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In preterm infants with patent ductus arteriosus, expectant management was noninferior to ibuprofen therapy with respect to necrotizing enterocolitis, bronchopulmonary dysplasia, or death at 36 weeks.

Objective Failure of closure of the patent ductus arteriosus (PDA) may be associated with harm. Early cardiac ultrasound-targeted treatment of a large PDA may result in a reduction in adverse outcomes and need for later PDA closure with no increase in adverse effects. Study design Multicentre, double-blind, placebo-controlled randomised trial. Setting Three neonatal intensive care units in Australia. Patients and interventions Eligible infants born <29 weeks were screened for a large PDA and received indomethacin or placebo before age 12 h. Main outcome Death or abnormal cranial ultrasound. Results The trial ceased enrolment early due to lack of availability of indomethacin. 164 eligible infants were screened before 12 h; of the 92 infants with a large PDA, 44 were randomised to indomethacin and 48 to placebo. There was no difference in the main outcome between groups. Infants receiving early indomethacin had significantly less early pulmonary haemorrhage (PH) (2% vs 21%), a trend towards less periventricular/intraventricular haemorrhage (PIVH) (4.5% vs 12.5%) and were less likely to receive later open-label treatment for a PDA (20% vs 40%). The 72 non-randomised infants with a small PDA were at low risk of pulmonary haemorrhage and had an 80% spontaneous PDA closure rate. Conclusions Early cardiac ultrasound-targeted treatment of a large PDA is feasible and safe, resulted in a reduction in early pulmonary haemorrhage and later medical treatment but had no effect on the primary outcome of death or abnormal cranial ultrasound. Registered Trial Australian New Zealand Clinical Trials Registry (ACTRN12608000295347).

In this prospective study, we compared the efficacy and side effects of indomethacin, ibuprofen, and paracetamol in patent ductus arteriosus (PDA) closure in preterm neonates. Three hundred preterm neonates with hemodynamically significant PDA (hs-PDA) admitted at our neonatal intensive care unit were enrolled in the study. They were randomized into three groups. Group I (paracetamol group) received 15 mg/kg/6 h IV paracetamol infusion for 3 days. Group II (ibuprofen group) received 10 mg/kg IV ibuprofen infusion followed by 5 mg/kg/day for 2 days. Group III (indomethacin group) received 0.2 mg/kg/12 h indomethacin IV infusion for three doses. Laboratory investigations such as renal function test, liver function test, complete blood count, and blood gases were conducted in addition to echocardiographic examinations. All investigations were done before and 3 days after treatment. There was no significant difference between all groups regarding efficacy of PDA closure ( P  = 0.868). There was a significant increase in serum creatinine levels and serum blood urea nitrogen (BUN) in the ibuprofen and indomethacin groups ( P  < 0.001). There was a significant reduction in platelet count and urine output (UOP) in both ibuprofen and indomethacin groups ( P  < 0.001). There was a significant increase in bilirubin levels in only the ibuprofen group ( P  = 0.003). No significant difference of hemoglobin (HB) level or liver enzymes in all groups ( P  > 0.05). Ventilatory settings improved significantly in patients with successful closure of PDA than those with failed PDA closure ( P  < 0.001). Conclusion : Paracetamol is as effective as indomethacin and ibuprofen in closure of PDA in preterm neonates and has less side effects mainly on renal function, platelet count, and GIT bleeding. What is Known: • Hemodynamically significant patent ductus arteriosus has many complications for preterm and low birth weight neonates and better to be closed. Many drugs were used for medical closure of PDA e.g. indomethacin, ibuprofen and recently paracetamol. Many studies compare safety and efficacy of paracetamol with either indomethacin or ibuprofen. What is New: • It is the first large study that compares the efficacy and side effects of the three drugs in one study.

IntroductionPatent ductus arteriosus (PDA) is the most common cardiovascular problem that develops in extremely preterm infants and is associated with poor clinical outcomes. Uncertainty exists on whether early pharmacotherapeutic treatment of a clinically symptomatic and echocardiography-confirmed haemodynamically significant PDA in extremely preterm infants improves outcomes. Given the wide variation in the approach to PDA treatment in this gestational age (GA) group, a randomised trial design is essential to address the question. Before embarking on a large RCT in this vulnerable population, it is important to establish the feasibility of such a trial.Methods and analysis Design: a multi-centre, open-labelled, parallel-designed pilot randomised controlled trial. Participants: preterm infants born <26 weeks of gestation with a PDA diagnosed within 72 hours after birth. Intervention (selective early medical treatment (SMART) strategy): selective early pharmacological treatment of a moderate-severe PDA shunt (identified based on pre-defined clinical signs and routine screening echocardiography) within the first 72 postnatal hours with provision for repeat treatment if moderate-severe shunt persists. Comparison (early conservative management strategy): no treatment of PDA in the first postnatal week. Primary outcomes: (1) proportion of eligible infants recruited during the study period; (2) proportion of randomised infants treated outside of protocol-mandated therapy. Sites and sample size: the study is being conducted in seven neonatal intensive care units across Canada and the USA with a target of 100 randomised infants. Analysis: the primary feasibility outcomes will be expressed as proportions. A pre-planned Bayesian analysis will be conducted for secondary clinical outcomes such as mortality, severe intraventricular haemorrhage, procedural PDA closure and chronic lung disease to aid stakeholders including parent representatives decide on the appropriateness of enrolling this vulnerable population in a larger trial if the feasibility of recruitment in the pilot trial is established.Ethics and disseminationThe study has been approved by the IWK Research Ethics Board (#1027298) and six additional participating sites. On the completion of the study, results will be presented at national and international meetings, published in peer-reviewed journals and incorporated into existing systematic reviews.Trial registration number NCT05011149 (WHO Trial Registration Data Set in Appendix A).Protocol versionVer 7.2 (dated July 19, 2023).

ObjectiveTo explore the efficacy and risks of oral paracetamol in later (>2 weeks old) treatment of patent ductus arteriosus (PDA).Study design A multicentre double-blind placebo-controlled randomised pilot trial in three neonatal intensive care units in Australia. Infants born <33 weeks with haemodynamically significant PDA were treated with a 5-day course of oral paracetamol or placebo. Cardiac ultrasounds were used to document haemodynamic parameters. The primary outcome analysed was ductal closure by 48 h after treatment completion. Secondary outcomes included reduction in ductal diameter >25% and safety.ResultsFifty-five infants were enrolled, of whom 27 received paracetamol and 28 placebo. Eighty percent had received previous non-steroidal anti-inflammatory drug. Mean postnatal age was 25 days. Four of the 27 ducts treated with paracetamol closed vs. 0/28 treated with placebo (p = 0.05). An additional 13/27 given paracetamol vs. 7/28 given placebo showed significant constriction (p = 0.008). No adverse effects were observed .ConclusionsThere was some evidence of increased closure with oral paracetamol at postnatal age >2 weeks; however, the overall efficacy was not high.

Background. Percutaneous occlusion under fluoroscopy guidance has become the preferred method for the treatment of patent ductus arteriosus (PDA). To avoid radiation exposure and contrast agent use, PDA occlusion under transthoracic echocardiography (TTE) guidance was conducted. Objectives. We assessed the hypothesis that the success rate of percutaneous PDA occlusion under TTE was noninferior to that under fluoroscopy guidance. Methods. In this single-center trial, 100 patients were randomly assigned in a 1 : 1 ratio to the TTE group (n = 50) or to the fluoroscopy group (n = 50). The primary endpoint was the success rate of occlusion, with the noninferiority margin set at 8% for the between-group difference in intention-to-treat analysis. Secondary endpoints were hospitalization duration, cost, procedure time, and rate of adverse events including occluder migration, hemolysis, peripheral vascular complications, and residual shunt at 1-month and 12-month follow-up. Results. Patient, defect, and device characteristics were similarly distributed between groups. The success rate of occlusion was 98% for the TTE group and 100% for the fluoroscopy group (absolute difference: −2%; 95% confidence interval: −5.9% to 1.9%). Cost and procedure duration were significantly lower in the TTE group, without adverse events in either group at a median of 12.0 months (range, 10.0–15.5 months) of follow-up. Conclusion. Percutaneous PDA occlusion can be performed via TTE guidance safely and effectively, and the success rate of the TTE-guided procedure was noninferior to that under fluoroscopy guidance, with reduced cost and procedure time. The trial is registered with http://www.chictr.org.cn (ChiCTR-ICR-15006334).

Background: Ibuprofen (IBU) has proved as effective as indomethacin in the pharmacological closure of hemodynamically significant patent ductus arteriosus (HsPDA), with an efficacy inversely related to gestational age (57-89%). Objective: This study aimed to establish whether continuous infusions of IBU could be more effective in very low birth weight infants with no additional adverse effects and reduce the need for surgical ligation. Methods: A prospective, randomized, double-dummy study was conducted on 112 very low birth weight infants (mean gestational age 27.2 weeks, SD 2; birth weight 1,019 g, SD 330) with HsPDA, 56 of whom were given IBU in conventional 15-min intermittent boluses, while the other 56 were administered IBU as a 24-hour continuous infusion, both at standard doses (10/5/5 mg/kg). Extensive echocardiography was performed before and after treatment, and adverse effects were monitored. Results: Pharmacological PDA closure was achieved after 1 or 2 IBU courses in 36 of 56 infants (64.3%) after bolus administration and in 46 of 55 (83.6%) after continuous infusion (p = 0.020), and in 9 of 26 (34.6%) and 24 of 30 (80.0%), respectively, in the infants with a gestational age of 23-27 weeks (p = 0.006). Sustained pharmacological closure was observed in 38 of 56 infants (67.9%) after bolus IBU and in 47 of 55 (85.5%) after continuous infusion (p = 0.029). Surgical ligation was used less after continuous infusion than after bolus IBU (5.5 vs. 19.6%; p = 0.024). The continuous infusion group had fewer symptoms of necrotizing enterocolitis (NEC), especially in the more preterm infants, while other neonatal morbidity and mortality rates were similar. Conclusion: Continuous IBU infusion is more effective than standard boluses for sustained closure of HsPDA, with fewer NEC symptoms and less need for surgical ligation in very low birth weight infants.

Background Patent ductus arteriosus (PDA) is one of most common complications in preterm infants. Although ibuprofen represents the first choice for the closure of PDA, this treatment can cause severe gastrointestinal and adverse renal effects and worsen platelet function. The successful closure of the PDA with paracetamol has been recently reported in several preterm infants, and the safety of paracetamol for this use has been suggested by the available data. Methods/design We present the design of a randomized, multicenter, controlled study, whose aim is to assess the effectiveness and safety of intravenous paracetamol in comparison to intravenous ibuprofen for the treatment of PDA in preterm infants. A total of 110 infants born at 25 +0 to 31 +6 weeks of gestational age will be enrolled and randomized to receive paracetamol or ibuprofen (55 patients per group) starting at 24–72 h of life. The primary endpoint of the study is the comparison of the PDA closing rate observed after a 3-day course with paracetamol or ibuprofen. The secondary endpoints include the closure rate of PDA after the second course of treatment with ibuprofen, the re-opening rate of the PDA, the incidence of surgical ligation, and the occurrence of adverse effects. Discussion The results of this study will provide new information about the possible use of paracetamol in the treatment of PDA. Paracetamol could offer several important therapeutic advantages over current treatment options, and it could become the treatment of choice for the management of PDA, mainly due to its more favorable side effect profile. Trial registration Clinicaltrials.gov NCT02422966 . Eudract no. 2013-003883-30.

Background:To date there is no firm conclusion as to the efficacy and safety of ibuprofen compared with indometacin for patent ductus arteriosus (PDA) closure in extremely premature infants.Objective:To conduct a randomised controlled trial to better address this problem.Methods:119 infants (gestational age ⩽28 weeks) with respiratory distress syndrome and PDA confirmed by echocardiography were randomly assigned to receive either indometacin (0.2 mg/kg) or ibuprofen (10 mg/kg), starting at <24 hours of life, followed by half these first doses within 48 hours at 24-hour intervals if indicated by echocardiographic PDA flow pattern.Results:The PDA closure rate and the doses of drug (mean (SD)) were similar in both groups: 53/60 (88.3%) and 1.9 (1.5) mg/kg in infants given ibuprofen, and 52/59 (88.1%) and 1.9 (1.7) mg/kg in infants given indometacin. No significant difference was found in the numbers of infants requiring surgical ligation, and the levels of post-treatment serum creatinine and urea nitrogen between the two groups. Although not significantly different, more infants (9/59 (15.3%)) treated with indometacin tended to develop oliguria (<1 ml/kg/h) than those treated with ibuprofen (4/60 (6.7%)). There were no significant differences in side effects or complications between the two groups.Conclusions:Ibuprofen is as effective as indometacin for the early-targeted PDA treatment in extremely premature infants, without increasing the incidence of complications. When the echocardiographic PDA flow pattern was used as a guide for PDA treatment, fewer doses of drugs were needed to achieve acceptable closing rates.

Purpose Smooth muscle dysfunction syndrome (SMDS) due to heterozygous ACTA2 arginine 179 alterations is characterized by patent ductus arteriosus, vasculopathy (aneurysm and occlusive lesions), pulmonary arterial hypertension, and other complications in smooth muscle–dependent organs. We sought to define the clinical history of SMDS to develop recommendations for evaluation and management. Methods Medical records of 33 patients with SMDS (median age 12 years) were abstracted and analyzed. Results All patients had congenital mydriasis and related pupillary abnormalities at birth and presented in infancy with a patent ductus arteriosus or aortopulmonary window. Patients had cerebrovascular disease characterized by small vessel disease (hyperintense periventricular white matter lesions; 95%), intracranial artery stenosis (77%), ischemic strokes (27%), and seizures (18%). Twelve (36%) patients had thoracic aortic aneurysm repair or dissection at median age of 14 years and aortic disease was fully penetrant by the age of 25 years. Three (9%) patients had axillary artery aneurysms complicated by thromboembolic episodes. Nine patients died between the ages of 0.5 and 32 years due to aortic, pulmonary, or stroke complications, or unknown causes. Conclusion Based on these data, recommendations are provided for the surveillance and management of SMDS to help prevent early-onset life-threatening complications.