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Indomethacin promotes nitric oxide function in the ductus arteriosus in the mouse.

ABSTRACT: BACKGROUND AND PURPOSE: Prenatal patency of ductus arteriosus is maintained by prostaglandin (PG) E(2) in concert with nitric oxide (NO) and carbon monoxide (CO). Accordingly, we have previously found that NO activity increases upon deletion of either COX. Here, we have examined whether COX inhibition by indomethacin mimics COX deletion in promoting NO. EXPERIMENTAL APPROACH: Experiments were performed in vitro and in vivo with wild-type (WT) and eNOS-/-, near-term mouse foetuses. Indomethacin was given p.o. to the mother as single (acute treatment) or repeated (daily for 3 days; chronic treatment) doses within a therapeutic range (2 mg kg(-1)). KEY RESULTS: Indomethacin promoted eNOS mRNA expression in the WT ductus. Coincidentally, the drug enhanced the contraction of the isolated ductus to the NOS inhibitor, N(G)-nitro-L-arginine methyl ester, and its effect augmented with the length of treatment. No such enhancement was seen with the eNOS-/- ductus. Chronic indomethacin also increased, albeit marginally, the contraction of the WT ductus to the CO synthesis inhibitor, zinc protoporphyrin. Whether given acutely or chronically, indomethacin induced a little narrowing of the ductus antenatally and had no effect on postnatal closure of the vessel. CONCLUSIONS AND IMPLICATIONS: We conclude that activation of NO and, to a much lesser degree, CO mechanisms is an integral part of the indomethacin effect on the ductus. This relaxing influence may oppose the contraction from PGE(2) suppression and could explain the failures of indomethacin therapy in premature infants with persistent duct.

SUBMITTER: Sodini D

PROVIDER: S-EPMC2438253 | biostudies-other | 2008 Apr

REPOSITORIES: biostudies-other

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Project description:BackgroundSymptomatic patent ductus arteriosus (PDA) is associated with mortality and morbidity in preterm infants. In these infants, prophylactic use of indomethacin, a non-selective cyclooxygenase inhibitor, has demonstrated short-term clinical benefits. The effect of indomethacin in preterm infants with a symptomatic PDA remains unexplored.ObjectivesTo determine the effectiveness and safety of indomethacin (given by any route) compared to placebo or no treatment in reducing mortality and morbidity in preterm infants with a symptomatic PDA.Search methodsWe used the standard search strategy of Cochrane Neonatal to search Cochrane Central Register of Controlled Trials (CENTRAL; 2020, Issue 7), in the Cochrane Library; Ovid MEDLINE(R) and Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Daily and Versions(R); and Cumulative Index to Nursing and Allied Health Literature (CINAHL), on 31 July 2020. We also searched clinical trials databases and the reference lists of retrieved articles for randomized controlled trials (RCTs) and quasi-RCTs.Selection criteriaWe included RCTs and quasi-RCTs that compared indomethacin (any dose, any route) versus placebo or no treatment in preterm infants.Data collection and analysisWe used the standard methods of Cochrane Neonatal, with separate evaluation of trial quality and data extraction by at least two review authors. We used the GRADE approach to assess the certainty of evidence for the following outcomes: failure of PDA closure within one week of administration of the first dose of indomethacin; bronchopulmonary dysplasia (BPD) at 28 days' postnatal age and at 36 weeks' postmenstrual age; proportion of infants requiring surgical ligation or transcatheter occlusion; all-cause neonatal mortality; necrotizing enterocolitis (NEC) (≥ Bell stage 2); and mucocutaneous or gastrointestinal bleeding.Main resultsWe included 14 RCTs (880 preterm infants). Four out of the 14 included studies were judged to have high risk of bias in one or more domains. Indomethacin administration was associated with a large reduction in failure of PDA closure within one week of administration of the first dose (risk ratio (RR) 0.30, 95% confidence interval (CI) 0.23 to 0.38; risk difference (RD) -0.52, 95% CI -0.58 to -0.45; 10 studies, 654 infants; high-certainty evidence). There may be little to no difference in the incidence of BPD (BPD defined as supplemental oxygen need at 28 days' postnatal age: RR 1.45, 95% CI 0.60 to 3.51; 1 study, 55 infants; low-certainty evidence; BPD defined as supplemental oxygen need at 36 weeks' postmenstrual age: RR 0.80, 95% CI 0.41 to 1.55; 1 study, 92 infants; low-certainty evidence) and probably little to no difference in mortality (RR 0.78, 95% CI 0.46 to 1.33; 8 studies, 314 infants; moderate-certainty evidence) with use of indomethacin for symptomatic PDA. No differences were demonstrated in the need for surgical PDA ligation (RR 0.66, 95% CI 0.33 to 1.29; 7 studies, 275 infants; moderate-certainty evidence), in NEC (RR 1.27, 95% CI 0.36 to 4.55; 2 studies, 147 infants; low-certainty evidence), or in mucocutaneous or gastrointestinal bleeding (RR 0.33, 95% CI 0.01 to 7.58; 2 studies, 119 infants; low-certainty evidence) with use of indomethacin compared to placebo or no treatment. Certainty of evidence for BPD, surgical PDA ligation, NEC, and mucocutaneous or gastrointestinal bleeding was downgraded for very serious or serious imprecision.Authors' conclusionsHigh-certainty evidence shows that indomethacin is effective in closing a symptomatic PDA compared to placebo or no treatment in preterm infants. Evidence is insufficient regarding effects of indomethacin on other clinically relevant outcomes and medication-related adverse effects.

Project description:BackgroundThe treatment of patent ductus arteriosus (PDA) in very low birth weight (VLBW) infants remains a challenge. The ability to predict which infants will respond to indomethacin could spare some from the risks of unnecessary medications. Our objective was to determine if indicators of acid-base homeostasis could predict response to indomethacin treatment for ductal closure, and thus help guide treatment decisions.MethodsWe performed a retrospective analysis of medical records of VLBW (<?1500?g) neonates with hemodynamically significant PDA born at our institution between January 2009 and December 2012; all infants included in the study were treated with indomethacin for ductal closure within the first 2?weeks of life. We extracted data for a number of clinical variables including gestational age, birth weight, blood chemistries, surfactant use, hematocrit, and blood gas parameters. Our primary outcome measure was successful closure of PDA following the first round of indomethacin. Using variables that were significant on initial testing, we created multivariable regression models to determine the independent association of selected variables with indomethacin response.ResultsOf the 91 infants included in the study, 62 (68%) responded to the first course of indomethacin with successful ductal closure. Multivariable regression modeling revealed that both base excess and hematocrit were independently associated with indomethacin response; odds of PDA closure increased with increasing base excess (OR [odds ratio]: 1.81; 95% confidence interval [CI]: 1.36-2.60) and increasing hematocrit (OR: 1.21; 95% CI: 1.01-1.45). The optimal cutoff value for base excess was -?4.56, with a sensitivity of 96.8% (95% CI: 89-100) and specificity of 79.3% (95% CI: 60-92); optimal cutoff value for hematocrit was 40, with 69.4% sensitivity (95% CI: 56-80) and 65.5% specificity (95% CI: 46-82).ConclusionsBase excess and hematocrit may be independent predictors of indomethacin response in VLBW infants with PDA. Low-cost and readily accessible, acid-base indicators such as base excess could help guide treatment decisions.

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Indomethacin promotes nitric oxide function in the ductus arteriosus in the mouse.

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