Patent Ductus Arteriosus Closure Rate Research Articles

Effect of age and birth weight on indomethacin pharmacodynamics in neonates treated for patent ductus arteriosus.

To determine patent ductus arteriosus (PDA) closure rates, and indomethacin (INDO) toxicity rates in neonates dosed with INDO using an individualized pharmacokinetic/pharmacodynamic (PK/PD) dosing approach. In addition, develop PD curves evaluating dose-response and concentration-response relationships for closure and renal toxicity, especially in select subgroups historically known as "poor responders" (<1000 g and > or = 10 days postnatal age). Prospective, cohort study. Level III neonatal intensive care unit. One hundred thirty-nine patients receiving 151 courses of INDO for PDA closure were evaluated. Patients initially received 0.25 mg/kg of INDO, followed immediately by 1 mg/kg of furosemide. INDO concentrations were obtained 2 hrs and 8 hrs after the dose and were assayed using high-performance liquid chromatography. Individualized PK parameters were calculated with subsequent INDO dosing based on the individualized PK variables to increase trough serum concentrations by 0.3-0.5 mg/L. Ductal closure was successful in 127 patients (91%). Renal toxicity occurred in 21 (15%) patients and was temporary and reversible. No significant differences in response rates based on treatment weight or postnatal age were observed. PD curves were similar for neonates <1000 g vs. > or = 1000 g. PD curves were also similar for neonates with postnatal age <10 days vs. > or = 10 days. Statistically significant differences were noted between neonates categorized for postnatal age <10 days vs. > or = 10 days in total days of therapy (1.8 vs. 2.3 days), total number of doses required to close PDA (3.5 vs. 5.6 doses), critical INDO dose (0.9 vs. 1.4 mg/kg), critical INDO concentration (1.9 vs. 1.4 mg/L), and critical dose/critical concentration ratio (0.52 vs. 2.2). These findings support the hypothesis that the poor PDA closure rates with INDO for neonates >10 days postnatal age are the result of pharmacokinetic differences only and that weight does not impact response rates. Individualized pharmacokinetic/pharmacodynamic dosing of INDO continues to achieve higher closure rate than current dosing standards. Patients historically known as poor responders significantly benefit from this dosing approach.

Prolonged versus short course of indomethacin for the treatment of patent ductus arteriosus in preterm infants.

Indomethacin is a prostaglandin inhibitor used to treat patent ductus arteriosus (PDA) in preterm infants. Although indomethacin produces ductal closure in the majority of cases, it is ineffective in up to 40% of patients. Furthermore, the ductus will re-open in up to 35% of infants who initially respond to the drug. A more prolonged course of indomethacin has been studied regarding the potential to achieve higher rates of ductal closure. To determine if a prolonged course of indomethacin (compared to a short course) reduces the rate of treatment failure in preterm infants with PDA without unwanted side-effects. The search included review of personal files, abstracts of conferences, and the following electronic databases: MEDLINE (1966 to April 2003), EMBASE (1974 to April 2003), and Oxford Database of Perinatal Trials, Cochrane Central Register of Controlled Trials (The Cochrane Library, Issue 3, 2003). No language restrictions were applied. 1) DESIGN AND POPULATION: Randomized or quasi-randomized controlled trials including preterm infants with PDA diagnosed on clinical and/or echocardiographic examination.2) INTERVENTION: Indomethacin treatment by any route given as a long course (four or more doses) vs a short course (three or fewer doses). 3) OUTCOMES: Report of at least one of the following outcomes: failure of PDA to close, need for re-treatment, PDA re-opening, PDA ligation, mortality, duration of assisted ventilation, chronic lung disease (CLD), duration of supplemental oxygen dependence, intraventricular hemorrhage (IVH) (all and severe), diminished urine output, increased serum creatinine, necrotizing enterocolitis (NEC), bleeding diathesis, retinopathy of prematurity (ROP), and duration of hospital stay. The three reviewers independently abstracted data from each study. Relative risk (RR) and Risk Difference (RD) with 95% confidence intervals (CI) using the fixed effect model for meta-analysis are reported. When a statistically significant RD was found, the number needed to treat (NNT) or number needed to harm (NNH) was also calculated with 95% CIs. A chi-square test was used to test for heterogeneity of results among included trials. Prolonged indomethacin treatment when compared to the short course resulted in a borderline statistically significant difference in PDA re-opening rate favoring the prolonged course [RR 0.54 (95% CI 0.3, 0.99); RD -0.12 (95% CI -0.24, -0.01); NNT = 8 (4, 100). There was no statistically significant treatment effect on PDA closure, re-treatment, or ligation rates. The prolonged course was associated with a decreased incidence of severe IVH [RR 0.49 (95% CI 0.25, 0.98); RD -0.12 (95% CI -0.24, -0.01); NNT 8 (4, 100)] and renal function impairment, as evidenced by a lower proportion of infants having an increased creatinine level [RR 0.52 (95% CI 0.34, 0.81); RD -0.20 (95% CI -0.33, -0.08); NNT 5 (3, 13)]. However, there was a trend for the prolonged course to increase the proportion of infants with CLD in the one trial reporting this outcome [RR 2.24 (95% CI 0.98, 5.12); RD 0.24 (95% CI 0.01, 0.47)]. Prolonged as compared to short course of indomethacin for the treatment of PDA in preterm infants has a borderline effect on reducing the rate of PDA re-opening and it may be associated with an increased risk for CLD. However, prolonged course of indomethacin appears to reduce the risk of severe intracranial hemorrhage and renal impairment in this population. Definitive recommendations about the preferred duration of indomethacin therapy, i.e. prolonged versus short course, for the treatment of PDA in premature infants cannot be made based on the current findings of this review. There is a paucity of data on optimal duration of indomethacin therapy for the treatment of PDA, in particular for ELBW premature infants. Future randomized clinical trials should include this high risk population and investigate the premature infants. Future randomized clinical trials should include this high risk population and investigate the possibility of tailoring duration of therapy (prolonged versus short) to individual response in terms of echocardiographic findings and/or prostaglandin levels, focusing on clinically significant outcomes and potential complications associated with either strategy. In addition, factors which may influence treatment effect need to be taken into account when designing such studies.

Early versus late indomethacin treatment for patent ductus arteriosus in premature infants with respiratory distress syndrome

Objective: To compare efficacy and side effects of early versus late indomethacin treatment for patent ductus arteriosus (PDA) in premature infants. Methods: One hundred twenty-seven neonates receiving ventilatory assistance (gestational age: 26-31 weeks) with PDA confirmed by echocardiography were randomly assigned in a prospective multicenter trial to either early (day 3, n = 64) or late (day 7, n = 63) intravenous indomethacin treatment (3 × 0.2 mg/kg every 12 hours). Treatment history and side effects were registered. Results: The PDA closure rate was higher in the early treatment group at both 6 (73% vs 44%, P =.0008) and 9 days of age (91% vs 78%, P =.047). However, there was no significant difference in PDA ligation. Urine output was significantly lower (P <.0001), serum creatinine level was higher (P =.016), and more indomethacin courses were administered in the early treatment group (70 vs 26). Respiratory support, number of deaths, and intraventricular hemorrhages were similar in both groups. However, on the whole, major adverse events (death, necrotizing enterocolitis, and/or localized perforation, extension of hemorrhage, or cystic leukomalacia) occurred more frequently in the early treatment group (P =.017). Conclusion: Early indomethacin treatment improves PDA closure but is associated with increased renal side effects and more severe complications and has no respiratory advantage over late indomethacin administration in ventilated, surfactant-treated, preterm infants <32 weeks’ gestational age. (J Pediatr 2001;138:205-11)

Indomethacin Treatment for Symptomatic Patent Ductus Arteriosus: A Double-Blind Control Study

A double-blind control study was designed to determine the efficacy and safety of indomethacin treatment of patients with symptomatic patent ductus arteriosus. Infants with severe respiratory distress syndrome and symptomatic patent ductus arteriosus were eligible for the prospective study if the ratio of left atrial/aortic root diameter remained greater than or equal to 1.3:1 following a 24-hour period of medical management. Thirty-nine eligible infants were randomly assigned to the control or indomethacin group and given 0.2 mg/kg of enteral indomethacin or placebo in a double-blind manner. Second and third doses were administered at 24-hour intervals in phase 1 (17 patients), and at eight-hour intervals in phase 2 (22 patients). The 75% patent ductus arteriosus closure rate with indomethacin treatment in phase 1 was not statistically significant due to a 44% spontaneous closure rate in the control group. In phase 2, however, 85% of the indomethacin group demonstrated patent ductus arteriosus closure vs only 11% in the matched control group (P less than .01). Although no indomethacin side effects occurred in phase 1, in phase 2 indomethacin administration was associated with minimal, but statistically significant, transient impaired renal function and, in three infants (23%), mild upper gastrointestinal bleeding. In summary, enteral administration of three 0.2 mg/kg indomethacin doses at eight-hour intervals thus appears to be a safe and effective alternative to surgical closure.