Ventricular Dysfunction in Patients With Congenital Diaphragmatic Hernia Who Die After Repair.

BACKGROUND: Quantitative echocardiographic (echo) measures of ventricular function predict mortality in pediatric pulmonary hypertension (PH), but studies in congenital diaphragmatic hernia (CDH)-related PH are limited. Few studies report quantitative echo data beyond the first week of life in CDH non-survivors. METHODS: A single-center retrospective, cross-sectional, cohort study included CDH patients born between January 2013 and April 2022 who survived to surgical repair but died during the neonatal hospitalization. Quantitative measures of right (RV) and left ventricular (LV) size and function including tricuspid annular plane systolic excursion Z-score (TAPSEZ), RV fractional area change (FAC), RV/LV ratio, LV eccentricity index, LV M-mode dimensions, and RV/LV systolic strain were performed offline on the last echocardiogram before death. Data were compared between patients who died ≤30 days after repair ("early") vs. >30 days after repair ("late") using the Wilcoxon rank sum test. RESULTS: Twenty-five (11 early, 14 late) deceased patients had echo images available for analysis. LV size by end-diastolic dimension Z-score was smaller in patients who died early vs. late after repair [-3.03 (-3.93, -2.51) vs. -0.24 (-2.11, 0.53), p = 0.021]. There were trends toward worse RV function (TAPSEZ, RVFAC, RV global and free wall strain) and LV function (apical 4 chamber strain) in patients who died early vs. late after repair. CONCLUSION: These preliminary findings support future study of the impact of ventricular hypoplasia and dysfunction on mortality and opportunities for risk stratification based on quantitative echo findings in CDH. LEVEL OF EVIDENCE: Cohort study, 4.

Safety and Effectiveness of Selexipag in Pediatric Pulmonary Hypertension: A Retrospective Multicenter Cohort Study.

OBJECTIVE: To describe the safety and effectiveness of treating pediatric patients who have pulmonary arterial hypertension (PAH) with selexipag in a real-world, multicenter cohort, given that data supporting its use in pediatric PAH are sparse. STUDY DESIGN: We report a multicenter, retrospective, cohort study of children with PAH treated with selexipag. Demographic and clinical variables were extracted from the medical records. Clinical parameters were analyzed at 3 timepoints: before selexipag, 3-12 months after selexipag, and >12 months follow-up. RESULTS: Eighty-seven patients were included, 32 received selexipag as add-on to background therapy, and 55 transitioned from another prostanoid. The median starting and final doses were 4.7 and 28.5 µg/kg/dose twice daily, respectively. Add-on patients demonstrated improved indexed pulmonary to systemic vascular resistance ratio after selexipag initiation (PVRi/SVRi, 0.62v0.53; P = .034) with a lower average mean pulmonary artery pressure (46 vs 39 mm Hg; P = NS), and oxygen consumption (maximal oxygen consumption during cardiopulmonary exercise testing [VO2 max] 27.8 mL/kg/min vs 30.9 mL/kg/min; P = NS). Transition patients demonstrated stable mean pulmonary artery pressure (47 mm Hg vs 45 mm Hg; P = NS) and a lower mean indexed pulmonary vascular resistance (10.9 Wood units∗m2 vs 8.2 Wood units∗m2; P = NS) but late functional worsening in some with VO2 max decreased at follow-up (26.0 mL/kg/min vs 19.5 mL/kg/min). Side effects were noted in 40% of the cohort, but prompted discontinuation in only 2%. CONCLUSIONS: In a large, multicenter cohort, the oral prostacyclin agonist selexipag demonstrates favorable tolerability and effectiveness. Add-on patients demonstrated early hemodynamic improvement. Transition patients demonstrated early stability with risk of late functional worsening, highlighting the importance of ongoing monitoring.

An interdisciplinary consensus approach to pulmonary hypertension in developmental lung disease.

It is increasingly recognised that diverse genetic respiratory disorders present as severe pulmonary hypertension (PH) in the neonate and young infant, but many controversies and uncertainties persist regarding optimal strategies for diagnosis and management to maximise long-term outcomes. To better define the nature of PH in the setting of developmental lung disease (DEVLD), in addition to the common diagnoses of bronchopulmonary dysplasia and congenital diaphragmatic hernia, we established a multidisciplinary group of expert clinicians from stakeholder paediatric specialties to highlight current challenges and recommendations for clinical approaches, as well as counselling and support of families. In this review, we characterise clinical features of infants with DEVLD/DEVLD-PH and identify decision-making challenges including genetic evaluations, the role of lung biopsies, the use of imaging modalities and treatment approaches. The importance of working with team members from multiple disciplines, enhancing communication and providing sufficient counselling services for families is emphasised to create an interdisciplinary consensus.

Elevated pulmonary capillary wedge pressure, higher blood pressure, and lower cardiac index in infants with bronchopulmonary dysplasia.

BACKGROUND: Left ventricular diastolic dysfunction indicated by elevated pulmonary capillary wedge pressure (ePCWP) may worsen cardiorespiratory status in bronchopulmonary dysplasia (BPD), but the scope of ePCWP by cardiac catheterization is not well described. METHODS: This single-center retrospective cohort study included infants with BPD without congenital heart disease, significant intracardiac shunts, or pulmonary vein stenosis who underwent cardiac catheterization from 2010 to 2021. ePCWP was defined as >10 mmHg. Quantitative measures of ventricular systolic and diastolic function were performed on existing echocardiograms. Patients with and without ePCWP were compared using the Chi-squared or Wilcoxon rank-sum tests. Associations between catheterization hemodynamics and echocardiographic parameters were assessed by simple linear regression. RESULTS: Seventy-one infants (93% Grade 2 or 3 BPD) met inclusion criteria, and 30 (42%) had ePCWP. Patients with ePCWP were older at catheterization (6.7 vs. 4.5 months, p < 0.001), more commonly underwent tracheostomy (66.7% vs. 29.3%, p = 0.003), and had higher mean systemic blood pressure [64.5 (56.0, 75.0) vs. 47.0 (43.0, 55.0) mm Hg, p < 0.001], higher systemic vascular resistance [11.9 (10.4, 15.6) vs. 8.7 (6.7, 11.2) WU*m2, p < 0.001), and lower cardiac index [3.9 (3.8, 4.9) vs. 4.7 (4.0, 6.3) L/min/m2, p = 0.03] at catheterization. Mean pulmonary artery pressure, pulmonary vascular resistance, and mortality were similar between the groups. Echocardiographic indices of left ventricular diastolic dysfunction did not correlate with PCWP. CONCLUSIONS: ePCWP was common in infants with severe BPD who underwent cardiac catheterization in this cohort. The association between ePCWP and higher systemic blood pressure supports further study of afterload reduction in this population.

Congenital Diaphragmatic Hernia Patients with Left Heart Hypoplasia and Left Ventricular Dysfunction Have Highest Odds of Mortality.

OBJECTIVES: To describe the scope of left ventricular (LV) dysfunction and left heart hypoplasia (LHH) in infants with congenital diaphragmatic hernia (CDH), to determine associations with CDH severity, and to evaluate the odds of extracorporeal membrane oxygenation (ECMO) and death with categories of left heart disease. STUDY DESIGN: Demographic and clinical variables were collected from a single-center, retrospective cohort of patients with CDH from January 2017 through May 2022. Quantitative measures of LV function and LHH were prospectively performed on initial echocardiograms. LHH was defined as ≥2 of the following: z score ≤ -2 of any left heart structure or LV end-diastolic volume <3 mL. LV dysfunction was defined as shortening fraction <28%, ejection fraction <60%, or global longitudinal strain <20%. The exposure was operationalized as a 4-group categorical variable (LV dysfunction +/-, LHH +/-). Logistic regression models evaluated associations with ECMO and death, adjusting for CDH severity. RESULTS: One hundred eight-two patients (80.8% left CDH, 63.2% liver herniation, 23.6% ECMO, 12.1% mortality) were included. Twenty percent demonstrated normal LV function and no LHH (LV dysfunction-/LHH-), 37% normal LV function with LHH (LV dysfunction-/LHH+), 14% LV dysfunction without LHH (LV dysfunction+/LHH-), and 28% both LV dysfunction and LHH (LV dysfunction+/LHH+). There was a dose-response effect between increasing severity of left heart disease, ECMO use, and mortality. LV dysfunction+/LHH + infants had the highest odds of ECMO use and death, after adjustment for CDH severity [OR (95% CI); 1.76 (1.20, 2.62) for ECMO, 2.76 (1.63, 5.17) for death]. CONCLUSIONS: In our large single-center cohort, patients with CDH with LV dysfunction+/LHH + had the highest risk of ECMO use and death.

Factors associated with discontinuation of pulmonary vasodilator therapy in children with bronchopulmonary dysplasia-associated pulmonary hypertension.

OBJECTIVE: To evaluate factors associated with discontinuation of pulmonary vasodilator therapy in bronchopulmonary dysplasia-related pulmonary hypertension (BPD-PH). STUDY DESIGN: Retrospective study of neonatal, echocardiographic, and cardiac catheterization data in 121 infants with BPD-PH discharged on pulmonary vasodilator therapy from 2009-2020 and followed into childhood. RESULT: After median 4.4 years, medications were discontinued in 58%. Those in whom medications were discontinued had fewer days of invasive support, less severe BPD, lower incidence of PDA closure or cardiac catheterization, and higher incidence of fundoplication or tracheostomy decannulation (p < 0.05). On multivariable analysis, likelihood of medication discontinuation was lower with longer period of invasive respiratory support [HR 0.95 (CI:0.91-0.99), p = 0.01] and worse RV dilation on pre-discharge echocardiogram [HR 0.13 (CI:0.03-0.70), p = 0.017]. In those with tracheostomy, likelihood of medication discontinuation was higher with decannulation [HR 10.78 (CI:1.98-58.59), p < 0.001]. CONCLUSION: In BPD-PH, childhood discontinuation of pulmonary vasodilator therapy is associated with markers of disease severity.

Right atrial function early after tetralogy of Fallot repair.

Diastolic dysfunction after repair for Tetralogy of Fallot (TOF) is associated with adverse long-term outcomes. Right atrial (RA) mechanics as a proxy of right ventricular (RV) diastolic function in the early post-operative period after surgical repair for TOF has not been reported. We sought to evaluate RA and RV strain prior to hospital discharge after TOF repair and to identify important patient factors associated with strain using a machine learning method. Single center retrospective cohort study of TOF patients undergoing surgical repair, with analysis of RA and RV strain from pre-and post-operative echocardiograms. RA function was assessed by the peak RA strain, systolic RA strain rate, early diastolic RA strain rate and RA emptying fraction. RV systolic function was measured by global longitudinal strain. Pre- and post-operative values were compared using Wilcoxon rank sum test. Gradient boosted machine (GBM) models were used to identify the most important predictors of post-operative strain. In total, 153 patients were enrolled, median age at TOF repair 3.5 months (25th-75th percentile: 2.2- 5.2), mostly male (67%), and White (64.1%). From pre-to post-operative period, there was significant worsening in all RA parameters and in RV strain. GBM models identified patient, anatomic, and surgical factors that were strong predictors of post-operative RA and RV strain. These factors included pulmonary valve and branch pulmonary artery Z scores, birth weight, gestational age and age at surgery, pre-operative RV fractional area change and oxygen saturation, type of outflow tract repair, duration of cardiopulmonary bypass, and early post-operative partial arterial pressure of oxygen. There is significant worsening in RA and RV strain early after TOF repair, indicating early alteration in diastolic and systolic function after surgery. Several patient and operative factors influence post-operative RV function. Most of the factors described are not readily modifiable, however they may inform pre-operative risk-stratification. The clinical application of RA strain and the prognostic implication of these early changes merit further study.

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.

Accuracy of Brain Natriuretic Peptide for Diagnosing Pulmonary Hypertension in Severe Bronchopulmonary Dysplasia.

BACKGROUND: Premature infants with severe bronchopulmonary dysplasia (sBPD) are at risk of pulmonary hypertension (PH). Serum brain natriuretic peptide (BNP) is used to predict disease severity in adult PH. Its diagnostic utility in sBPD-associated PH is unknown. OBJECTIVE: The aim of this paper was to determine the accuracy of BNP, against echocardiogram (echo), to diagnose PH in infants born <32 weeks' gestation with sBPD. METHODS: We conducted a retrospective cohort study of all infants with sBPD with an echo and BNP within a 24-h period, at ≥36 weeks postmenstrual age. PH was defined as: right ventricular pressure >½ systemic blood pressure estimated from tricuspid regurgitant jet or patent ductus arteriosus (PDA) velocity, bidirectional or right-to left-PDA, and/or flat/bowing ventricular septum at end-systole. Receiver-operating characteristic (ROC) curves were constructed to test the diagnostic accuracy of BNP. RESULTS: Of 128 infants, 68 (53%) had echo evidence of PH. BNP was higher among the infants with PH (median [interquartile range]: 127 pg/mL [39-290] vs. 35 [20-76], p < 0.001). The area under the ROC curve for diagnosing PH using BNP was 0.74 (95% CI 0.66-0.83). At an optimal cutpoint of 130 pg/mL, BNP correctly classified the presence or absence of PH in 70% of the infants (specificity: 92, sensitivity: 50%). CONCLUSIONS: BNP, relative to concurrent echo, demonstrated moderate accuracy for diagnosing PH in this cohort of preterm infants with sBPD. BNP may help rule in PH in this population but has low utility to rule out the disease.

Use of prostaglandin E1 to treat pulmonary hypertension in congenital diaphragmatic hernia.

BACKGROUND/PURPOSE: Prostaglandin E1 (PGE) has been used to maintain ductus arteriosus patency and unload the suprasystemic right ventricle (RV) in neonates with congenital diaphragmatic hernia (CDH) and severe pulmonary hypertension (PH). Here we evaluate the PH response in neonates with CDH and severe PH treated with PGE. METHODS: We performed a retrospective chart review of CDH infants treated at our center between 2011 and 2016. In a subset, PGE was initiated for echocardiographic evidence of severe PH, metabolic acidosis, or hypoxemia. To assess PH response, we evaluated laboratory data, including B-type natriuretic peptide (BNP) and echocardiograms before and after PGE treatment. Categorical and continuous data were analyzed with Fisher's exact tests and Mann-Whitney t-tests, respectively. RESULTS: Fifty-seven infants were treated with PGE a mean 17 ±â€¯2 days. BNP levels declined after 1.4 ±â€¯0.2 days of treatment and again after 5.2 ±â€¯0.6 days. After 6 ±â€¯0.8 days of treatment, echocardiographic estimates of severe PH by tricuspid regurgitation jet velocity, ductus arteriosus direction, and ventricular septum position also improved significantly. Treatment was not associated with postductal hypoxemia or systemic hypoperfusion. CONCLUSIONS: In patients with CDH and severe PH, PGE is well tolerated and associated with improved BNP and echocardiographic indices of PH, suggesting successful unloading of the RV. TYPE OF STUDY: Treatment study. LEVEL OF EVIDENCE: Level III.

Prevalence of Adverse Events in Children With Congenital Hyperinsulinism Treated With Diazoxide.

Context: Diazoxide, the only U.S. Food and Drug Administration-approved drug to treat hyperinsulinemic hypoglycemia, has been associated with several adverse events, which has raised concerns about the safety of this drug. Existing reports are limited to small studies and case reports. Objective: To determine prevalence of and clinical factors associated with adverse events in infants and children treated with diazoxide. Design: Retrospective cohort study of children with hyperinsulinism (HI) treated with diazoxide between 2003 and 2014. Setting: The Congenital Hyperinsulinism Center at the Children's Hospital of Philadelphia. Patients: Children and infants with laboratory-confirmed diagnosis of HI. Main Outcome Measures: Prevalence of pulmonary hypertension (PH), edema, neutropenia, thrombocytopenia, and hyperuricemia was determined. Tests of association and logistic regression were used to identify potential risk factors. Results: A total of 295 patients (129 female) met inclusion criteria. The median age at diazoxide initiation was 29 days (interquartile range, 10 to 142 days; n = 226 available start dates); 2.4% of patients were diagnosed with PH after diazoxide initiation. Children with PH (P = 0.003) or edema (P = 0.002) were born at earlier gestational age and more frequently had potential PH risk factors, including respiratory failure and structural heart disease (P < 0.0001 and P = 0.005). Other adverse events included neutropenia (15.6%), thrombocytopenia (4.7%), and hyperuricemia (5.0%). Conclusion: In this large cohort, PH occurred in infants with underlying risk factors, but no identifiable risk profile emerged for other adverse events. The relatively high prevalence of neutropenia, thrombocytopenia, and hyperuricemia suggests the value in proactively screening for these side effects in children treated with diazoxide.

High-Resolution, Contrast-Enhanced Cardiac Magnetic Resonance Detects an Intracardiac Thrombus in a Fontan Patient.

A 28-year-old male with Fontan physiology presented with chest pain, elevated troponin, regional dyskinesis, and an apical echogenicity in the right-sided morphologically left ventricle (LV) on echocardiogram. Cardiac magnetic resonance (CMR) imaging was performed with a three-dimensional respiratory-navigated inversion recovery FLASH (low flip angle, spoiled gradient echo technique) sequence during slow gadolinium infusion. A hypointense lesion in the LV apex was consistent with thrombus. Gadolinium-delayed enhancement imaging demonstrated increased signal in the mid-inferior LV free wall. In this case, progressive decline in ventricular function was likely followed by an intracardiac thrombus and embolic myocardial infarction. The CMR was instrumental in characterizing the mass and identifying myocardial scar.

Cardiac Magnetic Resonance Characterizes Myocarditis in a 16-Year-Old Female With Lyme Disease.

Myocarditis may occur during early disseminated Lyme disease. A 16-year-old girl with serologic evidence of Borrelia burgdorferi infection and transient first-degree atrioventricular block underwent cardiac magnetic resonance imaging, which demonstrated myocardial hyperemia, edema, and delayed gadolinium enhancement. We discuss the use of T1- and T2-weighted dark blood sequences in addition to inversion recovery delayed enhancement imaging to support the diagnosis of Lyme myocarditis.

Experience with biventricular intervention for neonates with mitral valve abnormalities in the setting of critical left-side heart obstruction.

BACKGROUND: Mitral valve (MV) abnormalities may adversely impact outcomes after biventricular repair of critical left-side heart obstruction. METHODS: Neonates with left-side heart obstruction and MV abnormality (anatomically abnormal or hypoplastic but otherwise normal [Z-score -1.5 to -4]) who underwent biventricular repair from December 2005 to December 2012 were included. Institutional selection criteria determined suitability for biventricular repair. Primary outcomes (death, univentricular conversion, pulmonary hypertension) and secondary outcomes (reinterventions) were compared between hypoplastic and anatomically abnormal MV groups. Freedom from reintervention was determined by Kaplan-Meier analysis. RESULTS: There were 55 patients with hypoplastic MV (n = 35) or anatomically abnormal MV (n = 20). Initial interventions included arch repair (n = 45, with ventricular septal defect closure in 7), balloon aortic valvuloplasty (n = 8), and Ross-Konno operation (n = 2). None had initial MV intervention. Follow-up was available on 46 patients (84%) at a median of 25 months. Primary outcome occurred in 6 patients (13%): 2 deaths, 1 univentricular conversion, and 3 pulmonary hypertension. Twenty-six patients (57%) underwent 36 follow-up interventions, often for arch obstruction (n = 26). All follow-up MV interventions (n = 4) occurred in patients with anatomically abnormal MV. Median reintervention-free time was 7.3 months. Freedom from reintervention at 6, 9, and 12 months was 65%, 38%, and 27%, respectively. Neither MV size nor anatomy was associated with primary outcome. CONCLUSIONS: Using our selection criteria, most neonates with left-side heart obstruction and MV abnormalities who underwent biventricular repair had reasonable survival with complex reintervention needs in early follow-up. The MV reintervention occurred in patients with abnormal anatomy, not hypoplasia.

Usefulness of insulin like growth factor 1 as a marker of heart failure in children and young adults after the Fontan palliation procedure.

Growth hormone and its mediator, insulinlike growth factor 1 (IGF-1), are key determinants of growth in children and young adults. As patients with Fontan physiology often experience diminished longitudinal growth, we sought to describe IGF-1 levels in this population and to identify factors associated with IGF-1 deficiency. Forty-one Fontan subjects ≥5 years were evaluated in this cross-sectional study. Age- and gender-specific height Z scores were generated using national data. Laboratory testing included IGF-1 and brain natriuretic peptide (BNP) levels. IGF-1 levels were converted to age-, gender-, and Tanner stage-specific Z scores. BNP levels were log transformed to achieve a normal distribution (log-BNP). Medical records were reviewed for pertinent clinical variables. Predictors of IGF-1 Z score were assessed through the Student t test and Pearson's correlation. Median age was 11.1 years (range 5.1 to 33.5 years), and time from Fontan was 8.2 years (1.1 to 26.7). Mean height Z score was -0.2 ± 0.9 with a mean IGF-1 Z score of -0.1 ± 1.3. There was no association between IGF-1 Z score and height Z score. Longer interval since Fontan (R = -0.32, p = 0.04), higher log-BNP (R = -0.40; p = 0.01), and lower indexed systemic flow on cardiac magnetic resonance (R = 0.55, p = 0.02) were associated with lower IGF-1 Z scores. In conclusion, in this cohort with Fontan physiology, higher BNP and lower systemic flow were associated with lower IGF-1 Z score. Longitudinal studies are needed to determine if these relations represent a mechanistic explanation for diminished growth in children with this physiology and with other forms of congenital heart disease.

A multifaceted approach to the management of plastic bronchitis after cavopulmonary palliation.

BACKGROUND: Plastic bronchitis is a rare, potentially life-threatening complication after Fontan operation. Hemodynamic alterations (elevated central venous pressure and low cardiac output) likely contribute to the formation of tracheobronchial casts composed of inflammatory debris, mucin, and fibrin. Pathologic studies of cast composition support medical treatment with fibrinolytics such as inhaled tissue plasminogen activator (t-PA). METHODS: This was a retrospective case series of medical, surgical, and catheter-based treatment of patients with plastic bronchitis after cavopulmonary palliation. RESULTS: Included were 14 patients (86% male, 93% white). Median age at Fontan operation was 2.7 years (range, 1.2 to 4.1 years), with median interval to plastic bronchitis presentation of 1.5 years (range, 9 days to 15.4 years). Cast composition was available for 11 patients (79%) and included fibrin deposits in 7. All patients were treated with pulmonary vasodilators, and 13 (93%) were treated with inhaled t-PA. Hemodynamically significant lesions in the Fontan pathway were addressed by catheter-based (n=9) and surgical (n=3) interventions. Three patients (21%) underwent heart transplantation. Median follow-up was 2.7 years (range, 0.6 to 8.7 years). Symptoms improved, such that 6 of 13 patients (46%) were weaned off t-PA. Rare or episodic casts are successfully managed with outpatient t-PA in most of the other patients. Of the 3 patients who underwent heart transplant, 2 are asymptomatic and 1 has recurrent casts in the setting of elevated filling pressures and rejection. CONCLUSIONS: A systematic step-wise algorithm that includes optimization of hemodynamics, aggressive pulmonary vasodilation, and inhaled t-PA is an effective treatment strategy for patients with plastic bronchitis after cavopulmonary connection.