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BACKGROUND: The purpose of this statement is to address the state of evidence on the routine use of pulse oximetry in newborns to detect critical congenital heart disease (CCHD). METHODS AND RESULTS: A writing group appointed by the American Heart Association and the American Academy of Pediatrics reviewed the available literature addressing current detection methods for CCHD, burden of missed and/or delayed diagnosis of CCHD, rationale of oximetry screening, and clinical studies of oximetry in otherwise asymptomatic newborns. MEDLINE database searches from 1966 to 2008 were done for English-language papers using the following search terms: congenital heart disease, pulse oximetry, physical examination, murmur, echocardiography, fetal echocardiography, and newborn screening. The reference lists of identified papers were also searched. Published abstracts from major pediatric scientific meetings in 2006 to 2008 were also reviewed. The American Heart Association classification of recommendations and levels of evidence for practice guidelines were used. In an analysis of pooled studies of oximetry assessment performed after 24 hours of life, the estimated sensitivity for detecting CCHD was 69.6%, and the positive predictive value was 47.0%; however, sensitivity varied dramatically among studies from 0% to 100%. False-positive screens that required further evaluation occurred in only 0.035% of infants screened after 24 hours. CONCLUSIONS: Currently, CCHD is not detected in some newborns until after their hospital discharge, which results in significant morbidity and occasional mortality. Furthermore, routine pulse oximetry performed on asymptomatic newborns after 24 hours of life, but before hospital discharge, may detect CCHD. Routine pulse oximetry performed after 24 hours in hospitals that have on-site pediatric cardiovascular services incurs very low cost and risk of harm. Future studies in larger populations and across a broad range of newborn delivery systems are needed to determine whether this practice should become standard of care in the routine assessment of the neonate. [ABSTRACT FROM AUTHOR]

Associations between ambient air pollution levels during weeks 3-7 of pregnancy and risks of cardiovascular malformations were investigated among the cohort of pregnancies reaching at least 20 weeks' gestation that were conceived during January 1, 1986-March 12, 2003, in Atlanta, Georgia. Surveillance records obtained from the Metropolitan Atlanta Congenital Defects Program, which conducts active, population-based surveillance on this cohort, were reviewed to classify cardiovascular malformations. Ambient 8-hour maximum ozone and 24-hour average carbon monoxide, nitrogen dioxide, particulate matter with an average aerodynamic diameter of <10 mum (PM(10)), and sulfur dioxide measurements were obtained from centrally located stationary monitors. Temporal associations between these pollutants and daily risks of secundum atrial septal defect, aortic coarctation, hypoplastic left heart syndrome, patent ductus arteriosus, valvar pulmonary stenosis, tetralogy of Fallot, transposition of the great arteries, muscular ventricular septal defect, perimembranous ventricular septal defect, conotruncal defects, left ventricular outflow tract defect, and right ventricular outflow defect were modeled by using Poisson generalized linear models. A statistically significant association was observed between PM(10) and patent ductus arteriosus (for an interquartile range increase in PM(10) levels, risk ratio = 1.60, 95% confidence interval: 1.11, 2.31). Of the 60 associations examined in the primary analysis, no other significant associations were observed. [ABSTRACT FROM AUTHOR]

BACKGROUND: Prenatal echocardiography can identify the fetus that has complex congenital heart disease and may improve early management and surgical outcome. Prenatal diagnosis may be particularly beneficial to patients who have hypoplastic left heart syndrome (HLHS) and who are at risk for hypoxic-ischemic insult at presentation. OBJECTIVES: We sought to determine whether prenatal diagnosis reduces neurologic morbidity and operative mortality in patients who undergo palliative surgery for the HLHS. METHODS: Data from all patients who had HLHS, except for those with lethal genetic anomalies, and who were admitted to our institution between July 1992 and September 1997 were analyzed to assess the impact of prenatal diagnosis on preoperative management, neurologic morbidity, and surgical mortality. The primary outcome measures were hospital mortality and the incidence of adverse neurologic events (seizure or coma). RESULTS: There were 216 patients who had HLHS and were referred for surgical palliation, 79 (36.6%) of whom had been diagnosed prenatally. All patients who had been diagnosed prenatally were delivered in an advanced nursery and were started on prostaglandin E(1) on the first day of life. Patients whose HLHS was diagnosed postnatally were begun on prostaglandin E(1) later in life (median = day 2 [range = 1-28 days]). There were 4 preoperative deaths and 53 operative or postoperative deaths. Overall hospital mortality was 26.4% and did not differ between patients whose HLHS had been diagnosed prenatally and those whose HLHS had been diagnosed postnatally. With the use of multivariable analysis, prenatal diagnosis was associated with fewer adverse perioperative neurologic events in the patients whose HLHS had been diagnosed prenatally than in those whose HLHS had been diagnosed postnatally (odds ratio = 0.46). CONCLUSIONS: These data suggest that prenatal diagnosis has a favorable impact on treatment of patients who have HLHS and are undergoing staged palliation and reduces early neurologic morbidity. Prenatal diagnosis was not associated with reduced hospital mortality. It is possible that prenatal diagnosis may improve long-term neurologic outcome. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Two strategies for surgical management are used for infants with hypoplastic left heart syndrome (HLHS), primary heart transplantation and the Norwood procedure. We sought to determine how these 2 surgical approaches influence neurodevelopmental outcomes at school age. METHODS: A multicenter, cross-sectional study of neurodevelopmental outcomes among school-aged children (>8 years of age) with HLHS was undertaken between July 2003 and September 2004. Four centers enrolled 48 subjects, of whom 47 completed neuropsychologic testing. Twenty-six subjects (55%) had undergone the Norwood procedure and 21 (45%) had undergone transplantation, with an intention-to-treat analysis. The mean age at testing was 12.4 +/- 2.5 years. Evaluations included the Wechsler Abbreviated Scale of Intelligence, Clinical Evaluation of Language Fundamentals, Wechsler Individual Achievement Test, and Beery-Buktenica Developmental Test of Visual-Motor Integration. RESULTS: The mean neurocognitive test results were significantly below population normative values. The mean full-scale IQ for the entire cohort was 86 +/- 14. In a multivariate model, there was no association of surgical strategy with any measure of developmental outcome. A longer hospital stay, however, was associated significantly with lower verbal, performance, and full-scale IQ scores. Aortic valve atresia was associated with lower math achievement test scores. CONCLUSIONS: Neurodevelopmental deficits are prevalent among school-aged children with HLHS, regardless of surgical approach. Complications that result in prolonged hospitalization at the time of the initial operation are associated with neurodevelopmental status at school age. [ABSTRACT FROM AUTHOR]

Background: Children awaiting heart transplant (Tx) have a high risk of death due to donor organ scarcity. Historically, ventricular assist devices (VADs) reduced waitlist mortality, prompting increased VAD use. We sought to determine whether the VAD survival benefit persists in the current era., Methods: Using the Scientific Registry of Transplant Recipients, we identified patients listed for Tx between 3/22/2016 and 9/1/2020. We compared characteristics of VAD and non-VAD groups at Tx listing. Cox proportional hazards models were used to identify risk factors for 1-year waitlist mortality., Results: Among 5054 patients, 764 (15%) had a VAD at Tx listing. The VAD group was older with more mechanical ventilation and renal impairment. Unadjusted waitlist mortality was similar between groups; the curves crossed ~90 days after listing (p = .55). In multivariable analysis, infant age (HR 2.77, 95%CI 2.13-3.60), Black race (HR 1.57, 95%CI 1.31-1.88), congenital heart disease (HR 1.23, 95%CI 1.04-1.46), renal impairment (HR 2.67, 95%CI 2.19-3.26), inotropes (HR 1.28, 95%CI 1.09-1.52), and mechanical ventilation (HR 2.23, 95%CI 1.84-2.70) were associated with 1-year waitlist mortality. VADs were not associated with mortality in the first 90 waitlist days but were protective for those waiting ≥90 days (HR 0.43, 95%CI 0.26-0.71)., Conclusions: In the current era, VADs reduce waitlist mortality, but only for those waitlisted ≥90 days. The differential effect by race, size, and VAD type is less clear. These findings suggest that Tx listing without VAD may be reasonable if a short waitlist time is anticipated, but VADs may benefit those expected to wait >90 days., (© 2024 Wiley Periodicals LLC.)

Background: There is no FDA-approved left ventricular assist device (LVAD) for smaller children permitting routine hospital discharge. Smaller children supported with LVADs typically remain hospitalized for months awaiting heart transplant-a major burden for families and a challenge for hospitals. We describe the initial outcomes of the Jarvik 2015, a miniaturized implantable continuous flow LVAD, in the NHLBI-funded Pumps for Kids, Infants, and Neonates (PumpKIN) study, for bridge-to-heart transplant., Methods: Children weighing 8 to 30 kg with severe systolic heart failure and failing optimal medical therapy were recruited at 7 centers in the United States. Patients with severe right heart failure and single-ventricle congenital heart disease were excluded. The primary feasibility endpoint was survival to 30 days without severe stroke or non-operational device failure., Results: Of 7 children implanted, the median age was 2.2 (range 0.7, 7.1) years, median weight 10 (8.2 to 20.7) kilograms; 86% had dilated cardiomyopathy; 29% were INTERMACS profile 1. The median duration of Jarvik 2015 support was 149 (range 5 to 188) days where all 7 children survived including 5 to heart transplant, 1 to recovery, and 1 to conversion to a paracorporeal device. One patient experienced an ischemic stroke on day 53 of device support in the setting of myocardial recovery. One patient required ECMO support for intractable ventricular arrhythmias and was eventually transplanted from paracorporeal biventricular VAD support. The median pump speed was 1600 RPM with power ranging from 1-4 Watts. The median plasma free hemoglobin was 19, 30, 19 and 30 mg/dL at 7, 30, 90 and 180 days or time of explant, respectively. All patients reached the primary feasibility endpoint. Patient-reported outcomes with the device were favorable with respect to participation in a full range of activities. Due to financial issues with the manufacturer, the study was suspended after consent of the eighth patient., Conclusion: The Jarvik 2015 LVAD appears to hold important promise as an implantable continuous flow device for smaller children that may support hospital discharge. The FDA has approved the device to proceed to a 22-subject pivotal trial. Whether this device will survive to commercialization remains unclear because of the financial challenges faced by industry seeking to develop pediatric medical devices. (Supported by NIH/NHLBI HHS Contract N268201200001I, clinicaltrials.gov 02954497)., (Copyright © 2024 International Society for the Heart and Lung Transplantation. All rights reserved.)

Background: The aims of the study were to assess the performance of a clinically available cell-free DNA (cfDNA) assay in a large cohort of pediatric and adult heart transplant recipients and to evaluate performance at specific cut points in detection of rejection., Methods: Observational, non-interventional, prospective study enrolled pediatric and adult heart transplant recipients from seven centers. Biopsy-associated plasma samples were used for cfDNA measurements. Pre-determined cut points were tested for analytic performance., Results: A total of 487 samples from 160 subjects were used for the analysis. There were significant differences for df-cfDNA values between rejection [0.21% (IQR 0.12-0.69)] and healthy samples [0.05% (IQR 0.01-0.14), p < .0001]. The pediatric rejection group had a median df-cfDNA value of 0.93% (IQR 0.28-2.84) compared to 0.09% (IQR 0.04-0.23) for healthy samples, p = .005. Overall negative predictive value was 0.94 while it was 0.99 for pediatric patients. Cut points of 0.13% and 0.15% were tested for various types of rejection profiles and were appropriate to rule out rejection., Conclusion: The study suggests that pediatric patients with rejection show higher levels of circulating df-cfDNA compared to adults and supports the specific cut points for clinical use in pediatric and adult patients with overall acceptable performance., (© 2024 Wiley Periodicals LLC.)

Background: Heart failure results in significant morbidity and mortality for young children with hypoplastic left heart syndrome (HLHS) following the Norwood procedure. The trajectory in later childhood is not well described., Methods: We studied the outcome into adolescence of participants enrolled in the Single Ventricle Reconstruction trial who underwent the Fontan procedure or survived to 6 years without having undergone Fontan procedure. The primary outcome was heart failure events, defined as heart transplant listing or death attributable to heart failure. Symptomatic heart failure for participants surviving 10 or more years was also assessed utilizing the Pediatric Quality of Life Inventory (PedsQL)., Results: Of the 345 participants who underwent a Fontan operation or survived to 6 years without Fontan, 25 (7.2%) had a heart failure event before the age of 12 years. Among these, 21 were listed for heart transplant, and 4 died from heart failure. Nineteen participants underwent heart transplant, all of whom survived to age 12 years. Factors associated with a heart failure event included longer Norwood hospital length of stay, aortic atresia, and no Fontan operation by age 6 years. Assessment of heart failure symptoms at 12 years of age revealed that 24 (12.2%) of 196 PedsQL respondents "often" or "almost always" had difficulty walking more than one block., Conclusions: Heart failure events occur in over 5% of children with palliated HLHS between preschool age and adolescence. Outcomes for children listed for transplant are excellent. However, a substantial portion of palliated HLHS children have significant symptoms of heart failure at 12 years of age., (Copyright © 2023. Published by Elsevier Inc.)

The aim of this study (CTOTC-09) was to assess the impact of "preformed" (at transplant) donor-specific anti-HLA antibody (DSA) and first year newly detected DSA (ndDSA) on allograft function at 3 years after pediatric heart transplantation (PHTx). We enrolled children listed at 9 North American centers. The primary end point was pulmonary capillary wedge pressure (PCWP) at 3 years posttransplant. Of 407 enrolled subjects, 370 achieved PHTx (mean age, 7.7 years; 57% male). Pre-PHTx sensitization status was nonsensitized (n = 163, 44%), sensitized/no DSA (n = 115, 31%), sensitized/DSA (n = 87, 24%), and insufficient DSA data (n = 5, 1%); 131 (35%) subjects developed ndDSA. Subjects with any DSA had comparable PCWP at 3 years to those with no DSA. There were also no significant differences overall between the 2 groups for other invasive hemodynamic measurements, systolic graft function by echocardiography, and serum brain natriuretic peptide concentration. However, in the multivariable analysis, persistent first-year DSA was a risk factor for 3-year abnormal graft function. Graft and patient survival did not differ between groups. In summary, overall, DSA status was not associated with worse allograft function or inferior patient and graft survival at 3 years, but persistent first-year DSA was a risk factor for late graft dysfunction., Competing Interests: Disclosure The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation., (Copyright © 2023 American Society of Transplantation & American Society of Transplant Surgeons. Published by Elsevier Inc. All rights reserved.)

Care and outcomes for the more than 40,000 patients undergoing pediatric and congenital heart surgery in the United States annually are known to vary widely. While consensus recommendations have been published across numerous fields as one mechanism to promote a high level of care delivery across centers, it has been more than two decades since the last pediatric heart surgery recommendations were published in the United States. More recent guidance is lacking, and collaborative efforts involving the many disciplines engaged in caring for these children have not been undertaken to date. The present initiative brings together professional societies spanning numerous care domains and congenital cardiac surgeons, pediatric cardiologists, nursing, and other healthcare professionals from diverse programs around the country to develop consensus recommendations for United States centers. The focus of this initial work is on pediatric heart surgery, and it is recommended that future efforts focus in detail on the adult congenital population. We describe the background, rationale, and methodology related to this collaborative effort, and recommendations put forth for Essential Care Centers (essential services necessary for any program), and Comprehensive Care Centers (services to optimize comprehensive and high-complexity care), encompassing structure, process, and outcome metrics across 14 domains., (Copyright © 2023 [Author/Employing Institution]. Published by Elsevier Inc. All rights reserved.)

Objective: In the SVR trial (Single Ventricle Reconstruction), newborns with hypoplastic left heart syndrome were randomly assigned to receive a modified Blalock-Taussig-Thomas shunt (mBTTS) or a right ventricle-to-pulmonary artery shunt (RVPAS) at Norwood operation. Transplant-free survival was superior in the RVPAS group at 1 year, but no longer differed by treatment group at 6 years; both treatment groups had accumulated important morbidities. In the third follow-up of this cohort (SVRIII [Long-Term Outcomes of Children With Hypoplastic Left Heart Syndrome and the Impact of Norwood Shunt Type]), we measured longitudinal outcomes and their risk factors through 12 years of age., Methods: Annual medical history was collected through record review and telephone interviews. Cardiac magnetic resonance imaging (CMR), echocardiogram, and cycle ergometry cardiopulmonary exercise tests were performed at 10 through 14 years of age among participants with Fontan physiology. Differences in transplant-free survival and complication rates (eg, arrhythmias or protein-losing enteropathy) were identified through 12 years of age. The primary study outcome was right ventricular ejection fraction (RVEF) by CMR, and primary analyses were according to shunt type received. Multivariable linear and Cox regression models were created for RVEF by CMR and post-Fontan transplant-free survival., Results: Among 549 participants enrolled in SVR, 237 of 313 (76%; 60.7% male) transplant-free survivors (mBTTS, 105 of 147; RVPAS, 129 of 161; both, 3 of 5) participated in SVRIII. RVEF by CMR was similar in the shunt groups (RVPAS, 51±9.6 [n=90], and mBTTS, 52±7.4 [n=75]; P =0.43). The RVPAS and mBTTS groups did not differ in transplant-free survival by 12 years of age (163 of 277 [59%] versus 144 of 267 [54%], respectively; P =0.11), percentage predicted peak Vo 2 for age and sex (74±18% [n=91] versus 72±18% [n=84]; P =0.71), or percentage predicted work rate for size and sex (65±20% versus 64±19%; P =0.65). The RVPAS versus mBTTS group had a higher cumulative incidence of protein-losing enteropathy (5% versus 2%; P =0.04) and of catheter interventions (14 versus 10 per 100 patient-years; P =0.01), but had similar rates of other complications., Conclusions: By 12 years after the Norwood operation, shunt type has minimal association with RVEF, peak Vo 2 , complication rates, and transplant-free survival. RVEF is preserved among the subgroup of survivors who underwent CMR assessment. Low transplant-free survival, poor exercise performance, and accruing morbidities highlight the need for innovative strategies to improve long-term outcomes in patients with hypoplastic left heart syndrome., Registration: URL: https://www., Clinicaltrials: gov; Unique identifier: NCT0245531., Competing Interests: Disclosures None.

Background: Recent large-scale sequencing efforts have shed light on the genetic contribution to the etiology of congenital heart defects (CHD); however, the relative impact of genetics on clinical outcomes remains less understood. Outcomes analyses using genetics are complicated by the intrinsic severity of the CHD lesion and interactions with conditionally dependent clinical variables., Methods: Bayesian Networks were applied to describe the intertwined relationships between clinical variables, demography, and genetics in a cohort of children with single ventricle CHD., Results: As isolated variables, a damaging genetic variant in a gene related to abnormal heart morphology and prolonged ventilator support following stage I palliative surgery increase the probability of having a low Mental Developmental Index (MDI) score at 14 months of age by 1.9- and 5.8-fold, respectively. However, in combination, these variables act synergistically to further increase the probability of a low MDI score by 10-fold. The absence of a damaging variant in a known syndromic CHD gene and a shorter post-operative ventilator support increase the probability of a normal MDI score 1.7- and 2.4-fold, respectively, but in combination increase the probability of a good outcome by 59-fold., Conclusions: Our analyses suggest a modest genetic contribution to neurodevelopmental outcomes as isolated variables, similar to known clinical predictors. By contrast, genetic, demographic, and clinical variables interact synergistically to markedly impact clinical outcomes. These findings underscore the importance of capturing and quantifying the impact of damaging genomic variants in the context of multiple, conditionally dependent variables, such as pre- and post-operative factors, and demography., (© 2023. Springer Nature Limited.)

Cardiac-derived c-kit+ progenitor cells (CPCs) are under investigation in the CHILD phase I clinical trial (NCT03406884) for the treatment of hypoplastic left heart syndrome (HLHS). The therapeutic efficacy of CPCs can be attributed to the release of extracellular vesicles (EVs). To understand sources of cell therapy variability we took a machine learning approach: combining bulk CPC-derived EV (CPC-EV) RNA sequencing and cardiac-relevant in vitro experiments to build a predictive model. We isolated CPCs from cardiac biopsies of patients with congenital heart disease (n = 29) and the lead-in patients with HLHS in the CHILD trial (n = 5). We sequenced CPC-EVs, and measured EV inflammatory, fibrotic, angiogeneic, and migratory responses. Overall, CPC-EV RNAs involved in pro-reparative outcomes had a significant fit to cardiac development and signaling pathways. Using a model trained on previously collected CPC-EVs, we predicted in vitro outcomes for the CHILD clinical samples. Finally, CPC-EV angiogenic performance correlated to clinical improvements in right ventricle performance., Competing Interests: Joshua M. Hare reports having a patent for cardiac cell-based therapy and holds equity in Vestion Inc. and maintains a professional relationship with Vestion Inc. as a consultant and member of the Board of Directors and Scientific Advisory Board. Vestion Inc. did not play a role in the design, conduct, or funding of the study. Dr. Joshua Hare is the Chief Scientific Officer, a compensated consultant and board member for Longeveron Inc. and holds equity in Longeveron. Dr. Hare is also the co-inventor of intellectual property licensed to Longeveron. The University of Miami is an equity owner in Longeveron Inc., which has licensed intellectual property from the University of Miami., (© 2023 The Author(s).)

Patients with hypoplastic left heart syndrome who have been palliated with the Fontan procedure are at risk for adverse neurodevelopmental outcomes, lower quality of life, and reduced employability. We describe the methods (including quality assurance and quality control protocols) and challenges of a multi-center observational ancillary study, SVRIII (Single Ventricle Reconstruction Trial) Brain Connectome. Our original goal was to obtain advanced neuroimaging (Diffusion Tensor Imaging and Resting-BOLD) in 140 SVR III participants and 100 healthy controls for brain connectome analyses. Linear regression and mediation statistical methods will be used to analyze associations of brain connectome measures with neurocognitive measures and clinical risk factors. Initial recruitment challenges occurred that were related to difficulties with: (1) coordinating brain MRI for participants already undergoing extensive testing in the parent study, and (2) recruiting healthy control subjects. The COVID-19 pandemic negatively affected enrollment late in the study. Enrollment challenges were addressed by: (1) adding additional study sites, (2) increasing the frequency of meetings with site coordinators, and (3) developing additional healthy control recruitment strategies, including using research registries and advertising the study to community-based groups. Technical challenges that emerged early in the study were related to the acquisition, harmonization, and transfer of neuroimages. These hurdles were successfully overcome with protocol modifications and frequent site visits that involved human and synthetic phantoms.

Human leukocyte antigen (HLA) molecular mismatch is a powerful biomarker of rejection. Few studies have explored its use in assessing rejection risk in heart transplant recipients. We tested the hypothesis that a combination of HLA Epitope Mismatch Algorithm (HLA-EMMA) and Predicted Indirectly Recognizable HLA Epitopes (PIRCHE-II) algorithms can improve risk stratification of pediatric heart transplant recipients. Class I and II HLA genotyping were performed by next-generation sequencing on 274 recipient/donor pairs enrolled in the Clinical Trials in Organ Transplantation in Children (CTOTC). Using high-resolution genotypes, we performed HLA molecular mismatch analysis with HLA-EMMA and PIRCHE-II, and correlated these findings with clinical outcomes. Patients without pre-formed donor specific antibody (DSA) (n=100) were used for correlations with post-transplant DSA and antibody mediated rejection (ABMR). Risk cut-offs were determined for DSA and ABMR using both algorithms. HLA-EMMA cut-offs alone predict the risk of DSA and ABMR; however, if used in combination with PIRCHE-II, the population could be further stratified into low-, intermediate-, and high-risk groups. The combination of HLA-EMMA and PIRCHE-II enables more granular immunological risk stratification. Intermediate-risk cases, like low-risk cases, are at a lower risk of DSA and ABMR. This new way of risk evaluation may facilitate individualized immunosuppression and surveillance., Competing Interests: M. Niemann works for PIRCHE AG, which develops and operates the PIRCHE web service. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer MM declared a past co-authorship with the author MN to the handling editor., (Copyright © 2023 Ellison, Mangiola, Marrari, Bentlejewski, Sadowski, Zern, Kramer, Heidt, Niemann, Xu, Dipchand, Mahle, Rossano, Canter, Singh, Zuckerman, Hsu, Feingold, Webber and Zeevi.)

Objectives: Donor-specific cell-free DNA shows promise as a noninvasive marker for allograft rejection, but as yet has not been validated in both adult and pediatric recipients. The study objective was to validate donor fraction cell-free DNA as a noninvasive test to assess for risk of acute cellular rejection and antibody-mediated rejection after heart transplantation in pediatric and adult recipients., Methods: Pediatric and adult heart transplant recipients were enrolled from 7 participating sites and followed for 12 months or more with plasma samples collected immediately before all endomyocardial biopsies. Donor fraction cell-free DNA was extracted, and quantitative genotyping was performed. Blinded donor fraction cell-free DNA and clinical data were analyzed and compared with a previously determined threshold of 0.14%. Sensitivity, specificity, negative predictive value, positive predictive value, and receiver operating characteristic curves were calculated., Results: A total of 987 samples from 144 subjects were collected. After applying predefined clinical and technical exclusions, 745 samples from 130 subjects produced 54 rejection samples associated with the composite outcome of acute cellular rejection grade 2R or greater and pathologic antibody-mediated rejection 2 or greater and 323 healthy samples. For all participants, donor fraction cell-free DNA at a threshold of 0.14% had a sensitivity of 67%, a specificity of 79%, a positive predictive value of 34%, and a negative predictive value of 94% with an area under the curve of 0.78 for detecting rejection. When analyzed independently, these results held true for both pediatric and adult cohorts at the same threshold of 0.14% (negative predictive value 92% and 95%, respectively)., Conclusions: Donor fraction cell-free DNA at a threshold of 0.14% can be used to assess for risk of rejection after heart transplantation in both pediatric and adult patients with excellent negative predictive value., (Copyright © 2022 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Background: The Single Ventricle Reconstruction (SVR) Trial was the first randomized clinical trial of a surgical approach for treatment of congenital heart disease. Infants with hypoplastic left heart syndrome (HLHS) and other single right ventricle (RV) anomalies were randomized to a modified Blalock Taussig Thomas shunt (mBTTS) or a right-ventricular-to-pulmonary-artery shunt (RVPAS) at the time of the Norwood procedure. The aim of the Long-term Outcomes of Children with HLHS and the Impact of Norwood Shunt Type (SVR III) study is to compare early adolescent outcomes including measures of cardiac function, transplant-free survival, and neurodevelopment, between those who received a mBTTS and those who received an RVPAS., Methods: Transplant-free survivors of the SVR cohort were enrolled at 10 to 15 years of age for multifaceted in-person evaluation of cardiac function (cardiac magnetic resonance [CMR], echocardiogram and exercise test) and neurodevelopmental evaluation. Right ventricular ejection fraction measured by CMR served as the primary outcome. Development of arrhythmias, protein losing enteropathy, and other comorbidities were assessed through annual medical history interview. Through the course of SVR III, protocol modifications to engage SVR trial participants were designed to enhance recruitment and retention., Conclusions: Evaluation of long-term outcomes will provide important data to inform decisions about the shunt type placed at the Norwood operation and will improve the understanding of cardiovascular and neurodevelopmental outcomes for early adolescents with HLHS., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Mortality in infants with hypoplastic left heart syndrome (HLHS) is strongly correlated with right ventricle (RV) dysfunction. Cell therapy has demonstrated potential improvements of RV dysfunction in animal models related to HLHS, and neonatal human derived c-kit + cardiac-derived progenitor cells (CPCs) show superior efficacy when compared to adult human cardiac-derived CPCs (aCPCs). Neonatal CPCs (nCPCs) have yet to be investigated in humans. The CHILD trial (Autologous Cardiac Stem Cell Injection in Patients with Hypoplastic Left Heart Syndrome) is a Phase I/II trial aimed at investigating intramyocardial administration of autologous nCPCs in HLHS infants by assessing the feasibility, safety, and potential efficacy of CPC therapy. Using an open-label, multicenter design, CHILD investigates nCPC safety and feasibility in the first enrollment group (Group A/Phase I). In the second enrollment group, CHILD uses a randomized, double-blinded, multicenter design (Group B/Phase II), to assess nCPC efficacy based on RV functional and structural characteristics. The study plans to enroll 32 patients across 4 institutions: Group A will enroll 10 patients, and Group B will enroll 22 patients. CHILD will provide important insights into the therapeutic potential of nCPCs in patients with HLHS.Clinical Trial Registration https://clinicaltrials.gov/ct2/home NCT03406884, First posted January 23, 2018., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background Clinical risk factors in neonatal cardiac surgery do not fully capture discrepancies in outcomes. Targeted metabolomic analysis of plasma from neonates undergoing heart surgery with cardiopulmonary bypass was performed to determine associations with clinical outcomes. Methods and Result Samples and clinical variables from 149 neonates enrolled in the Corticosteroid Therapy in Neonates Undergoing Cardiopulmonary Bypass trial with surgical treatment for congenital heart disease between 2012 and 2016 were included. Blood samples were collected before skin incision, immediately after cardiopulmonary bypass, and 12 hours after surgery. Outcomes include composite morbidity/mortality (death, extracorporeal membrane oxygenation, cardiac arrest, acute kidney injury, and/or hepatic injury) and a cardiac composite (extracorporeal membrane oxygenation, cardiac arrest, or increase in lactate level), hepatic injury, and acute kidney injury. Targeted metabolite levels were determined by high-resolution tandem liquid chromatography and mass spectrometry. Principal component and regression analyses were used to assess associations between metabolic profiles and outcomes, with 2 models created: a base clinical model and a base model+metabolites. Of the 193 metabolites examined, 40 were detected and quantified. The first principal component, principal component 1, was composed mostly of preoperative metabolites and was significantly associated with the composite morbidity/mortality, cardiac composite, and hepatic injury outcomes. In regression models, individual metabolites also improved model performance for the composite morbidity/mortality, cardiac composite, and hepatic injury outcomes. Significant disease pathways included myocardial injury (false discovery rate, 0.00091) and heart failure (false discovery rate, 0.041). Conclusions In neonatal cardiac surgery, perioperative metabolites were associated with postoperative outcomes and improved clinical model outcome associations. Preoperative metabolite levels alone may improve risk models and provide a basis for optimizing perioperative care.

Background: Clinical rejection (CR) defined as decision to treat clinically suspected rejection with change in immunotherapy based on clinical presentation with or without diagnostic biopsy findings is an important part of care in heart transplantation. We sought to assess the utility of donor fraction cell-free DNA (DF cfDNA) in CR and the utility of serial DF cfDNA in CR patients in predicting outcomes of clinical interest., Methods: Patients with heart transplantation were enrolled in two sequential, multi-center, prospective observational studies. Blood samples were collected for surveillance or clinical events. Clinicians were blinded to the results of DF cfDNA., Results: A total of 835 samples from 269 subjects (57% pediatric) were included for this analysis, including 28 samples associated with CR were analyzed. Median DF cfDNA was 0.43 (IQR 0.15, 1.36)% for CR and 0.10 (IQR 0.07, 0.16)% for healthy controls (p < .0001). At cutoff value of 0.13%, the area under curve (AUC) was 0.82, sensitivity of 0.86, specificity of 0.67, and negative predictive value of 0.99. There was serial decline in DF cfDNA post-therapy, however, those with cardiovascular events (cardiac arrest, need for mechanical support or death) showed significantly higher levels of DF cfDNA on Day 0 (2.11 vs 0.31%) and Day 14 (0.51 vs 0.22%) compared to those who did not have such an event (p < .0001)., Conclusion: DF cfDNA has excellent agreement with clinical rejection and, importantly, serial measurement of DF cfDNA predict clinically significant outcomes post treatment for rejection in these patients., (© 2022 Wiley Periodicals LLC.)

Background: Neurodevelopmental impairment is an important consequence for survivors of surgery for critical congenital heart disease. This study sought to determine whether intraoperative methylprednisolone during neonatal cardiac surgery is associated with neurodevelopmental outcomes at 12 months of age and to identify early prognostic variables associated with neurodevelopmental outcomes., Methods: We performed a planned secondary analysis of a 2-center, double-blind, randomized, placebo-controlled trial of intraoperative methylprednisolone in neonates undergoing cardiac surgery. A brain injury biomarker was measured during surgery. Bayley Scales of Infant and Toddler Development-III (BSID-III) were performed at 12 months of age. Two-sample t tests and generalized linear models were used., Results: There were 129 participants (n = 61 methylprednisolone; n = 68 placebo). There were no significant differences in BSID-III scores and brain injury biomarker levels between treatment groups. Participants who underwent a palliative (versus corrective) procedure had lower mean BSID-III cognitive (101 ± 15 versus 106 ± 14; P = .03) and motor scores (85 ± 18 versus 94 ± 16; P < .01). Longer ventilation time was associated with lower motor scores. Longer cardiac intensive care unit stay was associated with lower cognitive, language, and motor scores. Cardiopulmonary bypass time, aortic cross-clamp time, and deep hypothermic circulatory arrest were not associated with BSID-III scores., Conclusions: Neurodevelopmental outcomes were not associated with intraoperative methylprednisolone or intraoperative variables. Participants who underwent a neonatal palliative (versus corrective) procedure had longer cardiac intensive care unit stays and worse neurodevelopmental outcomes at 1 year. This work suggests that interventions focused solely on the operative period may not be associated with a long-term neurodevelopmental benefit., (Copyright © 2022 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

We aimed to describe the longitudinal risk of advanced heart failure (HF) leading to death, heart transplantation, or ventricular assist device (VAD) placement after congenital heart surgery (CHS) and how it varies across the spectrum of congenital heart disease. We linked the records of patients who underwent first CHS in the Pediatric Cardiac Care Consortium between 1982 and 2003 with the United States National Death Index and Organ Procurement and Transplantation Network databases. Primary outcome was time from CHS discharge to HF-related death, heart transplant, or VAD placement, analyzed with proportional hazards models accounting for competing mortality. In 35,610 patients who survived a first CHS, there were 799 HF deaths, transplants, or VADs over a median of 23 years (interquartile range, 19 to 27). Cumulative incidence at 25 years was 2.3% (95% confidence interval [CI] 2.1% to 2.4%). Compared to mild 2-ventricle defects, the adjusted subhazard ratio for moderate and severe 2-ventricle defects was 3.21 (95% CI 2.28 to 4.52) and 9.46 (95% CI 6.71 to 13.3), respectively, and for single-ventricle defects 31.8 (95% CI 22.2 to 45.6). Systemic right ventricle carried the highest risk 2 years after CHS (subhazard ratio 2.76 [95% CI 2.08 to 3.68]). All groups had higher rates of HF-related death compared with the general population (cause-specific standardized mortality ratio 56.1 [95% CI 51.0 to 61.2]). In conclusion, the risk of advanced HF leading to death, transplantation, or VAD was high across the spectrum of congenital heart disease. While severe defects carry the highest risk, those with mild disease are still at greater risk than the general population., Competing Interests: Disclosures The other authors have no conflicts of interest to declare., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objectives: Describe variability in developmental care practices, as documented in the electronic health record, for infants undergoing congenital heart surgery., Design: Multicenter, retrospective, cohort study., Setting: Six pediatric cardiac centers., Patients: One hundred eighty-two infants undergoing one of three index operations: Norwood palliation, aortic arch reconstruction with ventricular septal defect closure, or arterial switch., Interventions: None., Measurements and Main Results: Core domains of developmental care encompassing pain assessment, feeding, infant holding, caregiver involvement, therapy, and psychosocial services were reviewed. Practices varied across individuals, institutions, and the hospital stay. At five of six sites, greater than 90% of individuals had physical or occupational therapy services as part of their care, but the day of first evaluation ranged from day of admission to postoperative day 28. Similar patterns were seen in feeding team and social work involvement. Consistent documentation of developmental care was dependent on the domain and site. Of the total days reviewed (n = 1,192), pain scores were documented in 95%. In those same days, documentation of whether or not a patient was out of the crib to be held varied by site from 11% to 93%. Type of oral feeding, breast versus bottle, was documented on the day prior to discharge 48% of the time., Conclusions: There are significant, quantifiable variations in documented developmental care practices at both the individual and site level. More reliable documentation of developmental care practices is required to associate these variables with later outcomes and investigate disparities in individualized developmental care practices., Competing Interests: Drs. Miller’s and Lisanti’s institutions received funding from the Pediatric Heart Network supported by the National Heart, Lung, and Blood Institute. Drs. Miller, Mahle, and Lisanti received support for article research from the National Institutes of Health. Dr. Glotzbach’s institution received funding from the Pediatric Heart Network; she received support for article research from the Pediatric Heart Network. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2022 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.)

Background: There is wide variability in the timing of heart transplant (HTx) after pediatric VAD implant. While some centers wait months before listing for HTx, others accept donor heart offers within days of VAD surgery. We sought to determine if HTx within 30 days versus ≥ 30 after VAD impacts post-HTx outcomes., Methods: Children on VAD pre-HTx were extracted from the Pediatric Heart Transplant Study database. The primary endpoints were post-HTx length of hospital stay (LOS) and one-year survival. Confounding was addressed by propensity score weighting using inverse probability of treatment. Propensity scores were calculated based on age, blood type, primary cardiac diagnosis, decade, VAD type, and allosensitization status., Results: A total of 1064 children underwent VAD prior to HTx between 2000 to 2018. Most underwent HTx ≥ 30 days post-VAD (70%). Infants made up 22% of both groups. Patients ≥ 12 years old were 42% of the < 30 days group and children 1 to 11 years comprised 47% of the ≥ 30 days group (p < 0.001). There was no difference in the prevalence of congenital heart disease vs. cardiomyopathy (p = 0.8) or high allosensitization status (p = 0.9) between groups. Post-HTx LOS was similar between groups (p = 0.11). One-year survival was lower in the < 30 days group (adjusted mortality HR 1.76, 95% CI 1.11-2.78, p = 0.016)., Conclusions: A longer duration of VAD support prior to HTx is associated with a one-year survival benefit in children, although questions of patient complexity, post-VAD complications and the impact on causality remain. Additional studies using linked databases to understand these factors will be needed to fully assess the optimal timing for post-VAD HTx., (Copyright © 2021 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Cell-free DNA is an emerging biomarker. While donor fraction may detect graft events in heart transplant recipients, the prognostic value of total nuclear cell-free DNA (ncfDNA) itself is largely unexplored., Objective: Explore the relationship between ncfDNA and clinical events in heart transplant recipients., Methods: We conducted a multi-center prospective study to investigate the value of cell-free DNA in non-invasive monitoring following heart transplantation. Over 4000 blood samples were collected from 388 heart transplant patients. Total ncfDNA and donor fraction were quantified. Generalized linear models with maximum likelihood estimation for repeated measures with subjects as clusters were used to explore the relationship of ncfDNA and major adverse events. Receiver operating characteristic curves were used to help choose cutpoints., Results: A ncfDNA threshold (50 ng/ml) was identified that was associated with increased risk of major adverse events. NcfDNA was elevated in patients who suffered cardiac arrest, required mechanical circulatory support or died post heart transplantation as well as in patients undergoing treatment for infection., Conclusions: Elevated ncfDNA correlates with risk for major adverse events in adult and pediatric heart transplant recipients and may indicate a need for enhanced surveillance after transplant., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Pediatric cardiology has evolved over time with reductions in childhood mortality due to congenital heart disease. Surgical innovation drove early changes in care. Increasingly, the need for more robust evidence provided by randomised controlled trials (RCTs) has been recognised. Although the number of RCTs has increased, there remains a relative paucity of truly impactful trials in the field. However, those trials that have changed practice have demonstrated the potential and importance of this work. Examples include the PRIMACORP trial, which established the safety and efficacy of milrinone after cardiac surgery, and the Single Ventricle Reconstruction trial, which was the first multicentre pediatric cardiac surgical RCT. The successful conduct and important findings emanating from these trials serve as beacons as clinicians strive to improve the evidence base in this field. The establishment of national and international networks such as the Pediatric Heart Network and the Canadian Pediatric Cardiology Research Network provide a strong foundation for future collaborative work. Despite this progress, there remain important challenges to designing and executing RCTs in pediatric cardiology. These include issues of greater disease and patient heterogeneity and increased costs. The use of innovative study designs and analytic methods and the establishment of core outcome measures have the potential to overcome some of the issues related to the smaller patient numbers compared with adult disciplines. As pediatric cardiologists look to the future, it is imperative that we work together to derive the maximum benefit from the considerable efforts directed toward conducting impactful clinical trials in pediatric cardiology., (Copyright © 2021 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Objectives: Healthcare workload has emerged as an important metric associated with poor outcomes. To measure workload, studies have used bed occupancy as a surrogate. However, few studies have examined frontline provider (fellows, nurse practitioners, physician assistants) workload and outcomes. We hypothesize frontline provider workload, measured by bed occupancy and staffing, is associated with poor outcomes and unnecessary testing., Design: A retrospective single-center, time-stamped orders, ordering provider identifiers, and patient data were collected. Regression was performed to study the influence of occupancy on orders, length of stay, and mortality, controlling for age, weight, admission type, Society of Thoracic Surgery-European Association for Cardio-Thoracic Surgery Congenital Heart Surgery Mortality score, diagnosis, number of surgeries, orders, provider staffing, attending experience, and time fixed effects., Setting: Twenty-seven bed tertiary cardiac ICU in a free-standing children's hospital., Patients: Patients (0-18 yr) admitted to the pediatric cardiac ICU, January 2018 to December 2019., Interventions: None., Measurements and Main Results: There were 16,500 imaging and 73,113 laboratory orders among 1,468 patient admissions. Median age 6 months (12 d to 5 yr), weight 6.2 kg (3.7-16.2 kg); 840 (57.2%) surgical and 628 (42.8%) medical patients. ICU teams consisted of 16 attendings and 31 frontline providers. Mortality 4.4%, median stay 5 days (2-11 d), and median bed occupancy 89% (78-93%). Every 10% increase in bed occupancy had 7.2% increase in imaging orders per patient (p < 0.01), 3% longer laboratory turn-around time (p = 0.015), and 3 additional days (p < 0.01). Higher staffing (> 3 providers) was associated with 6% less imaging (p = 0.03) and 3% less laboratory orders (p = 0.04). The number of "busy days" (bed occupancy > 89%) was associated with longer stays (p < 0.01), and increased mortality (p < 0.01)., Conclusions: Increased bed occupancy and lower staffing were associated with increased mortality, length of stay, imaging orders, and laboratory turn-around time. The data demonstrate performance of the cardiac ICU system is exacerbated during high occupancy and low staffing., Competing Interests: The authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2021 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.)

Objectives: The Pediatric Heart Network Collaborative Learning Study used collaborative learning strategies to implement a clinical practice guideline that increased rates of early extubation after infant repair of tetralogy of Fallot and coarctation of the aorta. We assessed early extubation rates for infants undergoing cardiac surgeries not targeted by the clinical practice guideline to determine whether changes in extubation practices spilled over to care of other infants., Design: Observational analyses of site's local Society of Thoracic Surgeons Congenital Heart Surgery Database and Pediatric Cardiac Critical Care Consortium Registry., Setting: Four Pediatric Heart Network Collaborative Learning Study active-site hospitals., Patients: Infants undergoing ventricular septal defect repair, atrioventricular septal defect repair, or superior cavopulmonary anastomosis (lower complexity), and arterial switch operation or isolated aortopulmonary shunt (higher complexity)., Interventions: None., Measurements and Main Results: Aggregate outcomes were compared between the 12 month pre-clinical practice guideline and 12 months after study completion (Follow Up). In infants undergoing lower complexity surgeries, early extubation increased during Follow Up compared with Pre-Clinical Practice Guideline (30.2% vs 18.8%, p = 0.006), and hours to initial postoperative extubation decreased. We observed variation in these outcomes by surgery type, with only ventricular septal defect repair associated with a significant increase in early extubation during Follow Up compared with Pre-Clinical Practice Guideline (47% vs 26%, p = 0.006). Variation by study site was also seen, with only one hospital showing an increase in early extubation. In patients undergoing higher complexity surgeries, there was no difference in early extubation or hours to initial extubation between the study eras., Conclusions: We observed spillover of extubation practices promoted by the Collaborative Learning Study clinical practice guideline to lower complexity operations not included in the original study that was sustainable 1 year after study completion, though this effect differed across sites and operation subtypes. No changes in postoperative extubation outcomes following higher complexity surgeries were seen. The significant variation in outcomes by site suggests that center-specific factors may have influenced spillover of clinical practice guideline practices., Competing Interests: Dr. Witte’s institution received funding from the Pediatric Heart Network/National Heart, Lung, and Blood Institute. Drs. Witte, Mahle, Pasquali, and Gaies received support for article research from the National Institutes of Health (NIH). Dr. Pasquali’s institution received funding from the NIH. Dr. Zhang disclosed work for hire. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2020 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.)

Objective: To describe the assessment of Fontan-associated liver disease and determine the clinical and imaging measures that may identify hepatic morbidity risk in isolated heart transplantation candidates and trend those measures post-isolated heart transplantation., Study Design: Retrospective analysis of pre-isolated heart transplantation and post-isolated heart transplantation Fontan-associated liver disease (FALD) status using blood tests, magnetic resonance imaging (MRI), and liver biopsy analysis within 6 months before isolated heart transplantation and 12 months after isolated heart transplantation in 9 consecutive patients with Fontan. Pre- and post-isolated heart transplantation standard laboratory values; varices, ascites, splenomegaly, thrombocytopenia (VAST) score; Fontan liver MRI score; liver biopsy scores; Model for End-stage Liver Disease (MELD); MELD excluding the International Normalized Ratio (MELD-XI); AST to platelet ratio index, and cardiac catheterization data were compared., Results: Pretransplantation maximum MELD and MELD-XI was 15 and 16, respectively. Central venous pressures and VAST scores decreased significantly post-transplantation. In 5 paired studies, Fontan liver MRI score maximum was 10 pretransplantation and decreased significantly post-transplantation. Arterially enhancing nodules on MRI persisted in 2 patients post-transplantation. Pretransplantation and post-transplantation liver biopsy scores did not differ in 4 paired biopsy specimens., Conclusions: Patients with FALD and MELD <15, MELD-XI <16, Fontan liver MRI score <10, and VAST score ≤2 can have successful short-term isolated heart transplantation outcomes. Liver MRI and VAST scores improved post-transplantation. Post-transplantation liver biopsy scores did not change significantly. Pretransplantation liver biopsy demonstrating fibrosis alone should not exclude consideration of isolated heart transplantation. The persistence of hepatic vascular remodeling and fibrosis post-isolated heart transplantation suggests that continued surveillance for hepatic complications post-transplantation for patients with Fontan is reasonable., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objectives: To determine if neurodevelopmental deficits in children with single-ventricle physiology change with age and early developmental scores predict 6-year outcomes., Methods: In the Single Ventricle Reconstruction Trial, Bayley Scales of Infant Development, Second Edition, were administered at 14 months of age, and parents completed the Behavior Assessment System for Children, Second Edition (BASC-2) annually from the ages of 2 to 6 years. Scores were classified as average, at risk, or impaired. We calculated sensitivities, specificities, and positive and negative predictive values of earlier tests on 6-year outcomes., Results: Of 291 eligible participants, 244 (84%) completed the BASC-2 at 6 years; more Single Ventricle Reconstruction participants than expected on the basis of normative data scored at risk or impaired on the BASC-2 Adaptive Skills Index at that evaluation (28.7% vs 15.9%; P < .001). Children with Adaptive Skills Composite scores <2 SD below the mean at the age of 6 were more likely to have had delayed development at 14 months, particularly on the Psychomotor Development Index (sensitivity of 79%). However, the positive predictive value of the 14-month Mental Development Index and Psychomotor Development Index for 6-year BASC-2 Adaptive Scores was low (44% and 36%, respectively). Adaptive Skills Composite score impairments at the age of 6 were poorly predicted by using earlier BASC-2 assessments, with low sensitivities at the ages of 3 (37%), 4 (48%), and 5 years (55%)., Conclusions: Many children with hypoplastic left heart syndrome who have low adaptive skills at the age of 6 years will not be identified by screening at earlier ages. With our findings, we highlight the importance of serial evaluations for children with critical congenital heart disease throughout development., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2021 by the American Academy of Pediatrics.)

Introduction: Studies have suggested 5-20% of paediatric ICU patients may receive care felt to be futile. No data exists on the prevalence and impact of futile care in the Paediatric Cardiac ICU. The aim is to determine the prevalence and economic impact of futile care., Materials and Method: Retrospective cohort of patients with congenital cardiac disease 0-21 years old, with length of stay >30 days and died (2015-2018). Documentation of futility by the medical team was retrospectively and independently reviewed., Results: Of the 127 deaths during the study period, 51 (40%) had hospitalisation >30 days, 13 (25%) had received futile care and 26 (51%) withdrew life-sustaining treatment. Futile care comprised 0.69% of total patient days with no difference in charges from patients not receiving futile care. There was no difference in insurance, single motherhood, education, income, poverty, or unemployment in families continuing futile care or electing withdrawal of life-sustaining treatment. Black families were less likely than White families to elect for withdrawal (p = 0.01), and Hispanic families were more likely to continue futile care than non-Hispanics (p = 0.044)., Conclusions: This is the first study to examine the impact of futile care and characteristics in the paediatric cardiac ICU. Black families were less likely to elect for withdrawal, while Hispanic families more likely to continue futile care. Futile care comprised 0.69% of bed days and little burden on resources. Cultural factors should be investigated to better support families through end-of-life decisions.

Objective: Assess differences in approaches to and provision of developmental care for infants undergoing surgery for congenital heart disease., Study Design: A collaborative learning approach was used to stratify, assess, and compare individualized developmental care practices among multidisciplinary teams at 6 pediatric heart centers. Round robin site visits were completed with structured site visit goals and postvisit reporting. Practices of the hosting site were assessed by the visiting team and reviewed along with center self-assessments across specific domains including pain management, environment, cue-based care, and family based care coordination., Results: Developmental care for infants in the cardiac intensive care unit (CICU) varies at both a center and individual level. Differences in care are primarily driven by variations in infrastructure and resources, composition of multidisciplinary teams, education of team members, and use of developmental care champions. Management of pain follows a protocol in most cardiac intensive care units, but the environment varies across centers, and the provision of cue-based infant care and family-based care coordination varies widely both within and across centers. The project led to proposed changes in clinical care and center infrastructure at each participating site., Conclusions: A collaborative learning design fostered rapid dissemination, comparison, and sharing of strategies to approach a complex multidisciplinary care paradigm. Our assessment of experiences revealed marked variability across and within centers. The collaborative findings were a first step toward strategies to quantify and measure developmental care practices in the cardiac intensive care unit to assess the association of complex inpatient practices with long-term neurodevelopmental outcomes., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Endomyocardial biopsy (EMB) is the current standard for rejection surveillance in heart transplant recipients. The quantification of donor-specific cell-free DNA (cfDNA) may be an appropriate biomarker for non-invasive rejection surveillance. A multicenter prospective blinded study (DNA-Based Transplant Rejection Test, DTRT) investigated the value of donor fraction (DF), defined as the ratio of cfDNA specific to the transplanted organ to the total amount of cfDNA present in a blood sample., Methods: A total of 241 heart transplant patients were recruited from 7 centers. Age at transplant ranged from 8 days to 73 years, with 146 subjects <18 years and 95 ≥18 years. All the patients were followed for at least 1 year, with blood samples drawn at routine and for-cause biopsies. A total of 624 biopsy-paired samples were included for analysis through a commercially available cfDNA assay (myTAI HEART , TAI Diagnostics Inc.). A blinded analysis of repeated measures compared the outcomes using receiver operating characteristic (ROC) curves. All primary clinical end-points were monitored at 100%. All analysis and conclusions were reviewed by both an independent external oversight committee and the National Institutes of Health-mandated DTRT steering committee., Results: DF in acute cellular rejection (ACR) 1R/2R (n = 15) was higher than ACR 0R (n = 42) (p = 0.02); DF in antibody-mediated rejection pAMR1 (n = 8) and pAMR2 (n = 12) (p = 0.05) were higher than pAMR0 (n = 466) (p = 0.04 and p = 0.05 respectively). An optimal DF threshold was determined by the use of an ROC analysis, which ruled out the presence of either ACR or antibody-mediated rejection., Conclusions: The cell-free DNA DF holds promise as a non-invasive diagnostic test to rule out acute rejection in both adult and pediatric heart transplant populations., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: Neurodevelopmental disability is the most common complication among congenital heart surgery survivors. The Bayley scales are standardized instruments to assess neurodevelopment. The most recent edition (Bayley Scales of Infant and Toddler Development 3rd Edition, Bayley-III) yields better-than-expected scores in typically developing and high-risk infants than the second edition (Bayley Scales of Infant Development 2nd Edition, BSID-II). We compared BSID-II and Bayley-III scores in infants undergoing cardiac surgery., Methods: We evaluated 2198 infants who underwent operations with cardiopulmonary bypass between 1996 and 2009 at 26 institutions. We used propensity score matching to limit confounding by indication in a subset of patients (n = 705)., Results: Overall, unadjusted Bayley-III motor scores were higher than BSID-II Psychomotor Development Index scores (90.7 ± 17.2 vs 77.6 ± 18.8, P < 0.001), and unadjusted Bayley-III composite cognitive and language scores were higher than BSID-II Mental Development Index scores (92.0 ± 15.4 vs 88.2 ± 16.7, P < 0.001). In the propensity-matched analysis, Bayley-III motor scores were higher than BSID-II Psychomotor Development Index scores [absolute difference 14.1, 95% confidence interval (CI) 11.7-17.6; P < 0.001] and the Bayley-III classified fewer children as having severe [odds ratio (OR) 0.24; 95% CI 0.14-0.42] or mild-to-moderate impairment (OR 0.21; 95% CI 0.14-0.32). The composite of Bayley-III cognitive and language scores was higher than BSID-II Mental Development Index scores (absolute difference 4.0, 95% CI 1.4-6.7; P = 0.003), but there was no difference between Bayley editions in the proportion of children classified as having severe cognitive and language impairment., Conclusions: The Bayley-III yielded higher scores than the BSID-II and classified fewer children as severely impaired. The systematic bias towards higher scores with the Bayley-III precludes valid comparisons between early and contemporary cardiac surgery cohorts., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)