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Objectives: We measured behavioral, quality of life (QoL), and functional status outcomes for 6-year-old children with hypoplastic left heart syndrome enrolled in the Single Ventricle Reconstruction Trial. We sought to compare these outcomes with those in the normative population and to analyze risk factors for worse outcomes within the single-ventricle group., Methods: Parent-response instruments included the Vineland Adaptive Behavior Scales, Second Edition (Vineland-II) (primary outcome), Behavior Assessment System for Children 2, Pediatric Quality of Life Inventory 4.0, and other measures of QoL and functional status. We compared subjects with those in the normative sample using 1-sample Wilcoxon rank tests and assessed outcome predictors using multivariable regression., Results: Of 325 eligible patients, 250 (77%) participated. Compared with population norms, participants had lower scores on the Vineland-II motor skills domain (90 ± 17 vs 100 ± 15; P < .001), with 11% scoring >2 SDs below the normative mean. On nearly all major domains, more study subjects (3.3%-19.7%) scored outside the normal range than anticipated for the general population. Independent risk factors for lower Vineland-II scores included perioperative extracorporeal membrane oxygenation, male sex, use of regional cerebral perfusion, catheterization after stage 2 operation, visual problems, seizure history, and more complications after 2 years ( R 2 = 0.32). Independent predictors of worse Behavior Assessment System for Children 2 ( R 2 = 0.07-0.20) and Pediatric Quality of Life Inventory 4.0 ( R 2 = 0.17-0.25) domain scores also included sociodemographic factors and measures of morbidity and/or greater course complexity., Conclusions: At 6 years, children with hypoplastic left heart syndrome had difficulty in areas of adaptive behavior, behavioral symptoms, QoL, and functional status. Principal risks for adverse outcomes include sociodemographic factors and measures of greater course complexity. However, models reveal less than one-third of outcome variance., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2019 by the American Academy of Pediatrics.)

The frequency, indications, and outcomes for readmission following pediatric heart transplantation are poorly characterized. A better understanding of this phenomenon will help guide strategies to address the causes of readmission. Data from the Clinical Trials in Organ Transplantation for Children (CTOTC-04) multi-institutional collaborative study were utilized to determine incidence of, and risk factors for, hospital readmission within 30 days and 1 year from initial hospital discharge. Among 240 transplants at 8 centers, 227 subjects were discharged and had follow-up. 129 subjects (56.8%) were readmitted within one year; 71 had two or more readmissions. The 30-day and 1-year freedom from readmission were 70.5% (CI: 64.1%, 76.0%) and 42.2% (CI: 35.7%, 48.7%), respectively. The most common indications for readmissions were infection followed by rejection and fever without confirmed infection, accounting for 25.0%, 10.6%, and 6.2% of readmissions, respectively. Factors independently associated with increased risk of first readmission within 1 year (Cox proportional hazard model) were as follows: transplant in infancy (P = .05), longer transplant hospitalization (P = .04), lower UNOS urgency status (2/IB vs 1A) at transplant (P = .04), and Hispanic ethnicity (P = .05). Hospital readmission occurs frequently in the first year following discharge after heart transplantation with highest risk in the first 30 days. Infection is more common than rejection as cause for readmission, with death during readmission being rare. A number of patient factors are associated with higher risk of readmission. A fuller understanding of these risk factors may help tailor strategies to reduce unnecessary hospital readmission., (© 2019 Wiley Periodicals, Inc.)

Background: Immunosuppression strategies have changed over time in pediatric heart transplantation. Thus, comorbidity profiles may have evolved. Clinical Trials in Organ Transplantation in Children-04 is a multicenter, prospective, cohort study assessing the impact of pre-transplant sensitization on outcomes after pediatric heart transplantation. This sub-study reports 1-year outcomes among recipients without pre-transplant donor-specific antibodies (DSAs)., Methods: We recruited consecutive candidates (<21 years) at 8 centers. Sensitization status was determined by a core laboratory. Immunosuppression was standardized as follows: Thymoglobulin induction with tacrolimus and/or mycophenolate mofetil maintenance. Steroids were not used beyond 1 week. Rejection surveillance was by serial biopsy., Results: There were 240 transplants. Subjects for this sub-study (n = 186) were non-sensitized (n = 108) or had no DSAs (n = 78). Median age was 6 years, 48.4% were male, and 38.2% had congenital heart disease. Patient survival was 94.5% (95% confidence interval, 90.1-97.0%). Freedom from any type of rejection was 67.5%. Risk factors for rejection were older age at transplant and presence of non-DSAs pre-transplant. Freedom from infection requiring hospitalization/intravenous anti-microbials was 75.4%. Freedom from rehospitalization was 40.3%. New-onset diabetes mellitus and post-transplant lymphoproliferative disorder (PTLD) occurred in 1.6% and 1.1% of subjects, respectively. There was no decline in renal function over the first year. Corticosteroids were used in 14.5% at 1 year., Conclusions: Pediatric heart transplantation recipients without DSAs at transplant and managed with a steroid avoidance regimen have excellent short-term survival and a low risk of first-year diabetes mellitus and PTLD. Rehospitalization remains common. These contemporary observations allow for improved caregiver and/or patient counseling and provide the necessary outcomes data to help design future randomized controlled trials., (Copyright © 2019 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: The efficacy of intraoperative corticosteroids to improve outcomes following congenital cardiac operations remains controversial., Objectives: The purpose of this study was to determine whether intraoperative methylprednisolone improves post-operative recovery in neonates undergoing cardiac surgery., Methods: Neonates undergoing cardiac surgery with cardiopulmonary bypass at 2 centers were enrolled in a double-blind randomized controlled trial of methylprednisolone (30 mg/kg) or placebo after the induction of anesthesia. The primary outcome was a previously validated morbidity-mortality composite that included any of the following events following surgery before discharge: death, mechanical circulatory support, cardiac arrest, hepatic injury, renal injury, or rising lactate level (>5 mmol/l)., Results: Of the 190 subjects enrolled, 176 (n = 81 methylprednisolone, n = 95 placebo) were included in this analysis. A total of 27 (33%) subjects in the methylprednisolone group and 40 (42%) in the placebo group reached the primary study endpoint (odds ratio [OR]: 0.63; 95% confidence interval [CI]: 0.31 to 1.3; p = 0.21). Methylprednisolone was associated with reductions in vasoactive inotropic requirements and in the incidence of the composite endpoint in subjects undergoing palliative operations (OR: 0.38; 95% CI: 0.15 to 0.99; p = 0.048). There was a significant interaction between treatment effect and center. In this analysis, methylprednisolone was protective at 1 center, with an OR: 0.35 (95% CI: 0.15 to 0.84; p = 0.02), and not so at the other center, with OR: 5.13 (95% CI: 0.85 to 30.90; p = 0.07)., Conclusions: Intraoperative methylprednisolone failed to show an overall significant benefit on the incidence of the composite primary study endpoint. There was, however, a benefit in patients undergoing palliative procedures and a significant interaction between treatment effect and center, suggesting that there may be center or patient characteristics that make prophylactic methylprednisolone beneficial., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Neurodevelopmental disability is the most significant complication for survivors of infant surgery for congenital heart disease. In this study we sought to determine if perioperative circulating brain injury biomarker levels are associated with neurodevelopmental outcomes at 12 months., Methods: A secondary analysis of a randomized controlled trial of neonates who underwent cardiac surgery was performed. Glial fibrillary acidic protein (GFAP) was measured: (1) before skin incision; (2) immediately after bypass; (3) 4 and (4) 24 hours postoperatively. Linear regression models were used to determine an association with the highest levels of GFAP and Bayley Scales of Infant and Toddler Development third edition (BSID) composite scores., Results: There were 97 subjects who had cardiac surgery at a mean age of 9 ± 6 days and completed a BSID at 12.5 ± 0.6 months of age. Median (25th-75th percentile) levels of GFAP were 0.01 (0.01-0.02), 0.85 (0.40-1.55), 0.07 (0.05-0.11), and 0.03 (0.02-0.04) ng/mL at the 4 time points, respectively. In univariate analysis GFAP was negatively associated with cognitive, language, and motor composite scores. GFAP levels immediately after bypass differed between institutions; 1.57 (0.92-2.48) versus 0.77 (0.36-1.21) ng/mL (P = .01). After adjusting for center and potential confounders, GFAP was independently associated with BSID motor score (P = .04)., Conclusions: Higher GFAP levels at the time of neonatal cardiac operations were independently associated with decreased BSID motor scores at 12 months. GFAP might serve as a diagnostic means to acutely identify perioperative brain-specific injury and serve as a benchmark of therapeutic efficacy for investigational treatments, discriminate center-specific effects, and provide early prognostic information for intervention., (Copyright © 2019 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Background: The Pediatric Heart Network Collaborative Learning Study (PHN CLS) increased early extubation rates after infant tetralogy of Fallot (TOF) and coarctation of the aorta (CoA) repair across participating sites by implementing a clinical practice guideline (CPG). The impact of the CPG on hospital costs has not been studied., Methods: PHN CLS clinical data were linked to cost data from Children's Hospital Association by matching on indirect identifiers. Hospital costs were evaluated across active and control sites in the pre- and post-CPG periods using generalized linear mixed-effects models. A difference-in-difference approach was used to assess whether changes in cost observed in active sites were beyond secular trends in control sites., Results: Data were successfully linked on 410 of 428 eligible patients (96%) from four active and four control sites. Mean adjusted cost per case for TOF repair was significantly reduced in the post-CPG period at active sites ($42,833 vs $56,304, p < 0.01) and unchanged at control sites ($47,007 vs $46,476, p = 0.91), with an overall cost reduction of 27% in active versus control sites (p = 0.03). Specific categories of cost reduced in the TOF cohort included clinical (-66%, p < 0.01), pharmacy (-46%, p = 0.04), lab (-44%, p < 0.01), and imaging (-32%, p < 0.01). There was no change in costs for CoA repair at active or control sites., Conclusions: The early extubation CPG was associated with a reduction in hospital costs for infants undergoing repair of TOF but not CoA. This CPG represents an opportunity to both optimize clinical outcome and reduce costs for certain infant cardiac surgeries., (Copyright © 2019 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: The Pediatric Heart Network Collaborative Learning Study (PHN CLS) successfully changed practice at four hospitals to increase the rate of early extubation within 6 hours after infant heart surgery. It is unknown whether this practice continued after study completion., Methods: We linked the PHN CLS dataset to the Pediatric Cardiac Critical Care Consortium registry to compare outcomes at four active hospitals between the study period (post-clinical practice guideline [CPG]) and the first year after study completion (follow-up) after a 3-month washout. Inclusion and exclusion criteria were the same across eras. Primary outcome was early extubation rate after tetralogy of Fallot or aortic coarctation repair. Secondary outcomes included time to first extubation and intensive care and hospital lengths of stay., Results: There were 121 patients in the post-CPG era and 139 patients in the follow-up era with no difference in patient characteristics or operation subtypes. Post-CPG early extubation rate declined from 67% to 30% in follow-up (p < 0.0001); time to first extubation increased (4.5 versus 13.5 hours, p < 0.0001). One hospital maintained the rate of early extubation (72% versus 67%), whereas the other three hospitals had significantly lower rates in follow-up (p < 0.02 for each). Intensive care (2.8 versus 2.9 days) and postoperative hospital (6 versus 5 days) stays did not differ between eras (p > 0.05 for both). Findings were consistent across operation subtypes., Conclusions: Extubation practice in the first year of follow-up after the PHN CLS reverted toward prestudy levels. One of four hospitals maintained its early extubation strategy, suggesting that specific implementation and maintenance approaches may effectively sustain impact from quality initiatives., (Copyright © 2019 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: The Pediatric Heart Network Collaborative Learning Study (PHN CLS) increased early extubation after infant tetralogy of Fallot (TOF) and coarctation repair overall at participating sites through implementing a clinical practice guideline (CPG). We evaluated variability across sites in CPG implementation and outcomes., Methods: Patient characteristics and outcomes (time to extubation, length of stay [LOS]) were compared across sites, including pre-CPB to post-CPG changes. Semistructured interviews were analyzed to assess similarities and differences in implementation strategies across sites., Results: A total of 322 patients were included (4 active sites, 1 model site). Patient characteristics were similar across active sites, whereas pre-CPG median time to extubation varied from 15.4 to 35.5 hours. All active sites had a significant post-CPG decline (p < 0.001); however, there was variation in the post-CPG median time to extubation (0.3 to 5.3 hours, p = 0.01) and magnitude of change (-73.3% to -99.2%). Site A achieved the shortest post-CPG time to extubation and had the greatest percentage change. Two sites had significant decreases in medical ICU LOS in TOF patients; no hospital LOS changes were seen. All sites valued the collaborative learning strategy, site visits, CPG flexibility, and had similar core team composition. Site A used several unique strategies: inclusion of other staff and fellows, regular in-person data reviews, additional data collection, and creation of complementary protocols., Conclusions: All PHN CLS sites successfully reduced time to extubation. The magnitude of change varied and may be partly explained by different CPG implementation strategies. These data can guide CPG dissemination and design of future improvement projects., (Copyright © 2019 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: We examined the association of preoperative cell count abnormalities, which have been shown to be associated with outcomes in adult cardiac patients, with morbidity and mortality after operation for congenital heart disease (CHD) in children., Methods: We performed a retrospective cohort study on 4,865 children undergoing cardiac operation from 2004 to 2014. Our exposures of interest were presence of preoperative lymphopenia (lymphocyte count ≤ 3,000 cells/μL), thrombocytopenia (platelet count < 150 × 10 3 /μL), and neutrophilia (neutrophil count ≥ 7,000 cells/μL). Our outcomes of interest were mortality status, postoperative length of stay (LOS), and occurrence of postoperative complications. We performed logistic and linear regressions to determine the associations of preoperative cell counts with mortality, LOS, and complications, adjusting for age, sex, race or ethnicity, presence of a genetic syndrome, and Society of Thoracic Surgeons and European Association for Cardio-Thoracic Surgery Congenital Heart Surgery Mortality category., Results: Overall mortality was 2.8%, median LOS was 6 days, and 7.6% of patients had postoperative complications. Lymphopenia was associated with increased odds of postoperative mortality (odds ratio 1.67, 95% confidence interval: 1.15 to 2.43, p = 0.007). Lymphopenia, thrombocytopenia, and neutrophilia were all associated with longer postoperative LOS. Lymphopenia and thrombocytopenia were associated with increased occurrence of postoperative sepsis, and neutrophilia was associated with need for postoperative mechanical circulatory support., Conclusions: In children undergoing CHD operation, preoperative lymphopenia is associated with increased in-hospital mortality postoperatively. Preoperative lymphopenia, neutrophilia, and thrombocytopenia are associated with longer postoperative LOS and with development of postoperative complications. Preoperative cell counts may serve as important prognostic markers in preoperative planning for patients with CHD., (Copyright © 2018 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Objectives: As the number of adolescents and young adults (AYAs) surviving congenital heart disease (CHD) grows, studies of long-term outcomes are needed. CHD research documents poor executive function (EF) and cerebellum (CB) abnormalities in children. We examined whether AYAs with CHD exhibit reduced EF and CB volumes. We hypothesized a double dissociation such that the posterior CB is related to EF while the anterior CB is related to motor function. We also investigated whether the CB contributes to EF above and beyond processing speed., Methods: Twenty-two AYAs with CHD and 22 matched healthy controls underwent magnetic resonance imaging and assessment of EF, processing speed, and motor function. Volumetric data were calculated using a cerebellar atlas (SUIT) developed for SPM. Group differences were compared with t tests, relationships were tested with Pearson's correlations and Fisher's r to z transformation, and hierarchical regression was used to test the CB's unique contributions to EF., Results: CHD patients had reduced CB total, lobular, and white matter volume (d=.52-.99) and poorer EF (d=.79-1.01) compared to controls. Significant correlations between the posterior CB and EF (r=.29-.48) were identified but there were no relationships between the anterior CB and motor function nor EF. The posterior CB predicted EF above and beyond processing speed (ps<.001)., Conclusions: This study identified a relationship between the posterior CB and EF, which appears to be particularly important for inhibitory processes and abstract reasoning. The unique CB contribution to EF above and beyond processing speed alone warrants further study. (JINS, 2018, 24, 939-948).

Data on the clinical importance of newly detected donor-specific anti-HLA antibodies (ndDSAs) after pediatric heart transplantation are lacking despite mounting evidence of the detrimental effect of de novo DSAs in solid organ transplantation. We prospectively tested 237 pediatric heart transplant recipients for ndDSAs in the first year posttransplantation to determine their incidence, pattern, and clinical impact. One-third of patients developed ndDSAs; when present, these were mostly detected within the first 6 weeks after transplantation, suggesting that memory responses may predominate over true de novo DSA production in this population. In the absence of preexisting DSAs, patients with ndDSAs had significantly more acute cellular rejection but not antibody-mediated rejection, and there was no impact on graft and patient survival in the first year posttransplantation. Risk factors for ndDSAs included common sensitizing events. Given the early detection of the antibody response, memory responses may be more important in the first year after pediatric heart transplantation and patients with a history of a sensitizing event may be at risk even with a negative pretransplantation antibody screen. The impact on late graft and patient outcomes of first-year ndDSAs is being assessed in an extended cohort of patients., (© 2018 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Anti-HLA donor-specific antibodies are associated with worse outcomes after organ transplantation. Among sensitized pediatric heart candidates, requirement for negative donor-specific cytotoxicity crossmatch increases wait times and mortality. However, transplantation with positive crossmatch may increase posttransplantation morbidity and mortality. We address this clinical challenge in a prospective, multicenter, observational cohort study of children listed for heart transplantation (Clinical Trials in Organ Transplantation in Children-04 [CTOTC-04]). Outcomes were compared among sensitized recipients who underwent transplantation with positive crossmatch, nonsensitized recipients, and sensitized recipients without positive crossmatch. Positive crossmatch recipients received antibody removal and augmented immunosuppression, while other recipients received standard immunosuppression with corticosteroid avoidance. This first CTOTC-04 report summarizes study rationale and design and relates pretransplantation sensitization status using solid-phase technology. Risk factors for sensitization were explored. Of 317 screened patients, 290 were enrolled and 240 underwent transplantation. Core laboratory evaluation demonstrated that more than half of patients were anti-HLA sensitized. Greater than 80% of sensitized patients had class I (with or without class II) HLA antibodies, and one-third of sensitized patients had at least 1 HLA antibody with median fluorescence intensity of ≥8000. Logistic regression models demonstrated male sex, weight, congenital heart disease history, prior allograft, and ventricular assist device are independent risk factors for sensitization., (© 2018 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: Heart failure results in significant morbidity and mortality in young children with hypoplastic left heart syndrome (HLHS) after the Norwood procedure., Methods: We studied subjects enrolled in the prospective Single Ventricle Reconstruction (SVR) Trial who survived to hospital discharge after a Norwood operation and were followed up to age 6 years. The primary outcome was heart failure, defined as heart transplant listing after Norwood hospitalization, death attributable to heart failure, or symptomatic heart failure (New York Heart Association [NYHA] Class IV). Multivariate modeling was undertaken using Cox regression methodology to determine variables associated with heart failure., Results: Of the 461 subjects discharged home following a Norwood procedure, 66 (14.3%) met the criteria for heart failure. Among these, 15 died from heart failure, 39 were listed for transplant (22 had a transplant, 12 died after listing, and 5 were alive and not yet transplanted), and 12 had NYHA Class IV heart failure but were never listed. The median age at heart failure identification was 1.28 (interquartile range 0.30 to 4.69) years. Factors associated with early heart failure included post-Norwood lower fractional area change, need for extracorporeal membrane oxygenation, non-Hispanic ethnicity, Norwood perfusion type, and total support time (p < 0.05)., Conclusions: By 6 years of age, heart failure developed in nearly 15% of children after the Norwood procedure. Although transplant listing was common, many patients died from heart failure before receiving a transplant or without being listed. Shunt type did not impact the risk of developing heart failure., (Copyright © 2018 International Society for Heart and Lung Transplantation. All rights reserved.)

Background: In the SVR trial (Single Ventricle Reconstruction), 1-year transplant-free survival was better for the Norwood procedure with right ventricle-to-pulmonary artery shunt (RVPAS) compared with a modified Blalock-Taussig shunt in patients with hypoplastic left heart and related syndromes. At 6 years, we compared transplant-free survival and other outcomes between the groups., Methods: Medical history was collected annually using medical record review, telephone interviews, and the death index. The cohort included 549 patients randomized and treated in the SVR trial., Results: Transplant-free survival for the RVPAS versus modified Blalock-Taussig shunt groups did not differ at 6 years (64% versus 59%, P =0.25) or with all available follow-up of 7.1±1.6 years (log-rank P =0.13). The RVPAS versus modified Blalock-Taussig shunt treatment effect had nonproportional hazards ( P =0.009); the hazard ratio (HR) for death or transplant favored the RVPAS before stage II surgery (HR, 0.66; 95% confidence interval, 0.48-0.92). The effect of shunt type on death or transplant was not statistically significant between stage II to Fontan surgery (HR, 1.36; 95% confidence interval, 0.86-2.17; P =0.17) or after the Fontan procedure (HR, 0.76; 95% confidence interval, 0.33-1.74; P =0.52). By 6 years, patients with RVPAS had a higher incidence of catheter interventions (0.38 versus 0.23/patient-year, P <0.001), primarily because of more interventions between the stage II and Fontan procedures (HR, 1.72; 95% confidence interval, 1.00-3.03). Complications did not differ by shunt type; by 6 years, 1 in 5 patients had had a thrombotic event, and 1 in 6 had had seizures., Conclusions: By 6 years, the hazards of death or transplant and catheter interventions were not different between the RVPAS versus modified Blalock-Taussig shunt groups. Children assigned to the RVPAS group had 5% higher transplant-free survival, but the difference did not reach statistical significance, and they required more catheter interventions. Both treatment groups have accrued important complications., Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00115934., (© 2018 American Heart Association, Inc.)

Neutropenia has been reported in pediatric heart transplant recipients, but its association with infectious morbidity and mortality is unknown. We sought to determine neutropenia's prevalence and impact on infection, rejection, and survival. A retrospective analysis of pediatric heart transplant recipients from March 2005 to August 2015 was performed. Demographics, medications, infection, and rejection data were collected. Of 142 pediatric heart transplant recipients, 77 (54.2%) developed neutropenia within 4.7 months [3.3-12.1 months] of transplant. In all patients, the adjusted 5-year cumulative incidence of neutropenia was 30.2%. Fifty-one patients (66.2%) had recurrent neutropenia. Six of 14 tested had positive antineutrophil antibodies. Medications associated with neutropenia were decreased in 15 (19.5%) and discontinued in 42 (54.4%) patients with no change in 1-year rejection rates compared to published data. Fifteen patients developed infection within 30 days of neutropenia and two from 30 days to 1 year, with an infection rate similar to the non-neutropenic group. There was no significant difference in survival, ANC, rate of rejection or PTLD in neutropenic patients with and without infection at median follow-up (5.5 years). Neutropenia is common in pediatric heart transplant recipients. Neutropenia had <20% risk of associated infection, similar to non-neutropenic patients. Infection in neutropenic patients did not increase mortality., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: Children with hypoplastic left heart syndrome are at a risk for neurodevelopmental delays. Current guidelines recommend systematic evaluation and management of neurodevelopmental outcomes with referral for early intervention services. The Single Ventricle Reconstruction Trial represents the largest cohort of children with hypoplastic left heart syndrome ever assembled. Data on life events and resource utilisation have been collected annually. We sought to determine the type and prevalence of early intervention services used from age 1 to 4 years and factors associated with utilisation of services., Methods: Data from 14-month neurodevelopmental assessment and annual medical history forms were used. We assessed the impact of social risk and geographic differences. Fisher exact tests and logistic regression were used to evaluate associations., Results: Annual medical history forms were available for 302 of 314 children. Greater than half of the children (52-69%) were not receiving services at any age assessed, whereas 20-32% were receiving two or more therapies each year. Utilisation was significantly lower in year 4 (31%) compared with years 1-3 (with a range from 40 to 48%) (p<0.001). Social risk factors were not associated with the use of services at any age but there were significant geographic differences. Significant delay was reported by parents in 18-43% of children at ages 3 and 4., Conclusion: Despite significant neurodevelopmental delays, early intervention service utilisation was low in this cohort. As survival has improved for children with hypoplastic left heart syndrome, attention must shift to strategies to optimise developmental outcomes, including enrolment in early intervention when merited.

Objectives: The American College of Cardiology Foundation/American Heart Association guidelines for acute coronary syndrome (ACS) recommend immediate aspirin (ASA) administration, an electrocardiogram (ECG) in less than 10 minutes, and a door-in to door-out (DIDO) time less than 30 minutes for interfacility transfer. We sought to determine if compliance is hindered when adults with suspected ACS present to pediatric facilities., Methods: Visits to the 2 tertiary care emergency departments of a pediatric healthcare system using an adult chest pain protocol were examined from October 2006 to September 2012. Patients older than 18 years with a diagnosis suggestive of ACS and an initial ECG interpretation were identified. Proportions of patients receiving ASA were calculated as well as median times to ECG and DIDO. Bivariate analysis of ECG and DIDO time and the proportion of the patients receiving ASA was conducted for ECG findings positive and negative for ACS., Results: One hundred thirteen patients were identified. Aspirin was administered in 69% of eligible cases. Electrocardiogram and DIDO times met recommended intervals in 42% (median, 12 minutes) and 5% (median, 59 minutes) of the patients, respectively. No significant differences between positive (22% of total) and negative (78% of total) ECG findings groups were detected in median DIDO time (57 vs 59 minutes, P = 0.99), time to ECG (14 vs 12 minutes, P = 0.45), or the proportion receiving ASA (84% vs 64%, P = 0.08)., Conclusions: Despite the use of an emergency department protocol, compliance with the American College of Cardiology Foundation/American Heart Association guidelines for adults with suspected ACS remained challenging at this pediatric center. The ECG findings did not seem to impact ASA administration, ECG time, or DIDO time.

Objectives: Adrenergic receptor (ADR) genotypes have been associated with adverse outcomes in heart failure. Our objective was to evaluate the association of ADR genotypes with post-Norwood outcomes in infants with hypoplastic left heart syndrome (HLHS)., Methods: Infants with HLHS participating in the Pediatric Heart Network Single-Ventricle Reconstruction Trial underwent genotyping for 4 single-nucleotide polymorphisms in 3 ADR genes: ADRB1&#95;231A/G, ADRB1&#95;1165G/C, ADRB2&#95;5318C/G, and ADRA2A&#95;2790C/T. The association of genotype with freedom from serious adverse events (SAEs) (death, transplant, extracorporeal membrane oxygenation, cardiopulmonary resuscitation, acute shunt failure, unplanned reoperations, or necrotizing enterocolitis) during 14 months' follow-up was assessed with Cox regression and the association with post-Norwood complications was assessed with Poisson regression. Models were adjusted for clinical and surgical factors., Results: The study included 351 eligible patients (62% male; 83% white). The mean age at Norwood procedure was 5.6 ± 3.6 days. A total of 152 patients had SAEs during 14-month follow-up including 84 deaths and 10 transplants. ADRA2A&#95;2790CC genotype had lower SAE-free survival compared with CT/TT genotypes during follow-up (Log rank test, P = .02), and this association was independent of clinical and surgical risk factors (adjusted Cox regression, hazard ratio 1.54 [95% confidence interval 1.04, 2.30] P = .033). Post-Norwood complication rate did not differ by genotype., Conclusions: Infants with HLHS harboring ADR genotypes that are associated with greater catecholamine release or sensitivity had lower event-free survival after staged palliation. Excess catecholamine activation may adversely affect cardiovascular adaptation after the Norwood procedure. Future studies should explore whether targeting adrenergic activation in those harboring risk genotypes can improve outcomes. (ClinicalTrials.gov number NCT00115934)., (Copyright © 2017 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

For many neuromuscular diseases (NMDs), cardiac disease represents a major cause of morbidity and mortality. The management of cardiac disease in NMDs is made challenging by the broad clinical heterogeneity that exists among many NMDs and by limited knowledge about disease-specific cardiovascular pathogenesis and course-modifying interventions. The overlay of compromise in peripheral muscle function and other organ systems, such as the lungs, also makes the simple application of endorsed adult or pediatric heart failure guidelines to the NMD population problematic. In this statement, we provide background on several NMDs in which there is cardiac involvement, highlighting unique features of NMD-associated myocardial disease that require clinicians to tailor their approach to prevention and treatment of heart failure. Undoubtedly, further investigations are required to best inform future guidelines on NMD-specific cardiovascular health risks, treatments, and outcomes., Competing Interests: The American Heart Association makes every effort to avoid any actual or potential conflicts of interest that may arise as a result of an outside relationship or a personal, professional, or business interest of a member of the writing panel. Specifically, all members of the writing group are required to complete and submit a Disclosure Questionnaire showing all such relationships that might be perceived as real or potential conflicts of interest., (© 2017 American Heart Association, Inc.)

Background: Bacterial infections represent a major cause of morbidity and mortality in heart transplant recipients. However, data describing the epidemiology and outcomes of these infections in children are limited., Methods: We analyzed the Pediatric Heart Transplant Study database of patients transplanted between 1993 and 2014 to determine the etiologies, risk factors and outcomes of children with bacterial infections post-heart transplantation., Results: Of 4,458 primary transplants in the database, there were 4,815 infections that required hospitalization or intravenous therapy, 2,047 (42.51%) of which were bacterial. The risk of bacterial infection was highest in the first month post-transplant, and the bloodstream was the most common site (24.82%). In the early post-transplant period (<30 days post-transplant), coagulase-negative staphylococci were the most common pathogens (16.97%), followed by Enterobacter sp (11.99%) and Pseudomonas sp (11.62%). In the late post-transplant period, community-acquired pathogens Streptococcus pneumoniae (6.27%) and Haemophilus influenzae (2.82%) were also commonly identified. Patients' characteristics independently associated with acquisition of bacterial infection included younger age (p < 0.0001) and ventilator (p < 0.0001) or extracorporeal membrane oxygenation (p = 0.03) use at time of transplant. Overall mortality post-bacterial infection was 33.78%, and previous cardiac surgery (p < 0.001) and multiple sites of infection (p = 0.004) were independent predictors of death., Conclusions: Bacteria were the most common causes of severe infections in pediatric heart transplant recipients and were associated with high mortality rates. The risk of acquiring a bacterial infection was highest in the first month post-transplant, and a large proportion of the infections were caused by multidrug-resistant pathogens., (Copyright © 2017 International Society for the Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Neonates undergoing heart surgery for CHD are at risk for postoperative gastrointestinal complications and aspiration events. There are limited data regarding the prevalence of aspiration after neonatal cardiothoracic surgery; thus, the effects of aspiration events on this patient population are not well understood. This retrospective chart review examined the prevalence and effects of aspiration among neonates who had undergone cardiac surgery at the time of their discharge. Introduction This study examined the prevalence of aspiration among neonates who had undergone cardiac surgery. Demographic data regarding these patients were analysed in order to determine risk factors for postoperative aspiration. Post-discharge feeding routes and therapeutic interventions were extracted to examine the time spent using alternate feeding routes because of aspiration risk or poor caloric intake. Modified barium swallow study results were used to evaluate the effectiveness of the test as a diagnostic tool. Materials and methods A retrospective study was undertaken of neonates who had undergone heart surgery from July, 2013 to January, 2014. Data describing patient demographics, feeding methods, and follow-up visits were recorded and compared using a χ2 test for goodness of fit and a Kaplan-Meier graph., Results: The patient population included 62 infants - 36 of whom were male, and 10 who were born with single-ventricle circulation. The median age at surgery was 6 days (interquartile range=4 to 10 days). Modified barium swallow study results showed that 46% of patients (n=29) aspirated or were at risk for aspiration, as indicated by laryngeal penetration. In addition, 48% (n=10) of subjects with a negative barium swallow or no swallow study demonstrated clinical aspiration events. Tube feedings were required by 66% (n=41) of the participants. The median time spent on tube feeds, whether in combination with oral feeds or exclusive use of a nasogastric or gastric tube, was 54 days; 44% (n=27) of patients received tube feedings for more than 120 days. Premature infants were significantly more likely to have aspiration events than infants delivered at full gestational age (OR p=0.002). Infants with single-ventricle circulation spent a longer time on tube feeds (median=95 days) than infants with two-ventricle defects (median=44 days); the type of cardiac defect was independent of prevalence of an aspiration event., Conclusions: Aspiration is common following neonatal cardiac surgery. The modified barium swallow study is often used to identify aspiration events and to determine an infant's risk for aspirating. This leads to a high proportion of infants who require tube feedings following neonatal cardiac surgery.

Background: Proliferation signal inhibitors, such as sirolimus, are increasingly used in solid-organ transplantation. However, limited data exist on sirolimus-treated pediatric patients. We aimed to describe sirolimus use in pediatric heart transplant patients and test the hypothesis that sirolimus use is associated with improved outcomes., Methods: A retrospective review and propensity-matched analysis of the Pediatric Heart Transplant Study database was performed on patients undergoing primary heart transplantation from 2004 to 2013 with at least 1 year of follow-up comparing patients treated vs not treated with sirolimus at 1 year after transplant. The primary outcome of interest was patient survival, with secondary outcomes including cardiac allograft vasculopathy, rejection, malignancy, and renal insufficiency., Results: Between 2004 and 2013, 2,531 patients underwent transplantation. At least 1 year of follow-up was available for 2,080 patients, of whom 144 (7%) were on sirolimus at 1 year post-transplant. Sirolimus-treated and non-treated patients had similar survival in the overall cohorts and in the propensity-matched analysis. The secondary outcomes measures were also similar, including a composite end point of all outcome measures. There was a trend toward increased time to cardiac allograft vasculopathy (p = 0.09) and decreased time to infection (p = 0.05) among sirolimus-treated patients in the overall cohort (p = 0.19) but not in the propensity-matched cohort (p = 0.17)., Conclusions: Sirolimus was used in less than 10% of patients at 1 year post-transplant. Overall outcomes of sirolimus treated and non-treated patients were similar with respect to survival and major transplant adverse events. Further study of sirolimus in pediatric heart transplant patients is needed., (Copyright © 2017 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

The Infant Jarvik ventricular assist device (VAD; Jarvik Heart, Inc., New York, NY) has been developed to support the circulation of infants and children with advanced heart failure. The first version of the device was determined to have elevated hemolysis under certain conditions. The objective of this work was to determine appropriate modifications to the Infant Jarvik VAD that would result in acceptably low hemolysis levels. In vitro hemolysis testing revealed that hemolysis was related to the shape of the pump blade tips and a critical speed over which hemolysis would occur. Various design modifications were tested and a final design was selected that met the hemolysis performance goal. The new version was named the Jarvik 2015 VAD. Chronic in vivo tests, virtual fit studies, and a series of other performance tests were carried out to assess the device's performance characteristics. In vivo test results revealed acceptable hemolysis levels in a series of animals and virtual fit studies showed that the device would fit into children 8 kg and above, but could fit in smaller children as well. Additional FDA-required testing has been completed and all of the data are being submitted to the FDA so that a clinical trial of the Jarvik 2015 VAD can begin. Development of a Jarvik VAD for use in young children has been challenging for various reasons. However, with the hemolysis issue addressed in the Jarvik 2015 VAD, the device is well-poised for the start of the PumpKIN clinical trial in the near future., (Published by Elsevier Inc.)

Adolescents and young adults with surgically treated congenital heart disease (CHD) have been shown to exhibit difficulties with executive functions; however, the neural underpinnings of these impairments have not been previously examined with functional magnetic resonance imaging (fMRI). The current study employed fMRI to examine the neural mechanisms during a letter n-back task of working memory compared to vigilance. Seventeen participants with CHD (M age  = 17.76 ± 1.72 years; 88% Caucasian; 30% female; mean IQ = 104.12 ± 15.15) were compared to 17 controls (M age  = 18.40 ± 1.74 years; 70% Caucasian; 30% female; mean IQ = 110.59 ± 5.28) with similar declining performance as the n-back became more challenging. Overall, both groups activated similar frontal-parietal working-memory networks as seen in previous literature; however, some significant differences were detected between the groups. Specifically, the participants with CHD demonstrated differences within the left precuneus and the right inferior frontal gyrus. Secondary analyses indicated that this difference appeared to be due to less task-induced deactivation (TID) in the CHD group during working memory and greater working-memory TID in the control group. In CHD, prefrontal fMRI deactivation on working-memory tasks correlated with improved working-memory performance. Future complementary neuroimaging research with functional connectivity is warranted to further examine the neural underpinnings of disrupted executive function in the long-term outcomes of CHD.

Sickle cell disease is a risk factor for cerebrovascular accidents in the pediatric population. This risk is compounded by hypoxemia. Cyanotic congenital heart disease can expose patients to prolonged hypoxemia. To our knowledge, the long-term outcome of patients who have combined sickle cell and cyanotic congenital heart disease has not been reported. We retrospectively reviewed patient records at our institution and identified 5 patients (3 girls and 2 boys) who had both conditions. Their outcomes were uniformly poor: 4 died (age range, 12 mo-17 yr); 3 had documented cerebrovascular accidents; and 3 developed ventricular dysfunction. The surviving patient had developmental delays. On the basis of this series, we suggest mitigating hypoxemia, and thus the risk of stroke, in patients who have sickle cell disease and cyanotic congenital heart disease. Potential therapies include chronic blood transfusions, hydroxyurea, earlier surgical correction to reduce the duration of hypoxemia, and heart or bone marrow transplantation.

Background: Current knowledge of antibody-mediated rejection (AMR) after heart transplantation (HT) stems largely from adult data. Using the Pediatric Heart Transplant Study (PHTS) database, we report the incidence of AMR, describe treatment, and evaluate outcomes for treated AMR in children after HT., Methods: We queried the PHTS database for patients <18 years of age undergoing primary HT between January 2010 and December 2014. An AMR episode was defined as either a biopsy consistent with pathologic AMR or a rejection event based on immunotherapy augmentation directed against antibody production. Biopsy data, treatment strategies and survival were analyzed., Results: An episode of AMR was identified in 179 of 1,596 (11%) HT recipients and in 246 of 705 (35%) rejection episodes. AMR was diagnosed by biopsy in 182 of 246 episodes and by immunotherapy in 64 of 179 episodes. Mixed rejection was identified in 179. Freedom from AMR was 88% and 82% at 1 and 3 years, respectively. AMR therapies included intravenous immunoglobulin (IVIg) (58%), plasmapheresis (40%), rituximab (40%), bortezomib (11%) and eculizumab (0.4%). The most commonly used combination therapies included IVIg/plasmapheresis/rituximab (13%). Thirty-three patients (16%) died after developing AMR. Patient and graft survival were lower for the AMR + group. One- and 3-year survival after initial AMR diagnosis was 88% and 77%, respectively., Conclusions: In his study we report the largest experience of AMR in pediatric HT recipients. AMR was common and often occurred concurrently with acute cellular rejection. There is wide variability in the treatment of AMR. Short-term patient and graft outcomes were worse for those with treated AMR., (Copyright © 2016 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Objective: To determine whether a collaborative learning strategy-derived clinical practice guideline can reduce the duration of endotracheal intubation following infant heart surgery., Design: Prospective and retrospective data collected from the Pediatric Heart Network in the 12 months pre- and post-clinical practice guideline implementation at the four sites participating in the collaborative (active sites) compared with data from five Pediatric Heart Network centers not participating in collaborative learning (control sites)., Setting: Ten children's hospitals., Patients: Data were collected for infants following two-index operations: 1) repair of isolated coarctation of the aorta (birth to 365 d) and 2) repair of tetralogy of Fallot (29-365 d). There were 240 subjects eligible for the clinical practice guideline at active sites and 259 subjects at control sites., Interventions: Development and application of early extubation clinical practice guideline., Measurements and Main Results: After clinical practice guideline implementation, the rate of early extubation at active sites increased significantly from 11.7% to 66.9% (p < 0.001) with no increase in reintubation rate. The median duration of postoperative intubation among active sites decreased from 21.2 to 4.5 hours (p < 0.001). No statistically significant change in early extubation rates was found in the control sites 11.7% to 13.7% (p = 0.63). At active sites, clinical practice guideline implementation had no statistically significant impact on median ICU length of stay (71.9 hr pre- vs 69.2 hr postimplementation; p = 0.29) for the entire cohort. There was a trend toward shorter ICU length of stay in the tetralogy of Fallot subgroup (71.6 hr pre- vs 54.2 hr postimplementation, p = 0.068)., Conclusions: A collaborative learning strategy designed clinical practice guideline significantly increased the rate of early extubation with no change in the rate of reintubation. The early extubation clinical practice guideline did not significantly change postoperative ICU length of stay.

Objectives: Paediatric heart transplantation is performed to salvage children with end-stage heart failure from various underlying pathologies. Despite several developments in all management aspects of transplantation candidates, the effect of those advances on outcomes has not been consistent. We report our institutional experience with focus on examining era effect on early and late survival., Methods: Between 1988 and 2015, 320 children underwent heart transplantation. Competing risk analysis modelled events after transplantation (retransplantation, death without retransplantation). Multivariable parametric risk hazard analysis examined the risk factors affecting survival., Results: Patients were divided to three groups based on underlying pathology: congenital group (n = 132, 41%), acquired group (n = 153, 48%) and retransplant group (n = 35, 11%). Competing risk analysis showed that at 10 years following transplantation, 11% of patients had undergone retransplantation, 39% had died without retransplantation and 44% were alive without retransplantation. Ten-year survival was 61, 51 and 45% for acquired, congenital and retransplant groups, respectively. Overall, survival following heart transplantation for the late era (2005-15) was 63% compared with 49% for the early era (1988-2004) at 10 years (P = 0.022). Compared with early era, 1-year survival in the late era was 84 vs 79% {odds ratio (OR): 0.72 [95% confidence interval (CI) 0.3-1.8], P = 0.470} for congenital, 98 vs 86% [OR: 0.14 (95% CI 0.03-0.68), P = 0.006] for acquired and 73 vs 88% [OR: 2.6 (95% CI 0.4-1.9), P = 0.282] for retransplant. The effect of late era on survival was not significant for congenital [hazard ratio (HR) 0.6 (95% CI 0.2-1.4), P = 0.206] or retransplant patients [HR: 1.7 (95% CI 0.5-5.5), P = 0.400], but showed improvement trend for acquired patients [HR: 0.53 (95% CI 0.3-1.0), P = 0.052]., Conclusions: The era effect on early survival following heart transplantation is related to underlying pathology; there is a significant improvement in early survival in children with acquired pathology, whereas there is no significant change in early survival in children with congenital pathology or failed prior transplantation. This suggests a potential area for improvement that might include pretransplant stabilization and management of immunosuppression. On the other hand, era effect on late survival is not significant. This demonstrates that advances in the care of paediatric heart transplantation patients have not affected ongoing problems that diminish late survival., (© The Author 2016. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Background: There is increasing interest in reducing the duration of mechanical ventilation after pediatric cardiac operations. However, the contemporary use of an early extubation strategy and its effect on clinical outcomes is poorly understood., Methods: Data from The Society of Thoracic Surgeons Congenital Heart Surgery Database (2010 to 2013) were analyzed to determine the association of early extubation with postoperative length of stay (PLOS). Two operations were analyzed: complete repair of tetralogy of Fallot (TOF) in patients older than 45 days and the Fontan procedure. Centers were stratified into tertiles by frequency of early extubation, defined as less than 6 hours after leaving the operating room. Patients extubated after 48 hours were excluded., Results: Among 92 centers, early extubation was performed in 31.5% (478 of 1,519) of children undergoing TOF repair and in 69.8% (1,153 of 1,653) of those undergoing the Fontan procedure. Early extubation after TOF repair was associated with heavier weight at operation (p < 0.001) and fewer preoperative risk factors (p = 0.016). After adjustment for covariates, average PLOS after TOF repair was shorter for centers in the highest tertile of early extubation rate than for the lowest tertile centers, which have low early extubation rate (p = 0.04). No association was found between center early extubation rate and PLOS for Fontan procedures (p = 0.08)., Conclusions: Early extubation is common after repair of TOF and the Fontan procedure. A high institutional rate of early extubation after TOF repair is associated with shorter PLOS. Further analysis is needed to understand what effect early extubation might have on other meaningful measures such as resource use., (Copyright © 2016 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Objective: To determine whether implementation of a standardized clinical practice guideline (CPG) for the evaluation of syncope would decrease practice variability and resource utilization., Design: A retrospective review of medical records of patients presenting to our practice for outpatient evaluation of syncope before and after implementation of the CPG. The guideline included elements of history, physical exam, electrocardiogram, and "red flags" for further testing., Setting: Outpatient pediatric cardiology offices of a large pediatric cardiology practice., Patients: All new patients between 3 and 21 years old, who presented to cardiology clinic with a chief complaint of syncope., Interventions: The CPG for the evaluation of pediatric syncope was presented to the providers., Outcome Measures: Resource utilization was determined by the tests ordered by individual physicians before and after initiation of the CPG. Patient final diagnoses were recorded and the medical records were subsequently reviewed to determine if any patients, who presented again to the system, were ultimately diagnosed with cardiac disease., Results: Of the 1496 patients with an initial visit for syncope, there was no significant difference in the diagnosis of cardiac disease before or after initiation of the CPG: (0.6% vs. 0.4%, P = .55). Electrocardiography provides the highest yield in the evaluation of pediatric syncope. Despite high compliance (86.9%), there were no overall changes in costs ($346.31 vs. $348.53, P = .85) or in resource utilization. There was, however, a decrease in the variability of ordering of echocardiograms among physicians, particularly among those at the extremes of utilization., Conclusions: Although the CPG did not decrease already low costs, it did decrease the wide variability in echo utilization. Evaluation beyond detailed history, physical exam, and electrocardiography provides no additional benefit in the evaluations of pediatric patients presenting with syncope., (© 2015 Wiley Periodicals, Inc.)

Congenital heart disease (CHD) is the most common birth defect, affecting about 0.8% of live births. Advances in recent decades have allowed >85% of children with CHD to survive to adulthood, creating a growing population of adults with CHD. Little information exists regarding survival, demographics, late outcomes, and comorbidities in this emerging group, and multiple barriers impede research in adult CHD. The National Heart, Lung, and Blood Institute and the Adult Congenital Heart Association convened a multidisciplinary working group to identify high-impact research questions in adult CHD. This report summarizes the meeting discussions in the broad areas of CHD-related heart failure, vascular disease, and multisystem complications. High-priority subtopics identified included heart failure in tetralogy of Fallot, mechanical circulatory support/transplantation, sudden cardiac death, vascular outcomes in coarctation of the aorta, late outcomes in single-ventricle disease, cognitive and psychiatric issues, and pregnancy., (Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Collaborative learning is a technique through which individuals or teams learn together by capitalizing on one another's knowledge, skills, resources, experience, and ideas. Clinicians providing congenital cardiac care may benefit from collaborative learning given the complexity of the patient population and team approach to patient care., Rationale and Development: Industrial system engineers first performed broad-based time-motion and process analyses of congenital cardiac care programs at 5 Pediatric Heart Network core centers. Rotating multidisciplinary team site visits to each center were completed to facilitate deep learning and information exchange. Through monthly conference calls and an in-person meeting, we determined that duration of mechanical ventilation following infant cardiac surgery was one key variation that could impact a number of clinical outcomes. This was underscored by one participating center's practice of early extubation in the majority of its patients. A consensus clinical practice guideline using collaborative learning was developed and implemented by multidisciplinary teams from the same 5 centers. The 1-year prospective initiative was completed in May 2015, and data analysis is under way., Conclusion: Collaborative learning that uses multidisciplinary team site visits and information sharing allows for rapid structured fact-finding and dissemination of expertise among institutions. System modeling and machine learning approaches objectively identify and prioritize focused areas for guideline development. The collaborative learning framework can potentially be applied to other components of congenital cardiac care and provide a complement to randomized clinical trials as a method to rapidly inform and improve the care of children with congenital heart disease., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Significant noncardiac and genetic abnormalities (NC and GA) are common in neonates with congenital heart defects. We sought to examine current-era effect of those abnormalities on early and late outcomes following cardiac surgery. The method from 2002-2012, 1538 neonates underwent repair (n = 860, 56%) or palliation (n = 678, 44%) of congenital heart defects. Regression models examined the effect of NC and GA on operative results, resource utilization, and late outcomes. Neonates with NC and GA (n = 312, 20%) had higher incidence of prematurity (21% vs 13%; P < 0.001) and weight ≤2.5kg (24% vs 12%; P < 0.001) than neonates without NC and GA (n = 1226, 80%). Although the incidence of single ventricle was comparable (34% vs 31%; P = 0.37), neonates with NC and GA underwent more palliation (52% vs 42%; P = 0.001) and subsequently had higher percentage of STAT mortality categories (Society of Thoracic Surgeons (STS) and the European Association for Cardio-thoracic Surgery (EACTS) Congenital Heart Surgery Mortality Categories) 4 and 5 procedures (78% vs 66%; P < 0.001). Adjusted logistic regression models that included disparate patient and operative variables showed that the presence of NC and GA was associated with increased unplanned reoperation (odds ratio = 1.7; 95% CI: 1.1-2.7; P = 0.03) and hospital mortality (odds ratio = 2.2; 95% CI: 1.3-3.6; P = 0.002). Adjusted linear regression models showed significant association between NC and GA and increased postoperative mechanical ventilation duration, intensive care unit, and hospital stays (P < 0.001 each). Adjusted hazard analysis showed that the presence of NC and GA was associated with diminished late survival (hazard ratio = 2.4; 95% CI: 1.9-3.1; P < 0.001) and that was evident in all subgroups of patients (P < 0.001 each). Conclusion is neonates with NC and GA commonly have associated risk factors for morbidity and mortality such as prematurity and low weight. After adjusting for those factors, the presence of NC and GA continues to have significant association with increased unplanned reoperation, hospital mortality, and resource utilization after palliative and corrective cardiac surgery. Importantly, the hazard of death in those patients continues beyond the perioperative period for at least 1 year. Our findings show that the presence of NC and GA should be emphasized during parent counseling and decision making; and underscore the need to explore strategies to improve outcomes for this high-risk population that must address perioperative care, outpatient surveillance, and management., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Heart transplantation is a viable option for patients with congenital heart disease who manifest heart failure, predominantly post-surgical palliation. We present a case of complex congenital heart disease, where surgical palliation was considered not to be an option. Considerate medical management with close follow-up allowed for a nine-yr delay until eventual successful heart transplantation. The case also highlights the natural history over nine yr of the effects of right ventricular outflow tract obstruction on the left ventricular remodeling which is analogous to a PA banding in patients with dilated cardiomyopathy., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Left ventricular outflow tract obstruction (LVOTO) is an important problem after interrupted aortic arch (IAA) repair, especially when early reoperation is required during infancy. Several anatomic factors have been identified that increase LVOTO risk; surgical strategies such as concomitant resection of the conal septum or left ventricular outflow tract (LVOT) bypass (single-stage Yasui operation, or staged Norwood procedure, followed by the Rastelli procedure) have been proposed for such patients., Methods: From 2002 to 2013, a total of 77 neonates underwent IAA repair. Based on the presence of anatomic substrate for LVOTO, patients underwent standard IAA repair and ventricular septal defect closure (n = 53; 69%), concomitant conal resection (n = 7; 9%), or LVOT bypass (n = 17; 22%, staged in 14). We analyzed anatomic details that influence procedure choice, and explored reoperation risk and survival after repair., Results: Neonates who had conal resection or LVOT bypass had significantly smaller aortic valve and subaortic areas, as well as a trend toward a higher prevalence of type B IAA, aberrant right subclavian artery, and bicuspid aortic valve. Freedom from LVOT reoperation was 96% and 80%, at 1 and 8 years, respectively, and was lower after conal resection (P = .008). Most LVOT reoperations (73%) were for discrete subaortic obstruction. Survival was 86% at 8 years, and was not related to procedure choice, whereas freedom from all-cause reoperation was 65% at 8 years, and was higher after standard repair (P = .029)., Conclusions: Compared with published reports, this selective management strategy, which is customized to the degree of aortic valve and subaortic area narrowing, has mitigated and delayed LVOTO risk. With this tailored approach, most LVOT reoperations occur after infancy and are commonly for discrete subaortic obstruction. The effect of aortic valve and LVOT narrowing on increased LVOTO risk is neutralized with LVOT bypass procedures; however, it continues to be the highest after conal resection, suggesting the superiority of LVOT bypass, compared with enlargement in neonates who are at risk of developing LVOTO., (Copyright © 2016 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Background: Mortality for infants with single ventricle congenital heart disease remains as high as 8% to 12% during the interstage period, the time between discharge after the Norwood procedure and before the stage II palliation. The objective of our study was to determine the association between digoxin use and interstage mortality in these infants., Methods and Results: We conducted a retrospective cohort study using the Pediatric Heart Network Single Ventricle Reconstruction Trial public use dataset, which includes data on infants with single right ventricle congenital heart disease randomized to receive either a Blalock-Taussig shunt or right ventricle-to-pulmonary artery shunt during the Norwood procedure at 15 institutions in North America from 2005 to 2008. Parametric survival models were used to compare the risk of interstage mortality between those discharged to home on digoxin versus those discharged to home not on digoxin, adjusting for center volume, ascending aorta diameter, shunt type, and socioeconomic status. Of the 330 infants eligible for this study, 102 (31%) were discharged home on digoxin. Interstage mortality for those not on digoxin was 12.3%, compared to 2.9% among those on digoxin, with an adjusted hazard ratio of 3.5 (95% CI, 1.1-11.7; P=0.04). The number needed to treat to prevent 1 death was 11 patients. There were no differences in complications between the 2 groups during the interstage period., Conclusions: Digoxin use in infants with single ventricle congenital heart disease is associated with significantly reduced interstage mortality., (© 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

Background: Following the Norwood operation, unfavorable hemodynamic or anatomic factors might disqualify children from progressing through subsequent palliative surgeries necessitating listing for heart transplantation. Those patients often have immune, clinical, or anatomic risk factors that could preclude donor allocation, increase operative risk, and diminish late survival. We studied transplantation outcomes in those patients using the Pediatric Heart Transplant Study database., Methods: A total of 253 children who had prior Norwood were listed for transplantation (1993-2012). Competing risks analysis modeled events after listing (death, transplantation) and after transplantation (death, retransplantation) and examined factors affecting outcomes., Results: Patients were listed following Norwood (n = 89, 35%), Glenn (n = 96, 38%), and Fontan (n = 68, 27%). Competing risk analysis showed that 1 year after listing, 23% of patients had died, 70% had received transplantation, and 7% were alive without transplantation. Factors associated with death without transplantation included UNOS status I (HR 3.44 [1.58-7.49], P = .002) and mechanical circulatory support (HR 4.13 [2.04-8.34], P < .001). Overall, 188 patients received transplantation. Competing risk analysis showed that 10 years following transplantation, 40% had died, 7% had received retransplantation, and 53% were alive without retransplantation. Factors associated with death following transplantation were race other than white (HR 2.18 [1.19-3.99], P = .01), and donor mode of death other than anoxic brain injury (HR 2.23 [1.00-5.01], P = .05)., Conclusions: Heart transplantation can salvage children failing palliation following Norwood with outcomes comparable to those reported for other congenital cardiac anomalies. Efforts to stabilize patients and increase donor pool could improve survival by decreasing the high waiting list mortality. In patients who received transplantation, survival is not affected by last palliation stage or sensitization, reflecting current advances in perioperative management and immunosuppression management strategies., (Copyright © 2016 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Background: Blocking leukocyte function-associated antigen (LFA)-1 in organ transplant recipients prolongs allograft survival. However, the precise mechanisms underlying the therapeutic potential of LFA-1 blockade in preventing chronic rejection are not fully elucidated. Cardiac allograft vasculopathy (CAV) is the preeminent cause of late cardiac allograft failure characterized histologically by concentric intimal hyperplasia., Methods: Anti-LFA-1 monoclonal antibody was used in a multiple minor antigen-mismatched, BALB.B (H-2B) to C57BL/6 (H-2B), cardiac allograft model. Endogenous donor-specific CD8 T cells were tracked down using major histocompatibility complex multimers against the immunodominant H4, H7, H13, H28, and H60 minor Ags., Results: The LFA-1 blockade prevented acute rejection and preserved palpable beating quality with reduced CD8 T-cell graft infiltration. Interestingly, less CD8 T cell infiltration was secondary to reduction of T-cell expansion rather than less trafficking. The LFA-1 blockade significantly suppressed the clonal expansion of minor histocompatibility antigen-specific CD8 T cells during the expansion and contraction phase. The CAV development was evaluated with morphometric analysis at postoperation day 100. The LFA-1 blockade profoundly attenuated neointimal hyperplasia (61.6 vs 23.8%; P < 0.05), CAV-affected vessel number (55.3 vs 15.9%; P < 0.05), and myocardial fibrosis (grade 3.29 vs 1.8; P < 0.05). Finally, short-term LFA-1 blockade promoted long-term donor-specific regulation, which resulted in attenuated transplant arteriosclerosis., Conclusions: Taken together, LFA-1 blockade inhibits initial endogenous alloreactive T-cell expansion and induces more regulation. Such a mechanism supports a pulse tolerance induction strategy with anti-LFA-1 rather than long-term treatment.

Allosensitized children listed with a requirement for a negative prospective crossmatch have high mortality. Previously, we found that listing with the intent to accept the first suitable organ offer, regardless of the possibility of a positive crossmatch (TAKE strategy), results in a survival advantage from the time of listing compared to awaiting transplantation across a negative crossmatch (WAIT). The cost-effectiveness of these strategies is unknown. We used Markov modeling to compare cost-effectiveness between these waitlist strategies for allosensitized children listed urgently for heart transplantation. We used registry data to estimate costs and waitlist/posttransplant outcomes. We assumed patients remained in hospital after listing, no positive crossmatches for WAIT, and a base-case probability of a positive crossmatch of 47% for TAKE. Accepting the first suitable organ offer cost less ($405 904 vs. $534 035) and gained more quality-adjusted life years (3.71 vs. 2.79). In sensitivity analyses, including substitution of waitlist data from children with unacceptable antigens specified during listing, TAKE remained cost-saving or cost-effective. Our findings suggest acceptance of the first suitable organ offer for urgently listed allosensitized pediatric heart transplant candidates is cost-effective and transplantation should not be denied because of allosensitization status alone., (© Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Thymectomy is performed routinely in infants undergoing cardiothoracic surgery. Children post-sternotomy have decreased numbers of T lymphocytes, although the mechanisms involved and long-term consequences of this have not been defined. We hypothesized that lymphopenia in patients with adult congenital heart disease (ACHD) would be reflective of premature T cell maturation and exhaustion. Adults with ACHD who had sternotomy to repair congenital heart disease as infants (<1 year) and age-matched ACHD patients without prior sternotomy were studied using polychromatic flow cytometry interrogating markers of lymphocyte maturation, exhaustion and senescence. Group differences were analyzed using Mann-Whitney U and Fisher's exact tests. Eighteen ACHD patients aged 21-40 years participated: 10 cases and 8 controls. Median age at sternotomy for cases was 52 days. Cases and controls were matched for age (28.9 vs. 29.1 years; p = 0.83), gender (p = 0.15) and race (p = 0.62) and had similar case complexity. Cases had a lower mean percentage of cytotoxic CD8 lymphocytes compared to controls (26.8 vs. 33.9 %; p = 0.016), with fewer naive, undifferentiated CD8 T cells (31.0 vs. 53.6 %; p = 0.027). CD8 cells expressing PD1, a marker of immune exhaustion, trended higher in cases versus controls (25.6 vs. 19.0 %; p = 0.083). Mean percentage of CD4 cells was higher in cases versus controls (65.6 vs. 59.6 %; p = 0.027), without differences in CD4 T cell maturation subtype. In summary, ACHD patients who undergo sternotomy as infants exhibit differences in T lymphocyte composition compared to ACHD controls, suggesting accelerated immunologic exhaustion. Investigation is warranted to assess the progressive nature and clinical impact of this immune phenotypic change.

Background: We investigated the prevalence of receipt of special education services among children with congenital heart defects (CHDs) compared with children without birth defects., Methods: Children born from 1982 to 2004 in metropolitan Atlanta with CHDs (n = 3744) were identified from a population-based birth defect surveillance program; children without birth defects (n = 860 715) were identified from birth certificates. Cohorts were linked to special education files for the 1992-2012 school years to identify special education services. Children with noncardiac defects or genetic syndromes were excluded; children with CHDs were classified by presence or absence of critical CHDs (ie, CHDs requiring intervention by age one year). We evaluated the prevalence of receipt of special education services and prevalence rate ratios using children without birth defects as a reference., Results: Compared with children without birth defects, children with CHDs were 50% more likely to receive special education services overall (adjusted prevalence rate ratio [aPRR] = 1.5; 95% confidence interval [CI]: 1.4-1.7). Specifically, they had higher prevalence of several special education categories including: intellectual disability (aPRR = 3.8; 95% CI: 2.8-5.1), sensory impairment (aPRR = 3.0; 95% CI: 1.8-5.0), other health impairment (aPRR = 2.8; 95% CI: 2.2-3.5), significant developmental delay (aPRR = 1.9; 95% CI: 1.3-2.8), and specific learning disability (aPRR = 1.4; 95% CI: 1.1-1.7). For most special education services, the excess prevalence did not vary by presence of critical CHDs., Conclusions: Children with CHDs received special education services more often than children without birth defects. These findings highlight the need for special education services and the importance of developmental screening for all children with CHDs., (Copyright © 2015 by the American Academy of Pediatrics.)

Background: Current organ allocation algorithms direct hearts to the sickest recipients to mitigate death while waiting. This may result in lower post-transplant (Tx) survival for high-risk candidates mandating close examination to determine the appropriateness of different technologies as a bridge to Tx., Methods and Results: We analyzed all patients (<18 years old) from the Pediatric Heart Transplant Study (PHTS) database listed for heart Tx (1993-2013) to determine the effect of extracorporeal membrane oxygenation (ECMO) support at the time of listing and the time of Tx on waitlist mortality and post-Tx outcomes. Eight percent of patients were listed on ECMO, and within 12 months, 49% had undergone Tx, 35% were deceased, and 16% were alive waiting. Survival at 12 months after listing (censored at Tx) was worse in patients on ECMO at listing (50%) compared with ventricular assist device at listing (76%) or not on ECMO or ventricular assist device at listing (76%; P<0.0001). Two hundred three (5%) patients underwent Tx from ECMO; 135 (67%) had been on ECMO since listing, and 67 (33%) had deteriorated to ECMO support while waiting. Survival after Tx was worse in patients who underwent Tx from ECMO (3 years: 64%) versus on ventricular assist device at Tx (3 years: 84%) or not on ECMO/ventricular assist device at Tx (3 years: 85%; P<0.0001). Patients transplanted from ECMO at age <1 year had the worst survival., Conclusions: Pediatric patients requiring ECMO support before heart Tx have poor outcomes. Prioritization of donor hearts to children waitlisted on ECMO warrants careful consideration because of ECMO's high pre- and post-Tx mortality., (© 2015 American Heart Association, Inc.)