Interaction between pulmonary vasculature and the patent ductus arteriosus in very premature infants.

BACKGROUND: The benefits of closing the ductus arteriosus in very preterm infants have not been convincingly shown in numerous clinical trials. Because a large untreated ductus arteriosus can cause death from congestive heart failure in infants born at term, we need to explain why this might not occur in premature infants born at <28 weeks' gestation. METHODS: Based on information in the literature, I have commented on the possible relationship between the pulmonary vasculature and the shunt through the patent ductus arteriosus. RESULTS: Many of these infants have bronchopulmonary dysplasia, in which animal and human studies have shown a reduced number of capillaries and small pulmonary arteries as well as reduction in vascular endothelial growth factor (VEGF) and platelet endothelial cell adhesion molecule-1 (PECAM-1). Both of these import angiogenic factors. Some who do not have bronchopulmonary dysplasia may have a restricted pulmonary vascular bed. CONCLUSIONS: The increased pulmonary vascular resistance in very premature infants may restrict pulmonary blood flow even if the ductus is large, thus reducing the urgency for ductus closure.

Effect of In Utero Non-Steroidal Anti-Inflammatory Drug Therapy for Severe Ebstein Anomaly or Tricuspid Valve Dysplasia (NSAID Therapy for Fetal Ebstein anomaly).

Ebstein anomaly (EA) and tricuspid valve dysplasia (TVD) are rare congenital malformations associated with nearly 50% mortality when diagnosed in utero. The diseases often produce severe tricuspid regurgitation (TR) in the fetus and in some cases, pulmonary regurgitation (PR) and circular shunting ensue. Since the ductus arteriosus (DA) plays a critical role in the circular shunt and may be constricted by transplacental nonsteroidal anti-inflammatory drugs (NSAIDs), we sought to assess the effect of NSAIDs on fetuses with EA/TVD. We reviewed mothers of singleton fetuses with EA/TVD and PR, indicative of circular shunting, who were offered NSAIDs at multiple centers from 2010 to 2018. Initial dosing consisted of indomethacin, followed by ibuprofen in most cases. Twenty-one patients at 10 centers were offered therapy at a median gestational age (GA) of 30.0 weeks (range: 20.9 to 34.9). Most (15/21 = 71%) mothers received NSAIDs, and 12 of 15 (80%) achieved DA constriction after a median of 2.0 days (1.0 to 6.0). All fetuses with DA constriction had improved PR; 92% had improved Doppler patterns. Median GA at pregnancy outcome (live-birth or fetal demise) was 36.1 weeks (30.7 to 39.0) in fetuses with DA constriction versus 33 weeks (23.3 to 37.3) in fetuses who did not receive NSAIDs or achieve DA constriction (p = 0.040). Eleven of 12 patients (92%) with DA constriction survived to live-birth, whereas 4 of 9 patients (44%) who did not receive NSAIDs or achieve DA constriction survived (p = 0.046). In conclusion, our findings demonstrate the proof of concept that NSAIDs mitigate circular shunt physiology by DA constriction and improve PR among fetuses with severe EA/TVD. Although the early results are encouraging, further investigation is necessary to determine safety and efficacy.

Advances in Pediatric Ductal Intervention: an Open or Shut Case?

PURPOSE OF REVIEW: To review the most recent literature on pediatric transcatheter ductal intervention including ductus arteriosus occlusion and stenting. RECENT FINDINGS: With the development and FDA approval of smaller ductal devices, including most recently the Amplatzer Piccolo Occluder (Abbott, Abbott Park, IL), transcatheter ductus arteriosus device closure is now being safely performed in premature infants and patients < 6 kg using a transvenous approach. In patients with ductus-dependent pulmonary blood flow, ductal stenting with pre-mounted coronary artery stents has been shown to be an acceptable alternative to the surgically placed Blalock-Taussig shunt. Centers with experience in ductal stenting have demonstrated success, even with the tortuous ductus. Innovation in transcatheter device technology and procedural practices have allowed for significant advances. Transcatheter ductal device closure is a reasonable alternative to surgical ligation even in premature, low-birthweight infants. Ductal stenting is also an accepted alternative to the modified Blalock-Taussig shunt. We anticipate continued advancement and procedural refinement over the next several years.

Transcatheter ductus arteriosus stenting in paediatric cardiology: Indications, results and perspectives.

Stenting the arterial duct emerged in the early 1990s as an alternative to a variety of surgical interventions in neonates with a duct-dependent pulmonary or systemic circulation complex defect. Furthermore, palliative ductal stenting has been applied in older children with severe suprasystemic pulmonary arterial hypertension, as an alternative to surgical shunts, such as Potts anastomosis. Early results of this technique were discouraging, but by learning from the failures of the past, ductal stenting has become a reliable palliative therapy. In this review, we aim to describe the historical evolution of ductal stenting, its different clinical applications and outcomes, and future perspectives for this strategy in congenital cardiac catheterization.

Role of dopamine and selective dopamine receptor agonists on mouse ductus arteriosus tone and responsiveness.

BACKGROUND: Indomethacin treatment for patent ductus arteriosus (PDA) is associated with acute kidney injury (AKI). Fenoldopam, a dopamine (DA) DA1-like receptor agonist dilates the renal vasculature and may preserve renal function during indomethacin treatment. However, limited information exists on DA receptor-mediated signaling in the ductus and fenoldopam may prevent ductus closure given its vasodilatory nature. METHODS: DA receptor expression in CD-1 mouse vessels was analyzed by qPCR and immunohistochemistry. Concentration-response curves were established using pressure myography. Pretreatment with SCH23390 (DA1-like receptor antagonist), phentolamine (α -adrenergic receptor antagonist) or indomethacin addressed mechanisms for DA-induced changes. Fenoldopam's effects on postnatal ductus closure were evaluated in vivo. RESULTS: DA1 receptors were expressed equally in ductus and aorta. High-dose DA induced modest vasoconstriction under newborn O2 conditions. Phentolamine inhibited DA-induced constriction, while SCH23390 augmented constriction, consistent with a vasodilatory role for DA1 receptors. Despite this, fenoldopam had little effect on ductus tone nor indomethacin- or O2-induced constriction and did not impair postnatal closure in vivo. CONCLUSION(S): DA receptors are present in the ductus but have limited physiologic effects. DA-induced ductus vasoconstriction is mediated via α-adrenergic pathways. The absence of DA1-mediated impairment of ductus closure supports the study of potential role for fenoldopam during PDA treatment.

Impact of Palliation Strategy on Interstage Feeding and Somatic Growth for Infants With Ductal-Dependent Pulmonary Blood Flow: Results from the Congenital Catheterization Research Collaborative.

Background In infants with ductal-dependent pulmonary blood flow, the impact of palliation strategy on interstage growth and feeding regimen is unknown. Methods and Results This was a retrospective multicenter study of infants with ductal-dependent pulmonary blood flow palliated with patent ductus arteriosus (PDA) stent or Blalock-Taussig shunt (BTS) from 2008 to 2015. Subjects with a defined interstage, the time between initial palliation and subsequent palliation or repair, were included. Primary outcome was change in weight-for-age Z-score. Secondary outcomes included % of patients on: all oral feeds, feeding-related medications, higher calorie feeds, and feeding-related readmission. Propensity score was used to account for baseline differences. Subgroup analysis was performed in 1- (1V) and 2-ventricle (2V) groups. The cohort included 66 PDA stent (43.9% 1V) and 195 BTS (54.4% 1V) subjects. Prematurity was more common in the PDA stent group (P=0.051). After adjustment, change in weight-for-age Z-score did not differ between groups over the entire interstage. However, change in weight-for-age Z-score favored PDA stent during the inpatient interstage (P=0.005) and BTS during the outpatient interstage (P=0.032). At initial hospital discharge, PDA stent treatment was associated with all oral feeds (P<0.001) and absence of feeding-related medications (P=0.002). Subgroup analysis revealed that 2V but not 1V patients demonstrated significant increase in weight-for-age Z-score. In the 2V cohort, feeding-related readmissions were more common in the BTS group (P=0.008). Conclusions In infants with ductal-dependent pulmonary blood flow who underwent palliation with PDA stent or BTS, there was no difference in interstage growth. PDA stent was associated with a simpler feeding regimen and fewer feeding-related readmissions.

Comparison of Outcomes at Time of Superior Cavopulmonary Connection Between Single Ventricle Patients With Ductal-Dependent Pulmonary Blood Flow Initially Palliated With Either Blalock-Taussig Shunt or Ductus Arteriosus Stent: Results From the Congenital Catheterization Research Collaborative.

BACKGROUND: Patients with single ventricle anatomy and ductal-dependent pulmonary blood flow may be initially palliated with either modified Blalock-Taussig shunt (BTS) or ductus arteriosus stent (DAS). Comparisons of outcomes during the interstage period and at the time of superior cavopulmonary connection (SCPC) are lacking and may differ between palliation strategies. METHODS: Infants with single ventricle anatomy and ductal-dependent pulmonary blood flow palliated with either DAS or BTS from 2008 to 2015 were reviewed across 4 centers. Interstage outcomes, and for those who had SCPC, anatomy, hemodynamics, and perioperative clinical outcomes were compared. Thirty-five patients with DAS and 136 patients with BTS were included. RESULTS: At initial palliation, demographic, clinical variables, and pulmonary artery size were similar. Interstage death, transplant, or unplanned reintervention to treat cyanosis occurred in 25.7% of DAS and 35.8% of BTS, P=0.27. Reintervention was more common with DAS (48.6% versus 2.2%; P<0.001). Twenty-three DAS patients and 111 BTS patients underwent SCPC. Preoperative hemodynamics and overall pulmonary atresia growth were similar, although right pulmonary artery growth was better with DAS (change in z-score: 1.57 versus 0.65, P=0.026). SCPC intraoperative and postoperative courses were similar. CONCLUSIONS: In patients with single-ventricle anatomy and ductal-dependent pulmonary blood flow, interstage outcomes, hemodynamics before SCPC, and acute postoperative outcomes were similar. Overall reintervention was more common in the DAS group, driven by more frequent planned reintervention. Unplanned reintervention, death, and transplant were similar. Both groups demonstrated good pulmonary atresia growth. DAS is a reasonable initial palliative alternative to BTS in select patients.

Antenatal betamethasone augments early rise in pulmonary perfusion at birth in preterm lambs: role of ductal shunting and right ventricular outflow distribution.

The glucocorticosteroid betamethasone is routinely administered via maternal intramuscular injection to enhance fetal lung maturation before anticipated preterm birth. Although antenatal betamethasone increases fetal pulmonary arterial (PA) blood flow, whether this agent alters the contribution of 1) right ventricular (RV) output or 2) left-to-right shunting across the ductus arteriosus to rises in PA blood flow after preterm birth is unknown. To address this question, anesthetized control (n = 7) and betamethasone-treated (n = 7) preterm fetal lambs (gestation 127 ± 1 days, means ± SD) were instrumented with aortic, pulmonary, and left atrial catheters as well as ductus arteriosus and left PA flow probes to calculate RV output, with hemodynamics measured for 30 min after cord clamping and mechanical ventilation. Mean PA blood flow was higher in betamethasone-treated than in control lambs over the initial 10 min after birth (P < 0.05). This higher PA flow was accompanied by 1) a greater pulmonary vascular conductance (P ≤ 0.025), 2) a larger proportion of RV output passing to lungs (P ≤ 0.01), despite a fall in this output, and 3) earlier reversal and a greater magnitude (P ≤ 0.025) of net ductal shunting, due to the combination of higher left-to-right (P ≤ 0.025) and lesser right-to-left phasic shunting (P ≤ 0.025). These results suggest that antenatal betamethasone augments the initial rise in PA blood flow after birth in preterm lambs, with this augmented rise supported by the combination of 1) a greater redistribution of RV output toward the lungs and 2) a faster and larger reversal in net ductal shunting underpinned not only by greater left-to-right, but also by lesser right-to-left phasic shunting.

Percutaneous ultrasound guided thrombin injection for axillary artery pseudoaneurysm following stenting of the arterial duct in two infants: Case report with review of literature.

We report pseudoaneurysm of the axillary artery following stenting of the arterial duct in two infants. They were both successfully managed by ultrasound guided thrombin injection with preservation of native arterial flow. We also review the relevant literature.

Classification scheme for ductal morphology in cyanotic patients with ductal dependent pulmonary blood flow and association with outcomes of patent ductus arteriosus stenting.

OBJECTIVES: To devise a classification scheme for ductal morphology in patients with ductal dependent pulmonary blood flow (PBF) that can be used to assess outcomes. BACKGROUND: The impact of ductal morphology on outcomes following patent ductus arteriosus (PDA) stenting is not well defined. METHODS: Patients <1 year of age who underwent PDA stenting for ductal dependent PBF at the four centers comprising the Congenital Catheterization Research Collaborative (CCRC) were included. A classification scheme for PDA morphology was devised based on a tortuosity index (TI)-Type I (straight), Type II (one turn), and Type III (multiple turns). A subtype classification was used based upon the ductal origin. RESULTS: One hundred and five patients underwent PDA stenting. TI was Type I in 58, Type II in 24, and Type III in 23 PDAs, respectively. There was a significant association between ductal origin and vascular access site (p < 0.001). Procedure times and need for >1 stent did not differ based on TI. Greater TI was associated with pulmonary artery (PA) jailing (p = 0.003). Twelve (11.4%) patients underwent unplanned reintervention, more commonly with greater TI (p = 0.022) and PA jailing (p < 0.001). At the time of subsequent surgical repair/palliative staging, PA arterioplasty was performed in 32 patients, more commonly when a PA was jailed (p = 0.048). PA jailing did not affect PA size at follow up. CONCLUSIONS: The proposed qualitative and quantitative PDA morphology classification scheme may be helpful in anticipating outcomes in patients with ductal dependent PBF undergoing PDA stenting.

Natural evolution of ductus arteriosus with noninterventional conservative management in extremely preterm infants born at 23-28 weeks of gestation.

This study aimed to determine the natural course of patent ductus arteriosus (PDA) with noninterventional conservative management and whether the presence and/or prolonged duration of hemodynamically significant (HS) PDA increased the risk of mortality and morbidities in extremely preterm (EPT) infants. We retrospectively reviewed the medical records of EPT infants born at 23-28 weeks of gestation (n = 195) from January 2011 to June 2014, when PDA was managed with noninterventional conservative treatment. We stratified infants into three subgroups of 23-24, 25-26, and 27-28 weeks and analyzed the prevalence and natural evolution of HS PDA, defined as ventilator dependency and PDA size ≥2 mm. Multivariate regression analyses determined if the presence and/or prolonged duration of HS PDA increased the risk for mortality and/or morbidities. The overall incidence of HS PDA was 57% (111/195) at the end of the first postnatal week. In subgroup analyses, infants with 23-24 weeks of gestation had the highest incidence (93%, 50/54), with 64% (47/74) for 25-26 weeks and 21% (14/67) for 27-28 weeks. Six (5%) of 111 infants with HS PDA were discharged without ductus closure, 4 had spontaneous PDA closure on follow up, and device closure was performed for 2 infants. In the multivariate analyses, the presence or prolonged duration (per week) of HS PDA was not associated with the risk of mortality and/or morbidities. Spontaneous closure of HS PDA was mostly achieved, even in EPT infants, with a noninterventional conservative approach. In conclusion, our data showed the incidence and natural course of HS PDA in EPT infants and suggested that the presence or prolonged duration of HS PDA might not increase the rate of mortality or morbidities.

Echocardiography of the patent ductus arteriosus in premature infant.

Management of the patent ductus arteriosus (PDA) in the premature infant has been a point of controversy for decades as smaller and earlier gestational age infants have been surviving. Increasing experience with catheter-based device closure has generated a new wave of interest in this subject. In this era, echocardiography plays a central role for collaboration within a multispecialty team. Reliability of echocardiography is improved by applying an institutionally derived standard approach to imaging, data collection, and reporting. The key aspects of both the physiology and anatomy of the PDA to distinguish infants that may benefit from intervention are described.

Blalock-Taussig shunt versus patent ductus arteriosus stent as first palliation for ductal-dependent pulmonary circulation lesions: A review of the literature.

BACKGROUND: Infants with ductal-dependent pulmonary blood flow (PBF) often undergo a palliative procedure to provide a stable source of PBF prior to definitive palliation or repair. In the current era, a surgical shunt or ductal stent is used to provide PBF. We aimed to review the current literature comparing ductal stents to surgical shunts. METHODS AND RESULTS: Four small, single-center studies and two larger multicenter studies were identified comparing ductal stent to surgical shunt. Combined, these studies showed ductal stent resulted in similar or improved pulmonary artery growth, fewer complications, shorter length of stay, less diuretic use, and improved survival compared to surgical shunt. Despite inherent minor variability among the studies, ductal stent appears to be associated with more frequent reinterventions. CONCLUSIONS: Surgical shunts remain essential to the care of these patients, but ductal stent is a reasonable alternative, and may provide some advantages in select patients with ductal-dependent PBF.

Fetal hemodymanic effects on ductus arteriosus development and influences on postnatal management in infants with ductal-dependent pulmonary blood flow.

The ductus arteriosus (DA) has been studied since Galen. Initially after birth in neonates with obstruction to pulmonary blood flow, DA patency is integral to ensure output and oxygenation. While DA stenting dates back 25 years, there is emerging interest in better understanding how and when to utilize this strategy as an alternative to surgical shunt placement or ongoing prostaglandin administration. Understanding the normal fetal circulation and the perturbations that affect flow and oxygenation is integral to comprehending how normal DA anatomy and morphology may change and how this may influence technical and clinical considerations. In the normal human fetus the great majority of descending aorta circulation comes from the DA, whereas this is a small minority in pulmonary outflow lesions, resulting in size and angle abnormalities. Study of the DA morphology has previously sought to identify patients requiring early intervention and more novel classifications are contributing to knowledge of complications and increasing the likelihood of success. As well, optimal patient selection for aorto-pulmonary shunt vs DA stent remains unclear. This review seeks to convey how fetal circulation can affect the DA, how other clinical considerations such as neurocognitive development support these finding and influence management, and emphasize that the variability in the DA will affect suitability for stenting, which requires further study as guidelines and standards are developed.

Ebstein's anomaly with 'reversible' functional pulmonary atresia.

We present the case of an infant with prenatal diagnosis, at 32 weeks gestation, of Ebstein's anomaly without anterograde flow from right ventricular to pulmonary atresia (PA)-functional PA with flow reversal in the ductus arteriosus. Prostaglandin E1 was started after birth. Chest X-ray showed severe cardiomegaly and echocardiogram confirmed Ebstein's anomaly with a thickened non-opening pulmonary valve without anterograde flow but with mild regurgitation. Multidisciplinary team decision was to progressively reduce prostaglandins and have an expectant attitude. Peripheral oxygen saturation above 85% was maintained and serial echocardiograms documented progressive reduction of the ductus arteriosus and the opening of the pulmonic valve cusps, with the development of anterograde flow. The newborn was discharged at day 19 of life without the need for any intervention, and at last follow-up remains asymptomatic, with anterograde normal flow in the pulmonary valve.

Reopening of the ductus arteriosus in preterm infants; Clinical aspects and subsequent consequences.

OBJECTIVE: Patent ductus arteriosus is a common problem frequently encountered in preterm infants. We aimed to study the risk factors associated with reopening of patent ductus arteriosus and their short term outcomes in preterm infants. METHODS: A total of 162 preterm infants born between November 2013 and December 2015 with gestaional age less than 32 weeks and treated for hemodynamically significant patent ductus arteriosus are included in our study. RESULTS: 113(69.8%) showed permanent closure and 49(30.2%) infants revealed symptoms of reopening after effective closure of patent ductus arteriosus. Low birth weight and small gestational age were more common in reopening group. Multivariete analysis showed that sepsis and multiple courses of drug treatment were independent factors affecting reopening of hemodynamically significant patent ductus arteriosus (OR: 3.01, 95% CI 1.48-6.13, p = 0.002) and (OR: 2.67, 95% CI 1.23-5.82, p = 0.013) respectively. Reopened group had a remarkable higher rate of developing necrotising nnterocolitis, bronchopulmonary dysplasia and retinopathy of prematurity than the closed group. (16.3% vs 4.4%, p = 0.01, 55.1% vs 28.3%, p = 0.001 and 55.1% vs 23.0%, p = 0.0001 respectively). CONCLUSION: Late neonatal sepsis and the need of multiple drug courses to close patent ductus arteriosus are risk factors affecting the reopening of patent ductus arteriosus in preterm infants.

Application of NPE in the assessment of a patent ductus arteriosus.

In many preterm infants, the ductus arteriosus remains patent beyond the first few days of life. This prolonged patency is associated with numerous adverse outcomes, but the extent to which these adverse outcomes are attributable to the hemodynamic consequences of ductal patency, if at all, has not been established. Different treatment strategies have failed to improve short-term outcomes, with a paucity of data on the correct diagnostic and pathophysiological assessment of the patent ductus arteriosus (PDA) in association with long-term outcomes. Echocardiography is the selected method of choice for detecting a PDA, assessing the impact on the preterm circulation and monitoring treatment response. PDA in a preterm infant can result in pulmonary overcirculation and systemic hypoperfusion, Therefore, echocardiographic assessment should include evaluation of PDA characteristics, indices of pulmonary overcirculation with left heart loading conditions, and indices of systemic hypoperfusion. In this review, we provide an evidence-based overview of the current and emerging ultrasound measurements available to identify and monitor a PDA in the preterm infant. We offer indications and limitations for using Neonatologist Performed Echocardiography to optimize the management of a neonate with a PDA.