A Canadian, retrospective, multicenter experience with selexipag for a heterogeneous group of pediatric pulmonary hypertension patients.

Introduction: Selexipag, an oral nonprostanoid prostaglandin receptor agonist, has led to reduced morbidity and mortality in adults with pulmonary arterial hypertension (PAH). While the adult literature has been extrapolated to suggest selexipag as an oral treatment for severe pediatric pulmonary hypertension (PH), longitudinal, multicenter data on the benefits of selexipag in this population are lacking. The purpose of this study is to present a longitudinal, multicentre experience with selexipag in a relatively large cohort of pediatric PH patients and add to the existing selexipag literature. Materials and methods: We performed a retrospective, multicenter review describing the clinical outcomes of pediatric PH patients receiving selexipag in addition to standard oral pulmonary vasodilator therapy across three Canadian centers between January 2005 and June 2021. Results: Twenty-four pediatric patients (fifteen female) with a mean age of 9.7 (range 2.0-15.5) years were included. Of this cohort, eighteen (75.0%) were in group 1, one (4.2%) was in group 2, four (16.7%) were in group 3, and one (4.2%) was in group 4. Twenty-two (91.7%) patients were on dual PH therapy after six months. Dosing was targeted to achieve 20-30 mcg/kg/dose orally every twelve hours. Median dose after twelve months was 30 mcg/kg/dose. Twelve months following selexipag initiation, median decreases of 0.2 cm in tricuspid annular plane systolic excursion, 3.5 mmHg in right-ventricular systolic pressure, and 6.1 mmHg in mean pulmonary arterial pressure were observed; none of these changes were statistically significant. Three patients died, one clinically deteriorated and required admission to a pediatric intensive care unit, ten had gastrointestinal symptoms, and three had flushing. Conclusion: Selexipag appears to be a safe and effective adjunctive therapy for pediatric PH patients and has a tolerable adverse effect profile aside from gastrointestinal disturbances. Additional prospective studies of changes in hemodynamics and functional classification over a longer period and with a larger sample are needed. Future research should aim to identify subgroups that stand to benefit from the addition of selexipag as well as optimal timing and dosing for the pediatric population.

Drug Treatment of Pulmonary Hypertension in Children.

Pulmonary arterial hypertension (PAH) is a rare disease in infants and children that is associated with significant morbidity and mortality. The disease is characterized by progressive pulmonary vascular functional and structural changes resulting in increased pulmonary vascular resistance and eventual right heart failure and death. In many pediatric patients, PAH is idiopathic or associated with congenital heart disease and rarely is associated with other conditions such as connective tissue or thromboembolic disease. PAH associated with developmental lung diseases such as bronchopulmonary dysplasia or congenital diaphragmatic hernia is increasingly more recognized in infants and children. Although treatment of the underlying disease and reversal of advanced structural changes have not yet been achieved with current therapy, quality of life and survival have improved significantly. Targeted pulmonary vasodilator therapies, including endothelin receptor antagonists, prostacyclin analogs, and phosphodiesterase type 5 inhibitors have resulted in hemodynamic and functional improvement in children. The management of pediatric PAH remains challenging as treatment decisions depend largely on results from evidence-based adult studies and the clinical experience of pediatric experts. This article reviews the current drug therapies and their use in the management of PAH in children.

Prospective study of pulmonary hypertension in preterm infants with bronchopulmonary dysplasia.

OBJECTIVE: To evaluate the prevalence, risk factors, and optimal timing of echocardiogram for pulmonary hypertension (PH) in infants with bronchopulmonary dysplasia (BPD). DESIGN: In this prospective study, infants with gestational age (GA) <30 weeks admitted to a tertiary NICU between July 2015 and June 2017 who required positive pressure ventilation or oxygen therapy at ≥28 days of life were evaluated with serial echocardiograms at study enrollment (4-6 weeks of age), 32 weeks (only for ≤25 weeks), 36, and 40 weeks post-menstrual age (PMA) for PH. RESULTS: Of 126 infants (mean birth weight 858 ± 221 g; mean GA 26.1 ± 1.6 wks), 48 (38%) developed PH at any time during their hospital stay. The first study echocardiogram was performed at a median age of 31 weeks PMA. The prevalence of PH was 36/126 (28.5%) at enrollment, at 6/30 (20%) at 32 weeks, 24/111 (21.6%) at 36 weeks, and 10/59 (17%) at 40 weeks. No new cases of PH were identified at 40 weeks. At 36 weeks, none of the infants with mild BPD had PH, whereas 20% of moderate and 32% of severe BPD infants had PH. After controlling for confounding variables severe BPD (OR 3.31, 95%CI 1.12, 9.74), and ventilator associated pneumonia (VAP) (OR 17.9, 95%CI 3.9, 82.11) remained independent risk factors for BPD-associated PH. CONCLUSION: Echocardiographic screening for PH can be safely restricted to infants with moderate or severe BPD at 36 weeks PMA. We identified VAP as an independent risk factor for PH.

Non-invasive Investigations for the Diagnosis of Fontan-Associated Liver Disease in Pediatric and Adult Fontan Patients.

Fontan-associated liver disease (FALD) is a serious complication related to the chronically elevated venous pressure and low cardiac output of this abnormal circulation. However, diagnostic markers for this condition are limited. We hypothesized that specific tests for fibrosis developed for other chronic liver diseases would identify a higher prevalence of FALD than ultrasound and standard laboratory tests and that identified abnormalities would correlate with time post-Fontan. In this cross-sectional study, we assessed 19 children (average age 8.4 ± 4.3 and 5.4 ± 4.1 years post-Fontan) and 8 adults (average age 31.5 ± 8.9 and 21.1 ± 4 years post-Fontan) using standard serum laboratory investigations assessing hepatic integrity and function, the FibroTest, liver ultrasound, and transient elastography (FibroScan). In adult Fontan patients, hemoglobin, C-reactive protein, and gamma-glutamyl transpeptidase were significantly increased, and white blood cell and platelet counts were significantly decreased in comparison to the pediatric cohort. International normalized ratio was mildly elevated in both children and adults. FibroTest results were suggestive of fibrosis regardless of time post-Fontan. FibroScan measurements were significantly correlated with time post-Fontan, but the incidence of ultrasound-detected liver abnormalities was variable. No cases of hepatocellular carcinoma were identified. Abnormalities suggestive of FALD occur in both children and adults post-Fontan. Select laboratory tests, and possibly ultrasound and FibroScan in some patients, appear to have the most promise for the non-invasive detection of FALD.

Use of inhaled iloprost for the management of postoperative pulmonary hypertension in congenital heart surgery patients: review of a transition protocol.

Inhaled nitric oxide (iNO) is considered standard therapy for pediatric postcardiac surgical pulmonary hypertension (PH). Limited data suggest that inhaled iloprost (inIlo), an aerosolized prostacyclin, may be a feasible and more affordable therapeutic alternative. The goal of this study was to determine if significant hemodynamic change or adverse events would occur in postoperative congenital heart surgery (CHS) patients with PH after their transition from iNO to inIlo. This retrospective review investigated CHS patients with postoperative PH (mean pulmonary artery pressure [mPAP] >25 mmHg) between January 1, 2010 and December 31, 2011 who transitioned from iNO to inIlo. By protocol, CHS patients receiving stable doses of iNO were gradually transitioned to inIlo. After full transition, the patients received inIlo every 2 h, with a final dosing range of 1.25-5 µg/dose. Both PAP and systemic arterial pressure (SAP) were invasively measured during the transition period. Seven patients ages 10 days to 1.5 years completed the protocol. Measurements of mPAP (p = 0.27) and systolic PAP (p = 0.25) did not differ between iNO and inIlo therapy alone. No serious adverse events or complications (bleeding or thrombocytopenia) occurred. The ratio of systolic PAP to SAP decreased in all patients receiving inIlo alone (p = 0.03). Pulmonary hypertension in postoperative CHS patients can be managed successfully with inIlo, and the measured hemodynamics with this agent are similar to those observed with iNO. For the management of postoperative PH, inIlo may be a reasonable alternative, thus reducing the need for costly iNO. Larger confirmatory studies would more robustly facilitate its integration into standard care.

Echocardiographic evaluation of ventricular function in children with pulmonary hypertension.

Although described in adults, it remains unclear whether ventricular dysfunction exists in pediatric patients with pulmonary hypertension (PHN). The goal of this study was to identify differences in echocardiographic indices of ventricular function among pediatric PHN patients. From 2009 to 2011, pediatric PHN patients with normal intracardiac anatomy and age-matched controls (1:3 ratio) were enrolled in this retrospective case-control study. Diagnosis of PHN was based on tricuspid regurgitation velocity or septal position estimating right-ventricular (RV) pressure >50 % systemic. Measures of RV and left ventricular systolic and diastolic function, including tissue Doppler imaging (TDI) of the mitral annulus (MA) and tricuspid annulus (TA), were compared. Enrollees included 25 PHN patients and 75 age-matched controls (mean age 7.5 years [range 1 day to 19 years]). Parameters of RV systolic and diastolic function were worse in PHN patients. Compared with controls, PHN patients had significantly decreased tricuspid valve inflow ratio, decreased TA TDI early diastolic velocities, decreased systolic velocities, increased tricuspid E/E' ratio (all p < 0.01) and increased myocardial performance index. In an age-stratified analysis, TDI measures in PHN patients <1 year of age were similar to controls, whereas differences in TA TDI velocities and MA TDI velocities were noted in patients ≥1 year of age. Abnormalities in Doppler echocardiographic indices of ventricular systolic and diastolic function were identified in pediatric PHN patients and were more prominent with older age. These indices are promising for serial noninvasive monitoring of disease severity, but further correlation with catheterization-derived measures is needed.

Drug treatment of pulmonary hypertension in children.

Pulmonary arterial hypertension (PAH) is a rare disease in infants and children that is associated with significant morbidity and mortality. The disease is characterized by progressive pulmonary vascular functional and structural changes resulting in increased pulmonary vascular resistance and eventual right heart failure and death. In the majority of pediatric patients, PAH is idiopathic or associated with congenital heart disease and rarely is associated with other conditions such as connective tissue or thromboembolic disease. Although treatment of the underlying disease and reversal of advanced structural changes has not yet been achieved with current therapy, quality of life and survival have been improved significantly. Targeted pulmonary vasodilator therapies, including endothelin receptor antagonists, prostacyclin analogs, and phosphodiesterase type 5 inhibitors, have demonstrated hemodynamic and functional improvement in children. The management of pediatric PAH remains challenging, as treatment decisions continue to depend largely on results from evidence-based adult studies and the clinical experience of pediatric experts. This article reviews the current drug therapies and their use in the management of PAH in children.