Management Of Patent Ductus Arteriosus Research Articles

Patent ductus arteriosus management in very-low-birth-weight prematurity: a place for early surgery?

To evaluate neonatal outcomes based on treatment strategies and time points for haemodynamically significant patent ductus arteriosus (hsPDA) in very-low-birth-weight (VLBW) preterm infants, with a particular focus on surgical closure. This retrospective study included VLBW infants born between 2014 and 2021, received active treatment for hsPDA. Neonatal outcomes were compared between: (1) primary surgical closure vs primary ibuprofen, (2) early (<14th post-natal day) vs late primary surgical closure (≥14th post-natal day), and (3) primary vs secondary surgical closure after ibuprofen failure. Further analysis using 1:1 propensity score matching was performed. Logistic regression was conducted to analyze the risk factors for post-ligation cardiac syndrome (PLCS) and/or acute kidney injury (AKI). A total of 145 hsPDA infants underwent active treatment for closure. In-hospital death rate and severe bronchopulmonary dysplasia (BPD) were similar between the primary surgical closure group and primary ibuprofen group in 1:1 matched analysis. Severe BPD was significantly higher in late surgical closure group than in early primary surgical closure group with 1:1 propensity score matching (72.7% vs 40.9%, p=0.033). The secondary surgical closure group showed the mildest clinical condition, however, the probability of PLCS/AKI was highest (38.6%), compared to early (15.2%) or late primary surgical group (28.1%, p<0.001) especially in extremely premature infants (gestational age <28weeks). Surgical PDA closure is not inferior to pharmacological treatment. Timely decision and efforts should be made considering the harmful effect of prolonged PDA shunt exposure to minimize the risk of severe BPD and PLCS/AKI after surgical closure.

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.

Contemporary fluid management, humidity, and patent ductus arteriosus management strategy for premature infants among 336 hospitals in Asia.

The management of patent ductus arteriosus (PDA) is a critical concern in premature infants, and different hospitals may have varying treatment policies, fluid management strategies, and incubator humidity. The Asian Neonatal Network Collaboration (AsianNeo) collected data on prematurity care details from hospitals across Asian countries. The aim of this study was to provide a survey of the current practices in the management of PDA in premature infants in Asian countries. AsianNeo performed a cross-sectional international questionnaire survey in 2022 to assess the human and physical resources of hospitals and clinical management of very preterm infants. The survey covered various aspects of hospitals resources and clinical management, and data were collected from 337 hospitals across Asia. The data collected were used to compare hospitals resources and clinical management of preterm infants between areas and economic status. The policy of PDA management for preterm infants varied across Asian countries in AsianNeo. Hospitals in Northeast Asia were more likely to perform PDA ligation (p < 0.001) than hospitals in Southeast Asia. Hospitals in Northeast Asia had stricter fluid restrictions in the first 24 h after birth for infants born at <29 weeks gestation (p < 0.001) and on day 14 after birth for infants born at <29 weeks gestation (p < 0.001) compared to hospitals in Southeast Asia. Hospitals in Northeast Asia also had a more humidified environment for infants born between 24 weeks gestation and 25 weeks gestation in the first 72 h after birth (p < 0.001). A logistic regression model predicted that hospitals were more likely to perform PDA ligation for PDA when the hospitals had a stricter fluid planning on day 14 after birth [Odds ratio (OR) of 1.70, p = 0.048], more incubator humidity settings (<80% vs. 80%-89%, OR of 3.35, p = 0.012 and <80% vs. 90%-100%, OR of 5.31, p < 0.001). In advanced economies and Northeast Asia, neonatologists tend to adopt a more conservative approach towards fluid management, maintain higher incubator humidity settings and inclined to perform surgical ligation for PDA.

International Online Survey on the Management of Patent Ductus Arteriosus

Introduction: There is uncertainty and lack of consensus regarding optimal management of patent ductus arteriosus (PDA). We aimed to determine current clinical practice in PDA management across a range of different regions internationally. Materials and Methods: We surveyed PDA management practices in neonatal intensive care units using a pre-piloted web-based survey, which was distributed to perinatal societies in 31 countries. The survey was available online from March 2018 to March 2019. Results: There were 812 responses. The majority of clinicians (54%) did not have institutional protocols for PDA treatment, and 42% reported variable management within their own unit. Among infants <28 weeks (or <1,000 g), most clinicians (60%) treat symptomatically. Respondents in Australasia were more likely to treat PDA pre-symptomatically (44% vs. 18% all countries [OR 4.1; 95% CI 2.6–6.5; p < 0.001]), and respondents from North America were more likely to treat symptomatic PDA (67% vs. 60% all countries [OR 2.0; 95% CI 1.5–2.6; p < 0.001]). In infants ≥28 weeks (or ≥1,000 g), most clinicians (54%) treat symptomatically. Respondents in North America were more likely to treat PDAs in this group of infants conservatively (47% vs. 38% all countries [OR 2.3; 95% CI 1.7–3.2; p < 0.001]), and respondents from Asia were more likely to treat the PDA pre-symptomatically (21% vs. 7% all countries [OR 5.5; 95% CI 3.2–9.8; p < 0.001]). Discussion/Conclusion: There were marked international differences in clinical practice, highlighting ongoing uncertainty and a lack of consensus regarding PDA management. An international conglomeration to coordinate research that prioritises and addresses these areas of contention is indicated.

Personalized Evidence-Based Management of Patent Ductus Arteriosus in Preterm Infants.

There is no universal consensus on management of patent ductus arteriosus (PDA) in preterm infants and it varies significantly worldwide, even among the clinicians within units. The decision to treat requires a thorough understanding of the clinical status of the patient, clinical evaluation of PDA, echocardiographic diagnosis, and hemodynamic impact of ductal shunt on the pulmonary and systemic circulation. In this article, updated evidence on the efficacy and adverse effects of pharmacological treatment options and expectant management are presented, while highlighting the long-term benefits of PDA treatment remains equivocal and controversial. The authors propose a schematic targeted PDA treatment approach based on gestational and chronological age for practical clinical use, and they emphasize important future directions including advancement in PDA device closure techniques, diagnostic echo-parameters, hemodynamic evaluation to assess the impact on other organs, and understanding the long-term outcomes.

Secular Trends in Patent Ductus Arteriosus Management in Infants Born Preterm in the National Institute of Child Health and Human Development Neonatal Research Network

We evaluated changes in patent ductus arteriosus (PDA) diagnosis and treatment from 2012 through 2021 in a network of US academic hospitals. PDA treatment decreased among infants born at 26-28weeks but not among infants born at 22-25weeks. Rates of indomethacin use and PDA ligation decreased while acetaminophen use and transcatheter PDA closure increased.

Patent Ductus Arteriosus and Bronchopulmonary Dysplasia–Associated Pulmonary Hypertension

Bronchopulmonary dysplasia (BPD) is often associated with pulmonary vascular disease and secondary pulmonary hypertension (PH). The pathogenesis of BPD-associated PH (BPD-PH) is complex and involves prenatal and postnatal factors that disrupt pulmonary vascular development, and patent ductus arteriosus (PDA) is a factor potentially associated with risk of BPD-PH that has been identified in very recent studies. To explore the association of PDA with BPD-PH using a bayesian model-averaged (BMA) meta-analysis of studies. PubMed and Embase were searched up to April 2023. Key search terms included BPD and PH. Studies examining infants with gestational age 32 weeks or less and reporting data on PDA and risk of BPD-PH. This study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses and the Meta-Analysis of Observational Studies in Epidemiology reporting guidelines. Two independent reviewers extracted data, with a third reviewer checking for accuracy and completeness. Data pooling and effect size calculations were performed by BMA. The primary outcome was BPD-PH. BMA was used to calculate Bayes factors (BFs). The BF10 is the ratio of the probability of the data under the alternative hypothesis (H1, association of PDA with BPD-HP) over the probability of the data under the null hypothesis (H0). A total of 32 studies (8513 infants) were included. BMA showed that the evidence in favor of H1 was weak for any PDA (BF10 = 2.90; 10 studies), moderate for hemodynamically significant PDA (BF10 = 3.77; 3 studies), and extreme for surgically ligated or catheter-occluded PDA (BF10 = 294.9; 16 studies). In contrast, the evidence in favor of H0 was weak for medically treated PDA (BF10 = 0.55; 6 studies). In addition, BMA found strong evidence in favor of H1 when prolonged exposure to PDA was analyzed as a dichotomous variable (BF10 = 11.80; 6 studies) and extreme evidence (BF10 = 113.60; 3 studies) when PDA exposure time was analyzed as a continuous variable. In this bayesian meta-analysis, the data suggest that prolonged exposure to PDA might be associated with increased risk of pulmonary vascular disease in extremely preterm infants. This highlights the need to monitor for PH in high-risk preterm infants with prolonged exposure to PDA and to incorporate PH risk into clinical decisions regarding PDA management.

Impact of Targeted Neonatal Echocardiography on Patent Ductus Arteriosus Management in a Canadian Tertiary Care Neonatal Unit: A Retrospective Cohort Study.

Comprehensive assessment of hemodynamic significance of a patent ductus arteriosus (PDA) is a common indication to perform targeted neonatal echocardiography (TNE). Impact of implementation of such an assessment on PDA management decisions remains to be reported. The objective of this study is to compare PDA-related hemodynamic information and PDA treatment decisions before and after introduction of TNE service. This was a retrospective cohort study at a tertiary level neonatal intensive care unit in Southwestern Ontario. We investigated two time periods: Epoch-1 (non-TNE 2013-2016) versus Epoch-2 (TNE 2018-2021). We included neonates < 32 weeks with PDA. Data on baseline clinical characteristics, PDA-related echocardiographic parameters, PDA treatment details, and relevant long-term outcomes were collected. Primary outcome was defined as PDA treatment rates and need for multiple courses. Secondary outcomes included availability of PDA hemodynamic data and neonatal mortality/morbidity (PDA-related) RESULTS:  A total of 275 neonates were included. A total of 162 were assessed by conventional echocardiography in Epoch-1, whereas 113 were assessed by TNE in Epoch-2. Baseline clinical characteristics were similar. Epoch-2 had more echocardiographic assessments per patient of 2.7 (±1.8) versus 1.9 (± 1.3), p < 0.001 in Epoch1. The mean postnatal age at first echocardiographic assessment was higher in Epoch-2 (12.7 days [ ± 14.6]) than in Epoch-1 (7.9 days [ ± 10.4]), p < 0.001. Comprehensive hemodynamic assessment of PDA-related echocardiographic parameters such as PDA size, shunt pattern, effect on systemic circulation, and pulmonary circulation were higher in Epoch-2. Overall, PDA treatment rates were comparable in the two time periods. The use of multiple courses of treatment was higher in Epoch-1 than in Epoch-2 (47.8 vs. 31.7%, p = 0.047). In Epoch-1, neonates received PDA treatment earlier than in Epoch-2. With the implementation of the TNE service, increased echocardiographic evaluations per patient were completed with availability of more comprehensive hemodynamic information about PDA. PDA treatment rates were similar in the two epochs, but need for multiple courses were less in TNE era. · TNE allows comprehensive hemodynamic assessment of PDA.. · Implementation of dedicated TNE service led to increased use of echocardiography to assess PDA.. · Standardized hemodynamic assessment of PDA may allow improved individualization of treatment need..

Closing the Gap: Investigation of Various Approaches in the Management of Patent Ductus Arteriosus.

In preterm newborns with extremely low birth weights, patent ductus arteriosus (PDA), which is defined as a remnant connection between the aorta and pulmonary artery after 72 hours of birth, is frequently linked to substantial morbidity and mortality. If left untreated, a hemodynamically significant PDA (hsPDA) increases the risk for bronchopulmonary dysplasia, necrotizing enterocolitis, and intraventricular hemorrhage among other morbidities, and can even lead to death. While instances of patent ductus arteriosus (PDA) resolving on their own are frequent, the primary approach for managing PDA closure in premature infants involves pharmacological interventions, commonly utilizing indomethacin, ibuprofen, or paracetamol. However, with these pharmacological treatment options, there is an increased risk of renal toxicity, gastrointestinal bleeding, and reopening of PDA among other complications. If pharmacological interventions are not successful or contraindicated, PDA can be closed via transcatheter closure or surgical ligation. As with any medically invasive procedure, it is not without risks and can lead to long-term complications. This review explores the different management options and the benefits and outcomes of conservative management vs. active management in order to get one step closer to standardizing the treatment for PDA. With so much controversy surrounding the best management option, there is a lack of evidence to support one treatment method superior to the other in reducing overall mortality, and this needs to be explored further.

Expectant management of patent ductus arteriosus for preterm infants: A meta-analysis of randomized controlled trials

We conducted this meta-analysis to compare expectant management of patent ductus arteriosus (PDA) with active treatment for PDA closure in preterm infants. Data from 7 randomized controlled trials (RCTs) showed that all-cause mortality and other clinical adverse outcomes did not differ between expectant management of PDA and active treatment. Future large-scale and double-blinded RCTs with a consistent definition for hemodynamically significant PDA, and focusing on clearly delineated high-risk subgroups or later selective treatment are needed to further evaluate the role of expectant management.

A Global Perspective on PDA Management in the Extremely Premature: Shifting Trend Toward Transcatheter Closure

Patent ductus arteriosus (PDA) is a frequently encountered defect in infants born extremely premature (≤26 weeks’ gestation). Historically, closure of the PDA was performed using cyclooxygenase inhibitor medications or by surgical ligations. However, the benefits of PDA closure using these therapies have never been demonstrated, albeit studies have previously not focused on the extremely premature infants. Therefore, there was a worldwide trend toward conservative management of the PDA. With improved survival of extremely premature infants, comorbidities associated with the PDA has increased, resulting in finding alternate treatments such as transcatheter patent ductus arteriosus closure (TCPC) for this population. Currently, there is a renewed interest toward selective treatment of the PDA in this high-risk cohort of small infants. This Comprehensive Review article inspects the globally changing trends in the management of the PDA in premature infants, with a special focus on the rising adoption of TCPC. Moreover, this article compiles data from several neonatal networks worldwide to help understand the problem at hand. Understanding the current management of premature infants and their outcomes is fundamentally essential if pediatric cardiologists are to offer TCPC as a viable therapeutic option for this population. This article aims to serve as a guide for pediatric cardiologists on this topic by compiling the results on landmark clinical trials on PDA management and the controversies that arise from these trials. Comparative outcomes from several countries are presented, including interpretations and opinions of the data from experts globally. This is a step toward coming to a global consensus in PDA management in premature infants.

Increasing the dose of ibuprofen with postnatal age to close a hemodynamically significant patent ductus arteriosus in very preterm infants.

Patent ductus arteriosus (PDA) is associated with neonatal morbidities in high-risk preterm infants. Early neonatal treatment by ibuprofen induces the ductus arteriosus (DA) closure in approximatively 60% of infants. Dose escalation of ibuprofen according to postnatal age has been suggested for improving the DA closure rate. The aim of this study was to assess the efficacy and tolerance of an increasing dose regimen of ibuprofen. This single-center retrospective cohort study involved infants hospitalized from 2014 to 2019 in our neonatal unit. Selection criteria were gestational age < 30weeks, birth weight < 1000g, and treatment by ibuprofen. Three dose levels were used and consisted of a daily intravenous injection of ibuprofen-tris-hydroxymethyl-aminomethane (ibuprofen-THAM) for three consecutive days: (i) 10 -5 -5mg/kg before the 70th h of life (H70) (dose level 1), (ii) 14 -7 -7mg/kg between H70 and H108 (dose level 2), (iii) 18 -9 -9mg/kg after H108 (dose level 3). The ibuprofen-induced DA closure was compared between ibuprofen schedules, and the Cox proportional-hazard regression was performed to identify factors associated with the ibuprofen efficacy. Tolerance was assessed through renal function, acidosis, and platelet count. One hundred forty-three infants met the inclusion criteria. The ibuprofen-induced DA closure was observed in 67 infants (46.8%). One course of ibuprofen at dose level 1 was more efficient in closing the DA than other schedules (dose level 1, one course (n = 70): 71%, dose level 2 or 3, one course (n = 20): 45%, two-course schedules (n = 53): 15%, p < 0.0001). Independent factors associated with ibuprofen-induced DA closure were a complete antenatal schedule of steroids (p = 0.001), a lower CRIB II score (p = 0.009), and a lower and earlier exposure to ibuprofen (p < 0.0001 and p = 0.002). No severe side effects were observed. Neonatal mortality and morbidities were similar regardless of the infant's response to ibuprofen. Conclusion: Increasing ibuprofen doses with postnatal age failed to reach an efficacy similar to earlier treatment. Although the infant response to ibuprofen was likely to depend on multiple factors, the optimal use of ibuprofen included its early initiation. What is Known: • Ibuprofen is the current first-line treatment for patent ductus arteriosus during the early neonatal period in very preterm infants. • However, the ibuprofen efficacy rapidly declined with postnatal age during the first week of life. A dose escalation of ibuprofen according to postnatal age has been suggested to improve the ibuprofen-induced ductus arteriosus closure. What is New: • The rapid drop of ibuprofen's ability to close hemodynamically significant patent ductus arteriosus persisted beyond the postnatal day 2 despite the dose adjustment arguing for an early initiation to optimize its efficacy. • The early selection of patients who will suffer from patent ductus arteriosus-related morbidities and who will positively respond to ibuprofen is an issue that could determine the future place of ibuprofen in the patent ductus arteriosus management.

Interventions for patent ductus arteriosus (PDA) in preterm infants: an overview of Cochrane Systematic Reviews.

Patent ductus arteriosus (PDA) is associated with significant morbidity and mortality in preterm infants. Several non-pharmacological, pharmacological, and surgical approaches have been explored to prevent or treat a PDA. To summarise Cochrane Neonatal evidence on interventions (pharmacological or surgical) for the prevention of PDA and related complications, and interventions for the management of asymptomatic and symptomatic PDA in preterm infants. We searched the Cochrane Database of Systematic Reviews on 20 October 2022 for ongoing and published Cochrane Reviews on the prevention and treatment of PDA in preterm (< 37 weeks' gestation) or low birthweight (< 2500 g) infants. We included all published Cochrane Reviews assessing the following categories of interventions: pharmacological therapy using prostaglandin inhibitor drugs (indomethacin, ibuprofen, and acetaminophen), adjunctive pharmacological interventions, invasive PDA closure procedures, and non-pharmacological interventions. Two overview authors independently checked the eligibility of the reviews retrieved by the search, and extracted data from the included reviews using a predefined data extraction form. Any disagreements were resolved by discussion with a third overview author. Two overview authors independently assessed the methodological quality of the included reviews using the AMSTAR 2 (A MeaSurement Tool to Assess systematic Reviews) tool. We reported the GRADE certainty of evidence as assessed by the respective review authors using summary of findings tables. We included 16 Cochrane Reviews, corresponding to 138 randomised clinical trials (RCT) and 11,856 preterm infants, on the prevention and treatment of PDA in preterm infants. One of the 16 reviews had no included studies, and therefore, did not contribute to the results. Six reviews reported on prophylactic interventions for the prevention of PDA and included pharmacological prophylaxis with prostaglandin inhibitor drugs, prophylactic surgical PDA ligation, and non-pharmacologic interventions (chest shielding during phototherapy and restriction of fluid intake); one review reported on the use of indomethacin for the management of asymptomatic PDA; nine reviews reported on interventions for the management of symptomatic PDA, and included pharmacotherapy with prostaglandin inhibitor drugs in various routes and dosages, surgical PDA ligation, and adjunct therapies (use of furosemide and dopamine in conjunction with indomethacin). The quality of reviews varied. Two reviews were assessed to be high quality, seven reviews were of moderate quality, five of low quality, while two reviews were deemed to be of critically low quality. For prevention of PDA, prophylactic indomethacin reduces severe intraventricular haemorrhage (IVH; relative risk (RR) 0.66, 95% confidence interval (CI) 0.53 to 0.82; 14 RCTs, 2588 infants), and the need for invasive PDA closure (RR 0.51, 95% CI 0.37 to 0.71; 8 RCTs, 1791 infants), but it does not appear to affect the composite outcome of death or moderate/severe neurodevelopmental disability (RR 1.02, 95% CI 0.90 to 1.15; 3 RCTs, 1491 infants). Prophylactic ibuprofen probably marginally reduces severe IVH (RR 0.67, 95% CI 0.45 to 1.00; 7 RCTs, 925 infants; moderate-certainty evidence), and the need for invasive PDA closure (RR 0.46, 95% CI 0.22 to 0.96; 7 RCTs, 925 infants; moderate-certainty evidence). The evidence is very uncertain on the effect of prophylactic acetaminophen on severe IVH (RR 1.09, 95% CI 0.07 to 16.39; 1 RCT, 48 infants). Necrotising enterocolitis (NEC) was lower with both prophylactic surgical ligation (RR 0.25, 95% CI 0.08 to 0.83; 1 RCT, 84 infants), and fluid restriction (RR 0.43, 95% CI 0.21 to 0.87; 4 RCTs, 526 infants). For treatment of asymptomatic PDA, indomethacin appears to reduce the development of symptomatic PDA post-treatment (RR 0.36, 95% CI 0.19 to 0.68; 3 RCTs, 97 infants; quality of source review: critically low). For treatment of symptomatic PDA, all available prostaglandin inhibitor drugs appear to be more effective in closing a PDA than placebo or no treatment (indomethacin: RR 0.30, 95% CI 0.23 to 0.38; 10 RCTs, 654 infants; high-certainty evidence; ibuprofen: RR 0.62, 95% CI 0.44 to 0.86; 2 RCTs, 206 infants; moderate-certainty evidence; early administration of acetaminophen: RR 0.35, 95% CI 0.23 to 0.53; 2 RCTs, 127 infants; low-certainty evidence). Oral ibuprofen appears to be more effective in PDA closure than intravenous (IV) ibuprofen (RR 0.38, 95% CI 0.26 to 0.56; 5 RCTs, 406 infants; moderate-certainty evidence). High-dose ibuprofen appears to be more effective in PDA closure than standard-dose ibuprofen (RR 0.37, 95% CI 0.22 to 0.61; 3 RCTs, 190 infants; moderate-certainty evidence). With respect to adverse outcomes, compared to indomethacin administration, NEC appears to be lower with ibuprofen (any route; RR 0.68, 95% CI 0.49 to 0.94; 18 RCTs, 1292 infants; moderate-certainty evidence), oral ibuprofen (RR 0.41, 95% CI 0.23 to 0.73; 7 RCTs, 249 infants; low-certainty evidence), and with acetaminophen (RR 0.42, 95% CI 0.19 to 0.96; 4 RCTs, 384 infants; low-certainty evidence). However, NEC appears to be increased with a prolonged course of indomethacin versus a shorter course (RR 1.87, 95% CI 1.07 to 3.27; 4 RCTs, 310 infants). This overview summarised the evidence from 16 Cochrane Reviews of RCTs regarding the effects of interventions for the prevention and treatment of PDA in preterm infants. Prophylactic indomethacin reduces severe IVH, but does not appear to affect the composite outcome of death or moderate/severe neurodevelopmental disability. Prophylactic ibuprofen probably marginally reduces severe IVH (moderate-certainty evidence), while the evidence is very uncertain on the effect of prophylactic acetaminophen on severe IVH. All available prostaglandin inhibitor drugs appear to be effective in symptomatic PDA closure compared to no treatment (high-certainty evidence for indomethacin; moderate-certainty evidence for ibuprofen; low-certainty evidence for early administration of acetaminophen). Oral ibuprofen appears to be more effective in PDA closure than IV ibuprofen (moderate-certainty evidence). High dose ibuprofen appears to be more effective in PDA closure than standard-dose ibuprofen (moderate-certainty evidence). There are currently two ongoing reviews, one on fluid restriction for symptomatic PDA, and the other on invasive management of PDA in preterm infants.

Acetaminophen versus indomethacin for patent ductus arteriosus management in premature infants: systematic review and meta-analysis of randomized controlled trials.

Acetaminophen has gained interest in the neonatal community for its use in the management of hemodynamically significant patent ductus arteriosus (HsPDA) in preterm infants. We conducted a systematic review of randomized controlled trials (RCTs) comparing the efficacy and safety of acetaminophen with indomethacin for the management of HsPDA in preterm infants. We searched PROSPERO, OVID Medline, OVID EMBASE, Wiley Cochrane Library (CDSR and Central), EBSCO CINAHL, and SCOPUS from inception to June 15, 2021. Bibliographies of identified studies were searched for additional references. Data were analyzed with Review Manager (RevMan) Version 5.3. Four RCTs were identified, enrolling a total of 380 subjects. There was no difference between the interventions for the outcome of PDA closure after one course (RR 1.04 [95% CIs: 0.84, 1.29], P-value 0.70) or after two courses of treatment (RR 1.01 [95% CIs: 0.92, 1.12], P-value 0.77); and for the outcome of PDA ligation (RR 1.56 [95% CIs: 0.48, 5.12], P-value 0.46). However, patients who received acetaminophen had lower rates of necrotizing enterocolitis (RR 0.37 [95% CIs: 0.14, 0.95], P-value 0.04). There were no significant differences noted in the other clinical outcomes, that is, intraventricular hemorrhage, bronchopulmonary dysplasia, retinopathy of prematurity requiring treatment, and death. Two studies noted significant post-treatment elevation of serum creatinine and blood urea with indomethacin, as compared to none with acetaminophen use. Acetaminophen has comparable efficacy to indomethacin for the outcome of HsPDA closure, with a better safety profile, that is, lesser rates of necrotizing enterocolitis and post-treatment azotemia noted with its use.

Pathogenesis and Prevention of Intraventricular Hemorrhage in Preterm Infants.

Intraventricular hemorrhage (IVH) is a serious concern for preterm infants and can predispose such infants to brain injury and poor neurodevelopmental outcomes. IVH is particularly common in preterm infants. Although advances in obstetric management and neonatal care have led to a lower mortality rate for preterm infants with IVH, the IVH-related morbidity rate in this population remains high. Therefore, the present review investigated the pathophysiology of IVH and the evidence related to interventions for prevention. The analysis of the pathophysiology of IVH was conducted with a focus on the factors associated with cerebral hemodynamics, vulnerabilities in the structure of cerebral vessels, and host or genetic predisposing factors. The findings presented in the literature indicate that fluctuations in cerebral blood flow, the presence of hemodynamic significant patent ductus arteriosus, arterial carbon dioxide tension, and impaired cerebral venous drainage; a vulnerable or fragile capillary network; and a genetic variant associated with a mechanism underlying IVH development may lead to preterm infants developing IVH. Therefore, strategies focused on antenatal management, such as routine corticosteroid administration and magnesium sulfate use; perinatal management, such as maternal transfer to a specialized center; and postnatal management, including pharmacological agent administration and circulatory management involving prevention of extreme blood pressure, hemodynamic significant patent ductus arteriosus management, and optimization of cardiac function, can lower the likelihood of IVH development in preterm infants. Incorporating neuroprotective care bundles into routine care for such infants may also reduce the likelihood of IVH development. The findings regarding the pathogenesis of IVH further indicate that cerebrovascular status and systemic hemodynamic changes must be analyzed and monitored in preterm infants and that individualized management strategies must be developed with consideration of the risk factors for and physiological status of each preterm infant.

Bronchopulmonary Dysplasia in Extremely Premature Infants: A Scoping Review for Identifying Risk Factors

Over the years, bronchopulmonary dysplasia (BPD) affects the pulmonary function of infants, resulting in chronic health burdens for infants and their families. The aim of this scoping review was to screen available evidence regarding perinatal risk factors associated with the development and severity of BPD. The eligibility criteria of the studies were year of publication between 2016 and 2021; setting of a developed country; English or Japanese as the study language; and randomized controlled, cohort, or case-control design. The titles and abstracts of the studies were screened by independent reviewers. Of 8189 eligible studies, 3 were included for severe BPD and 26 were included for moderate BPD. The risk factors for severe BPD were male sex, iatrogenic preterm birth, maternal hypertensive disorders of pregnancy (HDP), low gestational age, small-for-gestational-age (SGA) birth weight, mechanical ventilation on day 1, and need for patent ductus arteriosus (PDA) management. The risk factors for moderate or severe BPD included male sex, premature rupture of membranes, clinical chorioamnionitis, maternal HDP, SGA birth weight, bubbly/cystic appearance on X-ray, and PDA management. We identified several risk factors for BPD. We plan to confirm the validity of the new classification using the existing dataset.

Reply to the comment on "Fluid restriction in management of patent ductus arteriosus in Italy: a nationwide survey".

The Authors Chang Liu B.S and Yuan Shi commented our paper on Fluid restriction in management of patent ductus arteriosus (PDA) in Italy. With our study, we conducted a prospective cross-sectional survey among all Italian Neonatal Intensive Care Units (NICUs) to address conservative management of patent ductus arteriosus (PDA) in preterm infants below 29 weeks' gestational age (GA), with specific regard to fluid restriction (FR). The Authors wondered if the heterogeneity of use of fluid restriction both as a prophylactic tool and as a conservative tool when a hemodynamically significant PDA is diagnosed, was due to economic disparities among areas of the included centers. Conducting a secondary analysis of our data, we observed that if we separately consider the responses of two areas, northern and central-southern Italy, FR is slightly more frequently applied in Central and Southern regions (82%) as compared to Northern regions (78%), although this finding does not reach statistical significance. No correlation between the likelihood to adopt conservative measures and the amount of allowed fluid intake was found. The hypothesis that "less fluid intake resulted in milder clinical and echocardiographic presentations of PDA, and thus a lower rate of pharmacological treatment" cannot be supported by our current study design and might deserve future investigations.

Different Medicinal Treatment Modalities in the Management of Patent Ductus Arteriosus in Paediatric Population- A Narrative Review of Available Drug Approaches

Regardless of the size of a patient’s Patent Ductus Arteriosus (PDA), it is crucial for paediatric and adult cardiologists to have a thorough understanding of the condition’s origin, clinical ramifications, and treatment options. Possessing a PDA, no matter how little, might cause complications. Ibuprofen and indomethacin, both cyclo-oxygenase (COX) inhibitors, are used as the gold standard pharmacologic therapy for closing a PDA that has been produced surgically. These non selective COX inhibitors bring about ductal constriction, in addition to lowering the synthesis of prostaglandin. However, these drugs may also have a broad array of unintended consequences. Interest in paracetamol for PDA constriction has recently increased due to fewer adverse effects than indomethacin or ibuprofen. Evidence that paracetamol is now a topic of intense study lends credence to this hypothesis. Information on the long term effects of paracetamol is scarce in paediatric population.

Conservative Management of Patent Ductus Arteriosus Is Feasible in the Peri-Viable Infants at 22-25 Gestational Weeks.

The purpose of this study was to determine the natural course of hemodynamically significant (HS) patent ductus arteriosus (PDA) with conservative management and whether the presence or prolonged duration of HS PDA affected mortality/morbidities in infants at 22-25 weeks estimated gestational age (EGA). We retrospectively reviewed the medical records of 77 infants born at 22-25 weeks EGA, stratified into 22-23 weeks (n = 21) and 24-25 weeks EGA (n = 56). HS PDA was present in 77%, 76%, and 77%, and open ductus at discharge was 12%, 13%, and 12% in the total and at 22-23 and 24-25 weeks EGA infants, respectively. For backup rescue treatment, 7% and 5% of the infants received oral ibuprofen and device closure, respectively. A mortality rate of 9% was found in the HS PDA (+) infants, significantly lower than the 28% in HS PDA (-) infants. There are no significant differences in morbidities. In multivariate analyses, the presence and/or prolonged duration of HS PDA was not associated with increased mortality or morbidity. Spontaneous closure of HS PDA was achieved through conservative management in the peri-viable infants at 22-25 weeks EGA.

Fluid restriction in management of patent ductus arteriosus in Italy: a nationwide survey.

Our survey shows an extreme variability among centers in terms of use of fluid restriction as a prophylactic tool but also in terms of its use (both opportunity and modality) when a hemodynamically significant PDA is diagnosed. This variability, that can be also found in randomized trials and observational studies, suggests that further evidence is needed to better understand its potential beneficial effects and its potential harms such as dehydration, hypotension, decreased end-organ perfusion, and reduced caloric intake. • The lack of demonstrable improvement following the treatment of patent ductus arteriosus has recently paved the way to a more conservative approach. • Fluid restriction is the most commonly applied conservative treatment of PDA. • Among Italian NICUs an extreme variability in terms of indications, timing and modalities of application of Fluid restriction can be found. • This variability reflects the lack of standardization of this practice and the contrasting evidence on its efficacy.