Corrigendum: Case report: Selexipag in pediatric pulmonary hypertension: initiation, transition, and titration.

[This corrects the article DOI: 10.3389/fped.2023.1050508.].

Case Report: Selexipag in pediatric pulmonary hypertension: Initiation, transition, and titration.

Selexipag, a selective prostacyclin receptor agonist, is approved for treating pulmonary arterial hypertension in WHO Group 1 adult patients. Compared to parenteral prostacyclin formulations, selexipag offers a significant improvement in patient's and caregiver's quality of life because of its oral formulation, frequency of administration, and mechanism of action. Although experience in the pediatric population is limited to case reports in older adolescent patients and selexipag is not approved for use in the pediatric pulmonary hypertension population, many pediatric centers are expanding the use of this therapy to this population. We report our institution's experience in the use of selexipag to treat pulmonary hypertension in children under 10 years of age, between 10 and 30 kg. Seven patients were initiated on selexipag therapy including de novo initiation and transition from intravenous treprostinil to oral selexipag. All patients were on stable background therapy with phosphodiesterase-5 inhibitor and endothelin receptor antagonist therapies at baseline. All patients reached their planned goal selexipag dose during admission without the need for changes to the titration schedule and without hemodynamic deterioration. In our experience, oral selexipag is safe and well-tolerated in young pediatric patients with pulmonary hypertension. Based on our favorable experience, we developed an institution-specific selexipag process algorithm for continued successful use in the pediatric population.

Surgical and Cardiac Catheterization Outcomes of Scimitar Syndrome Patients: A Three Decade Single-Center Experience.

Scimitar syndrome (SS) is a rare congenital condition which includes partial anomalous pulmonary venous return (PAPVR) and a variable degree of pulmonary hypoplasia. We describe the clinical features, therapeutic approach and outcomes of patients who underwent cardiac catheterization and/or surgical repair of the scimitar vein at a single institution in the United States. This retrospective cohort study included all patients with SS who underwent scimitar vein surgical repair or cardiac catheterization from October 1989 through August 2021 in a tertiary care center. A total of 84 patients with SS were included and median follow-up time was 74 months. Patients diagnosed with SS under the age of one year had a significantly greater incidence of congenital heart defects (CHD) (p < 0.001), non-cardiac anomalies (p = 0.02), pulmonary hypertension (p = 0.02), and mortality (p = 0.04) compared to those diagnosed over the age of 1 year. Twenty-eight patients underwent surgical repair of the scimitar vein. Overall, eight (10%) patients died. Compared to surviving patients, deceased patients had a significantly higher incidence of pulmonary hypertension (PH), neonatal SS diagnosis, and extracorporeal membrane oxygenation (ECMO) support. Median scimitar vein pressure (20 mmHg) of deceased patients was significantly higher compared to pressures in surviving patients (11 mmHg; p = 0.02). PH, CHD, neonatal SS diagnosis, ECMO support, and markedly elevated scimitar vein pressure are associated with mortality. Scimitar vein surgical repair during infancy is commonly associated with PH and restenosis that requires re-intervention.

Impact of surfactant when utilized during pediatric cardiac surgery admissions: analysis of a nationwide database.

OBJECTIVE: Surfactant has been routinely used in the neonatal population, particularly in the setting of prematurity and neonatal respiratory distress syndrome. Current evidence, however, does not delineate the effect of surfactant use in neonates and older children during cardiac surgery admissions. This study aimed to characterize the impact of surfactant on pediatric cardiac surgery admissions. METHODS: Admissions of those under 18 years of age with cardiac surgery were identified from the Pediatric Health Information System (PHIS) database between 2004 and 2015, using ICD-9 procedure codes. Univariate analyses were conducted to compare admission characteristics between those that did and not utilize surfactant. Variables shown to be significant were then entered as independent variables into the regression analyses. Surfactant was entered into each model as an independent variable. RESULTS: A total of 81,313 admissions met the inclusion criteria. Of these, 109 (0.1%) had surfactant utilized. Univariate analyses identified several differences between admissions with and without surfactant use and demonstrated significantly increased mortality in the surfactant group (38.5% versus 4.6%, p < .01). Regression analyses demonstrated that surfactant was independently associated with increased mortality (odds ratio 6.0, 95% confidence interval 3.9-9.3, p < .01). Univariate analysis in only surfactant admissions demonstrated the following to be associated with inpatient mortality: younger age, prematurity, Ebstein anomaly, and hypoplastic left heart syndrome. CONCLUSIONS: Surfactant administration during pediatric cardiac surgery admissions is independently associated with a sixfold increase in inpatient mortality. It is likely that these findings are mediated by augmentation of the decrease in pulmonary vascular resistance and a subsequent decrease in systemic blood flow in the setting of parallel circulation. Surfactant should be administered with special consideration in neonates with cardiac disease and may be best avoided in those with parallel circulation.

Outcomes of COVID-19 infection in pediatric pulmonary hypertension: A single-center experience.

BACKGROUND: The global COVID-19 pandemic was particularly concerning for the pediatric pulmonary hypertension (PH) population due to immature immune systems and developmental comorbidities. This study aims to describe a single-center experience of pediatric PH patients diagnosed with COVID-19 disease. METHODS: A retrospective cohort study of all pediatric patients followed by the PH Center at Texas Children's Hospital diagnosed with COVID-19 infection from April 2020 to February 2021. RESULTS: We identified 23 patients with a median age of 58 months (interquartile range [IQR]: 25-75th, 21-132 months), 48% being Hispanics. Eight patients (35%) required hospitalization; median length of stay was 6 days (IQR: 25-75th, 5-8 days). Only three of these eight patients required increased respiratory support. Targeted PH therapy was escalated in four patients (two in dual and two in triple therapy). There was one mortality in a patient with failing Fontan physiology. Ninety-one percent of patients have had post-COVID outpatient follow-up, median of 101 days (IQR: 25-75th, 50-159 days) from diagnosis. Of the five patients with 6 min walk test (6MWT) data, three (60%) children walked less distance, median of -12 m (IQR: 25-75th, -12 to +49 m) compared to pre-COVID testing. Postinfection pulmonary function testing (PFT) was notable for decrease in predicted forced vital capacity (FVC; median -6%, range -11% to +6%) and forced expiratory volume in one second (FEV1; median -14%, range -12% to -18%) in 75% of the patients with PFT data. CONCLUSION: In our institution, COVID-19 was found more frequently in Hispanics and associated with low mortality.

Epidemiology of Pediatric Heart Failure in the USA-a 15-Year Multi-Institutional Study.

The epidemiology of pediatric heart failure (HF) has been characterized for congenital heart disease (CHD) and cardiomyopathies (CM), but the impact of CM associated with CHD has not been studied. This study aims to describe the characteristics and outcomes of inpatient pediatric HF patients with CHD, CM, and CHD with CM (CHD + CM) across the USA. We included all HF patients with CM diagnoses with and without CHD using ICD 9/10 codes ≤ 19 years old from January 2004 to September 2019 using the Pediatric Health Information System database. We identified 67,349 unique patients ≤ 19 years old with HF, of which 87% had CHD, 7% had CHD + CM, and 6% had CM. Pediatric HF admissions increased significantly from 2004 to 2018 with an associated increase in extracorporeal circulatory support (ECLS) use. Heart transplantation (HTX) increased only in the CHD and CHD + CM groups. CHD patients required less ECLS with and without HTX; however, they had significantly higher inpatient mortality after those procedures than the other groups (p < 0.001). CM patients were older (median 115 months) and had the lowest inpatient mortality after HTX with and without ECLS (p < 0.05). CHD + CM showed the highest overall inpatient mortality (15%), and cumulative hospital billed charges (median US$ 541,374), all p < 0.001. Pediatric HF admissions have increased from 2004 to 2018. ECLS use and HTX have expanded in this population, with an associated decrease in inpatient mortality in the CHD and CM groups. CHD + CM patients are a growing population with the highest inpatient mortality.

Congenital heart disease and cardiac procedural outcomes in patients with trisomy 21 and Turner syndrome.

Congenital heart disease (CHD) is present in approximately 50% of patients with trisomy 21 (T21) and Turner syndrome (TS). According to the American Academy of Pediatrics, every patient with these genetic disorders should have a postnatal echocardiogram. T21 is usually associated with atrioventricular (30%-60%), atrial (16%-21%), or ventricular septal defects (14%-27%). TS is usually associated with left-sided heart disease. However, the spectrum of CHD in these genetic disorders is wider than those mentioned lesions. More cardiac surgical procedures are offered to these patients and that has influenced positively their life expectancy for some CHD conditions. Single ventricular anatomy is associated with high mortality in these genetic disorders (49% in T21 and 83%-91% in TS). The goal of this article is to describe the spectrum of CHD, screening guidelines, and cardiac surgical outcomes in patients with T21 or TS with CHD.

Trend of Endurance Level Among Healthy Inner-City Children and Adolescents Over Three Decades.

The aim of this study was to understand how endurance time, a proxy for physical fitness, has changed in healthy inner-city children and adolescents in the past three decades. This was a retrospective cross-sectional study. This study used exercise stress test in a laboratory of an inner-city teaching hospital. We reviewed all consecutive healthy children and adolescents who underwent an exercise Bruce protocol treadmill test from 1983 to 2010. The study population was divided into five groups of 5-year intervals based on the year of testing. Temporal trend in endurance time was analyzed, adjusting for gender, ethnicity, age, and body mass index (BMI). We analyzed the records of 435 healthy children and adolescents (mean age 12.6 ± 3.2 years, 57% males).There was a significant difference in the mean endurance time between children grouped in 5-year intervals (P < 0.001) with a significant downward trend in endurance time over the years (P < 0.001), especially after 2001. In contrast, there was no statistically significant change in the mean BMI between children grouped in 5-year intervals (P = 0.205). Multivariate linear regression model demonstrated that the date of testing was independently predictive of endurance time, adjusting for age, gender, BMI, and ethnicity (P < 0.001). Gender was the strongest independent predictor of endurance time, followed by age, BMI, and ethnicity. There is a downward trend in endurance time over the 27-year period among inner-city children and adolescents. Temporal decline in endurance time was independent of factors known to affect this parameter, such as age, gender, BMI, and ethnicity. Factors such as deconditioning due to sedentary lifestyle and lack of motivation to endure on the treadmill among later generations may have played a role in such decline.

Severe chronic kidney disease as a predictor of benefit from aminophylline administration in patients undergoing regadenoson stress myocardial perfusion imaging: A substudy of the ASSUAGE and ASSUAGE-CKD trials.

BACKGROUND: Regadenoson is predominantly renally metabolized. Patients with severe chronic kidney disease (CKD) experience more frequent gastrointestinal adverse effects (AE) from regadenoson. Aminophylline use following regadenoson reduces the incidence of regadenoson-related AE. We investigated whether patients with severe CKD receive incremental benefit from aminophylline administration in reducing regadenoson AE. METHODS: We performed post hoc analysis of the pooled database of the ASSUAGE and ASSUAGE-CKD trials. These were randomized placebo-controlled clinical trials which tested the benefit of intravenous aminophylline vs placebo after regadenoson injection in patients undergoing a clinically indicated stress MPI. Patients were categorized into two treatment arms: aminophylline vs placebo; and two groups: Severe CKD (GFR < 30 mL·min(-1)/1.73 m(2) or dialysis) and Control (GFR ≥ 30 mL·min(-1)/1.73 m(2)). The study endpoints were gastrointestinal AE, non-gastrointestinal AE and composite of any regadenoson AE. RESULT: The pooled database of the two trials yielded 548 patients, of whom 274 patients received aminophylline and 274 received placebo. Aminophylline was associated with greater absolute risk reduction (ARR) in gastrointestinal AE among patients with severe CKD vs controls (25% vs 4%, p < .001). A significant interaction was identified between severe CKD and aminophylline in reducing gastrointestinal AE (p = .007), indicating greater reduction in gastrointestinal AE with aminophylline use among patients with severe CKD. Aminophylline use was associated with a trend toward greater ARR in any regadenoson-related AE (32% vs 21%, p = .08). CONCLUSION: Aminophylline is associated with incremental benefit in reducing gastrointestinal AE in patients with severe CKD undergoing regadenoson stress MPI. Potentially, this population could be targeted for prophylactic administration of aminophylline in order to improve their overall experience with the test.

The impact of regimented aminophylline use on extracardiac radioisotope activity in patients undergoing regadenoson stress SPECT myocardial perfusion imaging: a substudy of the ASSUAGE trial.

BACKGROUND: In patients undergoing regadenoson stress SPECT myocardial perfusion imaging (MPI), the impact of the regimented administration of aminophylline on the cardiac-to-extracardiac photon activity ratio is unknown. METHODS: This is a substudy of the ASSUAGE trial (NCT01250496); a double-blinded, randomized, placebo-controlled clinical trial which investigated the attenuation of regadenoson-related adverse effects using 75 mg of intravenous aminophylline vs placebo, administered 90 seconds following (99m)Tc-tetrofosmin injection in patients undergoing regadenoson stress SPECT-MPI. In subjects with normal MPI enrolled in the trial, we sampled from the antero-posterior planar projection of the post-stress scintigraphic data the mean photon activity in the myocardium, liver, bowel, and lungs. The mean cardiac-to-extracardiac activity ratios were compared between patients randomized to aminophylline vs placebo. RESULTS: We studied 158 eligible subjects, randomized to receive aminophylline (n = 86) or placebo (n = 72). The means of photon activity ratios of the heart-to-liver, heart-to-bowel, heart-to-lungs, inferior wall of the heart-to-liver, and inferior wall of the heart-to-bowel were not statistically different between those who received aminophylline vs placebo (P values > .30). Only the time lapse between stress (99m)Tc-tetrofosmin injection and stress SPECT acquisition independently correlated with higher heart-to-liver and heart-to-bowel activity ratios (P values ≤ .01). Patients' body mass index independently correlated with lower heart-to-lung ratio (P = .009). CONCLUSION: The regimented intravenous aminophylline use following regadenoson stress does not significantly improve the cardiac-to-extracardiac photon activity ratio in patients undergoing regadenoson stress (99m)Tc-tetrofosmin SPECT-MPI.

The safety and tolerability of regadenoson in patients with end-stage renal disease: the first prospective evaluation.

BACKGROUND: There has not been any prospective evaluation of the safety and tolerability of regadenoson (REG)-stress in patients with end-stage renal disease (ESRD). METHODS: From the pooled database of two identically designed randomized, double-blinded, placebo-controlled clinical trials, ASSUAGE and ASSUAGE-CKD (IV-aminophylline vs placebo following REG-stress), we extracted the placebo-treated subjects to form 2 study groups: ESRD (dialysis or GFR < 15 mL/minute/1.73 m(2)) and control (GFR ≥ 30). The incidence of REG adverse effects and the hemodynamic and ECG responses to REG-stress were compared. RESULTS: We identified 146 ESRD subjects and 97 controls. There was no significant difference in the incidence of the composite of any REG adverse effect [ESRD 108 (74%) vs control 73 (75%), P = .82]. ESRD patients seem to have excess incidences of diarrhea [42 (29%) vs 14 (14%), P = .009] and fewer events of dizziness [28 (19%) vs 43 (44%), P < .001]. There were no serious adverse events in either group. There was no significant difference in the incidence of ST-segment deviation, tachyarrhythmias, atrioventricular block, or hypotension. CONCLUSION: This is the first prospective study to confirm the safety and tolerability of REG in patients with ESRD.

Attenuation of the side effect profile of regadenoson: a randomized double-blinded placebo-controlled study with aminophylline in patients undergoing myocardial perfusion imaging. "The ASSUAGE trial".

BACKGROUND: It is unknown whether the standardized intravenous aminophylline administration following regadenoson-stress can prevent the gastrointestinal and other adverse effects associated with regadenoson. METHODS: In a randomized, double-blinded, placebo-controlled clinical trial we compared the frequency and severity of regadenoson adverse effects in those who received 75 mg of intravenous aminophylline versus a matching placebo administered 2 minutes after regadenoson or 90 seconds post-radioisotope injection. RESULTS: 248 patients [44.8% women, mean age 62.2 (± 13.3) years] were randomized to receive aminophylline (124) or placebo (124). In the aminophylline arm, there was 50% reduction in the incidence of the primary endpoint of diarrhea and abdominal discomfort [11 (8.9%) vs 22 (17.7%), P = .04] and 70% reduction in the incidence of diarrhea [4 (3.2%) vs 13 (10.5%), P = .02]. Additionally, aminophylline use was associated with 34% reduction in the secondary endpoint of any regadenoson adverse effects [55 (44.4%) vs 83 (66.9%), P < .001] and 71% reduction in headache [9 (7.3%) vs 31 (25%), P < .001]. The stress protocol was better tolerated in the aminophylline group (P = .007). The quantitative summed difference score was similar in both study groups (P = .92). There were no excess adverse events in the aminophylline arm. CONCLUSIONS: This trial supports the routine administration of IV-aminophylline to reduce the frequency and severity of adverse effects associated with regadenoson-stress.