Combined Treatment With a Nonselective Nitric Oxide Synthase Inhibitor (L-NMMA) and Indomethacin Increases Ductus Constriction in Extremely Premature Newborns

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 [N G -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 Ͻ28 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 Ͻ28 weeks' gestation. However, the combined administration of L-NMMA and indomethacin was limited by acute side effects in this treatment protocol. Studies in premature animals demonstrate that prolonged, tight constriction of the ductus arteriosus is necessary to produce ischemia of the ductus wall, anatomic remodeling, and permanent closure (1-3). A persistent patent ductus arteriosus (PDA) in premature infants is due in large part to the increased sensitivity of the ductus to endogenous vasodilators like prostaglandins. Prostaglandin synthesis inhibitors, such as indomethacin, are the only drugs currently approved for treatment of PDA. Unfortunately, a three-dose course of indomethacin frequently fails to close the PDA in infants of Ͻ28 weeks gestational age (GA). Previous studies have shown that infants delivered before 28 weeks GA who still have evidence of ductus flow on Doppler examination (performed after a standard three-dose course of indomethacin), are unlikely to eliminate Doppler flow through their ductus even if a prolonged six-dose indomethacin course is administered (2).

Effects of ibuprofen treatment on the developing preterm baboon kidney

“…Similarly, NOS inhibition has been shown to significantly reduce renal blood flow, glomerular filtration rate, and alter tubular function in neonatal animals (27). Furthermore, a combination of a NOS inhibitor and NSAID treatment has been shown to produce significant renal side effects (such as increased serum creatinine) in human preterm neonates (16). In the current study, fluid intakes were reduced in all preterm neonates over the course of the study (Fig.…”

“…This failure to respond to treatment has been attributed to a compensatory increase in vasodilatory nitric oxide production (2,3,29). Recent studies in preterm baboon and human infants demonstrate that treatment of a PDA with a combination of NSAIDs and nitric oxide synthase inhibitors significantly increases the success of ductus closure compared with NSAID treatment alone (16,26).…”

How useful are B-type natriuretic peptide measurements for monitoring changes in patent ductus arteriosus shunt magnitude?

“…16-18,24 -31 The echocardiographic studies included two-dimensional imaging, M-mode, color flow mapping and Doppler interrogation as previously described. 32 Echocardiographic indices were obtained from standard subxiphoidal, precordial, apical and suprasternal imaging windows using standard imaging transducers (Sequoia ultrasound system, Siemens Medical Solutions, Mountain View, CA, USA). Results were recorded for subsequent analysis.…”

Patent Ductus Arteriosus – A Complex Problem in Need of a Solid Conceptual Foundation –

“…6 In • NOS inhibitor) and indomethacin than with indomethacin alone (92% vs. 42%), evidence of impaired renal function and systemic hypertension following L-NMMA treatment were noteworthy. 11 We recognize the potential clinical application of such exciting basic science research, but additional data on the safety and efficacy of • NOS inhibitors in premature human infants are needed. Along those lines, even after many years of exposing patients to indomethacin and ibuprofen, we do not yet fully know the risk-benefit profiles associated with these established pharmacologic interventions to close the ductus.…”