Patent Ductus Arteriosus Closure Rate Research Articles

Evaluation of Serum Acetaminophen Concentration Utility for Closure of Patent Ductus Arteriosus.

Acetaminophen for patent ductus arteriosus (PDA) closure has gained popularity over the last decade; however, therapeutic drug monitoring for this indication remains uncertain. The exact timing and goal trough serum acetaminophen concentration ranges are not well defined. The purpose of our study is to evaluate the impact of therapeutic drug monitoring on both PDA closure rates and identify real-world risk of hepatotoxicity. Retrospective single-center chart review of neonates admitted to the neonatal intensive care unit (NICU) between April 2016 and August 2022 with at least 1 serum acetaminophen concentration to monitor for PDA closure. Acetaminophen was initiated at 15 mg/kg administered intravenously every 6 hours and a trough serum concentration was obtained prior to the sixth or seventh dose. PDA closure was confirmed radiographically with corresponding provider documentation. Associations of efficacy to closure were -analyzed using descriptive statistics. Thirty-eight neonates were included in the analysis, of which 18 (47%) achieved PDA closure. First serum acetaminophen trough concentration was obtained before the seventh dose [IQR, 6-8] and ranged from undetectable (< 5 mg/L) to 30.8 mg/L. Subgroup analysis of first concentrations revealed therapeutic trough, defined as 10 to 20 mg/L, did not correlate to PDA closure (no closure median concentration = 14.7 [IQR, 13-15.6] vs closure median concentration = 15.4 [IQR, 11.4-18.5], p = 0.42), or duration of treatment. No neonate experienced acetaminophen-associated toxicity. PDA closure did not correlate to serum acetaminophen trough concentration. The regimen of 15 mg/kg every 6 hours appears safe as no neonate experienced acetaminophen toxicity or discontinued treatment early.

Oral Ibuprofen versus Placebo for Management of Patent Ductus Arteriosus in Preterm infants: A Double Blinded, Randomized Controlled Trial

Abstract Background A consensus on the management of patent ductus arteriosus (PDA) in premature neonates remains indefinable. Conservative PDA treatment is based on the premise that in most preterms PDAs spontaneously close before discharge. Ibuprofen has been used for treating PDA, however, no clear guidelines for management have been suggested. Aim of Work The aim of this work is to compare the effect of oral ibuprofen versus placebo on PDA closure in preterm infants less than 34 weeks’ gestation. Methodology This study was conducted on 80 preterm neonates with gestational age ≤ 34 weeks with a hemodynamically significant PDA. They were randomized into a medical treatment group (n = 40) and a placebo group (n = 40). Both groups received conservative PDA therapy in the form of fluid restriction, positive end-expiratory pressure, and/or diuretics. The medical treatment group received oral ibuprofen (at an initial dose of 10 mg/kg/day, followed by 5 mg/kg/day for the next 2 days) and the placebo group received an oral placebo. The open-label option and an extended oral ibuprofen therapy (an offered or a repeated course with the same dose) were only offered if there are concerns over a poor patient condition that was attributed to persistent PDA and only after meeting certain criteria like signs of pulmonary hyperperfusion and/or systemic hypoperfusion. Echocardiography was done on day 1 of recruitment (48-72 hours of age) and was followed up till discharge. The patients were followed up for adverse effects of ibuprofen by serum creatinine and total serum bilirubin after the first course of treatment. Results There was no significant difference in PDA closure rate following the first ibuprofen course (62.5% in the ibuprofen treated group vs 65% in the placebo group, p &amp;gt; 0.05). At discharge time (mean 13.5 days in the ibuprofen group, 14 days in the placebo group), a closure rate of 75% was achieved in both groups, respectively. There was no significant difference in initial serum creatinine levels between the two groups either on day 1 of recruitment or after the first course of the intervention, p &amp;gt; 0.05, respectively. Meanwhile, serum creatinine significantly decreased in both groups after treatment (p-value &amp;lt;0.001, respectively). Also, there was no difference between the two groups in serum bilirubin either on day 1 of recruitment or after the first course of treatment, p &amp;gt; 0.05, respectively. Conclusion Conservative treatment is not inferior to oral ibuprofen therapy in the management of PDA. Oral ibuprofen does not elevate serum creatinine levels or cause hyperbilirubinemia.

Use of echocardiography in percutaneous closure of patent ductus arteriosus at the Instituto Nacional de Salud del Niño, San Borja, Lima - Peru.

Percutaneous occlusion of patent ductus arteriosus (PDA) has classically been performed entirely by fluoroscopy, however in recent years, transthoracic echocardiography (TE) has been used as an aid to fluoroscopy or entirely by echocardiography, which avoids access of femoral artery, use of contrast and decrease in time and dose of radiation exposure. The objective of this study was to evaluate the success rate with the use of TE in percutaneous PDA closure. Descriptive, comparative, retrospective study between patients in whom PDA closure was performed with fluoroscopy plus angiography (group 1) and fluoroscopy plus ET (group 2), between January 2018 and December 2022. The data were obtained from the clinical history electronic and procedure report. One hundred eight patients were analyzed, fluoroscopy group (n: 57) and TE (n: 51). The success rate in PDA occlusion using TE was 100% and 98% for the fluoroscopy group, with no statistically significant difference The average age of group 2 was 2.9 years, while the average age of group 1 was 5 years (p=0.001), the average fluoroscopy time in group 1 was 16.9 min and 4.71 min in group 2 (p < 0.001); the fluoroscopy dose in group 1 was 68.98 mGy and 5.17 mGy in group 2 (p<0.001). Krichenko, but without significant difference in both groups. The success rate of percutaneous PDA closure using echocardiography and fluoroscopy is appropiate, with a success rate similar to the classic technique. In addition, it makes it possible to reduce the dose and time of fluoroscopy, avoid the use of contrast, and access the femoral artery.

Evaluating the Effectiveness of Ibuprofen from 2 Different Brands in Patent Ductus Arteriosus Closure in Preterm Neonates

Background: Patent ductus arteriosus (PDA) is a common condition in premature babies, with a prevalence rate of 30 - 60%, and often requires medical or surgical intervention. Objectives: This study aimed to assess the effectiveness of 2 different brands of ibuprofen in PDA closure in preterm infants weighing less than 1500 g. Methods: This single-blind clinical trial study was performed on 75 premature neonates with PDA in the pediatric ward of Vali-Asr Hospital in Birjand from March 2014 to March 2019. Patients were treated with two brands of ibuprofen at doses of 10 mg/kg for the first day and 5 mg/kg for the second and third days (24 and 48 hours afterward). Before and three days after the last dose, the children were examined by pediatric cardiologist echocardiography. The data were input into SPSS version 23 and analyzed using descriptive statistics, such as mean and SD. Inferential statistics, such as the chi-square test, were also employed with a significance level of P-value &lt; 0.05. Results: There was a significant difference between the rate of PDA closure, 78.8% in the Pedea group vs. 54.8% in the Ibuprofen group (P = 0.03). In the Ibuprofen group, there was no difference in drug efficacy in PDA closure between male and female neonates (P = 0.663). Also, in the Pedea group, there was a significant difference in terms of efficacy between male and female neonates (P = 0.049). No significant difference was observed in PDA closure between the two medications based on their sizes (P = 0.616 in small size, P = 0.266 in medium size, and P = 0.175 in large size). Conclusions: Pedea is more effective than Ibuprofen. It reduces complications and the need for surgery. However, there was no significant relationship between the two drugs based on the PDA sizes. Therefore, it seems logical to use the Iranian brand of ibuprofen, considering the benefits equal to the foreign one.

The chance of spontaneous patent ductus arteriosus closure in preterm infants born before 32 weeks of gestation is high and continues to increase until 5 years of follow-up.

The primary aim was to estimate premature infants' spontaneous patent ductus arteriosus closure rate. Secondly, to identify criteria associated with the chance of spontaneous closure. We performed a retrospective cohort study of 167 infants born before 32 weeks of gestation and diagnosed with a patent ductus arteriosus between 1 January 2008 and 31 December 2017. The spontaneous patent ductus arteriosus closure event rate was evaluated using the Kaplan-Meier estimator. The spontaneous closure rate within the first year of life was 66% (95% CI 58%-73%), increasing to 80% (95% CI 72%-86%) five years after birth. When including both spontaneous closure and closure following treatment, 96% (95% CI 86%-100%) closed within 5 years after birth. The chance of spontaneous closure was reduced in the case of a large patent ductus arteriosus: OR 0.16 (95% CI 0.05-0.52), left atrial enlargement: OR 0.16 (95% CI 0.05-0.51), and pulmonary hypertension: OR 0.23 (95% CI 0.07-0.74). The chance of spontaneous closure in premature infants born between 23 and 32 weeks of gestation was high, and the incidence continued increasing until 5 years of follow-up.

Efficacy and safety of high versus standard dose ibuprofen for patent ductus arteriosus treatment in preterm infants: A systematic review and meta-analysis.

Several small randomized controlled trials (RCTs) and observational studies have compared high (15-20/7.5-10/7.5-10 mg/kg/dose) versus standard dose (10/5/5 mg/kg/dose) ibuprofen for patent ductus arteriosus (PDA) closure, with limited evidence on efficacy and safety. To systematically review and meta-analyze studies of high versus standard dose ibuprofen for the closure of PDA in preterm infants. Databases were searched for RCTs and observational studies assessing high compared to standard dose of ibuprofen for PDA closure for preterm infants until August 2021. The primary outcome was failure of PDA closure after the first course of ibuprofen. The secondary outcomes were the failure of PDA closure after a second course of ibuprofen, rates of PDA ligation, all-cause mortality prior to hospital discharge, bronchopulmonary dysplasia, necrotizing enterocolitis, bleeding disorders, oliguria, and serum creatinine after treatment. There were 6 studies with 369 patients (3 RCT, N = 190; 3 observational studies, N = 179). Compared to standard dose, high dose ibuprofen did not significantly decrease the failure rate of PDA closure in preterm infants after the first course (Relative risk (RR) 0.74, 95% confidence interval (CI) 0.53 -1.03, 6 studies, N = 369). High dose ibuprofen significantly decreased the rates of PDA ligation compared to standard dose (RR 0.33, 95% CI 0.16 -0.70, 5 studies, N = 309). Based on low-grade evidence, high dose ibuprofen may more effectively reduce rates of PDA ligation compared to standard dose with no increase in adverse effects, neonatal morbidities and mortality.

Comparison of Ketorolac and Indomethacin for the Closure of Patent Ductus Arteriosus among Preterm Infants Born at the Philippine General Hospital: A Randomized Controlled Crossover Design

Background. Indomethacin has been the gold standard for the closure of patent ductus arteriosus (PDA). Still, the availability of the intravenous (IV) form has been a big issue precluding its use in the Philippines. IV ketorolac is another non-steroidal anti-inflammatory drug (NSAID) that is cheaper and more available in our country and used for post-cardiac surgery pain management among neonates.&#x0D; Objectives. To compare the efficacy of ketorolac versus indomethacin in the closure of patent ductus arteriosus among preterm infants.&#x0D; Methods. We conducted a randomized controlled, double-blind, crossover design, non-inferiority trial on the use of iindomethacin versus ketorolac among preterm infants with PDA. We enrolled preterm infants at 5-12 days postnatal life, diagnosed with PDA by echocardiography at the Philippine General Hospital (PGH). We excluded infants with upper gastrointestinal bleeding, renal failure, birthweight &lt; 500 grams, septic shock, and lethal anomalies. Patients were randomly allocated between two treatment groups (indomethacin versus ketorolac). The primary outcome measure was PDA closure measured after the treatment course. Adverse events like oliguria and bleeding were recorded.&#x0D; Results. A total of 27 preterm infants were randomly assigned to the indomethacin (0.2 mg/kg/dose) and ketorolac (0.6 mg/kg/dose) group. Ketorolac has a 60% success rate for PDA closure (9/15) compared to indomethacin 41.67% (5/12) (p=0.154). No renal insufficiency and bleeding diathesis were noted. Five patients died in the study, four in the group initially allocated in ketorolac and one in indomethacin. Causes of death were late-onset sepsis, bronchopulmonary dysplasia, and congenital adrenal hyperplasia.&#x0D; Conclusion. The success rate of PDA closure between IV ketorolac and IV indomethacin was not significantly different. There was neither oliguria nor bleeding observed in both groups.

Comparative safety and efficacy of paracetamol versus non-steroidal anti-inflammatory agents in neonates with patent ductus arteriosus: A systematic review and meta-analysis of randomized controlled trials.

Ibuprofen and indomethacin are the preferred drug treatment for patent ductus arteriosus (PDA) in preterm neonates. The comparative safety and efficacy of paracetamol as an alternative has not yet been well established. The aim of our study was to define the comparative efficacy and safety of paracetamol versus ibuprofen and indomethacin for PDA. We performed a systematic literature search in PubMed, Scopus and Cochrane databases on randomized controlled trials comparing the efficacy and/or the safety of paracetamol versus ibuprofen and/or indomethacin and meta-analysed the available data. There were 1718 neonates from 20 eligible studies. Paracetamol did not differ from ibuprofen or indomethacin regarding the primary (odds ratio [OR]: 0.93; 95% confidence interval [CI]: 0.69-1.26, P-value: 0.650, when compared to ibuprofen, and OR: 0.78; 95% CI: 0.20-3.02, P-value: 0.716, when compared to indomethacin) and overall (OR: 1.17; 95% CI: 0.82-1.66, P-value: 0.394, when compared to ibuprofen, and OR: 1.12; 95% CI: 0.58-2.15, P-value: 0.733, when compared to indomethacin) PDA closure rates. Paracetamol resulted in significantly reduced risk of oliguria and a tendency towards less gastrointestinal bleeding. There was no significant difference between paracetamol and ibuprofen or indomethacin in the PDA closure rates. However, paracetamol caused fewer adverse effects.

Oral versus intravenous paracetamol for patent ductus arteriosus closure in preterm infants.

To examine whether oral administration of paracetamol as a first-line agent had a greater effect on the closure of a patent ductus arteriosus than the intravenous route. We performed a retrospective study of preterm infants (<37 weeks of gestation) between 2012 and 2020 treated with oral or intravenous paracetamol as the first line for patent ductus arteriosus (PDA) constriction and compared rates of ductal closure, course duration, cumulative dose, PDA characteristics, and serum levels. Over the study period, 80 preterm infants received paracetamol, of which 50 received paracetamol as first-line treatment to augment constriction of the PDA. Closure rate was higher in the oral group (n = 15/19, 79%) compared to the intravenous group (n = 8/20, 40%, p < 0.01), and remained significant after adjusting for gestational age, length of treatment, and postnatal age (OR 0.14, 95% CI 0.03-0.67, p = 0.014, RR 0.51, 95% CI 0.28-0.91). Eleven preterm infants received a combination of both oral and intravenous paracetamol with a closure rate of 45% (n = 5). Oral administration of paracetamol as a first-line agent is more efficacious to constrict the PDA than the intravenous route, irrespective of gestational age or course duration. Our retrospective study comparing the use of oral versus intravenous paracetamol as the first line for patent ductus arteriosus (PDA) constriction in preterm infants demonstrates that oral administration of paracetamol is more efficacious to constrict the PDA than the intravenous route, irrespective of gestational age or course duration. To our knowledge, this is the first published study (prospective or retrospective) to compare the efficacy of oral versus intravenous paracetamol as a first-line treatment for PDA closure in preterm infants. Our finding may improve the rate of PDA closure when paracetamol is used as a first-line agent.

Immediate and Long-Term Results of Transcatheter Closure of Patent Ductus Arteriosus—Comparison of Two Decades before and after Change in Antibiotic Infective Endocarditis Prophylaxis Guidelines

Objectives: To determine immediate and long-term follow-up of transcatheter closure of patent ductus arteriosus (PDA) in children. Background: National antibiotic prophylaxis (AP) guideline for infective endocarditis changed after 2009, the effect on practice of PDA closure is unknown. Methods: Observational single center study analyzing follow-up of PDA closure comparing two time periods before (2002–2009) and after (2010–2019) changes in AP guideline. Results: 332 patients (68.1% female), median (interquartile range) age 3.0 years (1.5–5.7) and body weight 14.0 kg (10.0–19.3), were enrolled. PDA morphology was conical type A (50.3%), window type B (1.2%), tubular type C (40.1%), complex type D (2.1%), elongated type E (0.9%) and other (5.4%). Minimal PDA diameter and length were 1.9 mm (1.3–2.5) and 8.0 mm (6.2–10.2). PDA was closed using coils (56.3%), Amplatzer Duct Occluders (41.9%) and others (1.8%). Complete closure rate was 61.1% at catheter intervention, 72.3% on day 1, 87.7% after 6 months and 98.4% at last follow-up on echocardiography. Moderate complication rate (severity level 3) was 4.2% and major complication rate (severity level 4) 0.3%, with no catastrophic complications (severity level 5). Annual PDA closure rate declined in the second time period (22.6/year vs. 15.5/ year, p = 0.018), PDA size increased (1.6 mm vs. 2.0 mm, p = 0.002) and proportion of coils decreased (72.4% vs. 37.1%, p < 0.001). Conclusions: Interventional closure of PDA is associated with excellent closure rates during follow-up (>98%) and only a small number of complications leading to reintervention or surgery. Change in AP guidelines changed indication for and practice of PDA closure.

What Should be the First-line Treatment for the Closure of Hemodynamically Significant Patent Ductus Arteriosus in Premature Infants?

ResumoFundamento É importante saber qual medicamento usar como tratamento de primeira linha para fechar o duto.Objetivos O objetivo deste estudo é comparar a eficácia e os efeitos colaterais das formas intravenosas (IV) de ibuprofeno e paracetamol e contribuir para a literatura investigando o primeiro medicamento selecionado no tratamento clínico da persistência do canal arterial (PCA).Métodos Nosso estudo foi realizado entre janeiro de 2017 e dezembro de 2019. Foram incluídos no estudo bebês prematuros com peso ao nascer (PN) ≤1500 g e idade gestacional (IG) ≤32 semanas. No período do estudo, todos os bebês com persistência do canal arterial hemodinamicamente significativa (hsPCA) receberam ibuprofeno intravenoso (IV) como resgate como tratamento clínico primário ou tratamento com paracetamol IV se houvesse contraindicações para o ibuprofeno. Os pacientes foram divididos em dois grupos: pacientes que receberam ibuprofeno IV e pacientes que receberam paracetamol IV.Resultados Desses pacientes, 101 receberam paracetamol IV e 169 receberam ibuprofeno IV. A taxa de sucesso do fechamento da PCA com o primeiro curso do tratamento foi de 74,3% no grupo de paracetamol IV e 72,8% no grupo de ibuprofeno IV (p=0,212).Conclusões Nossos resultados mostram que o paracetamol IV é tão eficaz quanto o ibuprofeno IV no tratamento de primeira linha de hsPCA, podendo se tornar o tratamento preferencial para o controle de hsPCA.

Comparison of intravenous Paracetamol with oral Ibuprofen for medical closure of PDA (patent ductus arteriosus) in preterm newborns – can it be an effective, safe and preferable choice?

Introduction: In prematurely born newborns, the ductus arteriosus frequently fails to close and more than half of preterms might have Patent Ductus Arteriosus (PDA) after birth during the first 24hours. About 70% of infants born before 28 weeks may require medical or surgical closure of PDA. Objectives: To compare the effect of i/v PCM and oral Ibuprofen on PDA closure rate in preterm neonates with a gestational age of &gt; 37 weeks and evaluate the side effect profile of both drugs. Material and Methods: This time-bound prospective observational study for comparison of the efficacy of the two drugs on the closure of PDA in preterms admitted during 1.5 years of the study period in a neonatal ICU caring for inborn as well as outborn neonates in central India. After approval of the institutional ethics committee, initial clinical screening included all preterms but only those with PDA (open ductus arteriosus) confirmed by 2D-echocardiography were allocated to receive either of two treatment regimens (3-day courses of each oral Ibuprofen and i/v PCM) which already exist as evidence-based therapeutic practice options. Result: Out of a total of 43 cases clinically suspected on initial screening, 30 preterm babies confirmed by 2D-Echo to have PDA were finally enrolled and analysed. Twenty-one patients received i/v PCM with a resultant PDA closure rate of 85.7 % (n = 18/21), while nine cases could be allocated oral Ibuprofen arm and ductus closure was obtained in seven patients (77.78%). Although the PDA closure rate between two drug regimens was not statistically significant (p=0.593), i/v PCM resulted in slightly higher efficacy and fewer adverse effects. Conclusion: Paracetamol, preferably by the intravenous route, seems to be an effective, cheap, easily available and safe first-line alternative to oral Ibuprofen for the closure of PDA, especially in newborns with extreme prematurity, who are initially intolerant to oral feeds or drugs.

Current Controversy on Platelets and Patent Ductus Arteriosus Closure in Preterm Infants.

Platelets are critically involved in murine patent ductus arteriosus (PDA) closure. To date, the clinical significance of these findings in human preterm infants with PDA is still controversial. We discuss the available study data on the role of platelets for PDA closure in preterm infants: Several mostly retrospective studies have yielded conflicting results on whether thrombocytopenia contributes to failed spontaneous ductal closure. The same applies to investigations on the role of thrombocytopenia as a risk factor for unsuccessful ductus arteriosus closure by pharmacological treatment with cyclooxygenase inhibitors. Nonetheless, recent meta-analyses have concluded that thrombocytopenia constitutes an independent risk factor for both failed spontaneous and pharmacological PDA closure in preterm infants. However, the available investigations differ in regard to patient characteristics, diagnostic strategies, and treatment protocols. Several studies suggest that impaired platelet function rather than platelet number is critically involved in failure of ductus arteriosus closure in the preterm infant. A recent randomized-controlled trial on platelet transfusions in preterm infants with PDA failed to show any benefit for liberal vs. restrictive transfusion thresholds on PDA closure rates. Importantly, liberal transfusions were associated with an increased rate of intraventricular hemorrhage, and thus should be avoided. In conclusion, the available evidence suggests that thrombocytopenia and platelet dysfunction contribute to failure of spontaneous and pharmacological PDA closure in preterm infants. However, these platelet effects on PDA seem to be of only moderate clinical significance. Furthermore, platelet transfusions in thrombocytopenic preterm infants in order to facilitate PDA closure appear to cause more harm than good.

Safety and Efficacy of Oral and Parenteral Ibuprofen for Closure of Patent Ductus Arteriosus in Very Low Birth weight Asian Neonates - A retrospective Audit

Introduction: Patent ductus arteriosus (PDA) is common in preterm neonates. Indomethacin and ibuprofen are commonly used for medical closure of patent ductus arteriosus. This study aims to evaluate the safety and efficacy of ibuprofen for treatment of PDA in very low birth weight (VLBW) infants. Methods: A retrospective audit of VLBW infants who received ibuprofen for treatment of PDA in a single centre between March 2010 and December 2014 was conducted. Infants with hemodynamically significant PDA were treated with intravenous or oral ibuprofen after echocardiographic evaluation. Response to treatment was documented with follow up echocardiography. The baseline patient characteristics, the ductal closure rate, adverse effects and need for PDA ligation were analysed. Results: Total of 138 VLBW infants received ibuprofen. 108 infants with birth weight ranging from 430-1500g received intravenous ibuprofen (group 1) and 30 infants with birth weight ranging from 661-1483g received oral ibuprofen (group 2). The closure rate of PDA was 50.9% (55/108) in-group 1 and 43.3% (13/30) in-group 2. Necrotizing enterocolitis or spontaneous intestinal perforation was observed in 11.1% (12/108) of group 1 and 10% (3/30) of group 2 infants. PDA ligation rate was 20.4% (22/108) in-group 1 and 6.7% (2/30) in-group 2. Conclusion: The closure rate of PDA following intravenous ibuprofen was 50.9% in VLBW infants. Serious gastrointestinal adverse effects occurred in 10-11% of infants treated with ibuprofen. Relatively lower closure rates and serious gastrointestinal adverse effects should be considered when treatment decisions are made for closure of PDA with ibuprofen.

Comparison of gastrointestinal complications of paracetamol and ibuprofen in the management of infants with patent ductus arteriosus: A randomized clinical trial study

Background:Patent ductus arteriosus (PDA) is one of the more common congenital heart defects in preterm neonates. The closure of PDA can be done with ibuprofen; however, this drug is associated with many contraindications and potential side-effects. In the past years, paracetamol has been proposed for the treatment of PDA. This study was designed to evaluate the efficacy and gastrointestinal complications of paracetamol and ibuprofen for the pharmacological closure of PDA in preterm infants.Methods:In a clinical trial study, 40 preterm infants with echocardiographically confirmed PDA were randomly assigned to receive either paracetamol (n = 23; 15 mg/kg every 6 h for 2 days) or ibuprofen (n = 17; initial dose of 10 mg/kg, followed by 5 mg/kg every 12 h for 2 days). The neonates matched for gestational age and weight. We used t-test for parametric, Chi-square for categorial, and Wilcoxson for nonparametric variables. Significant level was considered less than 0.05.Results:Platelet count, BUN and creatinine levels, and closure of PDA had not significant difference between two groups (P > 0.05). Incidence and severity of GI bleeding, feeding intolerance, and NEC were significantly more in infants who received paracetamol than ibuprofen (P < 0.05).Conclusions:There were no differences in the rate of PDA closure between the two drugs, but with respect to complications, rate and severity of GI bleeding, feeding intolerance, and NEC were significantly more in infants who received paracetamol than ibuprofen. Therefore, paracetamol could not be used as a proper alternative agent for ibuprofen in the treatment of PDA in preterm infants.

A Pilot Randomized Controlled Trial of Early Targeted Patent Ductus Arteriosus Treatment Using a Risk Based Severity Score (The PDA RCT)

To evaluate the feasibility of recruiting preterm infants to a randomized controlled trial of patent ductus arteriosus (PDA) treatment based on a PDA severity score (PDAsc) and to characterize challenges in obtaining consent, compliance with the protocol, and PDA closure rates. This single-center, randomized control pilot study of 60 infants <29weeks of gestation with a high PDAsc (≥5.0) at 36-48hours of age receiving either ibuprofen or placebo intravenously. The study protocol did not allow for additional PDA therapy within the first 2weeks. We reported the rate of consent, open label treatment, and PDA closure rates. The primary outcome was chronic lung disease or death. We approached 83 families for enrollment with 73 (88%) providing consent; 13 infants had a PDAsc of <5; of the remaining infants, 30 were assigned ibuprofen and 30 received placebo. Eight infants received open label treatment in the first 2weeks (12%). The overall PDA closure rate after treatment was 57% in the intervention group and 17% in the control group (P<.01). There was no difference in the primary clinical outcome (OR, 0.8; 95% CI, 0.3-2.1). Using a PDAsc for infant recruitment to a PDA treatment randomized controlled trial is feasible. There is a high rate of consent and relatively low rate of open-label PDA treatment. The overall PDA closure rate in the intervention arm was low placing the emphasis on devising more effective PDA closure strategies in future randomized controlled trials. ISRCTN (13281214) and European Union Drug Regulating Authorities Clinical Trials Database (2015-004526-33).

A Randomized Placebo-Controlled Pilot Trial of Early Targeted Nonsteroidal Anti-Inflammatory Drugs in Preterm Infants with a Patent Ductus Arteriosus

To establish the feasibility of a future large randomized trial to compare early treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) while awaiting spontaneous patent ductus arteriosus (PDA) closure. Preterm infants at <29weeks of gestation with a PDA diameter >1.5mm and <72hours after birth were randomized to NSAIDs vs placebo. No open-label NSAID treatment was allowed in either arm, but all infants with PDA volume load received supportive management, including optimization of airway pressure, careful fluid management, and diuretics as needed. The pilot outcomes were recruitment rate and incidence of open-label treatment. Secondary clinical outcomes included chronic lung disease or death, the planned primary outcome for a future large trial. Overall, 54% of the approached parents consented to participate in the study. The median recruitment rate was 3 infants per month, and a total of 72 infants were randomized. One patient in each arm received open-label treatment. PDA closure rates were 74% for the NSAIDs arm vs 30% for the placebo arm, but this was not associated with significant changes in clinical outcomes. This pilot trial showed that recruitment of more than one-half of eligible infants with a low incidence of open-label treatment is feasible. PDA closure rates and clinical outcomes were similar to those reported in previous PDA trials.

An Observational, Prospective, Multicenter, Registry-Based Cohort Study Comparing Conservative and Medical Management for Patent Ductus Arteriosus

No consensus has been reached on which patent ductus arteriosus (PDAs) in preterm infants require treatment and if so, how, and when they should be treated. A prospective, multicenter, cohort study was conducted to compare the effects of conservative approaches and medical treatment options on ductal closure at discharge, surgical ligation, prematurity-related morbidities, and mortality. Infants between 240/7 and 286/7 weeks of gestation from 24 neonatal intensive care units were enrolled. Data on PDA management and patients' clinical characteristics were recorded prospectively. Patients with moderate-to-large PDA were compared. Among the 1,193 enrolled infants (26.7 ± 1.4 weeks and 926 ± 243 g), 649 (54%) had no or small PDA, whereas 544 (46%) had moderate-to-large PDA. One hundred thirty (24%) infants with moderate-to-large PDA were managed conservatively, in contrast to 414 (76%) who received medical treatment. Eighty (62%) of 130 infants who were managed conservatively did not receive any rescue treatment and the PDA closure rate was 53% at discharge. There were no differences in the rates of late-onset sepsis, necrotizing enterocolitis (NEC), retinopathy of prematurity, intraventricular hemorrhage (≥Grade 3), surgical ligation, and presence of PDA at discharge between conservatively-managed and medically-treated infants (p > 0.05). Multivariate analysis including perinatal factors showed that medical treatment was associated with increased risk for mortality (OR 1.68, 95% Cl 1.01–2.80, p = 0.046), but decreased risk for BPD or death (BPD/death) (OR 0.59, 95%Cl 0.37–0.92, p = 0.022). The preferred treatment options were ibuprofen (intravenous 36%, oral 31%), and paracetamol (intravenous 26%, oral 7%). Infants who were treated with oral paracetamol had higher rates of NEC and mortality in comparison to other treatment options. Infants treated before postnatal day 7 had higher rates of mortality and BPD/death than infants who were conservatively managed or treated beyond day 7 (p = 0.009 and 0.007, respectively). In preterm infants born at <29 weeks of gestation with moderate-to-large PDA, medical treatment did not show any reduction in the rates of open PDA at discharge, surgical or prematurity-related secondary outcomes. In addition to the high incidence of spontaneous closure of PDA in the first week of life, early treatment (<7 days) was associated with higher rates of mortality and BPD/death.

Use of combination therapy with acetaminophen and ibuprofen for closure of the patent ductus arteriosus in preterm neonates.

To compare effectiveness and safety of combination therapy (acetaminophen and ibuprofen) to monotherapy (ibuprofen, indomethacin, or acetaminophen alone) in treatment of the patent ductus arteriosus (PDA) in premature neonates. This was a retrospective cohort study of neonates admitted to a tertiary-level neonatal intensive care unit. Included neonates were born at <32 weeks gestation and received pharmacotherapy for PDA closure. Based on the primary therapy received, our cohort was divided into the following four groups: indomethacin alone, ibuprofen alone, acetaminophen alone, and ibuprofen and acetaminophen (in combination). Baseline characteristics, effectiveness, safety, neonatal mortality, and morbidities rates between these groups were compared. One hundred and forty neonates were analyzed; 17 received combination therapy, and 123 neonates received monotherapy: 22 (17.9%) ibuprofen, 29 (23.6%) acetaminophen, and 72 (58.5%) indomethacin. The PDA closure rates were 41.7% for indomethacin, 41.2% for combination therapy, 37.9% for acetaminophen, and 31.8% for ibuprofen (P=0.100). Rates of adverse effects were comparable between the groups. The rate of ductal closure was not different between combination therapy and monotherapy. The study did not demonstrate any increased adverse effects in the combination group. Future well-designed prospective clinical trials are needed to guide clinical practice.

The influence on renal function of ibuprofen treatment for patent ductus arteriosus in extremely low birthweight infants.

Ibuprofen (IBU) has been used recently for the treatment of patent ductus arteriosus (PDA) in Japan. We aimed to investigate the efficacy and adverse events of IBU and compare them with those of indomethacin (IND) as PDA treatment for extremely low-birthweight infants (ELBWIs), focusing on short-term renal function. A case-control study was conducted on 16 ELBWIs. The data from eligible patients were divided into two groups. Ten patients had undergone IND treatment (IND group) between January 2017 and June 2018, whereas six had undergone IBU treatment (IBU group) for PDA between July 2018 and December 2018. The IND group received 0.1mg/kg/12h IND IV infusion for three doses, whereas the IBU group received 10mg/kg IV IBU infusion followed by 5mg/kg/day for 2days. We compared the efficacy for PDA closure and renal impairment between the two groups. No significant differences in primary closure rates and the PDA ligation required were observed between the two groups. No significant differences were observed between the incidence of intraventricular hemorrhage and gastrointestinal complications in both groups. Changes in urine volume (%) in the IBU group were significantly higher than in the IND group at 24-36h post-administration. The urinary L-type fatty acid binding protein concentration level at 7days of life was significantly lower in the IBU group than in the IND group. Although IBU was comparable to IND in PDA closure rate, IBU was superior to short-term renal injury in ELBWIs.