Abstract
Studies in premature animals suggest that 1) prolonged tight constriction of the ductus arteriosus is necessary for permanent anatomic closure and 2) endogenous nitric oxide (NO) and prostaglandins both play a role in ductus patency. We hypothesized that combination therapy with an NO synthase (NOS) inhibitor [NG-monomethyl-l-arginine (l-NMMA)] and indomethacin would produce tighter ductus constriction than indomethacin alone. Therefore, we conducted a phase I and II study of combined treatment with indomethacin and l-NMMA in newborns born at <28 weeks' gestation who had persistent ductus flow by Doppler after an initial three-dose prophylactic indomethacin course (0.2, 0.1, 0.1 mg/kg/24 h). Twelve infants were treated with the combined treatment protocol [three additional indomethacin doses (0.1 mg/kg/24 h) plus a 72-hour l-NMMA infusion]. Thirty-eight newborns received three additional indomethacin doses (without l-NMMA) and served as a comparison group. Ninety-two percent (11/12) of the combined treatment group had tight ductus constriction with elimination of Doppler flow. In contrast, only 42% (16/38) of the comparison group had a similar degree of constriction. l-NMMA infusions were limited in dose and duration by acute side effects. Doses of 10–20 mg/kg/h increased serum creatinine and systemic blood pressure. At 5 mg/kg/h, serum creatinine was stable but systemic hypertension still limited l-NMMA dose. We conclude that combined inhibition of NO and prostaglandin synthesis increased the degree of ductus constriction in newborns born at <28 weeks' gestation. However, the combined administration of l-NMMA and indomethacin was limited by acute side effects in this treatment protocol.
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Abbreviations
- GA:
-
gestational age
- L-NMMA:
-
NG-monomethyl-l-arginine
- NO:
-
nitric oxide
- NOS:
-
nitric oxide synthase
- PDA:
-
patent ductus arteriosus
- PVR:
-
pulmonary vascular resistance
- VCFc:
-
rate-corrected velocity of fiber shortening
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Acknowledgements
We thank the fellows and attending staff of the Division of Pediatric Cardiology, who have been so helpful in performing and interpreting the echocardiographic studies, and the ICN and PCRC nurses, without whom this study would not have been possible. We also thank Drs. Julien Hoffman, James Bristow, and Jeffrey Fineman for their expert help with data and safety management.
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Supported by the Pediatric Clinical Research Center, Moffitt Hospital, University of California, San Francisco, with funds provided by the National Center for Research Resources (5 M01 RR-01271), U.S. Public Health Service (NHLBI U01-HL-56061 and HL-46691), and the University of California San Francisco Research and Allocation Committee. Roberta L. Keller is a recipient of the Glaser Pediatric Research Network Award.
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Keller, R., Tacy, T., Fields, S. et al. Combined Treatment With a Nonselective Nitric Oxide Synthase Inhibitor (L-NMMA) and Indomethacin Increases Ductus Constriction in Extremely Premature Newborns. Pediatr Res 58, 1216–1221 (2005). https://doi.org/10.1203/01.pdr.0000183659.20335.12
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DOI: https://doi.org/10.1203/01.pdr.0000183659.20335.12
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