Pediatrics, University of California Davis, Davis, California
    • ,
  • Emil Lin, PhD

      Affiliations

    • Cardiovascular Research Institute and Department of Pediatrics, University of California, San Francisco, California
    • ,
  • Scott Fields, PhD

      Affiliations

    • Cardiovascular Research Institute and Department of Pediatrics, University of California, San Francisco, California
    • ,
  • Anita Moon-Grady, MD

      Affiliations

    • Department of Pediatrics, University of California Davis, Davis, California
    • ,
  • Terri Tacy, MD

      Affiliations

    • Cardiovascular Research Institute and Department of Pediatrics, University of California, San Francisco, California
    • ,
  • Jay Milstein, MD

      Affiliations

    • Department of Pediatrics, University of California Davis, Davis, California
    • ,
  • Michael Schreiber, MD

      Affiliations

    • Department of Pediatrics, University of Chicago, Chicago, IL.
    • ,
  • James Padbury, MD

      Affiliations

    • Department of Pediatrics, Brown University, Providence, RI
    • ,
  • Ronald Clyman, MD

      Affiliations

    • Cardiovascular Research Institute and Department of Pediatrics, University of California, San Francisco, California
    • Corresponding Author InformationReprint requests: Ronald I. Clyman, MD, Box 0544, HSW 1408, University of California, San Francisco, 513 Parnassus Ave, San Francisco, CA 94143-0544.

Received 5 November 2007; received in revised form 19 December 2007; accepted 24 January 2008. published online 20 March 2008.

Objective

We conducted a multicenter, randomized, controlled trial to determine whether higher doses of indomethacin would improve the rate of patent ductus arteriosus (PDA) closure.

Study design

Infants (<28 weeks gestation) who received a conventional, prophylactic 3-dose course of indomethacin were eligible if they had continued evidence of persistent ductus patency on an echocardiogram obtained before the third prophylactic indomethacin dose. Infants (n = 105) were randomized to receive an extended 3-day course of either low-dose (0.1 mg/kg/d) or higher-dose (0.2 or 0.5 mg/kg/d) indomethacin. An echocardiogram was obtained 24 hours after the last dose of study drug.

Results

Despite increasing serum indomethacin concentrations by 2.9-fold in the higher-dose group, we failed to detect a significant decrease in the rate of persistent PDA (low = 52%; higher = 45%, P = .50). The higher-dose group had a significantly higher occurrence of serum creatinine >2 mg/100 mL (low = 6%, higher = 19%, P < .05) and moderate/severe retinopathy of prematurity (ROP) (low = 15%, higher = 36%, P < .025). The incidence of moderate/severe ROP was directly related to the poststudy indomethacin concentrations (odds ratio = 1.75, confidence interval: 1.15-2.68, P < .01).

Conclusion

Increasing indomethacin concentrations above the levels achieved with a conventional dosing regimen had little effect on the rate of PDA closure but was associated with higher rates of moderate/severe ROP and renal compromise.

Abbreviations: CLD, Chronic lung disease, PDA, Patent ductus arteriosus, Fio2, Fraction of inspired oxygen, GA, Gestational age, ICH, Intracranial hemorrhage, Indo, Indomethacin, MAP, Mean airway pressure, NEC, Necrotizing enterocolitis, PVL, Periventricular leukomalacia, RDS, Respiratory distress syndrome, ROP, Retinopathy of prematurity, UC Davis, University of California Davis, UCSF, University of California at San Francisco, U of C, University of Chicago, VEGF, Vascular endothelial growth factor

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 Supported in part by the Pediatric Clinical Research Center, University of California San Francisco (National Center for Research Resources grants 5 M01 RR-01271 and UL RR024131-01), and by grants from the U.S. Public Health Service, NHLBI (HL46691, HL56061), and a gift from the Jamie and Bobby Gates Foundation. Ovation Pharmaceuticals provided some of the study indomethacin vials.

PII: S0022-3476(08)00072-3

doi:10.1016/j.jpeds.2008.01.031

The Journal of Pediatrics
Volume 153, Issue 2 , Pages 183-189, August 2008

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