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Background: Understanding the clinical course and short-term outcomes of suspected myocarditis after the coronavirus disease 2019 (COVID-19) vaccination has important public health implications in the decision to vaccinate youth. Methods: We retrospectively collected data on patients Results: We report on 139 adolescents and young adults with 140 episodes of suspected myocarditis (49 confirmed, 91 probable) at 26 centers. Most patients were male (n=126, 90.6%) and White (n=92, 66.2%); 29 (20.9%) were Hispanic; and the median age was 15.8 years (range, 12.1–20.3; interquartile range [IQR], 14.5–17.0). Suspected myocarditis occurred in 136 patients (97.8%) after the mRNA vaccine, with 131 (94.2%) after the Pfizer-BioNTech vaccine; 128 (91.4%) occurred after the second dose. Symptoms started at a median of 2 days (range, 0–22; IQR, 1–3) after vaccination. The most common symptom was chest pain (99.3%). Patients were treated with nonsteroidal anti-inflammatory drugs (81.3%), intravenous immunoglobulin (21.6%), glucocorticoids (21.6%), colchicine (7.9%), or no anti-inflammatory therapies (8.6%). Twenty-six patients (18.7%) were in the intensive care unit, 2 were treated with inotropic/vasoactive support, and none required extracorporeal membrane oxygenation or died. Median hospital stay was 2 days (range, 0–10; IQR, 2–3). All patients had elevated troponin I (n=111, 8.12 ng/mL; IQR, 3.50–15.90) or T (n=28, 0.61 ng/mL; IQR, 0.25–1.30); 69.8% had abnormal ECGs and arrhythmias (7 with nonsustained ventricular tachycardia); and 18.7% had left ventricular ejection fraction Conclusions: Most cases of suspected COVID-19 vaccine myocarditis occurring in persons

Background The AHA/ACC Adult Congenital Heart Disease guidelines recommend that most adults with congenital heart disease (CHD) follow-up with CHD cardiologists every 1 to 2 years because longer gaps in care are associated with adverse outcomes. This study aimed to determine the proportion of patients in North Carolina who did not have recommended follow-up and to explore predictors of loss to follow-up. Methods Patients ages ≥18 years with a healthcare encounter from 2008 to 2013 in a statewide North Carolina database with an ICD-9 code for CHD were assessed. The proportion with cardiology follow-up within 24 months following index encounter was assessed with Kaplan-Meier estimates. Cox regression was utilized to identify demographic factors associated with differences in follow-up. Results 2822 patients were identified. Median age was 35 years; 55% were female. 70% were white, 22% black, and 3% Hispanic; 36% had severe CHD. The proportion with 2-year cardiology follow-up was 61%. Those with severe CHD were more likely to have timely follow-up than those with less severe CHD (72% vs 55%, P Conclusion 39% of adults with CHD in North Carolina are not meeting AHA/ACC recommendations for follow-up. Younger and minority patients and those with non-severe CHD were particularly vulnerable to inadequate follow-up; targeted efforts to retain these patients in care may be helpful.

Background: During the coronavirus disease 2019 (COVID-19) pandemic, children and families have had to adapt their daily lives. The purpose of this study was to describe changes in the weight-related behaviors of children with obesity after the onset of the COVID-19 pandemic. Methods: Semistructured interviews (n = 51) were conducted from April to June 2020 with parents of children with obesity. Families were participants in a randomized trial testing a clinic-community pediatric obesity treatment model. During interviews, families described their experience during the COVID-19 pandemic, with a particular emphasis on children's diet, physical activity, sleep, and screen time behaviors. Rapid qualitative analysis methods were used to identify themes around changes in children's weight-related behaviors. Results: The mean child age was 9.7 (±2.8) years and the majority of children were Black (46%) or Hispanic (39%) and from low-income families (62%). Most parent participants were mothers (88%). There were differences in the perceived physical activity level of children, with some parents attributing increases in activity or maintenance of activity level to increased outdoor time, whereas others reported a decline due to lack of outdoor time, school, and structured activities. Key dietary changes included increased snacking and more meals prepared and consumed at home. There was a shift in sleep schedules with children going to bed and waking up later and an increase in leisure-based screen time. Parents played a role in promoting activity and managing children's screen time. Conclusions: The COVID-19 pandemic has created unique lifestyle challenges and opportunities for lifestyle modification. Clinical Trials ID: NCT03339440.

Background The Fontan procedure is the final step of the 3-stage palliative procedure commonly performed in children with single ventricle physiology. Thrombosis remains an important complication in children after this procedure. To date, guideline recommendations for the type and duration of thromboprophylaxis after Fontan surgery are mainly based on extrapolation of knowledge gained from adults at risk for thrombosis in other clinical settings. Warfarin is being used off-label, and because of its multiple interactions with other drugs and food, a new alternative is highly desirable. Rivaroxaban, a direct Factor Xa inhibitor with a predictable pharmacokinetic profile, is a candidate to address this medical need. Study design The UNIVERSE study is a prospective, open-label, active-controlled, multicenter study in children 2 to 8 years of age who have single ventricle physiology and had the Fontan procedure within the 4 months preceding enrollment. This study consists of 2 parts. In Part A, rivaroxaban pharmacokinetics, pharmacodynamics, safety, and tolerability are assessed to validate the pediatric dosing selected. In Part B, safety and efficacy of rivaroxaban versus acetylsalicylic acid are evaluated for thromboprophylaxis in children post–Fontan procedure. Children in each part will receive study drug for 12 months. Part A has been completed with 12 children enrolled. Enrollment into Part B is currently ongoing. Conclusions The UNIVERSE study aims to provide dosing, pharmacokinetics/pharmacodynamics, safety, and efficacy information on the use of rivaroxaban, an oral anticoagulant, versus acetylsalicylic acid, an antiplatelet agent, in children with single ventricle physiology after the Fontan procedure.

Thrombosis remains an important complication for children with single ventricle physiology post-Fontan procedure and effective thromboprophylaxis is an important unmet medical need. To obviate conventional dose-finding studies and expedite clinical development, a rivaroxaban dose regimen for this indication was determined utilizing a model-informed drug development approach. A physiologically based pharmacokinetic (PBPK) rivaroxaban model was used to predict a pediatric dosing regimen that would produce drug exposures similar to that of 10 mg once daily in adults. This regimen was used in an open-label, multicenter Phase 3 study, which investigated the use of rivaroxaban for thromboprophylaxis in post-Fontan patients 2 to 8 years of age. The pharmacokinetics (PK) of rivaroxaban was assessed in Part A (n = 12) and in Part B (n = 64) of UNIVERSE. The safety and efficacy in the rivaroxaban group were compared to those in the acetylsalicylic acid group for 12 months. Pharmacodynamic endpoints were assessed in both parts of the study. Rivaroxaban exposures achieved in Part A and B were similar to the adult reference exposures. Prothrombin time also showed similarity to the adult reference. Exposure-response analysis did not identify a quantitative relationship between rivaroxaban exposures and efficacy/safety outcomes within the observed exposure ranges. A body-weight based dose regimen selected by PBPK modeling was shown in the UNIVERSE study to be appropriate for thromboprophylaxis in the post-Fontan pediatric population. Model-based dose selection can support pediatric drug development and bridge adult dose data to pediatrics, thereby obviating the need for dose-finding studies in pediatric programs. This article is protected by copyright. All rights reserved.

With improved surgical outcomes, infants and children with congenital heart disease (CHD) may die from other causes of death (COD) other than CHD. We sought to describe the COD in youth with CHD in North Carolina (NC). Patients from birth to 20 years of age with a healthcare encounter between 2008 and 2013 in NC were identified by ICD-9 code. Patients who could be linked to a NC death certificate between 2008 and 2016 were included. Patients were divided by CHD subtypes (severe, shunt, valve, other). COD was compared between groups. Records of 35,542 patients 20 years old were evaluated. There were 15,277 infants with an annual mortality rate of 3.5 deaths per 100 live births. The most frequent COD in infants (age 1 year) were CHD (31.7%), lung disease (16.1%), and infection (11.4%). In 20,265 children (age 1 to 20 years), there was annual mortality rate of 9.7 deaths per 1000 at risk. The most frequent COD in children were CHD (34.2%), neurologic disease (10.2%), and infection (9.5%). In the severe subtype, CHD was the most common COD. In infants with shunt-type CHD disease, lung disease (19.5%) was the most common COD. The mortality rate in infants was three times higher when compared to children. CHD is the most common underlying COD, but in those with shunt-type lesions, extra-cardiac COD is more common. A multidisciplinary approach in CHD patients, where development of best practice models regarding comorbid conditions such as lung disease and neurologic disease could improve outcomes in this patient population.

Objectives To determine the pharmacokinetics, pharmacodynamics, and safety of the hepatically metabolized endothelin receptor antagonist, ambrisentan in children after Fontan surgery. Design Prospective, randomized, double-blind, placebo-controlled pharmacokinetic/pharmacodynamics and safety trial. Setting Single-center, postoperative cardiac ICU. Patients Children undergoing elective Fontan surgery. Interventions Subjects randomized on postoperative day number 1 to short-term (3 d) treatment with oral ambrisentan (2.5 mg in suspension, daily) versus placebo (4:1 randomization). Measurements and main results Plasma drug concentrations were measured at 0.5, 1, 2, 4, and 18-36 hours after the first dose. We developed a population pharmacokinetic model in NONMEM 7.2 (Icon Solutions, Ellicott City, MD) and applied the model to dose-exposure simulations. Pharmacodynamics endpoints were assessed at baseline and 3 hours after study drug administration, using postoperative hemodynamic monitoring lines. The analysis included 16 patients, 13 on ambrisentan (77 plasma samples); median age 36 months (range, 26-72 mo), weight 13.3 kg (11.1-17.6 kg), and nine males. There were no differences in baseline characteristics between ambrisentan and controls. A one-compartment model with first-order absorption and lag-time characterized the data well. Allometrically scaled weight was the only covariate retained in the final model. Typical values for clearance and volume of distribution were lower than previously reported in adults, 1 L/hr/70 kg and 13.7 L/70 kg, respectively. Simulated exposures with doses of 0.1-0.2 mg/kg approximated therapeutic exposures in adults with pulmonary arterial hypertension receiving 5 mg or 10 mg doses. Ambrisentan lowered plasma brain natriuretic peptide concentrations (452 ± 479 to 413 ± 462; p = 0.046), Fontan pressures (16.8 ± 2.9 to 15.6 ± 2.9; p = 0.01), and indexed pulmonary vascular resistance (2.3 ± 0.9 to 1.8 ± 0.6; p = 0.01) with no drug-related adverse events. Conclusions Ambrisentan clearance is reduced following Fontan surgery, perhaps reflecting abnormal hepatic metabolism in this population. The observed safety profile appears favorable and hemodynamic effects of ambrisentan may be beneficial for Fontan patients.

Background Coronary artery aneurysms (CAAs) may occur after Kawasaki disease (KD) and lead to important morbidity and mortality. As CAA in patients with KD are rare and heterogeneous lesions, prognostication and risk stratification are difficult. We sought to derive the cumulative risk and associated factors for cardiovascular complications in patients with CAAs after KD. Methods and Results A 34‐institution international registry of 1651 patients with KD who had CAAs (maximum CAA Z score ≥2.5) was used. Time‐to‐event analyses were performed using the Kaplan–Meier method and Cox proportional hazard models for risk factor analysis. In patients with CAA Z scores ≥10, the cumulative incidence of luminal narrowing (>50% of lumen diameter), coronary artery thrombosis, and composite major adverse cardiovascular complications at 10 years was 20±3%, 18±2%, and 14±2%, respectively. No complications were observed in patients with a CAA Z score Z score and a greater number of coronary artery branches affected were associated with increased risk of all types of complications. At 10 years, normalization of luminal diameter was noted in 99±4% of patients with small (2.5≤ Z Z Z ≥10). CAAs in the left anterior descending and circumflex coronary artery branches were more likely to normalize. Risk factor analysis of coronary artery branch level outcomes was performed with a total of 893 affected branches with Z score ≥10 in 440 patients. In multivariable regression models, hazards of luminal narrowing and thrombosis were higher for patients with CAAs of the right coronary artery and left anterior descending branches, those with CAAs that had complex architecture (other than isolated aneurysms), and those with CAAs with Z scores ≥20. Conclusions For patients with CAA after KD, medium‐term risk of complications is confined to those with maximum CAA Z scores ≥10. Further risk stratification and close follow‐up, including advanced imaging, in patients with large CAAs is warranted.

Background Little is known about the contemporary mortality experience among adults with congenital heart disease (CHD). The objectives of this study were to assess the age at death, presence of cardiovascular comorbidities, and most common causes of death among adults with CHD in a contemporary cohort within the United States. Methods and Results Patients with CHD who had a healthcare encounter between 2008 and 2013 at 1 of 5 comprehensive CHD centers in North Carolina were identified by International Classification of Diseases, Ninth Revision ( ICD‐9 ), code. Only patients who could be linked to a North Carolina death certificate between 2008 and 2016 and with age at death ≥20 years were included. Median age at death and underlying cause of death based on death certificate data were analyzed. The prevalence of acquired cardiovascular risk factors was determined from electronic medical record data. Among the 629 included patients, the median age at death was 64.2 years. Those with severe CHD (n=157, 25%), shunts (n=202, 32%), and valvular lesions (n=174, 28%) had a median age at death of 46.0, 65.0, and 73.3 years, respectively. Cardiovascular death was most common in adults with severe CHD (60%), with 40% of those deaths caused by CHD. Malignancy and ischemic heart disease were the most common causes of death in adults with nonsevere CHD. Hypertension and hyperlipidemia were common comorbidities among all CHD severity groups. Conclusions The most common underlying causes of death differed by lesion severity. Those with severe lesions most commonly died from underlying CHD, whereas those with nonsevere disease more commonly died from non‐CHD causes.

Objective To test whether variants in ADRB1 and CYP2C9 genes identify subgroups of individuals with differential response to treatment for Marfan syndrome through analysis of data from a large, randomized trial. Study design In a subset of 250 white, non-Hispanic participants with Marfan syndrome in a prior randomized trial of atenolol vs losartan, the common variants rs1801252 and rs1801253 in ADRB1 and rs1799853 and rs1057910 in CYP2C9 were analyzed. The primary outcome was baseline-adjusted annual rate of change in the maximum aortic root diameter z-score over 3 years, assessed using mixed effects models. Results Among 122 atenolol-assigned participants, the 70 with rs1801253 CC genotype had greater rate of improvement in aortic root z-score compared with 52 participants with CG or GG genotypes (Time x Genotype interaction P =.005, mean annual z-score change +/- SE -0.20 +/- 0.03 vs -0.09 +/- 0.03). Among participants with the CC genotype in both treatment arms, those assigned to atenolol had greater rate of improvement compared with the 71 of the 121 assigned to losartan (interaction P =.002; -0.20 +/- 0.02 vs -0.07 +/- 0.02; P

Based on a review of a large patient cohort, published literature, and 3 newborn screening cohorts, we concluded that children diagnosed through newborn screening with late-onset Pompe disease and the common heterozygous c.-32-13T>G variant require frequent cardiac follow-up with electrocardiography for arrhythmias. However, there is limited evidence for performing repeated echocardiography for cardiomyopathy.

Objective To evaluate practice variation in pharmacologic management in the International Kawasaki Disease Registry (IKDR). Study design Practice variation in intravenous immunoglobulin (IVIG) therapy, anti-inflammatory agents, statins, beta-blockers, antiplatelet therapy, and anticoagulation was described. Results We included 1627 patients from 30 IKDR centers with maximum coronary artery aneurysm (CAA) z scores 2.5-4.99 in 848, 5.0-9.99 in 349, and ≥10.0 (large/giant) in 430 patients. All centers reported IVIG and acetylsalicylic acid (ASA) as primary therapy and use of additional IVIG or steroids as needed. In 23 out of 30 centers, (77%) infliximab was also used; 11 of these 23 centers reported using it in 20% of patients. Nonsteroidal anti-inflammatory agents were used in >10% of patients in only nine centers. Beta-blocker (8.8%, all patients) and abciximab (3.6%, all patients) were mainly prescribed in patients with large/giant CAAs. Statins (2.7%, all patients) were mostly used in one center and only in patients with large/giant CAAs. ASA was the primary antiplatelet modality for 99% of patients, used in all centers. Clopidogrel (18%, all patients) was used in 24 centers, 11 of which used it in >50% of their patients with large/giant CAAs. Conclusions In the IKDR, IVIG and ASA therapy as primary therapy is universal with common use of a second dose of IVIG for persistent fever. There is practice variation among centers for adjunctive therapies and anticoagulation strategies, likely reflecting ongoing knowledge gaps. Randomized controlled trials nested in a high-quality collaborative registry may be an efficient strategy to reduce practice variation.

Background:The presence of echocardiographic (echo) evidence is a major criterion for the diagnosis of infective endocarditis (IE) by modified Duke criteria. Pulmonary valve (PV) IE, however, can be challenging to identify by echo. We sought to evaluate the added utility of multimodal imaging in PV IE.Methods:This is a single-center case series. We retrospectively analyzed demographic, laboratory, imaging, clinical, and surgical data from patients diagnosed with PV IE from 2008 to 2018.Results:A total of 23 patients were identified with definite PV IE by Duke criteria (83% male and ages 2 months to 70 years). Twenty-two patients had congenital heart disease, with 21 involving the right ventricular outflow tract (including three with transcatheter PV implant). Overall, 20 (87%) of 23 had positive blood cultures. A total of 17 (74%) of 23 patients demonstrated echo evidence of PV IE. In three cases, echo was negative (did not show vegetations) but showed new PV obstruction. In four cases with negative transthoracic echocardiogram and transesophageal echocardiogram, evidence of PV IE was subsequently seen by positron emission tomography/computed tomography (n = 2) or cardiac magnetic resonance imaging (n = 2). Pulmonary valve IE was confirmed at surgery by evaluation of pathologic samples in 20 cases.Conclusions:Multimodal imaging improves the ability to preoperatively identify endocardial involvement in PV IE in cases where echo is negative. Consideration should be given to revise Duke criteria to include new obstruction and endocardial involvement by multimodal imaging for PV IE.

Hypertension affects >40% of the US population and is a major contributor to cardiovascular-related morbidity and mortality. Although less common among children and adolescents, hypertension affects 1% to 5% of all youth. The 2017 Clinical Practice Guideline for the Diagnosis and Management of High Blood Pressure in Children and Adolescents provided updates and strategies regarding the diagnosis and management of hypertension in youth. Despite this important information, many gaps in knowledge remain, such as the etiology, prevalence, and trends of hypertension; the utility and practicality of ambulatory blood pressure monitoring; practical goals for lifestyle modification that are generalizable; the long-term end-organ impacts of hypertension in youth; and the long-term safety and efficacy of antihypertensive therapy in youth. The Eunice Kennedy Shriver National Institute of Child Health and Human Development, in collaboration with the National Heart, Lung, and Blood Institute and the US Food and Drug Administration, sponsored a workshop of experts to discuss the current state of childhood primary hypertension. We highlight the results of that workshop and aim to (1) provide an overview of current practices related to the diagnosis, management, and treatment of primary pediatric hypertension; (2) identify related research gaps; and (3) propose ways to address existing research gaps.

Neurodevelopmental disability is common after operations for congenital heart defects. We previously showed that patient and preoperative factors, center, and calendar year of birth explained less than 30% of the variance for the Psychomotor Development Index (PDI) and the Mental Development Index (MDI) of the Bayley Scales of Infant Development-Second Edition. Here we investigate how much additional variance in PDI and MDI is contributed by operative variables and postoperative events.We analyzed neurodevelopmental outcomes after operations with cardiopulmonary bypass at age 9 months or younger between 1996 and 2009. We used linear regression to investigate the effect of operative factors (age, weight, and cardiopulmonary bypass variables) and postoperative events on neurodevelopmental outcomes, adjusting for center, type of congenital heart defect, year of birth, and preoperative factors.We analyzed 1,770 children from 22 institutions with neurodevelopmental testing at age 13.3 months (range, 6 to 30 months). Among operative factors, longer total support time was associated with lower PDI and MDI (p0.05). When postoperative events were added, use of either extracorporeal membrane oxygenation or ventricular assist device support, and longer postoperative length of stay were associated with lower PDI and MDI (p0.05). Longer total support time was not a significant predictor in these models. After adjusting for patient, preoperative, intraoperative, and postoperative factors, measured intraoperative and postoperative factors accounted for 5% of the variances in PDI and MDI.Operative factors may be less important than innate patient and preoperative factors and postoperative events in predicting early neurodevelopmental outcomes after cardiac operations in infants. Neurodevelopmental outcomes improved over calendar time when adjusted for patient and medical variables.

OBJECTIVE: To evaluate the agreement of an echocardiogram-based pulmonary hypertension diagnosis in premature infants at risk for bronchopulmonary dysplasia (BPD). STUDY DESIGN: Echocardiograms from infants born ≤ 28 weeks post-menstrual age were retrospectively reviewed with a standardized reading protocol by three pediatric cardiologists masked to patient’s clinical history to determine the presence of pulmonary hypertension. RESULTS: 483 echocardiograms from 49 unique patients were each reviewed by three pediatric cardiologists. Overall there was an 82.9% agreement on the presence of pulmonary hypertension among the three readers (95%CI: 78.4%, 85.4%) with a modified Fleiss’ kappa of 0.759 (95% CI: 0.711, 0.801). Percent agreement between rereads was 92.4%, and modified Fleiss’ kappa was 0.847 (95%CI: 0.750, 0.931). CONCLUSIONS: Using a standardized reading protocol and echocardiogram based definition of pulmonary hypertension, there is high inter- and intra-rater agreement for the diagnosis of pulmonary hypertension in at-risk premature infants, suggesting echocardiography can be successfully used for clinical and research monitoring of pulmonary hypertension in infants.

AimsSildenafil is frequently prescribed to children with single ventricle heart defects. These children have unique hepatic physiology with elevated hepatic pressures, which may alter drug pharmacokinetics. We sought to determine the impact of hepatic pressure on sildenafil pharmacokinetics in children with single ventricle heart defects.MethodsA population pharmacokinetic model was developed using data from 20 single ventricle children receiving single-dose intravenous sildenafil during cardiac catheterisation. Non-linear mixed effect modelling was used for model development, and covariate effects were evaluated based on estimated precision and clinical significance.ResultsThe analysis included a median (range) of 4 (2–5) pharmacokinetic samples per child. The final structural model was a two-compartment model for sildenafil with a one-compartment model for des-methyl-sildenafil (active metabolite), with assumed 100% sildenafil to des-methyl-sildenafil conversion. Sildenafil clearance was unaffected by hepatic pressure (clearance=0.62 L/hour/kg); however, clearance of des-methyl-sildenafil (1.94×(hepatic pressure/9)−1.33 L/hour/kg) was predicted to decrease ~7-fold as hepatic pressure increased from 4 to 18 mmHg. Predicted drug exposure was increased by ~1.5-fold in subjects with hepatic pressures ⩾10 versus DiscussionElevated hepatic pressure delays clearance of the sildenafil metabolite – des-methyl-sildenafil – and increases drug exposure. We speculate that this results from impaired biliary clearance. Hepatic pressure should be considered when prescribing sildenafil to children. These data demonstrate the importance of pharmacokinetic assessments in patients with unique cardiovascular physiology that may affect drug metabolism.

Hypertension and chronic kidney disease (CKD) are common comorbidities. Guidelines recommend treating hypertension in children with CKD because it is a modifiable risk factor for subsequent cardiovascular disease. Children with CKD are frequently excluded from antihypertensive drug trials. Consequently, safety and efficacy data for antihypertensive drugs are lacking in children with CKD. We determined the incidence of adverse events in 10 pediatric antihypertensive trials to determine the effect of renal function on antihypertensive safety and efficacy in children. These trials were submitted to the US Food and Drug Administration from 1998 to 2005. We determined the number and type of adverse events reported during the trials and compared these numbers in participants with normal renal function and those with decreased function (defined as an estimated glomerular filtration rate [eGFR]

To determine sildenafil exposure and hemodynamic effect in children after stage II single-ventricle surgery.Prospective, dose escalation trial.Single-center, pediatric catheterization laboratory.Twelve children poststage II single-ventricle surgical palliation and undergoing elective cardiac catheterization: median age 1.9 years (range, 0.8, 4.0), weight 11 kg (8, 13), nine females, and 10 with a single right ventricle.Catheterization and echocardiography performed before and immediately after single-dose IV sildenafil (0.125, 0.25, 0.35, or 0.45 mg/kg over 20 min).Peak sildenafil and desmethyl sildenafil concentration, change in hemodynamic parameters measured by cardiac catheterization and echocardiography including indexed pulmonary vascular resistance, and myocardial performance.Maximum sildenafil concentrations ranged from 92 to 775 ng/mL and were above the in vitro threshold needed for 77% phosphodiesterase type 5 (PDE-5) inhibition in 80% of subjects and 90% inhibition in 80% of subjects with doses ≥0.35 mg/kg. Sildenafil lowered pulmonary vascular resistance index in all 12 subjects (median pulmonary vascular resistance index 2.2 [range, 1.6, 7.9]; decreased to 1.7 [1.2, 5.4] WU × m; p0.01) with no dose-response effect. Sildenafil improved pulmonary blood flow (+8% [0, 20], p = 0.04) and saturations (+2% [0, 16], p = 0.04) in those with baseline pulmonary vascular resistance index ≥ 2 WU × m (n = 7). Change in saturations correlated inversely with change in pulmonary vascular resistance index (r = 0.74, p0.01). Sildenafil also lowered mean blood pressure (-12% [-20, +10]; p = 0.04). There was no change in cardiac index and no effect on myocardial performance. There were no adverse events.Sildenafil demonstrated nonlinear exposure with high interindividual variability but was well tolerated and effectively lowered pulmonary vascular resistance index in all subjects. Sildenafil did not acutely improve myocardial performance or increase cardiac index.

Background Administrative datasets are often used to assess outcomes and quality of pediatric cardiac programs; however their accuracy regarding case ascertainment is unclear. We linked patient data (2004–2010) from the Society of Thoracic Surgeons Congenital Heart Surgery (STS-CHS) Database (clinical registry) and the Pediatric Health Information Systems (PHIS) database (administrative database) from hospitals participating in both to evaluate differential coding/classification of operations between datasets and subsequent impact on outcomes assessment. Methods Eight individual benchmark operations and the Risk Adjustment in Congenital Heart Surgery, version 1 (RACHS-1) categories were evaluated. The primary outcome was in-hospital mortality. Results The cohort included 59,820 patients from 33 centers. There was a greater than 10% difference in the number of cases identified between data sources for half of the benchmark operations. The negative predictive value (NPV) of the administrative (versus clinical) data was high (98.8%–99.9%); the positive predictive value (PPV) was lower (56.7%–88.0%). Overall agreement between data sources in RACHS-1 category assignment was 68.4%. These differences translated into significant differences in outcomes assessment, ranging from an underestimation of mortality associated with truncus arteriosus repair by 25.7% in the administrative versus clinical data (7.01% versus 9.43%; p = 0.001) to an overestimation of mortality associated with ventricular septal defect (VSD) repair by 31.0% (0.78% versus 0.60%; p = 0.1). For the RACHS-1 categories, these ranged from an underestimation of category 5 mortality by 40.5% to an overestimation of category 2 mortality by 12.1%; these differences were not statistically significant. Conclusions This study demonstrates differences in case ascertainment between administrative and clinical registry data for children undergoing cardiac operations, which translated into important differences in outcomes assessment.

To determine the birth prevalence of congenital heart defects (CHDs) across the spectrum of common defects in very/extremely premature infants and to compare mortality rates between premature infants with and without CHDs.The Kids' Inpatient Databases (2003-2012) were used to estimate the birth prevalence of CHDs (excluding patent ductus arteriosus) in very/extremely premature infants born between 25 and 32 weeks' gestational age. Birth prevalence was compared with term infants for a subset of "severe" defects expected to be near universally diagnosed in the neonatal period. Weighted multivariable logistic regression was used to calculate aORs of mortality comparing very and extremely premature infants with vs without CHDs.We identified 249 011 very/extremely premature infants, including 28 806 with CHDs. The overall birth prevalence of CHDs was 116 per 1000 very/extremely premature births. Severe CHDs had significantly higher birth prevalence in very/extremely premature infants when compared with term infants (7.4 per 1000 very/premature births vs 1.5 per 1000 term births; P .001). Very/extremely premature infants with severe CHDs had an overall 26.3% in-hospital mortality and a 7.5-fold increased adjusted odds of death compared with those without CHDs. Mortality varied widely by defect in very/extremely premature infants, ranging from 12% for interrupted aortic arch to 67% for truncus arteriosus.Given the increased birth prevalence of severe CHDs in very/extremely premature infants, and significantly higher mortality, there is justification for intensive interventions aimed at decreasing the likelihood of premature delivery for patients where CHD is diagnosed in utero.

ObjectiveThe aim of the study was to evaluate the trends in respiratory syncytial virus-related hospitalisations and associated outcomes in children with haemodynamically significant heart disease in the United States of America.Study designThe Kids’ Inpatient Databases (1997–2012) were used to estimate the incidence of respiratory syncytial virus hospitalisation among children ⩽24 months with or without haemodynamically significant heart disease. Weighted multivariable logistic regression and chi-square tests were used to evaluate the trends over time and factors associated with hospitalisation, comparing eras before and after publication of the 2003 American Academy of Pediatrics palivizumab immunoprophylaxis guidelines. Secondary outcomes included in-hospital mortality, morbidity, length of stay, and cost.ResultsOverall, 549,265 respiratory syncytial virus-related hospitalisations were evaluated, including 2518 (0.5%) in children with haemodynamically significant heart disease. The incidence of respiratory syncytial virus hospitalisation in children with haemodynamically significant heart disease decreased by 36% when comparing pre- and post-palivizumab guideline eras versus an 8% decline in children without haemodynamically significant heart disease (pConclusionsThese data provide stakeholders with a means to evaluate the cost–utility of various immunoprophylaxis strategies.

Aortic arch reconstruction in children with single ventricle lesions may predispose to circulatory inefficiency and maladaptive physiology leading to increased myocardial workload. We sought to describe neoaortic anatomy and physiology, risk factors for abnormalities, and impact on right ventricular function in patients with single right ventricle lesions after arch reconstruction.Prestage II aortic angiograms from the Pediatric Heart Network Single Ventricle Reconstruction trial were analyzed to define arch geometry (Romanesque [normal], crenel [elongated], or gothic [angular]), indexed neoaortic dimensions, and distensibility. Comparisons were made with 50 single-ventricle controls without prior arch reconstruction. Factors associated with ascending neoaortic dilation, reduced distensibility, and decreased ventricular function on the 14-month echocardiogram were evaluated using univariate and multivariable logistic regression.Interpretable angiograms were available for 326 of 389 subjects (84%). Compared with controls, study subjects more often demonstrated abnormal arch geometry (67% vs 22%, P .01) and had increased ascending neoaortic dilation (Z score 3.8 ± 2.2 vs 2.6 ± 2.0, P .01) and reduced distensibility index (2.2 ± 1.9 vs 8.0 ± 3.8, P .01). Adjusted odds of neoaortic dilation were increased in subjects with gothic arch geometry (odds ratio [OR], 3.2 vs crenel geometry, P .01) and a right ventricle-pulmonary artery shunt (OR, 3.4 vs Blalock-Taussig shunt, P .01) but were decreased in subjects with aortic atresia (OR, 0.7 vs stenosis, P .01) and those with recoarctation (OR, 0.3 vs no recoarctation, P = .04). No demographic, anatomic, or surgical factors predicted reduced distensibility. Neither dilation nor distensibility predicted reduced right ventricular function.After Norwood surgery, the reconstructed neoaorta demonstrates abnormal anatomy and physiology. Further study is needed to evaluate the longer-term impact of these features.

Background Previous studies suggest center volume is associated with outcome after the Norwood operation; however, the impact of surgeon volume is less clear. We evaluated the relative impact of surgeon and center volume on mortality in a large Norwood cohort. Methods Patients in the Society of Thoracic Surgeons Congenital Heart Surgery Database undergoing the Norwood operation (2000 to 2009) were included. Using multivariable logistic regression, we evaluated the relationship between in-hospital mortality and annual center and surgeon volume, adjusting for patient factors. Results A total of 2,555 patients were operated on at 53 centers by 111 surgeons. Overall unadjusted mortality was 22.1%. When analyzed individually, both lower center and surgeon volume were associated with higher mortality (odds ratio for centers with 0 to 10 vs >20 cases per year 1.56 [95% confidence interval 1.05 to 2.31]; odds ratio for surgeons with 0 to 5 vs >10 cases per year 1.60 [95% confidence interval 1.12 to 2.27]). When analyzed together, the addition of surgeon volume to the center volume models attenuated but did not completely mitigate the association of center volume with outcome (relative attenuation of odds ratio=34%). Adjusted mortality rates in low, medium, and high volume centers were 25.6%, 22.3%, and 17.7%, respectively. Across all center volume strata, lower volume surgeons had higher adjusted mortality rates. Conclusions Both center and surgeon volumes appear to influence Norwood outcomes. These data suggest outcomes may potentially be improved through strategies that take advantage of the positive influence of both of these variables. This could include further investigation into the feasibility of regional collaborations, and the development of quality improvement initiatives within and across centers.

Little data on pediatric percent platelet aggregation (%PA) exist in the literature, particularly in cardiac patients and in response to clopidogrel. The objectives were to estimate the %PA range expected in pediatric patients and to measure the clopidogrel effect on %PA in the PICOLO (Platelet Inhibition in Children on Clopidogrel) trial. To estimate a neonatal/infant %PA response range, %PA induced by 5 µM adenosine diphosphate (ADP) was assessed using light transmission aggregometry in 16 cord and 11 normal adult blood samples and prior to clopidogrel therapy in 49 neonatal and 49 infant/toddler cardiac patients enrolled in PICOLO. The %PA induced by 5 µM thrombin receptor-activating peptide (TRAP) was also assessed for 10 neonates and 21 infants/toddlers enrolled in PICOLO and compared with 11 adult samples. Percent inhibition of platelet aggregation (%IPA) induced by 5 µM ADP at steady-state clopidogrel levels was assessed in 33 neonates and 39 infants/toddlers. ADP-induced %PA was lowest in cord blood samples, intermediate in study neonates and infants/toddlers, and highest in adults. Similarly, TRAP-induced platelet aggregation was lower in neonates and infants/toddlers than adults. For all groups, %PA and %IPA were highly variable, with 11% of neonates and 13% of infants/toddlers showing

OBJECTIVE:Previous analyses have suggested center volume is associated with outcome in children undergoing heart surgery. However, data are limited regarding potential mediating factors, including the relationship of center volume with postoperative complications and mortality in those who suffer a complication. We examined this association in a large multicenter cohort.METHODS:Children 0 to 18 years undergoing heart surgery at centers participating in the Society of Thoracic Surgeons Congenital Heart Surgery Database (2006–2009) were included. In multivariable analysis, we evaluated outcomes associated with annual center volume, adjusting for patient factors and surgical risk category.RESULTS:A total of 35 776 patients (68 centers) were included. Overall, 40.6% of patients had ≥1 complication, and the in-hospital mortality rate was 3.9%. The mortality rate in those patients with a complication was 9.0%. In multivariable analysis, lower center volume was significantly associated with higher in-hospital mortality. There was no association of center volume with the rate of postoperative complications, but lower center volume was significantly associated with higher mortality in those with a complication (P = .03 when volume examined as a continuous variable; odds ratio in centers with 350 cases per year = 1.59 [95% confidence interval: 1.16–2.18]). This association was most prominent in the higher surgical risk categories.CONCLUSIONS:These data suggest that the higher mortality observed at lower volume centers in children undergoing heart surgery may be related to a higher rate of mortality in those with postoperative complications, rather than a higher rate of complications alone.

BACKGROUND: Recent studies have called into question the benefit of perioperative corticosteroids in children undergoing heart surgery, but have been limited by the lack of placebo control, limited power, and grouping of various steroid regimens together in analysis. We evaluated outcomes across methylprednisolone regimens versus no steroids in a large cohort of neonates. METHODS: Clinical data from the Society of Thoracic Surgeons Database were linked to medication data from the Pediatric Health Information Systems Database for neonates (≤30 days) undergoing heart surgery (2004–2008) at 25 participating centers. Multivariable analysis adjusting for patient and center characteristics, surgical risk category, and within-center clustering was used to evaluate the association of methylprednisolone regimen with outcome. RESULTS: A total of 3180 neonates were included: 22% received methylprednisolone on both the day before and day of surgery, 12% on the day before surgery only, and 28% on the day of surgery only; 38% did not receive any perioperative steroids. In multivariable analysis, there was no significant mortality or length-of-stay benefit associated with any methylprednisolone regimen versus no steroids, and no difference in postoperative infection. In subgroup analysis by surgical-risk group, there was a significant association of methylprednisolone with infection consistent across all regimens (overall odds ratio 2.6, 95% confidence interval 1.3–5.2) in the lower-surgical-risk group. CONCLUSIONS: This multicenter observational analysis did not find any benefit associated with methylprednisolone in neonates undergoing heart surgery and suggested increased infection in certain subgroups. These data reinforce the need for a large randomized trial in this population.

Bed bugs are one of the most important human ectoparasites in the United States, and a growing problem in the emergency department. We evaluated 40 emergency department (ED) patients found with a bed bug. The data show that ED patients with bed bugs are statistically more likely to be male, older, more likely to be admitted to the hospital, have higher triage emergency severity index (ESI) scores, and arrive by ambulance than the general ED patient population (p

Purpose: We evaluated the prevalence of cardiovascular abnormalities and the efficacy and safety of enzyme replacement therapy in patients with late-onset Pompe disease. Methods: Ninety patients were randomized 2:1 to enzyme replacement therapy or placebo in a double-blinded protocol. Electrocardiograms and echocardiograms were obtained at baseline and scheduled intervals during the 78-week study period. Baseline cardiovascular abnormalities, and efficacy and safety of enzyme replacement therapy were described. Three pediatric patients were excluded. Results: Eighty-seven patients were included. Median age was 44 years; 51% were men. At baseline, a short PR interval was present in 10%, 7% had decreased left ventricular systolic function, and 5% had elevated left ventricular mass on echocardiogram (all in mild range). There was no change in cardiovascular status associated with enzyme replacement therapy. No significant safety concerns related to enzyme replacement therapy were identified. Conclusions: Although some patients with late-onset Pompe disease had abnormalities on baseline electrocardiogram or echocardiogram, those classically seen in infantile Pompe disease, such as significant ventricular hypertrophy, were not noted. Cardiovascular parameters were not impacted by enzyme replacement therapy, and there were no cardiovascular safety concerns. The cardiovascular abnormalities identified may be related to Pompe disease or other comorbid conditions.

OBJECTIVE: Recently, there has been a shift toward care of children undergoing heart surgery in dedicated pediatric cardiac intensive care units (CICU). The impact of this trend on patient outcomes is unclear. We evaluated postoperative outcomes associated with a CICU versus other ICU models. PATIENTS AND METHODS: Society of Thoracic Surgeons Congenital Heart Surgery Database participants (2007–2009) who completed an ICU survey were included. In multivariable analysis, we evaluated outcomes associated with a CICU versus other ICUs, adjusting for center volume, patient factors, and Society of Thoracic Surgeons–European Association for Cardiothoracic Surgery surgical risk category. RESULTS: A total of 20 922 patients (47 centers; 25 with a CICU) were included. Overall unadjusted mortality was 3.8%, median length of stay was 6 days (interquartile range: 4–13), and 21% had 1 or more complications. In multivariable analysis, there was no difference in mortality comparing CICUs versus other ICUs (odds ratio: 0.88 [95% confidence interval: 0.65–1.19]). In stratified analysis, CICUs were associated with lower mortality only among those in Society of Thoracic Surgeons–European Association for Cardiothoracic Surgery category 3 (odds ratio: 0.47 [95% confidence interval: 0.25–0.86]), primarily related to atrioventricular canal repair and arterial switch operation. There was no difference in length of stay or complications overall or in stratified analysis. CONCLUSIONS: We were not able to detect a difference in postoperative morbidity or mortality associated with the presence of a dedicated CICU for children undergoing heart surgery. There may be a survival benefit in certain subgroups .

Background— We investigated the effect of polymorphisms in the renin-angiotensin-aldosterone system (RAAS) genes on ventricular remodeling, growth, renal function, and response to enalapril in infants with single ventricle. Methods and Results— Single ventricle infants enrolled in a randomized trial of enalapril were genotyped for polymorphisms in 5 genes: angiotensinogen, angiotensin-converting enzyme, angiotensin II type 1 receptor, aldosterone synthase, and chymase. Alleles associated with renin-angiotensin-aldosterone system upregulation were classified as risk alleles. Ventricular mass, volume, somatic growth, renal function using estimated glomerular filtration rate, and response to enalapril were compared between patients with ≥2 homozygous risk genotypes (high risk), and those with P P Conclusions— Renin-angiotensin-aldosterone system–upregulation genotypes were associated with failure of reverse remodeling after SCPC surgery, less improvement in renal function, and impaired somatic growth, the latter especially in patients receiving enalapril. Renin-angiotensin-aldosterone system genotype may identify a high-risk subgroup of single ventricle patients who fail to fully benefit from volume-unloading surgery. Follow-up is warranted to assess long-term impact. Clinical Trial Registration— http://www.clinicaltrials.gov . Unique identifier: NCT00113087.

Background The impact of age and weight on outcomes after the Fontan operation is unclear. Previous analyses have suggested that lower weight-for-age z-score is an important predictor of poor outcome in patients undergoing bidirectional Glenn. We evaluated variation in age, weight, and weight-for-age z-score at Fontan across institutions, and the impact of these variables on postoperative morbidity and mortality. Methods Patients in The Society of Thoracic Surgeons Congenital Heart Surgery Database undergoing the Fontan operation (2000 to 2009) were included. Center variation in age, weight, and weight-for-age z-score were described. Multivariable analysis was performed to evaluate the impact of age, weight, and weight-for-age z-score on in-hospital mortality, Fontan failure (combined in-hospital mortality and Fontan takedown/revision), postoperative length of stay, and complications, adjusting for other patient and center factors. Results A total of 2,747 patients (68 centers) were included: 61% male; 45% right dominant lesions (38% left dominant, 17% undifferentiated). An extracardiac conduit Fontan (versus lateral tunnel) was performed in 63%; 65% were fenestrated. Median age, median weight at Fontan operation, and proportion with weight-for-age z-score less than −2 varied across centers and ranged from 1.7 to 4.8 years, 10.5 to 16.1 kg, and 0% to 30%, respectively. In multivariable analysis, age and weight were not significantly associated with outcome. Weight-for-age z-score less than −2 was associated with increased in-hospital mortality (odds ratio 2.73, 95% confidence interval: 1.09 to 6.86), Fontan failure (odds ratio 2.59, 95% confidence interval: 1.24 to 5.40), and longer length of stay (+1.2 days, 95% confidence interval: 0.1 to 2.4). Conclusions Weight-for-age z-score less than −2 is associated with significant morbidity and mortality after the Fontan operation independent of other patient and center characteristics.

Objective: To assess health-related quality of life (HRQOL) in a large multicenter cohort of children and young adults with Marfan syndrome participating in the Pediatric Heart Network Marfan Trial. Study design: The Pediatric Quality of Life Inventory (PedsQL) 4.0 Generic Core Scales were administered to 321 subjects with Marfan syndrome (5-25 years). PedsQL scores were compared with healthy population norms. The impact of treatment arm (atenolol vs losartan), severity of clinical features, and number of patient-reported symptoms on HRQOL was assessed by general linear models. Results: Mean PedsQL scores in children (5-18 years) with Marfan syndrome were lower than healthy population norms for physical (P ≤.003) and psychosocial (P

Echocardiography is the imaging modality of choice for the evaluation of coronary artery (CA) abnormalities in Kawasaki disease. Small series have established high specificity and sensitivity for detecting abnormalities, yet visualization rates of individual CA segments and factors associated with success are unknown.In the Pediatric Heart Network's randomized trial of primary steroid treatment for Kawasaki disease, echocardiograms were interpreted locally and by a core laboratory. Univariate and multivariate predictors of CA visualization by the local lab as determined by the core lab were explored, and agreement of CA size measured locally and by the core lab was assessed.A total of 589 echocardiograms from 199 patients were obtained over 27 months. Visualization rates for the left main, proximal and distal left anterior descending, and proximal right CAs ranged from 91% to 98% but were lower for the distal right (65%), circumflex (86%), and posterior descending (54%) CAs. For the distal right and circumflex CAs, visualization rates improved over the course of the study (P.05). In multivariate analysis, local center, CA segment, and time from study start to echocardiography were independent predictors of visualization (all P values.001). For segments for which visualization rates varied by center, higher percentage visualization was associated with larger center volume (P=.001). Routine sedation use was also associated with higher visualization rates.Successful CA visualization in Kawasaki disease is associated with the segment being evaluated and is influenced by center volume and sedation use. Increased visualization rates over time suggest a learning curve and underscore the value of core lab oversight in pediatric multicenter trials.

Objectives We explored the association of noncoronary cardiac abnormalities with coronary artery dilation and with laboratory inflammatory markers early after Kawasaki disease (KD) diagnosis. Background Left ventricular (LV) dysfunction, mitral regurgitation (MR), and aortic root dilation occur early after diagnosis; their associations with coronary artery dilation and inflammatory markers have not been well-described. Methods Centrally interpreted echocardiograms were obtained at KD diagnosis and 1 and 5 weeks after diagnosis on 198 subjects in the National Institutes of Health-sponsored Pediatric Heart Network KD pulsed steroid trial. Regression models were constructed to investigate the relationships among early LV dysfunction, MR, and aortic root dilation with coronary artery dilation and laboratory inflammatory markers. Results At diagnosis, LV systolic dysfunction was present in 20% of subjects and was associated with coronary artery dilation, seen in 29% (p = 0.004). Although LV dysfunction improved rapidly, LV dysfunction at diagnosis predicted greater odds of coronary artery dilation at 1 and 5 weeks after diagnosis (5-week odds ratio: 2.7, 95% confidence interval: 1.2 to 6.3). At diagnosis, MR was present in 27% of subjects and aortic root dilation was present in 8%; each was associated with larger coronary artery size at diagnosis. Left ventricular dysfunction was associated with higher erythrocyte sedimentation rate and, at diagnosis only, lower serum albumin; MR was associated with higher erythrocyte sedimentation rate and lower albumin at all times. Aortic root size had little association with inflammatory markers. Conclusions Noncoronary cardiac abnormalities are associated with coronary artery dilation and laboratory evidence of inflammation in the first 5 weeks after KD, suggesting a shared inflammatory mechanism. (Trial of Pulse Steroid Therapy in Kawasaki Disease [A Trial Conducted by the Pediatric Heart Network]; NCT00132080 )

Background The use of clinical registries and administrative data sets in pediatric cardiovascular research has become increasingly common. However, this approach is limited by relatively few existing datasets, each of which contain limited data, and do not communicate with one another. We describe the implementation and validation of methodology using indirect patient identifiers to link The Society of Thoracic Surgeons Congenital Heart Surgery (STS-CHS) Database to The Pediatric Health Information Systems (PHIS) Database (a pediatric administrative database). Methods Centers submitting data to STS-CHS and PHIS during 2004 to 2008 were included (n = 30). Both data sets were limited to patients 0 to 18 years old undergoing cardiac surgery. An exact match was defined as an exact match on each of the following: date of birth, date of admission, date of discharge, sex, and center. Likely matches were defined as an exact match for all variables except ±1 day for one of the date variables. Results Of 45,830 STS-CHS records, 87.4% matched to PHIS using the exact match criteria and 90.3% using the exact or likely match criteria. Validation in a subset of patients revealed that 100% of exact and likely matches were true matches. Conclusions This analysis demonstrates that indirect identifiers can be used to create high-quality link between a clinical registry and administrative data set in the congenital heart surgery population. This methodology, which can also be applied to other data sets, allows researchers to capitalize on the strengths of both types of data and expands the pool of data available to answer important clinical questions.

Background— Children undergoing congenital heart surgery often receive corticosteroids with the aim of reducing the inflammatory response after cardiopulmonary bypass; however, the value of this approach is unclear. Methods and Results— The Pediatric Health Information Systems Database was used to evaluate outcomes associated with corticosteroids in children (0 to 18 years of age) undergoing congenital heart surgery at 38 US centers from 2003 to 2008. Propensity scores were constructed to account for potential confounders: age, sex, race, prematurity, genetic syndrome, type of surgery (Risk Adjustment in Congenital Heart Surgery [RACHS-1] category), center, and center volume. Multivariable analysis, adjusting for propensity score and individual covariates, was performed to evaluate in-hospital mortality, postoperative length of stay, duration of ventilation, infection, and use of insulin. A total of 46 730 children were included; 54% received corticosteroids. In multivariable analysis, there was no difference in mortality among corticosteroid recipients and nonrecipients (odds ratio, 1.13; 95% confidence interval, 0.98 to 1.30). Corticosteroids were associated with longer length of stay (least square mean difference, 2.18 days; 95% confidence interval, 1.62 to 2.74 days), greater infection (odds ratio, 1.27; 95% confidence interval, 1.10 to 1.46), and greater use of insulin (odds ratio, 2.45; 95% confidence interval, 2.24 to 2.67). There was no difference in duration of ventilation. In analysis stratified by RACHS-1 category, no significant benefit was seen in any group, and the association of corticosteroids with increased morbidity was most prominent in RACHS-1 categories 1 through 3. Conclusion— In this observational analysis of children undergoing congenital heart surgery, we were unable to demonstrate a significant benefit associated with corticosteroids and found that corticosteroids may be associated with increased morbidity, particularly in lower-risk patients.

OBJECTIVE:We describe patient characteristics and postoperative morbidity and mortality rates for patients with Down syndrome undergoing congenital heart disease surgery.METHODS:This retrospective cohort study used the Society of Thoracic Surgeons Congenital Heart Surgery Database to compare patient characteristics and postoperative outcomes for patients (0–18 years) with or without Down syndrome who underwent surgery in 2000–2008.RESULTS:A total of 45 579 patients (4350 patients with Down syndrome and 41 229 without Down syndrome) were included (median age: 7 months [interquartile range [IQR]: 47 days to 4 years]; 56% male). Patients with Down syndrome were younger at surgery, with the exception of those undergoing tetralogy of Fallot repair or atrioventricular septal defect repair. Mortality rates for patients with or without Down syndrome did not differ significantly. Lengths of stay were prolonged for patients with Down syndrome undergoing atrial septal defect closure (median: 4 days [IQR: 3–5 days] vs 3 days [IQR: 2–4 days]; P < .0001), ventricular septal defect closure (median: 5 days [IQR: 4–8 days] vs 4 days [IQR: 3–6 days]; P < .0001), or tetralogy of Fallot repair (7 days [IQR: 5–10 days] vs 6 days [IQR: 5–9 days]; P < .001) and were associated with postoperative respiratory and infectious complications. Patients with Down syndrome undergoing ventricular septal defect closure had a higher rate of heart block requiring pacemaker placement (2.9% vs 0.8%; P < .0001).CONCLUSION:In this large, contemporary cohort, Down syndrome did not confer a significant mortality risk for the most common operations; however, postoperative morbidity remained common.

Background Aprotinin was used frequently in children undergoing congenital heart operations with the aim of reducing bleeding, until it was taken off the market after adult studies reported increased renal failure and death. We evaluated the safety of aprotinin in a large multicenter cohort of children undergoing congenital heart operations. Methods The Pediatric Health Information Systems Database was used to evaluate aprotinin in children (aged 0 to 18 years) undergoing congenital heart operations at 35 children's hospitals from 2003 to 2007. Propensity scores were constructed to account for potential confounders of age, sex, race, prematurity, genetic syndrome, type of operation (Risk Adjustment in Congenital Heart Surgery-1 category), center, and center volume. Multivariable analysis, adjusting for propensity score and individual covariates was performed to evaluate in-hospital mortality, postoperative renal failure requiring dialysis, and length of stay. Subanalysis was performed in the high-risk cohort undergoing reoperation. Results The study included 30,372 patients (56% male) who were a median age of 7 months (interquartile range, 36 days to 3.2 years). Overall, 44% received aprotinin. Multivariable analysis found no difference in postoperative mortality (odds ratio, 1.00; 95% confidence interval [CI], 0.99 to 1.01), dialysis (odds ratio, 1.00; 95% CI, 0.99 to 1.01), or length of stay (least square mean difference, −0.44 days; 95% CI, −1.01 to 0.13) between aprotinin recipients and nonrecipients. No difference was found in mortality or dialysis in patients undergoing reoperation. Aprotinin recipients in the reoperation subgroup had significantly reduced length of stay (least square mean difference, −2.05 days; 95% CI −3.29 to −0.81), Conclusions These data suggest aprotinin is not associated with increased mortality or dialysis in children undergoing congenital heart operations and that further evaluation of aprotinin in this population could be undertaken without undue risk.

Purpose: Glycogen Storage Disease Type III, glycogen debranching enzyme deficiency, causes accumulation of glycogen in liver, skeletal, and cardiac muscle. Some patients develop increased left ventricular thickness by echocardiography, but the rate of increase and its significance remain unclear. Methods: We evaluated 33 patients with Glycogen Storage Disease Type III, 23 with IIIa and 10 with IIIb, ages 1 month to 55.5 years, by echocardiography for wall thickness, left ventricular mass, shortening and ejection fractions, at 1 time point (n = 33) and at 2 time points in patients with more than 1 echocardiogram (13 of the 33). Results: Of 23 cross-sectional patients with type IIIa, 12 had elevated left ventricular mass, 11 had elevated wall thickness. One type IIIb patient had elevated left ventricular mass but four had elevated wall thickness. For those with multiple observations, 9 of 10 with type IIIa developed increased left ventricular mass over time, with three already increased at first measurement. Shortening and ejection fractions were generally normal. Conclusion: Elevated left ventricular mass and wall thickness is more common in patients with type IIIa but develops rarely in type IIIb, although ventricular systolic function is preserved. This suggests serial echocardiograms with attention to left ventricular thickness and mass are important for care of these patients.

Objective There is debate whether primary or delayed sternal closure is the best strategy after stage 1 palliation for hypoplastic left heart syndrome. We describe center variation in delayed sternal closure after stage 1 palliation and associated outcomes. Methods Society of Thoracic Surgeons Congenital Database participants performing stage 1 palliation for hypoplastic left heart syndrome from 2000 to 2007 were included. We examined center variation in delayed sternal closure and compared in-hospital mortality, prolonged length of stay (length of stay > 6 weeks), and postoperative infection in centers with low (≤25% of cases), middle (26%–74% of cases), and high (≥75% of cases) delayed sternal closure use, adjusting for patient and center factors. Results There were 1283 patients (45 centers) included. Median age at surgery was 6 days (interquartile range, 4–9 days), and median weight at surgery was 3.2 kg (interquartile range, 2.8–3.5 kg); 59% were male. Delayed sternal closure was used in 74% of cases (range, 3%–100% of cases/center). In centers with high (n = 23) and middle (n = 17) versus low (n = 5) delayed sternal closure use, there was a greater proportion of patients with prolonged length of stay and infection, and a trend toward increased in-hospital mortality in unadjusted analysis. In multivariable analysis, there was no difference in mortality. Centers with high and middle delayed sternal closure use had prolonged length of stay (odds ratio, 2.83; 95% confidence interval, 1.46–5.47; P = .002 and odds ratio, 2.23; confidence interval, 1.17–4.26; P = .02, respectively) and more infection (odds ratio, 2.34; confidence interval, 1.20–4.57; P = .01 and odds ratio, 2.37; confidence interval, 1.36–4.16; P = .003, respectively). Conclusion Use of delayed sternal closure after stage 1 palliation varies widely. These observational data suggest that more frequent use of delayed sternal closure is associated with longer length of stay and higher postoperative infection rates. Further evaluation of the risks and benefits of delayed sternal closure in the management of these complex infants is necessary.

Although congenital heart disease is associated with low birth weight and prematurity, there is little information about these birth outcomes in infants with single ventricle physiology. We describe the birth outcomes (i.e., gestational age and birth weight) in neonates with single ventricle physiology screened for enrollment in the Pediatric Heart Network's Infant Single Ventricle Trial, compare these outcomes with US norms, and examine the association of birth outcomes with anatomic diagnosis and race.All neonates with single ventricle physiology presenting to Infant Single Ventricle Trial centers were screened for enrollment. Demographic data and anatomic diagnoses were obtained from medical records.A total of 1245 neonates with single ventricle physiology were screened at 10 centers (63 to 266 per center). Diagnoses included hypoplastic left heart syndrome in 49%, unbalanced atrioventricular septal defect in 12%, and tricuspid atresia in 9%. Preterm birth occurred in 16% of neonates with single ventricle physiology vs. 12% in normal neonates (P.001), low birth weight (2.5 kg) in 18% vs. 8% in normals (P.001), and small for gestational age (10th percentile by definition) in 22% vs. 10% in normals (P.001). A genetic syndrome was reported in 8%. The percentage of preterm birth, low birth weight, and small for gestational age was similar between screened neonates with and without hypoplastic left heart syndrome.In this large, contemporary cohort of neonates with single ventricle physiology, rates of preterm birth, low birth weight, and small for gestational age were higher than in the general population, but similar between screened neonates with and without hypoplastic left heart syndrome.

The incidence of cough in children receiving antihypertension therapy with angiotensin-converting enzyme inhibitors (ACEis) or angiotensin receptor blockers (ARBs) is unknown. We analyzed patient-level data from eight randomized trials for the treatment of pediatric hypertension, six of them involving ACEis and two involving ARBs. The incidence of cough in children receiving ACEis (reported cough, 3.2%) was similar to that in children receiving ARBs (reported cough, 1.8%) (P = 0.34). Reports of cough were lower in children than in adults. Clinical Pharmacology & Therapeutics (2010) 87 6, 668–671. doi: 10.1038/clpt.2009.231

Surgical and perioperative improvements permit earlier repair of partial and transitional atrioventricular septal defects (AVSD). We sought to describe contemporary outcomes in a multicenter cohort.We studied 87 patients undergoing primary biventricular repair of partial or transitional AVSD between June 2004 and February 2006 across seven North American centers. One-month and 6-month postoperative data included weight-for-age z-scores, left atrioventricular valve regurgitation (LAVVR) grade, residual shunts, and left ventricular ejection fraction. Paired methods were used to assess 6-month change.Median age at surgery was 1.8 years; median weight z-score was -0.88. Median days for ventilation were 1, intensive care 2, and hospitalization 5, all independent of age, with 1 in-hospital death. At 1 month, 27% (16 of 73) had ejection fraction less than 55%; 20% (17 of 87) had significant LAVVR; 2 had residual shunts; 1 each had subaortic stenosis and LAVV stenosis. At 6 months (n = 60), there were no interim deaths, reinterventions, or new development of subaortic or LAVV stenosis. Weight z-score improved by a median 0.4 units (p0.001), especially for underweight children less than 18 months old. Left atrioventricular valve regurgitation occurred in 31% (change from baseline, p = 0.13), occurring more frequently in patients repaired at 4 to 7 years (p = 0.01). Three patients had ejection fraction less than 55%, and 1 had a residual atrial shunt.Surgical repair for partial/transitional AVSD is associated with low morbidity and mortality, short hospital stays, and catch-up growth, particularly in underweight children repaired between 3 and 18 months of age. Left atrioventricular valve regurgitation remains the most common residual defect, occurring more frequently in children repaired after 4 years of age.

Background— Patients after the Fontan procedure are at risk for suboptimal functional health status, and associations with laboratory measures are important for planning interventions and outcome measures for clinical trials. Methods and Results— Parents completed the generic Child Health Questionnaire for 511 Fontan Cross-Sectional Study patients 6 to 18 years of age (61% male). Associations of Child Health Questionnaire Physical and Psychosocial Functioning Summary Scores (FSS) with standardized measurements from prospective exercise testing, echocardiography, magnetic resonance imaging, and measurement of brain natriuretic peptide were determined by regression analyses. For exercise variables for maximal effort patients only, the final model showed that higher Physical FSS was associated only with higher maximum work rate, accounting for 9% of variation in Physical FSS. For echocardiography, lower Tei index (particularly for patients with extracardiac lateral tunnel connections), lower indexed end-systolic volume, and the absence of atrioventricular valve regurgitation for patients having Fontan procedure at age Conclusions— In relatively healthy Fontan patients, laboratory measures account for a small proportion of the variation in functional health status and therefore may not be optimal surrogate end points for trials of therapeutic interventions.

Deficiency of acid alpha glucosidase (GAA) causes Pompe disease, which is usually fatal if onset occurs in infancy. Patients synthesize a non-functional form of GAA or are unable to form native enzyme. Enzyme replacement therapy with recombinant human GAA (rhGAA) prolongs survival in infantile Pompe patients but may be less effective in cross-reactive immunologic material (CRIM)-negative patients. We retrospectively analyzed the influence of CRIM status on outcome in 21 CRIM-positive and 11 CRIM-negative infantile Pompe patients receiving rhGAA. Patients were from the clinical setting and from clinical trials of rhGAA, were 6 months of age, were not invasively ventilated, and were treated with IV rhGAA at a cumulative or total dose of 20 or 40 mg/kg/2 weeks. Outcome measures included survival, invasive ventilator-free survival, cardiac status, gross motor development, development of antibodies to rhGAA, and levels of urinary Glc(4). Following 52 weeks of treatment, 6/11 (54.5%) CRIM-negative and 1/21 (4.8%) CRIM-positive patients were deceased or invasively ventilated (p

Infantile Pompe disease (glycogen storage disease type 2) is a fatal disorder caused by deficiency of acid alpha-glucosidase. This deficiency results in glycogen accumulation in the lysosomes of many tissues including cardiac muscle. The disease is characterized by profound hypotonia, poor growth, organomegaly, and cardiomegaly. Severe hypertrophic cardiomyopathy often is present in early infancy, and most patients die of cardiac or respiratory failure in the first year of life. This report describes the cardiac response of infants with Pompe disease to a phase 2 trial of enzyme replacement therapy (ERT).Eight patients with classical infantile Pompe disease were given intravenous recombinant human GAA (rhGAA) for 1 year. Cardiac monitoring included echocardiography, electrocardiograms (ECGs), chest radiographs, and clinical cardiac evaluation at 4, 8, 12, 24, 36, and 52 weeks. At 52 weeks, 6 patients were alive.Most of the treated patients had rapid regression of ventricular hypertrophy in response to ERT, with near normalization of posterior wall thickness, ventricular mass, and ventricular size. Systolic ventricular function was preserved despite rapid changes in ventricular mass and size. Concomitantly, ECGs documented lengthening of the PR interval and decreased ventricular voltages, whereas chest radiographs documented a decreased cardiothoracic ratio. Symptoms of pulmonary congestion were diminished, and survival was improved.The cardiovascular system responds quickly and strikingly to ERT with rhGAA, suggesting rapid reversal of excessive glycogen storage in cardiac muscle cells. Changes in ventricular mass and function are maintained throughout 1 year of follow-up evaluation and associated with decreased morbidity and prolonged survival.

Background Hospitalized infants requiring cardiopulmonary resuscitation (CPR) represent a high-risk group. Recent data on risk factors for mortality following CPR in this population are lacking. Aims We hypothesized that infant demographic characteristics, diagnoses, and levels of cardiopulmonary support at the time of CPR requirement would be associated with survival to hospital discharge following CPR. Study design Retrospective cohort study. Subjects All infants receiving CPR on day of life 2 to 120 admitted to 348 Pediatrix Medical Group neonatal intensive care units from 1997 to 2012. Outcomes measures We collected data on demographics, interventions, center volume, and death prior to NICU discharge. We evaluated predictors of death after CPR using multivariable logistic regression with generalized estimating equations to account for clustering of the data by center. Results Our cohort consisted of 2231 infants receiving CPR. Of these, 1127 (51%) survived to hospital discharge. Lower gestational age, postnatal age, 5-min APGAR, congenital anomaly, and markers of severity of illness were associated with higher mortality. Mortality after CPR did not change significantly over time (Cochran–Armitage test for trend p = 0.35). Conclusions Mortality following CPR in infants is high, particularly for less mature, younger infants with congenital anomalies and those requiring cardiopulmonary support prior to CPR. Continued focus on at risk infants may identify targets for CPR prevention and improve outcomes.

Summary Background: Patients with infantile-onset Pompe disease suffer from marked hypertrophic cardiomyopathy and an increased risk of arrhythmia. A noncompliant left ventricle predisposes these infants to diastolic heart failure with elevated left ventricular enddiastolic pressure (LVEDP); these patients also commonly develop systolic heart failure. Given this baseline cardiac physiology, coronary perfusion pressure becomes highly sensitive to abrupt changes in diastolic blood pressure (DBP). Methods: We retrospectively reviewed the experiences of 139 patients enrolled in clinical trials investigating the treatment of infantile-onset Pompe disease with recombinant human acid α-glucosidase (rhGAA). Adverse events were screened for those involving anesthesia. Results: Nine patients (6%) with infantile-onset Pompe disease experienced an arrhythmia or cardiopulmonary arrest soon after the induction of general anesthesia. Of these events, propofol was involved in four arrhythmias; sevoflurane without propofol was associated with an additional two. Deaths resulting from arrhythmia appeared to correlate with left ventricular mass indices >350 g·m−2. Conclusions: With the advent of enzyme replacement therapy (ERT) using rhGAA, and increased survivability, more infantile Pompe patients will likely present for surgical procedures. Additional care in maximizing coronary perfusion pressure and minimizing arrhythmia risk must be given. For these reasons, it is recommended that anesthesia for infantile Pompe patients specifically avoid propofol or high concentrations of sevoflurane and, instead, use an agent such as ketamine as the cornerstone for induction in order to better support coronary perfusion pressure and to avoid decreasing DBP with vasodilatory agents.

Treatment of acute Kawasaki disease with intravenous immune globulin and aspirin reduces the risk of coronary-artery abnormalities and systemic inflammation, but despite intravenous immune globulin therapy, coronary-artery abnormalities develop in some children. Studies have suggested that primary corticosteroid therapy might be beneficial and that adverse events are infrequent with short-term use.We conducted a multicenter, randomized, double-blind, placebo-controlled trial to determine whether the addition of intravenous methylprednisolone to conventional primary therapy for Kawasaki disease reduces the risk of coronary-artery abnormalities. Patients with 10 or fewer days of fever were randomly assigned to receive intravenous methylprednisolone, 30 mg per kilogram of body weight (101 patients), or placebo (98 patients). All patients then received conventional therapy with intravenous immune globulin, 2 g per kilogram, as well as aspirin, 80 to 100 mg per kilogram per day until they were afebrile for 48 hours and 3 to 5 mg per kilogram per day thereafter.At week 1 and week 5 after randomization, patients in the two study groups had similar coronary dimensions, expressed as z scores adjusted for body-surface area, absolute dimensions, and changes in dimensions. As compared with patients receiving placebo, patients receiving intravenous methylprednisolone had a somewhat shorter initial period of hospitalization (P=0.05) and, at week 1, a lower erythrocyte sedimentation rate (P=0.02) and a tendency toward a lower C-reactive protein level (P=0.07). However, the two groups had similar numbers of days spent in the hospital, numbers of days of fever, rates of retreatment with intravenous immune globulin, and numbers of adverse events.Our data do not provide support for the addition of a single pulsed dose of intravenous methylprednisolone to conventional intravenous immune globulin therapy for the routine primary treatment of children with Kawasaki disease. (ClinicalTrials.gov number, NCT00132080 [ClinicalTrials.gov].)