Patent Ductus Arteriosus Closure Rate Research Articles

Patent ductus arteriosus in infants <29 weeks gestation — outcomes and factors affecting closure

To determine Patent ductus arteriosus (PDA) closure rates for extremely preterm infants in a tertiary care centre, factors affecting response to indomethacin and outcomes of these infants relative to their PDA status. Neonatal intensive care unit in tertiary-care children's hospital. Retrospective medical record review. A retrospective chart review of all infants <29 weeks gestation between 1st Jan 2003 and 30th June 2006 was carried out. Multiple courses of standard intravenous indomethacin (dose: 0.2 mg/kg 12 hourly; 3 doses) followed by a tail course (0.1 mg/kg/day; 3 doses) were used to treat PDA depending on clinical and hemodynamic status. Data on demographic characteristics, PDA status, use of indomethacin, and outcome factors such as chronic lung disease and mortality were collected. A total of 166 infants were identified in the study period, of which 15 were excluded. The median gestation was 27 weeks [IQR (25, 28)] and the mean (SD) birthweight was 950 (244) grams. The remaining infants (n=151) were divided into three groups. Group1 (n=47): no or non-significant PDA, Group 2 (n=91): significant PDA closed after indomethacin treatment (= 1 course) and Group 3 (n=13): significant PDA not responding to indomethacin. The closure rate of PDA with indomethacin treatment (group 2) was 87%. A low gestational age < 26 weeks (OR 5.6, 95% CI 1.6-19.9) and female sex (OR 5.8, 95% CI 1.5-22.8) was associated with poor response to indomethacin in our study population. Multiple indomethacin courses using the standard dosing approach result in high PDA closure rates for infants < 29 weeks gestation.

The Effectiveness and Safety of Repeated Oral Ibuprofen Treatment in Prematures with Patent Ductus Arteriosus

Although patent ductus arteriosus (PDA) leading to significant hemodynamic changes in premature babies can be cured by medical or surgical methods, debate is ongoing about the selection of the treatment method, and there is still no consensus about the benefit-side effect relation.The aim of this study was to determine the effectiveness of enteral ibuprofen on PDA closure and its adverse effects in premature with hemodynamically significant PDA. All infants had hemodynamically significant PDA determined clinically and echocardiographically (left atrial/aorta (LA/Ao) ratio >1.3 or the narrowest diameter of the PDA shunt on color Doppler echocardiography >1.5 mm). The first dose of ibuprofen is administered, and then two consecutive doses of 5 mg/kg are given after 24-hour intervals. If the treatment is unsuccessful, the 2nd and 3rd cure treatments are administered if the laboratory and clinical status of the patients are deemed suitable.The rate of PDA closure with enteral ibuprofen treatment was determined as 88%. The rate was 71% after 1st cure, 40% after the 2nd course and 35% after the 3rd course. Among patients in whom the PDA closed after the 1st cure, the bronchopulmonary dysplasia (BPD) frequency was 26.9%; this rate was 48.1% among patients in whom PDA closed after multiple courses.In conclusion, enteral ibuprofen, as a readily available and easily applicable agent, is effective and safe, with minimal side effects. In case of treatment failure, earlier surgical ligation should be kept in mind to prevent the complications that can occur due to prolonged ductal patency.

Effects of Ibuprofen and Indomethacin for Prophylaxis of Patent Ductus Arteriosus in Premature Infants

Purpose: The aim of our study was to compare the efficacy and safety of ibuprofen and indomethacin in the prophylaxis of patent ductus arteriosus (PDA) in preterm infants and to determine whether ibuprofen could be an alternative agent in prophylactic use. Methods: A retrospective study including 37 preterm infants <1,500 g of birth weight, <34 weeks of gestation, whom were administrated indomethacin (n=17; January 2009-December 2009) or ibuprofen (n=20; January 2010-February 2011) within 24 hr after birth was conducted. The rate of ductal closure, need for surgical ligation, clinical outcomes such as necrotizing enterocolitis, intraventricular hemorrhage, bronchopulmonary dysplasia, retinopathy of prematurity (ROP) and death rate were compared. Results: There were no statistically significant differences between the two groups in mean gestational age, mean birth weight, Apgar score, sex, type of delivery, maternal dexamethasone treatment, frequency and duration of ventilator and surfactant treatment. The closure of PDA on day 7 of life was in 19 of 20 infants of the ibuprofen group and 13 of 17 infants of the indomethacin group ( P=0.159). Between the two groups, there were no significant differences with respect to clinical outcomes. Conclusion: Ibuprofen has similar effects to indomethacin in the rate of PDA closure. Our study demonstrates that prophylactic ibuprofen is relatively effective without significant differences with respect to clinical outcomes compared with indomethacin. Therefore, ibuprofen may be used as an alternative agent in the prophylaxis of PDA in preterm infants.

623 Does Early Spontaneous Closure of the Ductus Arteriosus in Very Preterm Infants Predict Final Closure?

Background: A patent ductus arteriosus (PDA) is a common problem in very premature infants. Echocardiography is the gold standard for diagnosis, although there is no agreement about a most discriminating parameter. Not much is known about the spontaneous closure of the duct. Reports concerning this issue differ widely.We investigated closure rate of PDA on day 2 after birth in premature infants with a gestational age ≤32 weeks.Methods: During a prospective cohort study on diagnosis of hemodynamic significant PDA we performed echocardiography at 3 standard time points (day 2,4 and 6 after birth) in 200 premature infants (GA ≤32 weeks).Results: In 70 patients (35%) the duct was closed on day 2 after birth. Gestational age and birth weight of this group was not different from the group (n=130 (65%)) in which the duct was still open. None of the the closed ducts on day 2 after birth reopened at a later point of time.Of the 130 patients with an open ductus ateriosus on day 2, 33 (16.5% of the total group) needed treatment.Conclusions: When the ductus arteriosus was closed on day 2 treatment for closure was never needed.We recommand to perform echocardiography on day 2 after birth in every very premature infant, to make a risk assessment for further clinical course.

ORIGINAL ARTICLE: Comparison of Two Neonatal Indomethacin Protocols: Efficacy and Outcome for Patent Ductus Arteriosus Closure

Indomethacin, a non-selective inhibitor of prostaglandin synthesis, is the gold standard treatment for patent ductus arteriosus (PDA). Indomethacin has been shown to permanently close the ductus and when given prophylactically, it reduces the incidence of PDA (1, 2). This study compares PDA closure and surgical ligation rates between patients using two different indomethacin administration protocols. This is a retrospective comparison analysis of 72 neonates, who received one of two indomethacin administration protocols. Our previous protocol suggested an initial dose of 0·2 mg/kg followed by two 0·1 mg/kg, with doses infused over 4 h and a 24-h dosing interval. A new potentially more useful protocol using the same mg/kg dose regimen but with doses infused over 30 min and a 12-h dosing interval, was evaluated. Each neonate was allowed three courses of treatment before surgical ligation was performed for persistent PDA. There were no statistically significant differences between the two protocol groups when comparing percentages of neonates with gestational age≤28 weeks, birth weight≤1000 g, male gender or receiving indomethacin for the indication of PDA prophylaxis vs. treatment. There was a trend towards a higher PDA closure rate and subsequently a lower PDA ligation rate in the new protocol when compared with the previous protocol. In this small population of premature neonates, there was a trend, but no significant difference, towards increasing PDA closure and lower surgical ligation rates in neonates given indomethacin with more frequent dosing and shorter infusion time. A well-powered randomized controlled trial is now needed.

Ibuprofen Treatment in 53 Premature Infants of Patent Ductus Arteriosus

Objective To explore the efficacy and safety of ibuprofen in patent ductus arteriosus (PDA) treatment in premature infants, and investigate correlation factors that effected the efficacy. Methods 53 cases of PDA that matched the selected standards were treated with ibuprofen orally. The closure of ductus arteriosus and adverse reactions were under observation. Results Effective power of first treatment in our research was 84. 91% ,8 cases failed. Two cases of PDA were closed after the second course of treatment. The total effective rate was 88.68%. This research also indicated that the time to use ibuprofen and the birth weight of children were of positive and notable effect on closure rate of PDA. No serious adverse reaction occurred during the research. Conclusion Ibuprofen in PDA treatment is safe and of certain efficacy. It can obviously elevate the rate of PDA closure in premature infants to use ibuprofen early. Key words: Patent ductus arteriosus; Ibuprofen; Premature infant

Effect of Furosemide on Ductal Closure and Renal Function in Indomethacin-Treated Preterm Infants during the Early Neonatal Period

Background: Furosemide is known to increase renal prostaglandin synthesis. However, its influence on ductal closure and renal toxicities of indomethacin in preterm infants has not been conclusive, especially during the early neonatal period. Objectives: To identify the effects of furosemide after indomethacin administration on the rate of patent ductus arteriosus (PDA) closure and renal function in preterm infants. Methods: 68 infants (gestational age <34 weeks and birth weight <2,000 g) receiving indomethacin therapy (one course: 0.2–0.1–0.1 mg/kg q 12 h, mostly started <48 h after birth) were randomly assigned to the furosemide (n = 35) or control (n = 33) group. Each indomethacin dose was followed by furosemide (1.0 mg/kg) or placebo. The primary (PDA closure) and secondary (acute renal failure (ARF) and others) outcomes were assessed. Renal parameters before and 0–12 and 24–36 h after the first course of indomethacin were also investigated. Results: In an intention-to-treat analysis, there were no differences in the PDA closure rate between the furosemide (29/34) and the control (27/29) group (p = 0.437). The incidence of ARF (serum creatinine >1.6 mg/dl) was greater in the furosemide group (20/34) than in the control group (3/29) (p < 0.001). Compared with the control group, serum creatinine and cystatin C levels and fractional excretion of sodium were significantly increased in the furosemide group for 24–36 h after indomethacin therapy (p < 0.01). There were no between-group differences in mortality and other neonatal morbidity rates. Conclusions: Use of furosemide in combination with indomethacin increased the incidence of ARF but did not affect the PDA closure rate in preterm infants.

Oral Ibuprofen and Ductus Arteriosus Closure in Full-Term Neonates: A Prospective Case–Control Study

Management of patent ductus arteriosus (PDA) in full-term neonates remains controversial. We evaluated the effects of oral ibuprofen on PDA closure in 51 full-term neonates. All neonates were >3-days-old and had a gestational age > or = 37 weeks. Patients with ductal-dependent congenital heart disease or severe pulmonary artery hypertension (gradient >40 mmHg) were excluded. Patients were randomly assigned to the treatment group (n = 30) or the control group (n = 21). The treated group received ibuprofen suspension (initially 10 mg/kg, then two 5-mg/kg doses 24 h apart), and control neonates received a placebo. Physicians who treated the patients were blinded to group assignment. There was a statistically significant difference in the closure rate of PDA between the treated (73.3%) and control groups (42.9%, P = 0.029). Among neonates with PDA closure, there was a significant difference in the day of closure between the two groups (25.49 and 17.65% on the days 4 and 14 after diagnosis of PDA in treated neonates versus 1.96 and 15.69% in controls, respectively). This study showed the efficacy of oral ibuprofen in achieving earlier closure of PDA in full-term neonates.

Patent Ductus Arteriosus: Indomethacin, Ibuprofen, Surgery, or No Treatment at All?

Patent Ductus Arteriosus: Indomethacin, Ibuprofen, Surgery, or No Treatment at All?

Ibuprofen Versus Continuous Indomethacin in Premature Neonates With Patent Ductus Arteriosus: Is the Difference in the Mode of Administration?

Ibuprofen has been proposed as a preferential alternative to indomethacin in treating patent ductus arteriosus (PDA), because it is purported to have less renal, mesenteric, and cerebral vasoconstrictive effects. However, short and long-term safety concerns regarding ibuprofen remain. Continuous slow infusion of indomethacin also eliminates peripheral vasoconstriction and may thus offer similar benefits to ibuprofen without safety concerns. In this study, our objective was to show that treating a PDA with continuous indomethacin is similar to ibuprofen in its effect on urine output, renal function, and blood flow velocities in the renal, superior mesenteric, and anterior cerebral arteries. Sixty four prematures with PDA were randomly, prospectively assigned to either treatment. PDA closure rates were similar (74 versus 59%; p = 0.123). Nine indomethacin-treated babies (29%) versus twelve ibuprofen babies (38%) underwent repeated therapy (p = 0.656). Two indomethacin and four ibuprofen infants required surgical ligation (p = 0.672). Serum creatinine, oliguria, estimated glomerular filtration rate, and fractional excretion of sodium were similar in both groups, as were blood flow velocity parameters in the vessels studied. There were no differences in necrotizing enterocolitis, BPD, intraventricular hemorrhage, and/or retinopathy of prematurity. In conclusion, PDA treatment with either continuous indomethacin infusion or ibuprofen was equally devoid of adverse renal effects and/or peripheral vasoconstrictive effects.

Factors affecting successful closure of hemodynamically significant patent ductus arteriosus with indomethacin in extremely low birth weight infants

The incidence of patent ductus arteriosus (PDA) is high in extremely low birth weight (ELBW) infants. Indomethacin has been widely used in the prophylaxis and treatment of hemodynamically significant PDA. This retrospective study was undertaken to identify factors such as birth weight, gestational age, gender, fetal growth retardation, ductal size, timing of the first dose of indomethacin and side effects of indomethacin, which may affect the successful closure of the PDA with indomethacin in ELBW infants. A cohort of 139 ELBW infants who had received indomethacin treatment for PDA during a consecutive period of more than three years (September 2000 to December 2003) was retrospectively analyzed. Administration of indomethacin was associated with closure of PDA in 108 (77.7%) of 139 ELBW infants, and only 19.4% of infants required surgical ligation of the ductus eventually. There was no significant relationship between closure of PDA with gestational age, gender, fetal growth retardation, and ductal size. A higher birth weight and early use of indomethacin after birth could significantly increase the closure rate of PDA (P<0.05). Side effects of indomethacin such as transient oliguria and hyponatremia during indomethacin therapy did not affect PDA closure. Indomethacin is effective for the treatment of PDA in ELBW infants. A higher rate of ductal closure is related to the increase of birth weight. PDA closure with indomethacin is age-related, and early administration of indomethacin could increase PDA closure and reduce the incidence of hyponatremia. There is no significant difference in major morbidities such as bronchopulmonary dysplasia (BPD), intraventricular hemorrhage (IVH), necrotizing enterocolitis (NEC), and retinopathy of prematurity (ROP) after early treatment. Early screening for hemodynamically significant PDA in ELBW infants and early treatment with indomethacin are recommended.

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

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

An optimized ibuprofen dosing scheme for preterm neonates with patent ductus arteriosus, based on a population pharmacokinetic and pharmacodynamic study

Ibuprofen is a nonsteroidal anti-inflammatory agent that induces closure of the patent ductus arteriosus in neonates. Few studies of ibuprofen pharmacokinetics have been performed and were limited to small groups of preterm infants, showing a large intersubject variability and an increase in clearance with either postnatal or gestational age. A population pharmacokinetic study was performed on 66 neonates to characterize the concentration-time courses of ibuprofen. Ibuprofen clearance significantly increased from postnatal age day 1 to day 8, but not with gestational age. A relationship was shown between ibuprofen area under the curve (AUC) and patent ductus arteriosus closure rate, and an effective threshold AUC was evidenced. Dosing schemes were proposed as a function of postnatal age, to achieve this AUC and to improve the efficacy of treatment for patent ductus arteriosus in neonates. AIMS To describe ibuprofen pharmacokinetics in preterm neonates with patent ductus arteriosus (PDA) and to establish relationships between doses, plasma concentrations and ibuprofen efficacy and safety. Sixty-six neonates were treated with median daily doses of 10, 5 and 5 mg kg(-1) of ibuprofen-lysine by intravenous infusion on 3 consecutive days. A population pharmacokinetic model was developed with NONMEM. Bayesian individual pharmacokinetic estimates were used to calculate areas under the curve (AUC) and to simulate doses. A logistic regression was performed on PDA closure. Ibuprofen pharmacokinetics were described by a one-compartment model with linear elimination. Mean population pharmacokinetic estimates with corresponding intersubject variabilities (%) were: elimination clearance CL = 9.49 ml h(-1) (62%) and volume of distribution V = 375 ml (72%). Ibuprofen CL significantly increased with postnatal age (PNA): CL = 9.49*(PNA/96.3)(1.49). AUC after the first dose (AUC1D), the sum of AUC after the three doses (AUC3D) and gestational age were significantly higher in 57 neonates with closing PDA than in nine neonates without PDA closure (P = 0.02). PDA closure was observed in 50% of the neonates when AUC1D < 600 mg l(-1) h (or AUC3D < 900 mg l(-1) h) and in 91% when AUC1D > 600 mg l(-1) h (or AUC3D > 900 mg l(-1) h) (P = 0.006). No correlation between AUC and side-effects could be demonstrated. To achieve these optimal AUCs, irrespective of gestational age, three administrations at 24 h intervals are recommended of 10, 5, 5 mg kg(-1) for neonates younger than 70 h, 14, 7, 7 mg kg(-1) for neonates between 70 and 108 h and 18, 9, 9 mg kg(-1) for neonates between 108 and 180 h.

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. Prolonging the course of indomethacin has the potential to achieve higher rates of ductal closure. To determine the effect of a prolonged course of indomethacin (compared to a short course) on the rate of treatment failure without unwanted side-effects in preterm infants with PDA. The search included review of personal files, abstracts of conferences, and the following electronic databases: MEDLINE (1966 to December 2006), EMBASE (1974 to December 2006), and Oxford Database of Perinatal Trials, Cochrane Central Register of Controlled Trials (The Cochrane Library, Issue 4, 2006). No language restrictions were applied. Randomized or quasi-randomized controlled trials including preterm infants with PDA, diagnosed on clinical and/or echocardiographic examination that evaluated indomethacin treatment by any route given as a long course (four or more doses) vs. a short course (three or fewer doses) were included in the review. Trials needed to report on 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 review authors 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. The I squared statistic was used to test for heterogeneity of results among included trials. Five trials met inclusion criteria and included 431 infants. Prolonged indomethacin treatment when compared to the short course did not result in a statistically significant difference in PDA closure, re-treatment, re-opening, or ligation rates. The prolonged course was associated with an increased risk of NEC [typical RR 1.87 (95% CI 1.07, 3.27); typical RD 0.08 (95% CI 0.01, 0.15); NNH 13 (7, 100)] and a decreased incidence of renal function impairment, as evidenced by a lower proportion of infants having diminished urine output [typical RR 0.27 (95% CI 0.13, 0.6); typical RD -0.19 (95% CI -0.28, -0.09); NNT 5 (4, 11)] and increased serum creatinine level [typical RR 0.51 (95% CI 0.33, 0.77); typical RD -0.14 (95% CI -0.23, -0.06); NNT 7 (4, 16)]. Implications for practiceProlonged indomethacin course does not appear to have a significant effect on improving important outcomes, such as PDA treatment failure, CLD, IVH, or mortality. The reduction of transient renal impairment does not outweigh the increased risk of NEC associated with the prolonged course. Based on these results, a prolonged course of indomethacin cannot be recommended for the routine treatment of PDA in preterm infants. Implications for researchThere is a paucity of data on optimal dosing and duration of indomethacin therapy for the treatment of PDA, in particular for extremely low birth weight infants (ELBW) premature infants. It is likely that a single standard indomethacin regime is not the ideal for every premature infant. Therefore, individual patient response should be considered and evaluated, in particular in ELBW infants. Future randomized clinical trials should include this high risk population and investigate the effect of tailoring dose and duration of therapy to individual response in terms of echocardiographic findings and/or prostaglandin levels, focusing on clinically significant outcomes, including long-term neurodevelopmental outcomes. In addition, factors that may influence treatment effect, such as birth weight, gestational age, age at the time of randomization, total fluid intake, feeding practice, and severity of PDA, need to be taken into account when designing such studies.

Conservative treatment for patent ductus arteriosus in the preterm

Background: A patent ductus arteriosus (PDA) is common among preterms, and prophylactic medical treatment has been advocated as the first-line approach. Conservative treatment may result in similar outcome, but without...

Clinical Experience with Intravenous Ibuprofen Lysine in the Pharmacologic Closure of Patent Ductus Arteriosus

Patent ductus arteriosus (PDA) is the failure of the ductus that arises from the distal dorsal aortic arch to close during the first few days of life. The treatment options for PDA include "watchful waiting," pharmacologic therapy with cyclooxygenase (COX) inhibitors (COX-1 and COX-2), such as indomethacin or intravenous (IV) ibuprofen lysine, and surgery when medical interventions have proved ineffective. The clinical trials evaluating the utilization of IV ibuprofen lysine focus on either preventing the persistence of a PDA or treating the PDA in premature infants in whom the ductus does not close within 48 hours of birth. Although the role of COX inhibitors in prophylaxis of PDA has been studied, it has not been clearly delineated. Treatment of PDA in preterm low birth weight infants from the second day of life on with IV ibuprofen lysine has been studied in 4 major and 3 smaller clinical trials. Overall, in 7 studies with 492 patients, the closure rate of PDA was 75.1% with IV ibuprofen lysine compared to 73.5% with indomethacin. In addition, neonates treated with IV ibuprofen lysine had significantly better creatinine clearance, urine output, serum creatinine, and blood urea nitrogen (BUN) profiles than indomethacin-treated patients. Overall, IV ibuprofen lysine is as effective as indomethacin for closure of PDA, yet is associated with a better safety profile with fewer negative side effects when compared to indomethacin.

Indomethacin therapy for patent ductus arteriosus in premature infants: efficacy of a dosing strategy based on a second-dose peak plasma indomethacin level and estimated plasma indomethacin levels.

The objective of this study was to determine the rate of patent ductus arteriosus (PDA) closure in premature infants using an adjustable indomethacin (INDO) dosing strategy, based on a second-dose peak plasma INDO level. We conducted a retrospective review of the medical records of premature infants that were treated with INDO for a PDA, had a second dose peak plasma NDO levels, and followed predetermined guidelines for INDO dosing adjustments, over a 4-year period (1995 to 1998). Of 103 infants treated with the adjustable INDO dosing strategy, 66 (64%) achieved PDA closure whereas 37 (36%) did not. No differences in the second-dose peak plasma INDO levels (830 +/- 339 versus 702 +/- 381 ng/mL), day of life treatment was started (4 +/- 3 versus 4 +/- 2 days), or the number of doses of INDO received (4 +/- 1 versus 5 +/- 2 dose) were observed between responders and nonresponders. However, fourth-dose peak plasma INDO levels, which were available from 38 of 66 (57%) of the responders and 20 of 37 (54%) of the nonresponders, were lower in nonresponders (1553 +/- 413 versus 1829 +/- 609 ng/mL, p < 0.05). Patient demographics, including birth weight and gestational age, were similar between these groups. Using an adjustable INDO dosing strategy, based on a second-dose peak plasma INDO level and estimated plasma levels, PDA closure rates of 64% can be achieved. Although a clear relationship between INDO plasma levels and PDA closure was evident form this study, the rate of PDA closure in our study was lower than has been observed in studies with serial plasma INDO level monitoring.

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)