Furosemide for patent ductus arteriosus during cyclooxygenase inhibitor therapy: A systematic review.

BACKGROUND: Although furosemide is used during cyclooxygenase (COX) inhibitor therapy for patent ductus arteriosus (PDA), there are concerns regarding increased ductal closure failure and acute renal failure (ARF). This systematic review explores the effects of furosemide during COX inhibitor therapy. METHODS: We searched MEDLINE, Embase, Cumulative Index to Nursing and Allied Health Literature, Cochrane Central Register of Controlled Trials, and Igaku Chuo Zasshi databases for randomized clinical trials that assessed furosemide during COX inhibitor therapy for PDA in preterm infants. The primary outcome measure was PDA closure failure. Mortality and other complications were also assessed. The risk of bias was assessed using the Cochrane risk-of-bias tool for randomized control trials, and the certainty of evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation criteria. RESULTS: Overall, three trials involving 121 patients were included in the analysis. The overall incidence of PDA closure failure was 28%. Although the result of PDA closure failure, mortality, and ARF were obtained, other outcomes were not described in any of the studies. The risk of bias was high. The risk of PDA closure failure did not increase with furosemide administration. Furosemide was not associated with decreased mortality but was associated with an increased risk of ARF (risk ratio, 4.96 [95% confidence interval: 1.80-13.6]). The certainty of evidence for all outcomes was very low. CONCLUSION: Although furosemide is not associated with an increased risk of PDA closure failure or mortality, the risk of ARF increases after furosemide administration during COX inhibitor therapy.

Hemodynamically significant patent ductus arteriosus profile in preterm neonates (26-34 weeks' gestation) undergoing surfactant replacement therapy in India: a prospective observational study.

Surfactant administration significantly improves respiratory outcomes in preterm infants with respiratory distress syndrome (RDS). However, surfactant administration may lead to hemodynamic alterations, particularly in the heart, affecting the patent ductus arteriosus (PDA), the consequences of which are not fully understood. This prospective observational study took place in an Indian neonatal care unit from July 2019 to November 2020, enrolling preterm neonates (26-34 weeks' gestation) with RDS needing non-invasive positive pressure ventilation. They were divided into two groups: those who received surfactant while on respiratory support and those who did not. All newborns in the study had an initial echocardiogram within 24 h to detect PDA flow. Subsequent echocardiograms were conducted between 48 and 72 h or earlier based on symptoms. Of 220 infants requiring respiratory support, 84 were enrolled, with 42 in each group. While demographic variables were similar, the surfactant group had a lower median gestational age (29.0 vs. 31.0 weeks). In the surfactant group, a significantly higher percentage of neonates had hemodynamically significant PDA (hsPDA) compared to the non-surfactant group (54.76% vs. 26.19%, P-value = .008). Multiple logistic regression found no significant association between gestation, birth weight, or shock and hsPDA occurrence. Pulmonary hemorrhage occurred more often in the surfactant group. Bronchopulmonary dysplasia (BPD), intraventricular hemorrhage (IVH) > grade 2, and necrotizing enterocolitis (NEC) ≥ grade 2 did not differ significantly between the groups. Surfactant therapy via the less invasive surfactant administration technique was associated with a higher incidence of hsPDA. While surfactant is crucial for neonatal respiratory care, its potential hemodynamic effects, including hsPDA, should be considered.

Efficacy of paracetamol in the management of hemodynamically significant patent ductus arteriosus in preterm newborns.

OBJECTIVE: The objective is to determine the efficacy and safety of paracetamol in preterm babies with hemodynamically significant patent ductus arteriosus (hsPDA). BACKGROUND: In preterm babies, patent ductus arteriosus, when hemodynamically significant, causes considerable morbidity and mortality and also affects 20% of very low birth weight infants. Medical therapy is the mainstay of treatment. Currently used drug cyclooxygenase inhibitor has multiple serious adverse effects, including gastrointestinal perforation, bleeding, and renal failure. Hence, an alternative drug like paracetamol has been proposed for the treatment of hsPDA for fewer side effects. Hence, we used paracetamol in our neonatal intensive care unit in preterm neonates with hsPDA. METHODS: A total of 14 preterm babies diagnosed to have hsPDA on clinical and echocardiographic evaluation in neonatal ICU on days 3-14 of life during 13 months were included. Birth weight was between 1000 g and 1650 g and gestation was between 28 weeks and 33 weeks. Paracetamol in a dose of 15 mg/kg/dose every six hourly given to all the included babies for 3 days and re-evaluated echocardiographically after 3 days of treatment. RESULTS: In 12 (86%) out of 14 cases, PDA was closed, whereas in 2 (14%) hemodynamic closure with insignificant residual flow was achieved. Paracetamol was effective in 100% of cases. No adverse event was observed during treatment. CONCLUSIONS: Paracetamol is a very safe and efficacious drug for treating hemodynamically significant patent ductus arteriosus in premature babies.

Selective early medical treatment of the patent ductus arteriosus in extremely low gestational age infants: a pilot randomised controlled trial protocol (SMART-PDA).

INTRODUCTION: Patent 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 DISSEMINATION: The 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 VERSION: Ver 7.2 (dated July 19, 2023).

Acetaminophen for Patent Ductus Arteriosus and Risk of Mortality and Pulmonary Morbidity.

OBJECTIVE: Emerging data indicate that acetaminophen may adversely affect lung health. We examined whether acetaminophen compared with cyclooxygenase (COX) inhibitor alone for patent ductus arteriosus (PDA) is associated with mortality or respiratory morbidity in extremely preterm infants. METHODS: This is a retrospective cohort study using data from the National Institute of Child Health and Human Development Neonatal Research Network. Infants were born at 22 to 28 weeks' gestation or weighing 401 to 1000 g between 2016 and 2020 and received acetaminophen, ibuprofen, and/or indomethacin for PDA closure. The primary outcome was death or grade 2 to 3 bronchopulmonary dysplasia (BPD) at 36 weeks' postmenstrual age. Secondary outcomes included predischarge mortality and respiratory morbidities. Risk ratios were adjusted for baseline and early postnatal factors. Additional exploratory analyses were adjusted for later postnatal covariates. RESULTS: Of 1921 infants, 627 (32.6%) received acetaminophen and 1294 (67.3%) received COX inhibitor only. Multidrug therapy (42.9% vs 4.7%) and surgical or catheter PDA closure (26.5% vs 19.9%) were more common among acetaminophen-exposed infants. Death or grade 2 to 3 BPD at 36 weeks' postmenstrual age was similar between infants treated with acetaminophen versus COX inhibitor only (57.1% vs 58.3%; adjusted relative risk [aRR] 0.96, 95% confidence interval [CI] 0.87-1.06). Acetaminophen was associated with increased risk of predischarge mortality (13.3% vs 10.0%) when adjusting for perinatal and early postnatal factors (aRR 1.42, 95% CI 1.02-1.93), but not in exploratory analyses that included later postnatal factors (aRR 1.28, 95% CI 0.91-1.82). CONCLUSIONS: Treatment with acetaminophen versus COX inhibitor alone for PDA was not associated with the composite outcome of death or BPD in extremely preterm infants. Our results support further evaluation of whether acetaminophen for PDA increases mortality.

At a crossroads for early medical treatment of persistent patent ductus arteriosus in preterm infants.

Administration of early medical therapy for the patent ductus arteriosus has ebbed and flowed through the years, with a multitude of studies failing to demonstrate a reduction in morbidity or mortality from ductal closure in the preterm population. Concerningly, an increasing number of studies have demonstrated an increase in morbidity, such as bronchopulmonary dysplasia and mortality with the use of early medical therapy to close the ductus. Considering information regarding potential risk without clear benefit in an overall cohort of preterm patients with a patent ductus, use of early medical therapy is increasingly challenging to justify and necessitates studies that will aid in identifying a patient population that would benefit from ductal closure and timing of therapy.

Efficacy and safety of different inhaled corticosteroids for bronchopulmonary dysplasia prevention in preterm infants: A systematic review and meta-analysis.

BACKGROUND: This systematic review and meta-analysis aimed to evaluate the efficacy and safety of inhaled corticosteroids (budesonide, beclomethasone, or fluticasone propionate) in preventing bronchopulmonary dysplasia (BPD) for premature infants. METHOD: Electronic databases, including PubMed, EMBASE, Web of science, Scopus, and Cochrane library, were searched from databases inception to January 2022 for eligible randomized controlled trials. Clinical outcomes such as BPD, mortality, BPD or death, adverse events, and neurodevelopmental outcomes were assessed. RESULTS: Overall, budesonide was significantly associated with a reduction in BPD at 36 weeks' postmenstrual age (RR 0.48; 95 % CI [0.38, 0.62]) and patent ductus arteriosus (PDA) (RR 0.75; 95 % CI [0.63, 0.89]) compared with control treatments. Early longer duration inhalation of budesonide alone was associated with a lower risk of BPD at 36 weeks' postmenstrual age and PDA compared with controls. Early shorter duration intratracheal instillation of budesonide with surfactant as vehicle was associated with a lower risk of BPD at 36 weeks' postmenstrual age and all-cause mortality compared with surfactant. There was no statistically significant difference between budesonide and control groups regarding neurodevelopmental impairment. Beclomethasone and fluticasone propionate did not show any superior or inferior effect on clinical outcomes compared to control treatments. CONCLUSION: These findings suggest that budesonide, especially intratracheal instillation of budesonide using surfactant as a vehicle, is a safe and effective option in preventing BPD for preterm infants. More well-design large-scale trials with long-term follow-ups are necessary to verify the present findings.

Use of Paracetamol for Treatment of Patent Ductus Arteriosus in Preterm Neonates: A 5-Year Experience From a Tertiary Hospital in India.

OBJECTIVE: We evaluated ductal closure rates in preterm neonates with hemodynamically significant patent ductus arteriosus (hsPDA) who received paracetamol (PCM) as first-line therapy. METHODS: In this retrospective chart review, we included inborn preterm (< 37 weeks) neonates (January 2017-December 2021) with hsPDA (ductal diameter > 1.5 mm and left atrium-to-aortic root ratio (La/Ao > 1.4) who were treated with oral or intravenous PCM. Primary outcome was hsPDA closure (defined as small or no PDA) following 3-day treatment. Secondary outcomes were need for retreatment and surgical ligation, pulmonary hypertension (PH), and in-hospital morbidities. RESULTS: Out of 2784 preterm birth, 117 neonates were diagnosed with hsPDA. Out of 96 neonates who received PCM in the first course, 20 died before the completing the first course. The median (IQR) gestation and birth weight of neonates who received PCM were 28 (26, 29) weeks and 841 (714, 1039) g, respectively. Out of 76 neonates who completed treatment with first course of PCM (57 intravenous, 19 oral), 43 (56.6%) achieved successful closure and five (6.6%) developed PH. Out of 14 neonates who received a second course of PCM, 10 achieved closure of hsPDA while one neonate expired. CONCLUSION: Paracetamol is associated with successful closure of hsPDA in 56.6% of preterm neonates after one course and 70% of premies after two courses.

A comparison of different dosing regimen of intravenous paracetamol for hemodynamically significant patent ductus arteriosus closure in premature neonates <32 weeks: a prospective observational study.

OBJECTIVE: To compare the efficacy of low vs conventional dose intravenous paracetamol in early closure of haemodynamically significant patent ductus arteriosus within 7 days of life. METHODS: Preterm infants (<32 weeks of gestation) having echocardiographic evidence of hsPDA were given low dose (15 mg/kg initially followed by 7.5 mg/kg every 6 hourly) vs conventional dose (15 mg/kg every 6 hourly) for 5-7 days. RESULTS: In total, 56 infants (28 in each group) were enrolled. Ductal closure was achieved in 96% infants in the low-dose group and 100% infants in the conventional group (P = 1.00). Secondary outcomes, including ductal reopening and need for the second course of medical treatment (21% vs 3.5%, P = 0.1), median duration of hospital stay [30 (15, 43.5) vs 27 (18.5,45), P = 0.64], cumulative oxygen requirement [17.5 (7, 25) vs 14 (8.5, 25), P = 0.89], mortality (10.7% vs 25%, P = 0.29) and other morbidities, were comparable in both the groups. Median paracetamol levels were comparable in both the groups [53.4 µg/L (47, 2,70) vs 62.5 (55.6, 81.2), P = 0.67]. CONCLUSION: Low-dose paracetamol was non-inferior to conventional dose paracetamol for early ductal closure in preterm infants.

Proactive Diagnosis and Tailor-Made Treatment of Patent Ductus Arteriosus in Very Preterm Infants with Routine Echocardiography in Japan: A post hoc Analysis of the PLASE Study.

INTRODUCTION: A feature of the management of extremely preterm infants in Japan is proactive circulatory management using early routine echocardiography performed by neonatologists. METHODS: This study was a post hoc analysis of the Patent ductus arteriosus and Left Atrial Size Evaluation in preterm infants (PLASE) study, which is a prospective cohort study including preterm infants admitted to 34 tertiary neonatal intensive care units in Japan between October 2015 and December 2016. We described the details of the treatment strategy of patent ductus arteriosus (PDA) based on early routine echocardiography. RESULTS: In total, 613 preterm infants were included into the analysis. Twenty percent of infants with prophylactic indomethacin were switched to therapeutic cyclooxygenase inhibitor (COX-I) before the completion of the full prophylactic indomethacin course. Therapeutic COX-I was mostly administered based on echocardiographic findings before PDA became symptomatic or hemodynamically significant. Therapeutic COX-I was frequently discontinued after one or two doses before the full course (three doses) was completed. The proportion of infants requiring additional treatment (additional therapeutic COX-I course or surgical PDA closure) after discontinued COX-I courses (<3 doses) compared to infants after completed 3 doses course was significantly lower (after the first therapeutic COX-I course 46% vs. 68%, p < 0.001) or without a significant difference (after the second or third course). CONCLUSIONS: The clinical management of PDA in Japan featured (1) COX-I administration based on echocardiographic findings before symptomatic or hemodynamically significant PDA appeared and (2) frequent discontinuation of therapeutic COX-I before completing the standard three doses course.

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OBJECTIVES: To investigate the risk factors for the failure of ibuprofen treatment in preterm infants with hemodynamically significant patent ductus arteriosus (hsPDA). METHODS: A retrospective collection of clinical data was conducted on preterm infants with a gestational age of <34 weeks who were diagnosed with hsPDA and treated at the Department of Neonatology, Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, from January 2018 to June 2023. The subjects were divided into two groups based on the treatment approach: the ibuprofen group (95 cases) and the ibuprofen plus surgery group (44 cases). The risk factors for the failure of ibuprofen treatment in preterm infants with hsPDA were identified by binary logistic regression analysis. RESULTS: The binary logistic regression analysis revealed that an increased diameter of the ductus arteriosus, a resistance index (RI) value of the middle cerebral artery ≥0.80, and prolonged total invasive mechanical ventilation time were risk factors for the failure of ibuprofen treatment in preterm infants with hsPDA (P<0.05). Receiver operating characteristic curve analysis showed that a ductus arteriosus diameter >2.85 mm, a middle cerebral artery RI value ≥0.80, and a total invasive mechanical ventilation time >16 days had significant predictive value for the failure of ibuprofen treatment in preterm infants with hsPDA (P<0.05). The combined predictive value of these three factors was the highest, with an area under the curve of 0.843, a sensitivity of 86.5%, and a specificity of 75.0% (P<0.05). CONCLUSIONS: A ductus arteriosus diameter >2.85 mm, a middle cerebral artery RI value ≥0.80, and a total invasive mechanical ventilation time >16 days are risk factors for the failure of ibuprofen treatment in preterm infants with hsPDA, and they are of significant predictive value for the necessity of surgical treatment following the failure of ibuprofen treatment.

Comparative Analysis of Machine Learning Algorithms Evaluating the Single Nucleotide Polymorphisms of Metabolizing Enzymes with Clinical Outcomes Following Intravenous Paracetamol in Preterm Neonates with Patent Ductus Arteriosus.

AIMS: Pharmacogenomics has been identified to play a crucial role in determining drug response. The present study aimed to identify significant genetic predictor variables influencing the therapeutic effect of paracetamol for new indications in preterm neonates. BACKGROUND: Paracetamol has recently been preferred as a first-line drug for managing Patent Ductus Arteriosus (PDA) in preterm neonates. Single Nucleotide Polymorphisms (SNPs) in CYP1A2, CYP2A6, CYP2D6, CYP2E1, and CYP3A4 have been observed to influence the therapeutic concentrations of paracetamol. OBJECTIVES: The purpose of this study was to evaluate various Machine Learning Algorithms (MLAs) and bioinformatics tools for identifying the key genotype predictor of therapeutic outcomes following paracetamol administration in neonates with PDA. METHODS: Preterm neonates with hemodynamically significant PDA were recruited in this prospective, observational study. The following SNPs were evaluated: CYP2E1*5B, CYP2E1*2, CYP3A4*1B, CYP3A4*2, CYP3A4*3, CYP3A5*3, CYP3A5*7, CYP3A5*11, CYP1A2*1C, CYP1A2*1K, CYP1A2*3, CYP1A2*4, CYP1A2*6, and CYP2D6*10. Amongst the MLAs, Artificial Neural Network (ANN), C5.0 algorithm, Classification and Regression Tree analysis (CART), discriminant analysis, and logistic regression were evaluated for successful closure of PDA. Generalized linear regression, ANN, CART, and linear regression were used to evaluate maximum serum acetaminophen concentrations. A two-step cluster analysis was carried out for both outcomes. Area Under the Curve (AUC) and Relative Error (RE) were used as the accuracy estimates. Stability analysis was carried out using in silico tools, and Molecular Docking and Dynamics Studies were carried out for the above-mentioned enzymes. RESULTS: Two-step cluster analyses have revealed CYP2D6*10 and CYP1A2*1C to be the key predictors of the successful closure of PDA and the maximum serum paracetamol concentrations in neonates. The ANN was observed with the maximum accuracy (AUC = 0.53) for predicting the successful closure of PDA with CYP2D6*10 as the most important predictor. Similarly, ANN was observed with the least RE (1.08) in predicting maximum serum paracetamol concentrations, with CYP2D6*10 as the most important predictor. Further MDS confirmed the conformational changes for P34A and P34S compared to the wildtype structure of CYP2D6 protein for stability, flexibility, compactness, hydrogen bond analysis, and the binding affinity when interacting with paracetamol, respectively. The alterations in enzyme activity of the mutant CYP2D6 were computed from the molecular simulation results. CONCLUSION: We have identified CYP2D6*10 and CYP1A2*1C polymorphisms to significantly predict the therapeutic outcomes following the administration of paracetamol in preterm neonates with PDA. Prospective studies are required for confirmation of the findings in the vulnerable population.

Effect of Antenatal Magnesium Sulfate Exposure on Patent Ductus Arteriosus in Premature Infants.

OBJECTIVE: Magnesium sulfate (MgSO4) provides effective fetal neuroprotection. However, there is conflicting evidence regarding the association between antenatal MgSO4 exposure and patent ductus arteriosus (PDA). Thus, herein, we aimed to evaluate the association between antenatal MgSO4 exposure and PDA. STUDY DESIGN: Preterm infants born between 240/7 and 316/7 weeks of gestation were included in this retrospective study. Infants who died within the first 72 hours of life and those with significant congenital anomalies were excluded from the study. Echocardiographic and clinical assessment parameters were used to define PDA and hemodynamically significant PDA (hsPDA). Treatments were planned according to the standard protocols of the unit. The following data were collected from hospital medical records: perinatal characteristics, neonatal outcomes, detailed PDA follow-up findings, and maternal characteristics including MgSO4 exposure and doses. RESULTS: Of the 300 included infants, 98 (32.6%) were exposed to antenatal MgSO4. hsPDA rates were similar in the infants exposed and not exposed to antenatal MgSO4, when adjusted for antenatal steroid administration, gestational age, and birth weight (OR: 1.6, 95% CI: 0.849-3.118, p = 0.146). The rates of PDA ligation and open PDA at discharge were similar between the groups. A cumulative MgSO4 dose of >20 g was associated with an increased risk of hsPDA (crude OR: 2.476, 95% CI: 0.893-6.864, p = 0.076; adjusted OR: 3.829, 95% CI: 1.068-13.728, p = 0.039). However, the cumulative dose had no effect on the rates of PDA ligation or open PDA at discharge. Rates of prematurity-related morbidities and mortality were similar between the groups. CONCLUSION: Although antenatal MgSO4 exposure may increase the incidence of hsPDA, it may not affect the rates of PDA ligation or open PDA at discharge. Further studies are required to better evaluate the dose-dependent outcomes and identify the MgSO4 dose that not only provides neuroprotection but also has the lowest risk of adverse effects. KEY POINTS: · Antenatal exposure of MgSO4 may cause PDA.. · Antenatal MgSO4 exposure may not increase the rates of PDA ligation or open PDA at discharge.. · Further studies are required to better evaluate the dose-dependent outcomes and optimal MgSO4 dose..