Persistent Patent Ductus Arteriosus Research Articles

168 - The impact of furosemide on preterm infants during treatment for persistent patent ductus arteriosus

168 - The impact of furosemide on preterm infants during treatment for persistent patent ductus arteriosus

The Transcatheter Closure of Patent Ductus Arteriosus in Extremely Low-Birth-Weight Infants: Technique and Results.

Persistent patent ductus arteriosus is a very common condition in preterm infants. Although there is no management agreed by consensus, despite numerous randomized controlled trials, hemodynamically significant patent ductus arteriosus increases morbidity and mortality in these vulnerable patients. Medical treatment is usually offered as first-line therapy, although it carries a limited success rate and potential severe adverse events. In recent years, transcatheter patent ductus arteriosus closure has fast developed and become widely accepted as a safe and efficient alternative to surgical ductal ligation in extremely low birth weight infants >700 g, using most often the dedicated Amplatzer Piccolo Occluder device. This article aims to provide an appraisal of the patients' selection process, and a step-by-step description of the procedure as well as a comprehensive review of its outcomes.

Chiral pharmacokinetics of ibuprofen enantiomers in Chinese preterm neonates with patent ductus arteriosus using a validated UHPLC-MS/MS method

Persistent patent ductus arteriosus (PDA) is generally observed in preterm neonates. Oral ibuprofen is the standard treatment for closing PDA in China. To investigate the chiral pharmacokinetics of ibuprofen enantiomers in Chinese premature infants with PDA, a simple, fast, and sensitive analytical enantioselective technology was developed with ultra-performance liquid chromatography (UPLC) – tandem mass spectrometry (MS/MS). Chromatographic separation of (R)-ibuprofen and (S)-ibuprofen was accomplished on a Lux® 3 µm Cellulose-3 (150 mm × 2.0 mm, 3 μm) at a flow rate of 0.2 mL/min within 6 min. UPLC separation was achieved by isocratic elution with a mobile phase consisting of formic acid:water (75:1000000, v/v) and acetonitrile:methanol (1:1, v/v). Only 50 µL of plasma samples were pre-treated with acetonitrile precipitation. Ibuprofen-d3 was used as an internal standard. The standard curves of both enantiomers were linear over a concentration range of 0.0500 μg/mL to 50.00 μg/mL. The method has been validated for selectivity, carryover effect, lower limit of quantification, precision, accuracy, matrix effect, extraction recovery, dilution integrity, and stability based on the existing guidelines of the National Medical Products Administration, the United States Food and Drug Administration, and the European Medicines Agency. This method has been successfully applied to investigate the pharmacokinetics of ibuprofen enantiomers in 9 preterm infants with PDA. Our results showed that a high chiral inversion ratio of (R)- to (S)-ibuprofen exists in Chinese preterm neonates. Further studies should be conducted to monitor drug concentration following oral administration of ibuprofen and to consider the effect of individual variations and ethnic differences in metabolizing enantiomers of ibuprofen in premature neonates with PDA.

Association between gastrointestinal perforation and patent ductus arteriosus in extremely-low-birth-weight infants: a retrospective study of our decade-long experience.

Management of persistently patent ductus arteriosus (PDA) in extremely low-birth-weight infants (ELBWIs) requires attention due to the risk of tissue hypoperfusion. We investigated the association between PDA and gastrointestinal perforation. We performed a retrospective chart review from 2012 to 2021. Preterm (≤ 32weeks) ELBWIs with PDA after birth who developed necrotizing enterocolitis (NEC), focal intestinal perforation (FIP), and idiopathic gastric perforation were included; ELBWIs with congenital heart disease were excluded. Data were analyzed using chi-squared tests with Yates; correction, and Student's t test. Five hundred thirty-five preterm ELBWIs were analyzed, including 20 with NEC, 22 with FIP, and 1 with gastric perforation. In NEC and FIP, the ductus arteriosus remained open in 40% (4/10) and 63.6% (14/22) of cases, respectively, and cyclo-oxygenase inhibitor treatment showed poor efficacy (p = 0.492 and 0.240). The incidence of perforation in NEC (4/9 vs. 6/11, p = 0.653), mortality in NEC (3/4 vs. 3/6, p = 0.895) and FIP (6/14 vs. 3/8, p = 0.838) did not differ according to whether the PDA persisted or resolved. The presentation of PDA did not affect the mortality or morbidity of ELBWIs. However, it is essential to consider the possibility of gastrointestinal perforation due to decreased organ blood flow caused by ductal steal.

Transcatheter Closure vs. Surgical Ligation in Preterm Infants with Patent Ductus Arteriosus: A Systematic Review and Meta-Analysis

<b>Background:</b> Persistent patent ductus arteriosus (pPDA) is a common condition in preterm infants. This meta-analysis aimed to assess the safety and efficacy of transcatheter closure (TC) when compared to surgical ligation (SL) in preterm infants with pPDA. <b>Methods:</b> A literature search of Ovid Cochrane Library, Medline, Embase, Epub, Scopus, PMC Preprints, and was conducted from inception to May 06, 2022. Eligible studies reported infants diagnosed with pPDA born at ≤2000 g birth weight or at ≤37 weeks’ who underwent TC or SL as treatment. This review was registered in PROSPERO (CRD42022325944). <b>Results:</b> From 97 studies screened, 8 studies met the eligibility criteria, with a total of 756 preterm infants undergoing either TC (n = 366) or SL (n = 390). Compared to TC, SL had higher mortality rates (OR = 0.32, 95% CI: 0.16, 0.66, I² = 0%). No difference was seen in post-procedural complication rate (OR = 0.90, 95% CI: 0.18, 4.44, I² = 79%), mean duration of post-procedural mechanical ventilation (MD = −2.21 days, 95% CI: −4.88, 0.47, I² = 60%), hospital stay length (MD = −8.30 days, 95% CI: −17.03, 0.44, I² = 0%) or neonatal intensive care unit stay length (MD = −3.50 days, 95% CI: −10.27, 3.27, I² = 0%). <b>Conclusion:</b> Our meta-analysis demonstrated TC as a viable alternative option in managing preterm infants with pPDA in the context of SL. Despite the promising trends demonstrated in this meta-analysis, further studies with larger sample size and controlled baseline characteristics are needed to evaluate the safety and efficacy of TC and SL for preterm infants with pPDA.

Clinical and echocardiographic characteristics associated with evolution of patent ductus arteriosus in preterm neonates: A prospective cohort study

In preterm infants, persistence of ductus arteriosus is an important medical condition. Functional echocardiography for patent ductus arteriosus (PDA) may guide clinical decision-making regarding treatment requirement strategies. Objectives of the study were to assess the trends of clinical and functional echocardiographic parameters with evolution of ductus arteriosus in babies≤1250 gm of birth weight and to evaluate whether there is any association of these parameters with persistence of ductus. In this prospective observational study, recruited babies were assessed serially for clinical events and functional echocardiography. Babies were classified into three groups: without PDA, with PDA but PDA spontaneously closed (within 7 days) and persistent PDA. We included 143 infants (Birth weight 1017±179 g, gestational age 30.8±2.7 weeks). Out of 60 babies with PDA, PDA failed to close spontaneously in first week in 32 (53.4 %) infants. PDA Doppler flow pattern on day 3 was found to be one of the most significant markers for future ductus. The highest frequency of growing pattern (37.5%) and pulsatile pattern (59.4%) was seen in persistence ductus group. PDA diameter and LA/Ao ratio were found strongly correlated with all other variables except E/A ratio. We noticed persistence of ductus in preterm infants had significant clinical and echocardiographic association. PDA doppler flow pattern on day 3 was found to be a significant marker for future behaviour of ductus. Significant correlation was found among individual functional echocardiographic parameters in babies with PDA. This would guide judicious treatment of PDA in preterm neonates.

Single-dose prophylactic ibuprofen therapy for patent ductus arteriosus in preterm infants.

This study aimed to evaluate the short-term morbidities and efficacy of single-dose prophylactic intravenous ibuprofen for patent ductus arteriosus (PDA) on the first day of life in preterm infants.Data of 69 preterm infants with birth weight < 1250 g and gestational age < 30 weeks admitted to the neonatal intensive care unit were analyzed. Of these, 37 infants were assigned to the prophylactic treatment (PT) group and 32 were assigned to the nonprophylactic treatment (non-PT) group. Only the PT group administered intravenous ibuprofen (10 mg/kg) once within 6 hours after birth.Until postnatal day 7, ductal closure occurred in 11 (34.4%) infants in the non-PT group, and in 35 (94.6%) infants in the PT group, of which 30 (81.1%) infants had ductal closure on postnatal day 1. There were 2 (5.4%) infants in the PT group and 9 (28.1%) in the non-PT group who needed ibuprofen treatment due to moderate-to-large PDA after postnatal day 7. Preterm infants in the PT group were less likely to develop an intraventricular hemorrhage (≥grade 2) (adjusted odds ratio 0.007, 95% confidence interval 0.01–0.45), had a shorter duration of invasive ventilatory support and central venous catheter, and earlier postnatal age to achieve feeding of 50 and 100 mL/kg/day compared with those in the non-PT group.Single-dose prophylactic intravenous ibuprofen on the first day of life decreased the occurrence of a persistent PDA and intraventricular hemorrhage (≥grade 2), and reduced the duration of invasive ventilatory support, central venous catheter use, and hospital stay.

Sex Differences in Patent Ductus Arteriosus Incidence and Response to Pharmacological Treatment in Preterm Infants: A Systematic Review, Meta-Analysis and Meta-Regression.

A widely accepted concept in perinatal medicine is that boys are more susceptible than girls to complications of prematurity. However, whether this ‘male disadvantage of prematurity’ also involves persistent patent ductus arteriosus (PDA) has been scarcely investigated. Our aim was to conduct a systematic review and meta-analysis on studies addressing sex differences in the risk of developing PDA among preterm infants. We also investigated whether the response to pharmacological treatment of PDA differs between boys and girls. PubMed/Medline and Embase databases were searched. The random-effects male/female risk ratio (RR) and 95% confidence interval (CI) were calculated. We included 146 studies (357,781 infants). Meta-analysis could not demonstrate sex differences in risk of developing any PDA (37 studies, RR 1.03, 95% CI 0.97 to 1.08), hemodynamically significant PDA (81 studies, RR 1.00, 95% CI 0.97 to 1.02), or in the rate of response to pharmacological treatment (45 studies, RR 1.01, 95% CI 0.98 to 1.04). Subgroup analysis and meta-regression showed that the absence of sex differences was maintained over the years and in different geographic settings. In conclusion, both the incidence of PDA in preterm infants and the response rate to pharmacological treatment of PDA are not different between preterm boys and girls.

Fetal Doppler Evaluation to Predict NEC Development.

Antenatal factors play a role in NEC pathogenesis. This study aimed to investigate the predictive value of fetal ductus venosus doppler (DV) for NEC in fetal growth restriction fetuses (FGRF) and to assess the predictive accuracy of IG21 and Fenton curves in NEC development. Data from FGRF, postnatal findings, and Doppler characteristics were collected between 2010 and 2020 at a single center. Patients were then divided into two groups (i.e., with and without NEC). Bivariate and multivariate analyses were performed. We identified 24 cases and 30 controls. Absent or reversed end-diastolic flow (AREDF) and increased resistance in the DV were more impaired in cases (p < 0.05). Although the median birthweight was not different, the Fenton z-score was lower in NEC (p < 0.05). Fetal cardiopulmonary resuscitation, synchronized intermittent mandatory ventilation, neonatal respiratory distress, persistent patent ductus arteriosus (PDA), and inotropic support were more frequent in the NEC group. Furthermore, NEC patients had lower white blood cells (WBC) (p < 0.05). The predictive model for NEC (model 4), including Fenton z-score, WBC, PDA, and DV had an AUC of 84%. Fetal Doppler findings proved effective in predicting NEC in FGR. The Fenton z-score was the most predictive factor considering the fetal growth assessment showing high sensitivity.

Definitive Closure of the Patent Ductus Arteriosus in Preterm Infants and Subsequent Short-Term Respiratory Outcomes.

A persistent patent ductus arteriosus (PDA) can have significant clinical consequences in preterm infants, depending on the degree of left-to-right shunting, its impact on cardiac performance, and associated perinatal risk factors that can mitigate or exacerbate the shunt. Although the best management strategy remains contentious, PDAs that have contraindications to, or have failed medical management have historically undergone surgical ligation. Recently smaller occluder devices and delivery systems have allowed for minimally invasive closure in the catheterization laboratory even in extremely premature infants. The present review summarizes the pathophysiologic manifestations, treatment options and management of hemodynamically significant PDA in preterm infants. Additionally, we review the available literature surrounding the respiratory support and outcomes of preterm infants following definitive PDA closure.

Management of the patent ductus arteriosus in preterm infants.

Management of the patent ductus arteriosus (PDA) is one of the most contentious topics in the care of preterm infants. PDA management can be broadly divided into prophylactic and symptomatic therapy. Prophylaxis with intravenous indomethacin in extremely low birth weight infants may reduce severe intraventricular hemorrhage. Echocardiography should be routinely used to confirm the presence of a PDA before considering symptomatic therapy. A symptomatic PDA can be managed conservatively, using pharmacotherapy or with procedural closure. Ibuprofen should be considered as the pharmacotherapy of choice for a symptomatic PDA. High-dose ibuprofen may be preferable, especially for preterm infants beyond the first 3 to 5 days of age. If pharmacotherapy fails (after two courses) or is contraindicated, procedural closure may be considered for infants with a persistent PDA with significant clinical symptoms in addition to echocardiographic signs of a large PDA shunt volume and pulmonary over-circulation.

Efficacy and Costs of Three Pharmacotherapies for Patent Ductus Arteriosus Closure in Premature Infants

The hemodynamic impact of persistent patent ductus arteriosus (PDA) is associated with neonatal morbidities and mortality in preterm newborns. While there has been considerable debate about optimal management of PDA and its impact on clinical outcomes, there is widespread variation in practice, such as using different pharmacotherapies to achieve closure of hemodynamically significant PDA during the first week of life in very low birth weight infants. The objective was to estimate the efficacy of acetaminophen, ibuprofen, and indomethacin with regard to ductal closure and to compare the costs of these three commonly used medications to treat PDA in preterm infants. PubMed, Embase, and Cochrane Registry were searched for trials from the years 2010-2020. We identified 17 randomized clinical trials (RCTs) and 14 case series that enrolled preterm infants <37 weeks gestational age for inclusion. Pooled estimates of closure rates for acetaminophen (n = 630), ibuprofen (n = 694), and indomethacin (n = 312) were analyzed using the weighted proportion ratio using a Mantel‑Haenszel random effects model. The chi-squared test of proportions was used to determine significance between groups. We accessed cost estimates of pharmacotherapy from the Lexi-Comp average wholesale price database and utilized a decision tree model to appraise cost benefits for the outcome measure of successful PDA closure. The pooled proportional point estimates of closure rates from RCTs for acetaminophen, ibuprofen, and indomethacin were 70.1% (95% confidence interval [CI] 60-80), 63.4% (95% CI 52.8-74.1), and 71.5% (95% CI 62.3-80.7), respectively. There was no significant statistical difference in closure rates when RCTs and uncontrolled case series were combined. Pairwise comparisons showed both acetaminophen and indomethacin were each more effective in closing PDA than ibuprofen (acetaminophen vs indomethacin: p = 0.01; ibuprofen vs indomethacin: p = 0.02; acetaminophen vs indomethacin: p = 0.93). Comparing costs for successful closure of PDA, at the average wholesale price of different medications, suggested that treatment with acetaminophen costs significantly less, with a mean of $1487 (95% CI 1300-1737), compared to ibuprofen, with a mean of $2585 (95% CI 2214-3104), and indomethacin, with a mean of $2661 (95% CI 2358-3052), per course of treatment. Our meta-analysis suggests acetaminophen is non-inferior to both indomethacin and ibuprofen, and costs relatively less for successful PDA constriction in premature infants. Further clinical trials are warranted to compare acetaminophen's safety, along with short- and long-term effects, to help resolve the clinical conundrum of the necessity of early treatment in the management of PDA, and the optimal pharmacological course, if indicated.

EBNEO Commentary: Paracetamol/acetaminophen to avoid PDA ligation: How to interpret impact on 18- to 24-month outcomes.

Mashally S, Banihani R, Jasani B, Nield LE, Martins FF, Jain A, Weisz DE. Is late treatment with acetaminophen safe and effective in avoiding surgical ligation among extremely preterm neonates with persistent patent ductus arteriosus? J Perinatol 2021; Aug 21; 1–7. Online ahead of print. PMID 34453113. Acetaminophen (APAP) use among ELBW infants is increasing worldwide.1, 2 There is an urgent need to evaluate both the safety and efficacy of APAP for PDA treatment. In this retrospective study, Mashally and colleagues have compared outcomes of ELGANS in which differing approaches across two epochs were used for the treatment of a persistent PDA (pPDA) at a single centre: surgical ligation and APAP with ligation after failed closure. Comparing the neurodevelopmental outcomes of these infants at 18–24 months corrected age, the authors found no difference in the risk of NDI or death between infants treated for a pPDA between the two epochs. They conclude that APAP is a safe and effective therapy for late treatment of the PDA to avoid surgical ligation. These results add to the growing body of literature evaluating the use of APAP for PDA treatment. However, a number of issues must be considered. Although the authors state that the objective was to evaluate the ‘association of late treatment with acetaminophen vs. immediate surgical ligation with death or neurodevelopmental impairment (NDI) among extremely low gestational age neonates (ELGANs) with persistent patent ductus arteriosus (pPDA)’, this precise goal could not be met with the retrospective design and included subjects. Specifically, in epoch1 – the PDA ligation epoch – over 25% of the subjects did not undergo PDA ligation. In epoch2 – the APAP epoch – 20% were not exposed to APAP. Therefore, it is more accurate to state that this study compared outcomes across epochs with different prevailing clinical approaches to treatment of a late PDA. Furthermore, the small sample size also limits the ability to detect clinically relevant differences in outcomes. Larger observational and interventional studies that balance patient characteristics, avoid treatment contamination and minimise treatment selection bias are needed to determine the safety of APAP for pPDA. Lastly, any conclusion regarding the ‘safety’ of APAP must be considered in relation to the comparison therapy. In this study, the comparison was surgical ligation, which is an independent risk factor for poor neurodevelopmental outcomes.3 Given the risks of ligation, it could be argued that a pharmacologic approach that limits these exposures, and yet is not clearly safer, may potentially carry underappreciated risks that must be considered. The authors previously reported that late APAP exposure was associated with an increase in chronic lung disease.4 Although referenced in their methods, they do not comment further on this association here. The present report indicates that rates of moderate-severe bronchopulmonary dysplasia were 65% in epoch1 and 81% in epoch2 (p = 0.11). Although this difference did not reach statistical significance, a 16% absolute increase in the rates of this outcome is of possible clinical significance, particularly in the light of the reduced frequency of PDA ligation. This potential signal for harm, as well as the potential impact of APAP exposures on the developing lung, brain and endocrine function, reminds us that studies evaluating APAP safety should include broad measures of end-organ injury.5-7 With these points in mind, the conclusion regarding the safety of APAP should be regarded cautiously. URL LINK: URL TO THE FULL REVIEW ON THE EBNEO WEBSITE https://ebneo.org/apap-pda-ligation-18-24-month-outcomes None stated.

Multi-centre, randomised non-inferiority trial of early treatment versus expectant management of patent ductus arteriosus in preterm infants (the BeNeDuctus trial): statistical analysis plan

BackgroundControversy exists about the optimal management of a patent ductus arteriosus (PDA) in preterm infants. A persistent PDA is associated with neonatal mortality and morbidity, but causality remains unproven. Although both pharmacological and/or surgical treatment are effective in PDA closure, this has not resulted in an improved neonatal outcome. In most preterm infants, a PDA will eventually close spontaneously, hence PDA treatment potentially increases the risk of iatrogenic adverse effects. Therefore, expectant management is gaining interest, even in the absence of convincing evidence to support this strategy.Methods/designThe BeNeDuctus trial is a multicentre, randomised, non-inferiority trial assessing early pharmacological treatment (24–72 h postnatal age) with ibuprofen versus expectant management of PDA in preterm infants in Europe. Preterm infants with a gestational age of less than 28 weeks and an echocardiographic-confirmed PDA with a transductal diameter of > 1.5 mm are randomly allocated to early pharmacological treatment with ibuprofen or expectant management after parental informed consent.The primary outcome measure is the composite outcome of mortality, and/or necrotizing enterocolitis Bell stage ≥ IIa, and/or bronchopulmonary dysplasia, all established at a postmenstrual age of 36 weeks. Secondary short-term outcomes are comorbidity and adverse events assessed during hospitalization and long-term neurodevelopmental outcome assessed at a corrected age of 2 years. This statistical analysis plan focusses on the short-term outcome and is written and submitted without knowledge of the data.Trial registrationClinicalTrials.gov NTR5479. Registered on October 19, 2015, with the Dutch Trial Registry, sponsored by the United States National Library of Medicine Clinicaltrials.gov NCT02884219 (registered May 2016) and the European Clinical Trials Database EudraCT 2017-001376-28.

Is late treatment with acetaminophen safe and effective in avoiding surgical ligation among extremely preterm neonates with persistent patent ductus arteriosus?

ObjectiveEvaluate the association of late treatment with acetaminophen vs. immediate surgical ligation with death or neurodevelopmental impairment (NDI) among extremely low gestational age neonates (ELGANs) with persistent patent ductus arteriosus (pPDA).Study designRetrospective comparative epoch study of ELGANs with pPDA being considered for surgical ligation. ELGANs in epoch 1 (2009–2012) were referred for ligation, while infants in epoch 2 (2012–2015) were treated with oral acetaminophen and referred for ligation in the absence of improvement. The primary outcome was a composite of death/NDI at 18–24 months.ResultsNinety-two ELGANs with median[IQR] GA 25.2 weeks [24.4, 26.3] had pPDA (43 in epoch 1, 49 in -epoch 2) with acetaminophen-exposed neonates receiving 7 days [7, 7] of treatment. ELGANs in epoch 2 had reduced ligation (aOR 0.30; 95%CI: [0.11, 0.87]), but there was no difference in death/NDI (aOR 1.03; 95%CI: [0.30, 3.56]).ConclusionsLate treatment with acetaminophen to avoid surgery for pPDA is associated with reduced ligation but no difference in death/NDI, supporting the safety and effectiveness of this approach.

Low Rate of Spontaneous Closure in Premature Infants Discharged with a Patent Ductus Arteriosus: A Multicenter Prospective Study

To assess the rate of spontaneous closure and the incidence of adverse events in infants discharged home with a patent ductus arteriosus. In a prospective multicenter study, we enrolled 201 premature infants (gestational age of 23-32weeks at birth) discharged home with a persistently patent ductus arteriosus (PDA) and followed their PDA status at 6-month intervals through 18months of age. The primary study outcome was the rate and timing of spontaneous ductal closure. Secondary outcomes included rate of assisted closure and the incidence of serious adverse events. Spontaneous ductal closure occurred in 95 infants (47%) at 12months and 117 infants (58%) by 18months. Seventeen infants (8.4%) received assisted closure with surgical ligation or device assisted occlusion. Three infants died (1.5%). Although infants with spontaneous closure had a higher mean birth weight and gestational age compared with infants with a persistent PDA or assisted closure, we did not identify other factors predictive of spontaneous closure. Spontaneous closure of the PDA occurred in slightly less than one-half of premature infants discharged with a patent ductus by 1year, lower than prior published reports. The high rate of assisted closure and/or adverse events in this population warrants close surveillance following discharge. ClinicalTrials.gov: NCT02750228.

The molecular mechanisms of oxygen-sensing in human ductus arteriosus smooth muscle cells: A comprehensive transcriptome profile reveals a central role for mitochondria

The ductus arteriosus (DA) connects the fetal pulmonary artery and aorta, diverting placentally oxygenated blood from the developing lungs to the systemic circulation. The DA constricts in response to increases in oxygen (O2) with the first breaths, resulting in functional DA closure, with anatomic closure occurring within the first days of life. Failure of DA closure results in persistent patent ductus arteriosus (PDA), a common complication of extreme preterm birth. The DA's response to O2, though modulated by the endothelium, is intrinsic to the DA smooth muscle cells (DASMC). DA constriction is mediated by mitochondrial-derived reactive oxygen species, which increase in proportion to arterial partial pressure of oxygen (PaO2). The resulting redox changes inhibit voltage-gated potassium channels (Kv) leading to cell depolarization, calcium influx and DASMC constriction. To date, there has not been an unbiased assessment of the human DA O2-sensors using transcriptomics, nor are there known molecular mechanisms which characterize DA closure. DASMCs were isolated from DAs obtained from 10 term infants at the time of congenital heart surgery. Cells were purified by flow cytometry, negatively sorting using CD90 and CD31 to eliminate fibroblasts or endothelial cells, respectively. The purity of the DASMC population was confirmed by positive staining for α-smooth muscle actin, smoothelin B and caldesmon. Cells were grown for 96 h in hypoxia (2.5% O2) or normoxia (19% O2) and confocal imaging with Cal-520 was used to determine oxygen responsiveness. An oxygen-induced increase in intracellular calcium of 18.1% ± 4.4% and SMC constriction (−27% ± 1.5% shortening) occurred in all cell lines within five minutes. RNA sequencing of the cells grown in hypoxia and normoxia revealed significant regulation of 1344 genes (corrected p < 0.05). We examined these genes using Gene Ontology (GO). This unbiased assessment of altered gene expression indicated significant enrichment of the following GOterms: mitochondria, cellular respiration and transcription. The top regulated biologic process was generation of precursor metabolites and energy. The top regulated cellular component was mitochondrial matrix. The top regulated molecular function was transcription coactivator activity. Multiple members of the NADH-ubiquinone oxidoreductase (NDUF) family are upregulated in human DASMC (hDASMC) following normoxia. Several of our differentially regulated transcripts are encoded by genes that have been associated with genetic syndromes that have an increased incidence of PDA (Crebb binding protein and Histone Acetyltransferase P300). This first examination of the effects of O2 on human DA transcriptomics supports a putative role for mitochondria as oxygen sensors.

Investigation of echocardiographic characteristics and predictors for persistent defects of patent foramen ovale or patent ductus arteriosus in Chinese newborns

BackgroundPersistent patent foramen ovale (PFO) and patent ductus arteriosus (PDA) increase the adult risk of cryptogenic embolic stroke and chronic pulmonary hypertension. To understand the characteristics of PFO and PDA in newborns, we investigated the spontaneous closure rate and derived the determinants for residual defects. MethodsWe utilized the database of congenital heart disease (CHD) in Xiamen ChangGung Memorial Hospital from 2015 to 2017 and allocated 2523 eligible newborns into four groups according to PDA, PFO, both or neither at birth. A total of 574, 1229, 202 and 518 newborns were assigned into the group of PFO and PDA, PFO alone, PDA alone and non-PFO/non-PDA, respectively. Regular echocardiographic follow-ups at baseline, 6, 12 and 24 months after birth were performed for evaluating the spontaneous closure rate in the subjects. Regression analysis was carried out to study the risk factors of residual congenital defects. ResultsNewborns with PFO alone had the youngest birth age and lowest birth weight among the four groups. About one in four PDA-alone newborns had concomitant small ASD, i.e., <5 mm in diameter. Echocardiographic study showed that 71.3% and 30.8% of CHD newborns had PFO and PDA, respectively, compared to less than 10% of them having ASD or VSD. However, more than 95% of newborns with PFO or PDA closed spontaneously at 6 months, in contrast to about 30% of newborns with ASD or VSD had persistent existence of the intracardiac defects. Complex CHD significantly linked to persistent PFO or PDA at 6 and 12 months, with an adjusted hazard ratio of 9.03 (95% CI 1.97–41.46) and 12.11 (95% CI 2.11–69.72), respectively. ConclusionsChinese newborns with PFO or PDA expressed differences in characteristics and concomitant congenital defects. Additionally, persistent PFO or PDA is strongly associated with complex CHD and requires long-term regular monitoring for future associated complications.

Patent ductus arteriosus shunt elimination results in a reduction in adverse outcomes: a post hoc analysis of the PDA RCT cohort.

A post hoc appraisal of the PDA RCT to assess the relationship between early patent ductus arteriosus (PDA) shunt elimination and chronic lung disease or death (CLD/Death). Infants <29 weeks were divided into four groups: intervention arm in whom PDA closure was achieved (n = 17); intervention arm in whom PDA closure was not achieved (n = 13); placebo arm (n = 30); low risk infants (n = 13). The main outcome measure was CLD/Death. The rates of CLD/Death were lower in the Intervention Success Group (29%) when compared to the Intervention Failure Group (85%) or the Placebo Group (60%, all p < 0.05). There was no difference in CLD/Death between the Intervention Success and Low Risk Groups (8%, p > 0.05). A persistent PDA beyond Day 8 was associated with CLD/Death (aOR 6.5 [1.7-25.5]). Early shunt elimination in preterm infants with a PDA may reduce respiratory morbidity when compared to infants with prolonged shunt exposure.

A comparison of the effect of bi-level positive airway pressure and synchronized intermittent mandatory ventilation in preterm infants with respiratory distress syndrome

Objective Bi-level positive airway pressure (BiPAP) and synchronized intermittent mandatory ventilation (SIMV) can be used to achieve peak inspiratory pressure and positive end-expiratory pressure to avoid alveolar collapse and improve oxygenation in preterm infants during the treatment of respiratory distress syndrome (RDS), and there is an urgent demand for evaluating the effects and prognoses of these two ventilation modes. Study design We conducted a retrospective study on preterm infants (≤32 weeks and <2500 g) from March 2015 to March 2020 with BiPAP (n = 63) and SIMV (n = 63). The primary outcomes were successful treatment and weaning within 72 h, the demand for a second pulmonary surfactant supply and the need for a second respiratory support. The secondary outcome was the incidence of complications. Results There were no significant differences (p > .05) in the primary outcomes or the incidence of complications (pneumonia, apnea, respiratory failure, air leak syndrome, persistence of patent ductus arteriosus, neonatal sepsis, necrotizing enterocolitis, retinopathy of prematurity, and intraventricular hemorrhage). There were significant differences (p < .05) in the incidence of pulmonary hemorrhage, bronchopulmonary dysplasia and IVH (≥grade II). Conclusions Although both BiPAP and SIMV achieved good early treatment outcomes of RDS in preterm infants, BiPAP support is recommended for reducing the incidence of pulmonary hemorrhage, bronchopulmonary dysplasia and IVH (≥grade II) if infants are tolerant. Attempts should be made to prevent these complications from happening with the use of SIMV support if infants are intolerant.