Treatment Of Patent Ductus Arteriosus Research Articles

Intravenous acetaminophen (at 15 mg/kg/dose every 6 hours) in critically ill preterm neonates with patent ductus arteriosus: A prospective study.

Acetaminophen has been increasingly used in treating patent ductus arteriosus (PDA) in preterm neonates. Variations were observed in the dosing regimen of acetaminophen across the studies. There is hardly any data available for a relatively higher dose of intravenous acetaminophen (15mg/kg/dose every 6 hours) in the preterm population. We present here the results of a prospective study with this dose of intravenous acetaminophen for treating PDA in critically ill preterm neonates. Preterm neonates (≤37weeks of gestational age) with haemodynamically significant PDA were enrolled. Intravenous acetaminophen at 15mg/kg/dose every 6 hours was administered. Echocardiographic monitoring, liver and renal function tests were carried out. Standard definitions were adhered for defining acute kidney injury (AKI) and hepatotoxicity. Fifty-five neonates were recruited. Following the first dose, less than half had their serum acetaminophen concentrations in the therapeutic range. Extreme preterm neonates were less likely to have a sustained therapeutic acetaminophen concentration after the first dose. Following multiple doses and at steady state, 97.2% and 98.8% respectively were in the therapeutic range. Forty-three (78.2%) neonates had successful closure of the ductus arteriosus of which 22 were extreme preterm, 17 were very preterm and 4 were late preterm neonates; and considering their birthweights, 21 were extremely low, 16 were very low and 6 were low birthweight categories. Ten neonates had elevated alanine aminotransferase levels with three in the low-to-moderate risk of hepatotoxicity category. Eight neonates had altered renal function tests indicating AKI. Intravenous acetaminophen at 15mg/kg/dose every 6 hours was efficacious in 78.2% of the preterm neonates with PDA. We observed a lower incidence of hepatotoxicity, and AKI in the study population. No association was observed between the serum acetaminophen concentrations and PDA closure.

Study protocol: baby-OSCAR trial: Outcome after Selective early treatment for Closure of patent ductus ARteriosus in preterm babies, a multicentre, masked, randomised placebo-controlled parallel group trial

BackgroundThe question of whether to treat patent ductus arteriosus (PDA) early or wait until symptoms appear remains high on the research agenda for neonatal medicine. Around 7000 extremely preterm babies under 29 weeks’ gestation are born in the UK every year. In 40% of cases the PDA will fail to close spontaneously, even by 4 months of age. Untreated PDA can be associated with several serious and life-threatening short and long-term complications. Reliable data to support clinical decisions about PDA treatment are needed to prevent serious complications in high risk babies, while minimising undue exposure of infants. With the availability of routine bedside echocardiography, babies with a large PDA can be diagnosed before they become symptomatic.MethodsThis is a multicentre, masked, randomised, placebo-controlled parallel group trial to determine if early-targeted treatment of a large PDA with parenteral ibuprofen in extremely preterm babies (23+ 0–28+ 6 weeks’ gestation) improves short and long-term health and economic outcomes. With parental informed consent, extremely preterm babies (born between 23+ 0–28+ 6 weeks’ gestation) admitted to tertiary neonatal units are screened using echocardiography. Babies with a large PDA on echocardiography, defined by diameter of at least 1.5 mm and unrestricted pulsatile PDA flow pattern, are randomly allocated to either ibuprofen or placebo within 72 h of birth. The primary endpoint is the composite outcome of death by 36 weeks’ postmenstrual age or moderate or severe bronchopulmonary dysplasia (BPD) at 36 weeks postmenstrual age.DiscussionProphylactic pharmacological treatment of all preterm babies unnecessarily exposes them to potentially serious side effects of drug treatment, when their PDA may have closed spontaneously. However, delaying treatment until babies become symptomatic could result in loss of treatment benefit as irreversible damage may have already been done.Targeted, early pharmacological treatment of PDA in asymptomatic babies has the potential to overcome the disadvantages of both prophylactic (overtreatment) and symptomatic approaches (potentially too late). This could result in improvements in the clinically important short-term clinical (mortality and moderate or severe BPD at 36 weeks’ postmenstrual age) and long-term health outcomes (moderate or severe neurodevelopment disability and respiratory morbidity) measured at 2 years corrected age.Trial registrationISRCTN84264977. Date assigned: 15/09/2010.

Predictive Model of Early Spontaneous Ductus Arteriosus Closure Based on Neonatologist Performed Echocardiography in Preterm Infants.

Background: Patent ductus arteriosus (PDA) treatment remains controversial. Modeling on the predictive capacity of early spontaneous PDA closure would help in decision-making.Aim: To design a predictive model of early spontaneous PDA closure.Methods: As part of a trial to assess efficacy and safety of two ibuprofen treatment schemes for PDA, infants below 29 weeks' gestation were scanned between 18 and 72 h of birth, and serially if indicated. PDA treatment was decided based on echocardiography signs of lung overflow or systemic hypoperfusion and clinical criteria. A PDA score that included the echocardiographic parameters significantly associated with treatment prescription was retrospectively applied. Perinatal variables and screening score were included in a backwards elimination model to predict early spontaneous closure.Results: Among 87 eligible infants (27 weeks' gestation; age at screening 45 h), 21 received ibuprofen at 69 h of life [screening score = 7 (IQR = 5–8.5); score at treatment = 9 (IQR = 8–9)], while 42 infants had conservative management, [screening score = 1 (IQR = 0–4)]. Twenty four infants were excluded (ibuprofen contraindication, declined consent or incomplete echocardiography). Screening score showed an AUC = 0.93 to predict early spontaneous PDA closure, [cut-off value = 4.5 (sensitivity = 0.90, specificity = 0.86)]. The predictive model for early spontaneous PDA closure followed the equation: Log (p/1-p) = −28.41 + 1.23* gestational age −0.87* PDA screening score.Conclusions: A predictive model of early spontaneous PDA closure that includes gestational age and the screening PDA score is proposed to help clinicians in the decision- making for PDA treatment. In addition, this model could be used in future intervention trials aimed to prevent PDA related morbidities to improve the eligibility criteria.

Bevacizumab and neurodevelopmental outcomes of preterm infants with retinopathy of prematurity: should we still worry?

Aim Bevacizumab may affect preterm infants’ ongoing organogenesis with its antiangiogenic effects. We aimed to compare neurodevelopmental outcomes (NDO) of preterm infants treated for retinopathy of prematurity (ROP) with laser photocoagulation (LP), intravitreal bevacizumab (IVB) or both treatments, and to find out the effects of IVB on NDO. Methods Medical records of preterm infants with ROP treatment and evaluation for NDO were retrospectively collected between 1 January 2017 and 31 June 2019. Primary outcome was Bayley Scales of Infant and Toddler Development 3rd Edition (Bayley-III) scores including cognitive, language, and motor scores. Secondary outcomes were neurodevelopmental impairments (NDIs) classified as the presence of any of cerebral palsy (CP), sensorineural/mixed hearing loss, visual impairment, and developmental delay with any Bayley-III score <85. Severe NDI (sNDI) was defined as presence of any of CP with a Gross Motor Function Classification Scale of 3, 4, or 5, requirement for hearing aids or cochlear implants, bilateral visual impairment or severe developmental delay with any Bayley-III score <70. Results LP, IVB, and IVB + LP groups included 32, 12, and 10 patients, respectively. Patent ductus arteriosus treatment rates were as 68.7, 75, and 90% in groups, respectively (p<.05 between LP and IVB + LP groups). Grades 3 and 4 intraventricular hemorrhage (IVH) was lower in LP group than IVB group (9.4% vs. 33.4%, p<.05) while IVB + LP group had no grades 3 and 4 IVH. Other neonatal characteristics were similar (p > .05). CP was in 50%, 28%, and 0% of LP, IVB, and IVB + LP groups (p<.05). There was no difference in median Bayley-III cognitive, language, and motor scores between groups (p > .05). Moderate and severe developmental delays were similar between groups (p > .05) whereas IVB group had more moderate cognitive delay; and more severe cognitive, language, and motor delay. NDI rate was not different (59.3%, 50%, and 40% in groups, p > .05). sNDI was highest in IVB group but not statistically significant (31.2, 41.7, and 10% in groups, p > .05). Multiple logistic regression analysis showed that ROP treatment type and grades 3 and 4 IVH did not have any significant effect on NDO (p > .05). Odds of NDI was not effected by ROP treatment type (p > .05). Conclusions Patients treated with bevacizumab should be carefully monitored for neurodevelopmental problems, although the frequency of grades 3 and 4 IVH in the bevacizumab group is thought to contribute to higher rates of sNDI and Bayley-III score <70.

Acetaminophen and the Developing Lung: Could There Be Lifelong Consequences?

Acetaminophen and the Developing Lung: Could There Be Lifelong Consequences?

Прогностична цінність концентрації NT-proBNP у сироватці крові значно недоношених немовлят щодо гемодинамічної значущості відкритої артеріальної протоки

Hemodynamically significant patent ductus arteriosus (PDA) is a common complication in very preterm infants born at less than 32 weeks of gestation. At the same time, currently, there are no uniform criteria to identify the actual hemodynamic significance of PDA and generally accepted management approaches to such infants. Purpose — to assess the predictive value of serum N-terminal pro-brain natriuretic peptide (NT-proBNP) levels for hemodynamically significant PDA in very preterm infants. Materials and methods. Fifty-two preterm infants with gestational age &lt;32 weeks, chronological age &lt;72 h, and PDA diameter &gt;1.5 mm were involved in a randomized study. Twenty-seven (52%) of them were treated with ibuprofen or paracetamol starting within the first 3 days of life. Expectant management was applied to 25 (48%) infants. All patients underwent daily echocardiographic and two serum NT-proBNP measurements within the first 10 days after birth. According to the results of echocardiographic and clinical monitoring, 2 groups of patients were formed retrospectively. In 22 (42%) of them hemodynamically significant PDA (hsPDA) was diagnosed, and 30 (58%) had hemodynamically insignificant ductus arteriosus. Results. The percentage of infants who received pharmacological PDA treatment was not significantly different between the groups (p&gt;0.05). Serum NT-proBNP concentrations at the median age of 2 and 8 days were significantly higher in infants with hsPDA (p&lt;0.01). By the eighth day of life, the NT-proBNP level in both groups significantly decreased but remained considerably higher in newborns with hsPDA. Serum NT-proBNP concentrations on the second-third day of life could reliably predict hsPDA (AUC=0.93; 95% confidence interval: 0.86–1.0; p&lt;0.05). Conclusions. Serum NT-proBNP concentrations on the second day of life &gt;12000 pg/ml could reliably predict hsPDA. The research was carried out in accordance with the principles of the Helsinki Declaration. The study protocol was approved by the Local Ethics Committee of these Institutes. The informed consent of the patient was obtained for conducting the studies. No conflict of interest was declared by the authors. Key words: hemodynamically significant patent ductus arteriosus, PDA, NT-proBNP, prognostic value, very preterm infants.

Transcatheter patent ductus arteriosus closure: what have we learned after over 25 years? A single--center experience with 1036 patients.

Transcatheter patent ductus arteriosus (PDA) closure has become the first‑choice method of treatment in the majority of patients. However, device selection poses a challenge. This study aimed to analyze periprocedural and 1‑year outcomes of PDA transcatheter closure performed with different devices throughout a 25‑year time period in a single center. All 1036 patients who underwent transcatheter PDA closure between 1993 and 2020 were included in retrospective analysis. Various devices were used: the Rashkind device (RD; n = 25), coils (n = 469), nitinol duct occluders type I (DO I; n = 300), type II (n = 32), type II additional sizes (ADO II AS; n = 209), as well as off‑label devices: vascular plugs and atrial septal and muscular ventricular septal defect occluders (n = 17). Data on 24‑hour and 1‑year follow‑up were available for 100% and 78.9% of the study patients, respectively. The procedure was successful in 98.6% of the study patients, with a major complication rate of 0.2%. Complete PDA closure after a year was observed in 81.8% of the patients treated with RD, 93.7% of those with coils, and 100% of those with duct occluders. There were no differences between Amplatzer DO I (n = 159) and its DO I copies manufactured in China (n = 141) with regard to success, efficacy, and complication rates. Recently, ADO II AS has replaced coils and become the preferred device to close small‑to‑moderate PDA. Transcatheter PDA closure with all types of nitinol duct occluders is safe and effective, with no residual shunting at 1‑year follow‑up. Due to higher efficacy, ADO II AS has replaced coils in the treatment of smaller PDA.

Selective Treatment of PDA in High-Risk VLBW Infants With Birth Weight ≤800 g or

Background: Patent ductus arteriosus (PDA) causing significant left to right shunt can increase key morbidities in preterm infants. Yet, treatment does not improve outcomes and spontaneous closure is the natural course of PDA. The Impact of PDA on 23–26-week gestation infants is uncertain. Selective treatment of such infants would likely balance outcomes.Objective: To test the hypothesis that treatment of PDA in high-risk VLBW infants [birth weight ≤800 g or gestation <27 weeks, hemodynamically significant, ductal diameter (DD, ≥1.6 mm), and mechanical ventilation] and expectant management in low-risk infants will reduce the need for treatment and surgical ligation, without altering short term morbidities.Methods: This prospective observational study was initiated subsequent to the introduction of a new treatment protocol in 2016. The 12-months before and after protocol introduction were, respectively, defined as standard and early selective treatment periods. In the early selective treatment cohort, PDA was treated with indomethacin, maximum of two courses, 1 week apart. Surgical ligation was considered after 30 days of age if indicated (DD ≥2 mm, mechanical ventilation). Primary outcomes were need for treatment and rate of ligation. Protocol compliance and secondary outcomes were documented.Results: 415 infants were studied, 202 and 213 in the standard treatment and early selective treatment cohorts, respectively. Numbers treated (per protocol) in the standard treatment and early selective treatment cohorts were 27.7 and 19.3% (56/202 and 41/213) (p = 0.049), and the respective ligation rates were 7.54 and 2.96% (P = 0.045). Secondary outcomes were comparable.Conclusion: The early selective treatment protocol reduced the rates of treatment and surgical ligation of PDA, without altering key morbidities. Further studies under a randomized control trial setting is warranted.

The perfusion index histograms predict patent ductus arteriosus requiring treatment in preterm infants.

The impact of patent ductus arteriosus (PDA) on vital sign trends represented as histograms, and perfusion index in particular, is unknown. This study aimed to split continuously obtained PI and other vital signs before, during, and after medical treatment of PDA, into histogram bins, and determine the utility of PI and other vital sign histograms in the early prediction of hemodynamically significant PDA (hsPDA). In 34 infants at a mean gestational age of 26 ± 2.1weeks, we prospectively collected vital signs for three different periods, 24h before starting treatment of PDA, during PDA treatment, and 24h after completion of the course of treatment, and confirmed PDA closure by echo. Histograms with three comparable periods were obtained from preterm infants who did not require treatment for PDA and analyzed for comparison. The duration of time spent in each histogram bin was determined for each time epoch. Episodes of low PI < 0.4 and high PI > 2 were significantly longer in duration in infants with PDA before treatment compared to those in infants with PDA during and after treatment. The arterial oxygen saturation (SpO2) < 80% was also longer in duration in infants with PDA before compared to that in infants with PDA during and after treatment. Low PI < 0.4 correlated with most echocardiography indices of hsPDA.Conclusion: We conclude that a patent ductus arteriosus requiring treatment in preterm infants ≤ 29weeks GA was associated with significant fluctuations between a low PI < 0.4 alternating with a high PI > 2, reflecting the dynamic nature of hsPDA shunt volume. PI variability may be an early marker of hsPDA. What is Known: • The perfusion index is a continuous underutilized parameter provided by pulse oximetry to assess the peripheral perfusion. • The perfusion index helps predict conditions with hemodynamic instability. What is New: • The perfusion index assessed as daily histogram trends can predict patent ductus arteriosus requiring treatment.

Comparação entre os anti-inflamatórios não esteroidais para o tratamento da persistência do canal arterial: uma revisão integrativa

Objetivo: Comparar o uso dos anti-inflamatórios não esteroidais no tratamento farmacológico da persistência do canal arterial. Métodos: Trata-se de uma revisão integrativa, realizada em revistas indexadas na base de dados PubMed. A estratégia de busca foi realizada utilizando os descritores em inglês “Anti-Inflammatory Agents”, “Ductus Arteriosus, Patent” AND “Drug Therapy”. Resultados: Ao utilizar os descritores em conjunto, foram encontradas 972 publicações. Destas, foram selecionadas 758 que apresentavam o texto na íntegra e disponível online, 132 relativos ao ano da publicação (entre 2010 e 2020) e a espécie humana. Após a seleção por uma triagem dos títulos e resumos restaram apenas 9 artigos elegíveis. Considerações Finais: Dessa forma, é necessário que o médico conheça o melhor tratamento farmacológico, visto que estes podem trazer efeitos colaterais graves além da possibilidade de variar a sua eficácia de acordo com alguns parâmetros. Isso mostra a importância desse tema e a necessidade de mais estudos que possam determinar o melhor fármaco para o tratamento da doença.

Patent Ductus Arteriosus Clinical Trials: Lessons Learned and Future Directions

The identification of an optimal management strategy for the patent ductus arteriosus (PDA) in the context of extreme prematurity remains elusive. Observational studies have reported a persistent association between PDA and neonatal adverse outcomes, but by and large, no clinical trial, to date, has demonstrated that treating a PDA results in a reduction of those morbidities. This discrepancy has led many to assume that the PDA is an innocent bystander in the physiological mechanisms responsible for such complications and a reluctance to actively pursue shunt elimination. It would be remiss to discount the volume of evidence available clearly documenting a strong association between longstanding PDA exposure and negative outcomes. There needs to be a radical change in the design, patient selection and possible outcome assessment in any further trials addressing the PDA. The purpose of this review is to explore the reasons that preclude existing clinical trials from definitively ascribing a causal relationship between PDA patency and adverse outcomes in the context of extreme prematurity, why previous studies have failed to demonstrate significant beneficial effects following PDA treatment and how future research may be conducted to allow us to draw concrete conclusions regarding the potential merits of ductal closure.

The Comparison Between Intravenous Acetaminophen Versus Oral Ibuprofen in Preterm Newborns With Patent Ductus Arteriosus: A Clinical Trial

Oral ibuprofen has been known as a conventional treatment for closing patent ductus arteriosus (PDA) in preterm newborns. Since the use of it might lead to various side effects, other treatments needed to be evaluated. Therefore in a prospective study, we compared the efficacy and safety of intravenous acetaminophen versus oral ibuprofen for the closure of PDA. In this study which was done prospectively and under control, 50 preterm neonates with gestational ages and weights less than 37 weeks old and 2500 grams, respectively, who had PDA, large enough hemodynamically, were included in the study. The patients were divided into two groups: A (intravenous acetaminophen) &amp; B (oral ibuprofen). The two groups were given at most two 3-day courses of the medication (the second course if necessary) and evaluated at the end of each course by echocardiography so as to determine the response to the treatment at each step. The rate of ductal closure, the need for additional treatment, side effects, complications and the newborn’s clinical status were recorded. The rate of ductal closure in the both groups after one course of treatment was similar and showed no meaningful significance statistically (P=0.306). But that of the side effects was much higher in group B with a P=0.021. Intravenous Acetaminophen is not only as efficacious as oral Ibuprofen for the treatment of PDA in preterm infants, but also is less likely to lead to side effects and complications.

Factors affecting the effectiveness of oral ibuprofen in the treatment of patent ductus arteriosus in preterm infants.

Background Data on the effectiveness of oral ibuprofen treatment for patent ductus arteriosus are limited, and the factors affecting its effectiveness remain unclear. Objective The aim was to identify the potential factors affecting the clinical effectiveness of oral ibuprofen in preterm infants. Setting Neonatal intensive care unit in a prefecture-level maternal and child healthcare hospital in China. Method Over a 5-years period, the medical records of 327 preterm infants with patent ductus arteriosus who were admitted to the neonatal intensive care unit of our hospital to receive a single course of oral ibuprofen were retrospectively reviewed. Main outcome measures The prevalence of risk factors affecting the effectiveness of oral ibuprofen. Results In total, 201 (61.47%) preterm infants were considered to have undergone "effective therapy" and classified accordingly, whereas 11 (3.36%) showed certain adverse events. Factors affecting therapeutic effectiveness were postnatal age at the initiation of treatment and Day 1/Day 0 ratio of urine output/fluid intake during the treatment course, with odds ratios of 0.892 (95% CI: 0.835-0.953; P = 0.001) and 0.473 (95% CI 0.265-0.845; P = 0.011), respectively. Conclusion A single course of oral ibuprofen for patent ductus arteriosus closure among preterm infants is effective and safe. Preterm infants with postnatal age of ≤ 9days at the initiation of treatment and Day 1/Day 0 ratio of ≤ 0.708 of the urine output/fluid intake during the treatment course can be considered predictors of effectiveness of patent ductus arteriosus.

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.

Worse outcomes of early targeted ibuprofen treatment compared to expectant management of patent ductus arteriosus in extremely premature infants

Aims: The aim of the study is to evaluate two different patent ductus arteriosus (PDA) management approaches and their impact on neonatal mortality and/or bronchopulmonary dysplasia (BPD) and 2-year outcomes. Subjects and Methods: For two consecutive periods, data on early mortality and morbidity were obtained retrospectively, while long-term morbidity data in children born before 28 weeks of gestation were collected prospectively. In the early targeted treatment period (TTP), ibuprofen was early indicated on patients with high clinical risk and PDA diameter of more than two millimeters in the first 3 days. In the expectant treatment period (EXP), the expectant approach was used. Results: A total of 201 eligible infants were screened. Of these, 99 were managed in the TTP and 102 in the EXP. From 99 infants in the TTP, 24 patients were treated early and 17 later. From 102 infants in the EXP, 17 infants with symptomatic PDA were treated. Severe BPD and/or death were more frequent in the TTP as compared to EXP (28 and 16 infants, respectively; P = 0.007; odds ratio = 2.12; confidence interval = 1.06–4.23; c = 0.216). Moreover, infants who underwent the expectant approach did not need further cardiological interventions after discharge. Conclusions: Early targeted treatment of large PDAs was associated with an increased risk of severe BPD and/or death. We must pay attention to the side effects of early ibuprofen treatment because these may outweigh the benefits of ductus closure, especially in the vulnerable population of extremely preterm infants.

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.

A new therapeutic target for patent ductus arteriosus

The ductus arteriosus (DA) maintains the fetal circulation by connecting the aorta and pulmonary arteries. Patent ductus arteriosus (PDA) occurs in >70% extremely-low-birth-weight infants. Patients with PDA exhibit circulatory failure, which is caused by left-to-right shunt. The DA immediately contracts after birth in response to the elevation of blood oxygen tension and to the decline in circulating prostaglandin E2 (PGE2). Cyclooxygenase inhibitors targeting smooth muscle cell (SMC) contraction represent only pharmacological treatment for PDA. However, it is important for DA anatomical closure that intimal thickening (IT) is appropriately formed between SMC layer and endothelial cells (EC). IT begins to form before the second-trimester and becomes prominent toward the end of third-trimester as an increase in placenta-derived PGE2. Immature DAs frequently fail to be close due to poorly formed IT. IT consists of extracellular matrices (ECM) and migrated DA-SMCs from the tunica media. A glycoprotein fibulin-1 is expressed in developing cardiovascular system and binds to multiple ECMs. We found that PGE2 increased fibulin-1 via EP4 in DA-SMCs, and Fbln1-deficient mice exhibited PDA with poor IT formation. Although EP4 is a Gs-coupled GPCR, fibulin-1 was secreted from DA-SMCs through the phospholipase C-protein kinase C-non-canonical NFκB signaling pathway. Fibulin-1 bound to DA-EC-derived versican which is a binding partner of hyaluronan, which promoted directional DA-SMC migration toward ECs and contributed to IT formation in the DA. Fibulin-1 upregulation by the activation of specific downstream pathway of EP4 may serve a new pharmacological strategy for PDA.

Effect of Early Targeted Treatment of Ductus Arteriosus with Ibuprofen on Survival Without Cerebral Palsy at 2 Years in Infants with Extreme Prematurity: A Randomized Clinical Trial

Objective To examine the effects of early echocardiography-targeted ibuprofen treatment of large patent ductus arteriosus (PDA) on survival without cerebral palsy at 24 months of corrected age. Study design We enrolled infants born at <28 weeks of gestation with a large PDA on echocardiography at 6-12 hours after birth to ibuprofen or placebo by 12 hours of age in a multicenter, double blind, randomized-controlled trial. Open-label ibuprofen was allowed for prespecified criteria of a hemodynamically significant PDA. The primary outcome was survival without cerebral palsy at 24 months of corrected age. Results Among 337 enrolled infants, 109 had a small or closed ductus and constituted a reference group; 228 had a large PDA and were randomized. The primary outcome was assessed at 2 years in 108 of 114 (94.7%) and 102 of 114 (89.5%) patients allocated to ibuprofen or placebo, respectively. Survival without cerebral palsy occurred in 77 of 108 (71.3%) after ibuprofen, 73 of 102 (71.6%) after placebo (adjusted relative risk 0.98, 95% CI 0.83-1.16, P = .83), and 77 of 101 (76.2%) in reference group. Infants treated with ibuprofen had a lower incidence of PDA at day 3. Severe pulmonary hemorrhage during the first 3 days occurred in 2 of 114 (1.8%) infants treated with ibuprofen and 9 of 114 (7.9%) infants treated with placebo (adjusted relative risk 0.22, 95% CI 0.05-1.00, P = .05). Open-label rescue treatment with ibuprofen occurred in 62.3% of infants treated with placebo and 17.5% of infants treated with ibuprofen (P < .001), at a median (IQR) age of 4 (3, 5) and 4 (4, 12) days, respectively. Conclusions Early echocardiography-targeted ibuprofen treatment of a large PDA did not change the rate of survival without cerebral palsy. Trial registration Eudract 2011-003063-30 and ClinicalTrials.gov: NCT01630278. To examine the effects of early echocardiography-targeted ibuprofen treatment of large patent ductus arteriosus (PDA) on survival without cerebral palsy at 24 months of corrected age. We enrolled infants born at <28 weeks of gestation with a large PDA on echocardiography at 6-12 hours after birth to ibuprofen or placebo by 12 hours of age in a multicenter, double blind, randomized-controlled trial. Open-label ibuprofen was allowed for prespecified criteria of a hemodynamically significant PDA. The primary outcome was survival without cerebral palsy at 24 months of corrected age. Among 337 enrolled infants, 109 had a small or closed ductus and constituted a reference group; 228 had a large PDA and were randomized. The primary outcome was assessed at 2 years in 108 of 114 (94.7%) and 102 of 114 (89.5%) patients allocated to ibuprofen or placebo, respectively. Survival without cerebral palsy occurred in 77 of 108 (71.3%) after ibuprofen, 73 of 102 (71.6%) after placebo (adjusted relative risk 0.98, 95% CI 0.83-1.16, P = .83), and 77 of 101 (76.2%) in reference group. Infants treated with ibuprofen had a lower incidence of PDA at day 3. Severe pulmonary hemorrhage during the first 3 days occurred in 2 of 114 (1.8%) infants treated with ibuprofen and 9 of 114 (7.9%) infants treated with placebo (adjusted relative risk 0.22, 95% CI 0.05-1.00, P = .05). Open-label rescue treatment with ibuprofen occurred in 62.3% of infants treated with placebo and 17.5% of infants treated with ibuprofen (P < .001), at a median (IQR) age of 4 (3, 5) and 4 (4, 12) days, respectively. Early echocardiography-targeted ibuprofen treatment of a large PDA did not change the rate of survival without cerebral palsy.

Early targeted patent ductus arteriosus treatment in premature neonates using a risk based severity score: study protocol for a randomised controlled trial (PDA RCT).

A patent ductus arteriosus (PDA) in preterm infants is associated with increased ventilator dependence and chronic lung disease, necrotizing enterocolitis, intraventricular haemorrhage, and poor neurodevelopmental outcome. Randomised controlled trials of early PDA treatment have not established a drop in the aforementioned morbidities. Those trials did not physiologically categorise PDA severity. Incorporating the specific physiological features of a haemodynamic significant PDA may evolve our understanding of this phenomenon, allowing accurate triaging using echocardiography and targeted treatment. Our group has recently demonstrated that a PDA severity score (PDAsc) derived at 36-48 hours of age can accurately predict the later occurrence of chronic lung disease or death (CLD/Death). Using echocardiography, we assessed PDA characteristics, as well as left ventricular diastolic function and markers of pulmonary overcirculation, and from this formulated a PDAsc. Gestation was also incorporated into the score. We hypothesise that in preterm infants at high risk of developing CLD/Death based on a PDAsc, early treatment with Ibuprofen compared with placebo will result in a reduction in CLD/Death. This is a single centre double-blind two arm randomised controlled trial conducted in the neonatal intensive care unit in the Rotunda Hospital, Dublin. Echocardiogram is carried out in the first 36-48 hours of life to identify preterm infants with a PDAsc ≥ 5.0 and these infants are randomised to Ibuprofen or placebo. Primary outcomes are assessed at 36 weeks post menstrual age. This pilot study's purpose is to assess the feasibility of performing the trial and to obtain preliminary data to calculate a sample size for a definitive multi-centre trial of early PDA treatment using a PDAsc. We aim to recruit a total of 60 infants with a high risk PDA over three years. Trial Registration: ISRCTN ISRCTN13281214 (26/07/2016) and the European Union Drug Regulating Authorities Clinical Trials Database 2015-004526-33 (03/12/2015).

Association between changes in urine output and successful indomethacin treatment for patent ductus arteriosus in preterm neonates.

To investigate the relationship between changes in urine output during indomethacin treatment and ductal closure in preterm neonates. It is a retrospective study in neonates ≤32 weeks who had received two courses of indomethacin for PDA treatment over a 5-year period. Indomethacin courses with pre- and post-echocardiography confirmation of PDA status were included. Various urine output indices were collected and compared between successful versus unsuccessful indomethacin courses. Indomethacin treatment success was defined as: (i) where PDA closed or became haemodynamically insignificant (hisPDA) after treatment and (ii) only including neonates where PDA had complete closure after treatment. ROC analysis was performed to examine predictive ability of urine output during indomethacin for treatment success. One hundred and eight indomethacin courses (first course: 52, second course: 56) in 80 neonates were included. The mean gestational age and birthweight were 25.4 ± 1.3 weeks and 762 ± 165 g, respectively. Irrespective of the definition used, there was no significant differences seen in any of urine output parameters between groups, except for a higher urine output during indomethacin associated with complete PDA closure (3.6 ± 1.3 vs. 3.0 ± 1.0 mL/kg/h, P = 0.02). The incidence of significant oliguria, hyponatraemia and need to withhold/delay indomethacin doses were also similar across groups. Urine output was not a useful predictor of ductal response to indomethacin treatment in preterm neonates.