Multimodal Assessment and Intramodal Comparison of Imaging Techniques for Pediatric Pulmonary Vein Stenosis with Pulmonary Hypertension.

Pulmonary vein stenosis (PVS) is a rare, serious, and progressive disease in the pediatric population. Evaluation is complex and involves multimodality imaging. Diagnosis is important as early treatment to prevent progressive pulmonary hypertension and right ventricular dysfunction is essential. Adult studies have shown good correlation between various imaging modalities; however, there are limited data in children. This is a single-center retrospective pilot study to determine the reliability of measurement of pulmonary vein stenosis and pulmonary hypertension across different imaging modalities-computed tomography angiography (CTA), echocardiography (echo), lung perfusion scan (LPS), and cardiac catheterization (cath). PVS was defined as > 2 mmHg by echo and cath and/or 50% reduction in diameter by CTA. Patients had to have an echo, CTA and cath performed within a 1-month timeframe of one another to be included in the study, with LPS data included if testing was completed at initial evaluation. Fifteen total patients were enrolled; 87% were categorized as primary PVS; a condition not directly related to direct injury or prior surgical intervention. Twenty-seven total stenotic pulmonary veins were identified (mean 1.8, range 1-4). CTA had a slightly better agreement with cath than echo in identifying PVS in different vein locations except in the LLPV. Additionally, echo and CTA had excellent sensitivity (91%) and specificity (100%) compared to cath for diagnosis of PH. We conclude that non-invasive imaging of echo and CTA has an acceptable correlation to cardiac catheterization for screening and initial evaluation of PVS and PH, as directly related to PVS, in pediatrics.

The Effect of Udenafil on Heart Rate and Blood Pressure in Adolescents With the Fontan Circulation.

The Fontan Udenafil Exercise Longitudinal (FUEL) trial showed that treatment with udenafil was associated with improved exercise performance at the ventilatory anaerobic threshold in children with Fontan physiology. However, it is not known how the initiation of phosphodiesterase 5 inhibitor therapy affects heart rate and blood pressure in this population. These data may help inform patient selection and monitoring after the initiation of udenafil therapy. The purpose of this study is to evaluate the effects of udenafil on vital signs in the cohort of patients enrolled in the FUEL trial. This international, multicenter, randomized, double-blind, placebo-controlled trial of udenafil included adolescents with single ventricle congenital heart disease who had undergone Fontan palliation. Changes in vital signs (heart rate [HR], systolic [SBP] and diastolic blood pressure [DBP]) were compared both to subject baseline and between the treatment and the placebo groups. Additional exploratory analyses were performed to evaluate changes in vital signs for prespecified subpopulations believed to be most sensitive to udenafil initiation. Baseline characteristics were similar between the treatment and placebo cohorts (n = 200 for each). The groups demonstrated a decrease in HR, SBP, and DBP 2 hours after drug/placebo administration, except SBP in the placebo group. There was an increase in SBP from baseline to after 6-min walk test in the treatment and placebo groups, and the treatment group showed an increase in HR (87.4 ± 15.0 to 93.1 ± 19.4 beats/min, p <0.01) after exercise. When comparing changes from baseline to the 26-week study visit, small decreases in both SBP (-1.9 ± 12.3 mm Hg, p = 0.03) and DBP (-3.0 ± 9.6 mm Hg, p <0.01) were seen in the treatment group. There were no clinically significant differences between treatment and placebo group in change in HR or blood pressure in the youngest age quartile, lightest weight quartile, or those on afterload-reducing agents. In conclusion, initiation of treatment with udenafil in patients with Fontan circulation was not associated with clinically significant changes in vital signs, implying that for patients similar to those enrolled in the FUEL trial, udenafil can be started without the requirement for additional monitoring after initial administration.

Multicenter review of a tadalafil suspension formulation for infants and children with pulmonary hypertension: A North American experience.

Introduction: Phosphodiesterase type 5 (PDE5) inhibitors, with sildenafil the earliest among them, are widely used in the management of pediatric pulmonary arterial hypertension (PAH). Tadalafil is a PDE5 inhibitor with a long half life (16 h), stable pharmacokinetics and pharmacodynamics, and minimal adverse effects. However, the utility of tadalafil suspensions in this setting has not been widely explored due to a lack of clinical experience. We present a multicenter experience that details the safety and tolerability of a tadalafil suspension, either alone or in combination with another vasodilator, for the management of pediatric pulmonary hypertension (PH). Methods and materials: This is a retrospective chart review of infants and children at Children's Wisconsin and the Stollery Children's Hospital enrolled in pediatric PH programs between December 2013 and April 2022 managed with a tadalafil suspension. Patients aged six years of age and under who were treated with a tadalafil suspension were included. Demographics, clinical information, echocardiographic and hemodynamic measurements, and laboratory data were collected before and six months after tadalafil initiation. Results: Over the study period, 154 children with a median age of 1.0 (range 0.0-6.9) years were treated with tadalafil therapy. Of these, 39 (25.3%) were in group 1 (PAH), 79 (51.3%) were in group 3 (lung disease), and 33 (21.4%) were in group 5 (pulmonary hypertensive vascular disease). The median initial dose of tadalafil was 1.0 mg/kg once daily. Eleven (7.1%) patients in the cohort were established on tadalafil therapy de novo. The suspension formulation was necessary for 103 (66.9%) patients due to an inability to take enteral tablets and for 49 (31.8%) due to a need for feeding via gastric or jejunal tubes. We observed a statistically significant increase in tricuspid annular plane systolic excursion as well as significant decreases in right-ventricular systolic pressure and NT-proBNP. Tadalafil therapy was well tolerated over the six-month period: at six months, no adverse effects were reported aside from gastrointestinal disturbances by 2 (1.3%) patients. Conclusion: Tadalafil, a long-acting PDE5 inhibitor, when administered in a suspension formulation, has a safe and tolerable adverse effect profile. Following six months of therapy, our cohort showed improvements in clinical parameters, echocardiographic measurements, and laboratory results. Patient compliance was good and adverse effects were rare, minor, and manageable with nonpharmacological means.

Pulmonary Vein Stenosis: Moving From Past Pessimism to Future Optimism.

Pulmonary Vein Stenosis (PVS) is a rare disease with a prevalence of around 1. 7 cases per 100,000 children under 2 years old. Treatment options for this disease have not provided great results and pathophysiology of this condition is still poorly understood. Here, we will review the history of PVS including diagnostic tools and treatments, the current management approach, and what the future holds for this devastating disease.

Pulmonary-to-Systemic Arterial Shunt to Treat Children With Severe Pulmonary Hypertension.

BACKGROUND: The placement of a pulmonary-to-systemic arterial shunt in children with severe pulmonary hypertension (PH) has been demonstrated, in relatively small studies, to be an effective palliation for their disease. OBJECTIVES: The aim of this study was to expand upon these earlier findings using an international registry for children with PH who have undergone a shunt procedure. METHODS: Retrospective data were obtained from 110 children with PH who underwent a shunt procedure collected from 13 institutions in Europe and the United States. RESULTS: Seventeen children died in-hospital postprocedure (15%). Of the 93 children successfully discharged home, 18 subsequently died or underwent lung transplantation (20%); the mean follow-up was 3.1 years (range: 25 days to 17 years). The overall 1- and 5-year freedom from death or transplant rates were 77% and 58%, respectively, and 92% and 68% for those discharged home, respectively. Children discharged home had significantly improved World Health Organization functional class (P < 0.001), 6-minute walk distances (P = 0.047) and lower brain natriuretic peptide levels (P < 0.001). Postprocedure, 59% of children were weaned completely from their prostacyclin infusion (P < 0.001). Preprocedural risk factors for dying in-hospital postprocedure included intensive care unit admission (hazard ratio [HR]: 3.2; P = 0.02), mechanical ventilation (HR: 8.3; P < 0.001) and extracorporeal membrane oxygenation (HR: 10.7; P < 0.001). CONCLUSIONS: A pulmonary-to-systemic arterial shunt can provide a child with severe PH significant clinical improvement that is both durable and potentially free from continuous prostacyclin infusion. Five-year survival is comparable to children undergoing lung transplantation for PH. Children with severely decompensated disease requiring aggressive intensive care are not good candidates for the shunt procedure.

Pulmonary Hypertension as a Complication of Pediatric Cancer.

Pediatric cancer is a life threatening disease known to create multi-organ complications that further compromise medical management affecting patient morbidity and mortality. Pulmonary hypertension (PH) is becoming more recognized as a complication of cancer and its therapies but has not been well characterized in pediatrics. Cancer pathophysiology can be uniquely set up to promote pulmonary vascular injury and remodeling that is similar to PH patients without cancer. This highlights the need to evaluate for PH clinically and with routine testing such as echocardiography during the course of a patient's care even into adulthood. This review article will discuss the direct, indirect and therapy related aspects of cancer which can promote PH in these patients. This understanding is essential to target effective treatment options in a potentially fatal complication. Diagnostic and treatment algorithms are presented in relation to the most recent pediatric PH management guidelines.

Pharmacokinetics of Oral Treprostinil in Children With Pulmonary Arterial Hypertension.

As part of a clinical trial, this study examined the pharmacokinetics (PK) of oral treprostinil (TRE) in children with pulmonary arterial hypertension. The trial consisted of the following 3 cohorts: transition from parenteral (cohort 1) or inhaled (cohort 2) TRE, or de novo addition (cohort 3). Oral TRE was dosed 3 times daily. PK samples were obtained before an oral TRE dose, and at 2, 4, 6, and 8 hours thereafter. The PK parameters were calculated using noncompartmental analysis. Thirty-two children (n = 10 in cohorts 1 and 2, n = 12 in cohort 3) were enrolled; the median age was 12 years (range 7-17 years), and the median weight was 42.2 kg (range 19.3-78 kg). The median oral TRE dose for all subjects was 3.8 mg (5.9, 3.5, and 4.0 mg for cohorts 1, 2, and 3, respectively). The TRE concentration versus time profile demonstrated a peak concentration at a median of 3.8 hours with wide variability. In cohort 1, oral dosing led to higher peak (5.9 ng/mL) and lower trough (1 ng/mL) concentrations than parenteral (peak 5.4 ng/mL and trough 4.2 ng/mL), but a lower mean concentration (3.61 vs. 4.46 ng/mL), likely due to variable metabolism and noncomparable dosing. Both the area under the curve and average concentration were linearly correlated with oral TRE dose and dose normalized to body weight, but not with weight or age alone. In pediatric patients, an increased oral TRE dose or dose frequency may be required to minimize PK variability and achieve greater correlation with parenteral dosing.

Oral treprostinil in transition or as add-on therapy in pediatric pulmonary arterial hypertension.

Treprostinil, a prostacyclin analogue, is approved for the treatment of pulmonary arterial hypertension (PAH) in adults. Transition from parenteral to oral treprostinil has been successfully accomplished in adults with PAH but not in children. In this multicenter study, pediatric patients treated with parenteral (Cohort 1) or inhaled (Cohort 2) treprostinil were transitioned to oral treprostinil. Prostacyclin-naïve individuals on background oral PAH therapy received oral treprostinil as add-on therapy (Cohort 3). Successful transition was oral treprostinil dose maintenance through week 24. Patients were monitored for adverse events (AEs), 6-min walk distance (6MWD), PAH symptoms, World Health Organization (WHO) Functional Class (FC), cardiac magnetic resonance imaging (cMRI), cardiopulmonary exercise testing (CPET), and quality of life through 24 weeks. A total of 32 patients were enrolled in the study; 23 (72%) were girls (mean age = 12.2 years). All patients were on background oral PAH therapy. Overall, patients (96.9%) maintained transition to oral treprostinil; one patient (Cohort 1) transitioned to oral treprostinil, then back to parenteral after experiencing syncope and WHO FC change from II to III. Cohorts 1, 2, and 3 received a final mean oral treprostinil dose of 5.6, 3.3, and 4.5 mg t.i.d., respectively. All cohorts had variable changes in 6MWD, cMRI, and CPET. Overall, 12 serious AEs were reported. All patients had drug-related AEs including headache (81%), diarrhea (69%), nausea (66%), vomiting (66%), and flushing (56%). Pediatric patients maintained transition to oral treprostinil with preservation of exercise capacity and WHO FC. Prostanoid-related AEs were most common and similar to those reported in adults.

Assessment of quality of life in pediatric patients with pulmonary hypertension.

The aim of this study is to evaluate quality of life in four domains (physical, emotional, social, and school) in pediatric patients with pulmonary hypertension (PH) using a validated survey (PedsQL). This is a prospective cohort study of pediatric patients aged 2-18 years with PH. Parents of all children and patients aged 8-18 years with appropriate developmental capacity completed the PedsQL survey in the clinic. Results were compared with published norms for pediatric patients, those with congenital heart disease (CHD) and cancer. Thirty-three children were enrolled yielding 32 parent and 18 patient self-reports: seven patients were aged 2-4 years; three were aged 5-7 years; 11 were aged 8-12 years, and 12 were aged 13-18 years. Twenty-one patients were classified as World Health Organization (WHO) Group I pulmonary arterial hypertension (PAH), 11 WHO Group III PH due to lung disease, and one WHO Group V with segmental PH. Thirteen patients were NYHA functional class (FC) 1, 12 were FC 2, eight were FC 3, and none were FC 4. The PH cohort had significantly lower scores than healthy children in all domains on both parent and self-report. The PH cohort also had significantly lower scores than patients with CHD (parent report: total, physical, social, school; patient self-report: total, physical, school) and cancer (parent report: school; patient self-report: physical, school). Close to 50% of participants reported at risk scores in each domain. The quality of life in pediatric PH patients assessed by PedsQL revealed functional impairment in multiple domains. Administration of the PedsQL during outpatient encounters may provide an easy, reproducible method to assess quality of life and direct referral for interventional services.

Pulmonary Vein Doppler Patterns in Infants with Single Right Ventricle Anomalies After Initial Staged Palliations.

The aim of this study was to describe serial changes in echocardiographic Doppler pulmonary vein flow (PVF) patterns in infants with single right ventricle (RV) anomalies enrolled in the Single Ventricle Reconstruction trial. Measurement of PVF peak systolic (S) and diastolic (D) velocities, velocity time integrals (VTI), S/D peak velocity and VTI ratios, and frequency of atrial reversal (Ar) waves were made at three postoperative time points in 261 infants: early post-Norwood, pre-stage II surgery, and 14 months. Indices were compared over time, between initial shunt type [modified Blalock-Taussig shunt (MBTS) and right ventricle-to-pulmonary artery shunt (RVPAS)] and in relation to clinical outcomes. S velocities and VTI increased over time while D wave was stable, resulting in increasing S/D peak velocity and VTI ratios, with a median post-Norwood S/D VTI ratio of 1.14 versus 1.38 at pre-stage II and 1.89 at 14 months (P < 0.0001 between intervals). MBTS subjects had significantly higher S/D peak velocity and VTI ratios compared to RVPAS at the post-Norwood and pre-stage II time points (P < 0.0001) but not by 14 months. PVF patterns did not correlate with survival or hospitalization course at 1 year. PVF patterns after Norwood palliation differ from normal infants by having a dominant systolic pattern throughout infancy. PVF differences based upon shunt type resolve by 14 months and did not correlate with clinical outcomes. This study describes normative values and variations in PVF for infants with a single RV from shunt-dependent pulmonary blood flow to cavopulmonary blood flow.

Predicting the Need for Neoaortic Arch Intervention in Infants with Hypoplastic Left Heart Syndrome Through the Glenn Procedure.

Neoaortic recoarctation is present in up to over one-third of patients having undergone the Norwood procedure for hypoplastic left heart syndrome. Some of these patients will require reintervention by catheterization or surgery through the time of the Glenn procedure. Echocardiography and catheterization are often utilized in this period to assess hemodynamics although no specific criteria have been identified to predict whether and when neoaortic arch reintervention will be needed. We sought to identify predictors, including but not limited to echocardiographic and catheterization gradients, to predict such intervention. A retrospective analysis was conducted including patients with hypoplastic left heart syndrome. Patients with significantly comorbid lesions such as isomerism, anomalous pulmonary venous connections, and significant atrioventricular valve insufficiency were excluded as were patients without interstage echocardiographic and catheterization data. Receiver operator curve analysis was performed to establish peak-value gradients by echocardiography and catheterization that were predictive of neoaortic reintervention from the time of the Norwood through the time of the Glenn. These values were then entered into a multivariate regression with several other factors to determine what factors were predictive of need for such intervention. Bland-Altman analysis was conducted to compare echocardiographic and catheterization gradients. A peak echocardiographic gradient of 26 mmHg (100 % sensitivity, 85 % specificity) and a peak-to-peak catheterization gradient of 8.5 mm Hg (83 % sensitivity, 86 % specificity) were found to be predictive of need for neoaortic arch reintervention after multivariate analysis. Echocardiographic and catheterization gradients were found to have poor correlation with one another. A peak gradient of 26 mmHg or greater by echocardiography and a peak-to-peak gradient of 8.5 mmHg or greater by catheterization after the Norwood but prior to the Glenn are predictive of need for neoaortic reintervention through the time of the Glenn hospitalization.

Role of the Egami Score in Predicting Intravenous Immunoglobulin Resistance in Kawasaki Disease Among Different Ethnicities.

Early treatment with intravenous immunoglobulin (IVIG) is necessary to help reduce the risk of coronary artery abnormalities, such as coronary artery aneurysms and to help alleviate symptoms, in Kawasaki disease. Some patients, however, do not respond to an initial dose of IVIG and require additional doses. Prediction of these IVIG nonresponders may be of assistance in altering initial therapy to make it more effective. The Egami score has been validated in the Japanese population to predict IVIG nonresponders but has shown to be ineffective in US populations. This study evaluates the Egami score in a Midwest US population, subdividing patients by race and the diagnosis of typical or atypical type of Kawasaki disease. Patients were included in the study if they met criteria for Kawasaki disease and received IVIG in the inpatient setting. A total of 182 patients were studied, and in all studied groups, the Egami score had poor sensitivity at predicting IVIG nonresponders. Sensitivity of the score differed between races and differed between typical and atypical Kawasaki disease. The Egami score, as well as other systems, have been validated to predict IVIG nonresponders. These, however, lack sensitivity in the US population. Other scores developed in the United States have also lacked sensitivity, likely due to the absence of race or Kawasaki disease classification as variables. The development of a sensitive scoring system to predict IVIG nonresponders in US populations will require the incorporation of race and Kawasaki disease classification, factors that seem to alter IVIG response.

An Unusual Case of Severe Stenosis of the Coronary Sinus Ostium in Association With Double Inlet Left Ventricle.

We present a patient with complex single ventricle physiology who was subsequently diagnosed with atresia of the coronary sinus ostium in the setting of myocardial dysfunction following operative palliation. Although a rare cardiac defect, awareness is important as the coronary venous system will often drain to a left superior vena cava (LSVC). If the LSVC is ligated without knowing of this defect, cardiac dysfunction and death can occur.

Echocardiography in pediatric pulmonary hypertension.

Pediatric pulmonary hypertension is a complicated disease with multiple etiologies and high mortality. Echocardiography is at the forefront of evaluation as a noninvasive, portable imaging modality that can yield diagnostic and prognostic information regarding this disease. Echocardiography is known for its ability to give an anatomic assessment of the heart and proximal blood vessels. With the additional use of Doppler echocardiography and myocardial motion assessment, the effects of elevated pulmonary pressures on the heart can be evaluated. This can allow for estimation of pulmonary artery pressures and resistances and assessment of ventricular systolic and diastolic functions. However despite its advantages, echocardiography is still an indirect assessment of pulmonary hypertension and not a substitute for cardiac catheterization. The purpose of this review is to discuss common techniques for the assessment of pulmonary hypertension by echocardiography as well as their limitations.

Etanercept as adjunctive treatment for acute Kawasaki disease: study design and rationale.

BACKGROUND: Kawasaki disease (KD) is a multisystem vasculitis affecting coronary arteries in children. Patients, refractory to standard treatment with intravenous immunoglobulin and aspirin, show higher rates of coronary artery dilation. Early tumor necrosis factor α receptor antagonism in KD may provide effective adjunctive therapy. STUDY DESIGN: The EATAK trial is a multicenter, double-blind, randomized, and placebo-controlled trial intended to assess the efficacy of etanercept in reducing the intravenous immunoglobulin refractory rate during treatment of acute KD. Each arm will enroll 110 patients who will receive 3 doses of study drug over 2 weeks in conjunction with standard therapy. Coronary artery dilation parameters will serve as secondary end points. DISCUSSION: The EATAK trial will test a new paradigm for treatment of acute KD involving tumor necrosis factor α antagonism by etanercept.

A single center's experience with the Ross procedure in pediatrics.

The use of a pulmonary autograft for aortic valve replacement (AVR) has become more prevalent than other forms of AVR in the pediatric population. We reviewed the data on pediatric patients who underwent the Ross procedure at our institution from 1993 to 2005. Sixty patients <18 years old who underwent a Ross procedure had available clinical and echocardiographic data collected and statistical analysis performed. Mortality rate was 3.3%, while overall survival and freedom from reoperation of either the homograft or the autograft were 96.7% and 66.2%, respectively, at 10 years. Freedom from reoperation of the left ventricular outflow tract was 60.5% at 10 years. Echocardiographic data showed aortic regurgitation to be mild or less in 76% of patients by last follow-up, while dilation of the sinuses of Valsalva had occurred in 52%. Compared to other AVR options, the Ross procedure in eligible pediatric patients demonstrates good intermediate survival rates and continued growth potential, yet a time-dependent need for reoperation.