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Individuals with Fontan circulation are at risk of late mortality from both cardiac and noncardiac causes. Despite the known risk of mortality, referral indications for advanced heart failure care vary between centers, and many individuals die from Fontan circulation-related complications either after late consideration for advanced heart failure therapies or having never seen a heart failure specialist. There is a critical need for guidelines to direct appropriately timed referral for advanced heart failure consultation. The Advanced Cardiac Therapies Improving Outcomes Network (ACTION) Fontan Committee has developed recommended thresholds for advanced heart failure referral to guide primary cardiologists. These recommendations are divided into 4 categories of clinical Fontan circulatory dysfunction including (1) cardiac/systemic ventricular dysfunction, (2) Fontan pathway dysfunction, (3) lymphatic dysfunction, and (4) extracardiac dysfunction.

Background: The Fontan operation creates a total cavopulmonary connection, a circulation in which the importance of pulmonary vascular resistance is magnified. Over time, this circulation leads to deterioration of cardiovascular efficiency associated with a decline in exercise performance. Rigorous clinical trials aimed at improving physiology and guiding pharmacotherapy are lacking. Methods: The FUEL trial (Fontan Udenafil Exercise Longitudinal) was a phase III clinical trial conducted at 30 centers. Participants were randomly assigned udenafil, 87.5 mg twice daily, or placebo in a 1:1 ratio. The primary outcome was the between-group difference in change in oxygen consumption at peak exercise. Secondary outcomes included between-group differences in changes in submaximal exercise at the ventilatory anaerobic threshold, the myocardial performance index, the natural log of the reactive hyperemia index, and serum brain-type natriuretic peptide. Results: Between 2017 and 2019, 30 clinical sites in North America and the Republic of Korea randomly assigned 400 participants with Fontan physiology. The mean age at randomization was 15.5±2 years; 60% of participants were male, and 81% were white. All 400 participants were included in the primary analysis with imputation of the 26-week end point for 21 participants with missing data (11 randomly assigned to udenafil and 10 to placebo). Among randomly assigned participants, peak oxygen consumption increased by 44±245 mL/min (2.8%) in the udenafil group and declined by 3.7±228 mL/min (–0.2%) in the placebo group ( P =0.071). Analysis at ventilatory anaerobic threshold demonstrated improvements in the udenafil group versus the placebo group in oxygen consumption (+33±185 [3.2%] versus –9±193 [–0.9%] mL/min, P =0.012), ventilatory equivalents of carbon dioxide (–0.8 versus –0.06, P =0.014), and work rate (+3.8 versus +0.34 W, P =0.021). There was no an improvement in myocardial performance index (–0.02 vs 0.01, P =0.030), but no change in reactive hyperemia index, or serum brain-type natriuretic peptide level. Conclusions: In the FUEL trial, treatment with udenafil (87.5 mg twice daily) was not associated with an improvement in oxygen consumption at peak exercise but was associated with improvements in multiple measures of exercise performance at the ventilatory anaerobic threshold. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02741115.

Introduction: Traditional weight & height ratios as measures of donor-recipient (D-R) matching have been challenged in adult heart transplantation (HT). The optimal metrics for D-R matching in pediatric HT remain unclear, and were evaluated in the present study. Methods: All primary pediatric HT recipients in the Pediatric Heart Transplant Society database transplanted from 1993-2019 were included. Multiple metrics of size matching - height, weight, body mass index (BMI), body surface area (BSA), predicted heart mass (PHM) and total cardiac volume (TCV) were assessed to identify the metrics that would best predict 1-year post-transplant (PTx) graft loss (death/re-transplant). Kaplan-Meier analyses (risk unadjusted) and multivariate Cox proportional hazard models (risk adjusted) were used to assess the effect of differences of various size matching metrics on survival. Results: Among 6903 D-R pairs, multivariable hazard modeling identified the following risk factors for PTx mortality: female sex, black race, bilirubin, ECMO, VAD, mechanical ventilation, ICU admission at the time of transplant, presence of congenital heart disease, early era of transplant, donor ischemic time and cardiopulmonary bypass time. After adjusting for all covariates, increasing size mismatch by height, BSA, or PHM was associated with increased 1-year PTx graft loss, with a disproportionately higher hazard for undersized donors than oversized donors (Figure). Weight, BMI and TCV were not predictive of 1-year PTx graft loss on multivariate analysis. Conclusions: In pediatric HT recipients, increasing size mismatch by height, BSA and PHM is associated with increased 1-year PTx graft loss. Undersizing donors appears to carry a higher risk than oversizing.

Background: The Pediatric Heart Network’s Fontan Udenafil Exercise Longitudinal (FUEL) Trial (Mezzion Pharma Co. Ltd., NCT 02741115) demonstrated improvements in exercise capacity and ventricular performance following six months of treatment with udenafil (87.5 mg twice daily). In this analysis we evaluated whether subgroups within the population experienced a differential effect on exercise performance in response to treatment. Methods: The effect of udenafil on exercise was evaluated within subgroups defined by gender, race, ventricular morphology, and baseline peak oxygen consumption (VO 2 ). Linear regression modeling evaluated for differential response to udenafil (interaction of subgroup with treatment arm). Individual subgroups were excluded if the number of participants was Results: Subgroup analyses demonstrated qualitative improvements in peak VO 2 , work rate at the ventilatory anaerobic threshold (VAT), VO 2 at VAT, and ventilatory efficiency (VE/VCO 2 ) for those randomized to udenafil compared to placebo in all subgroups (Table). There was not a differential response to udenafil based on gender, race, ventricular morphology, or baseline peak VO 2 , although participants in the lowest tertile of baseline peak VO 2 and those with single left ventricles trended toward larger improvements. Conclusion: The relatively uniform improvement among subgroups in response to treatment with udenafil is consistent with the findings from the primary analysis of the FUEL trial. While the absence of a statistically significant differential effect between subgroups suggests that the effect of udenafil may not be gender, race, or morphology specific, and may not vary based on baseline exercise performance, the possibility of a larger improvements in those with poor baseline peak VO 2 and those with single left ventricle warrants further investigation.

Introduction: The Institute of Medicine called for scientific investigation and the development of guidelines to improve end of life care for pediatric patients with serious illnesses. Despite high morbidity and mortality in pediatric heart transplantation (HTx), research on the end of life care needs of this population is extremely limited. Aims: This study aimed to describe the circumstances surrounding death of pediatric HTx patients and examine associations between location of death and technological interventions at end-of-life with demographic, disease, and HTx-related factors. Methods: This retrospective analysis of the Pediatric Heart Transplant Society registry utilized descriptive statistics and standard univariate analysis to examine associations between location of death and patient factors. Results: Of 9,217 registry entries, 2,804 (30%) deaths occurred; 1,310 while awaiting HTx; 1,494 post-HTx. Location of death was only recorded for 1,113 patients which included 804 waitlist deaths; 89% occurred in the hospital, primarily in ICU settings (74%) with most requiring mechanical ventilation (77%). A subset (39%) were supported by ECMO/VAD at time of death with 69% receiving inotrope support. Location of death was captured for 309 post-HTx patients with only 22% occurring in hospital; primarily in the ICU (74%) with half receiving mechanical ventilation (52%) and a smaller proportion supported by ECMO/VAD (18%) or inotropes (21%) at time of death. Overall, location of death was not associated with patient sex, race, ethnicity, insurance type, or primary etiology. Out of hospital death was associated with older patient age (p Conclusions: Death occurred in ~1/3 of patients captured in this pediatric HTx registry. ICU deaths with high use of technological interventions were common, particularly in waitlisted patients, but family decision to discontinue interventions was infrequently cited. Findings underscore the need for palliative care interventions and improved research strategies to better understand end of life in pre- and post-HTx pediatric populations.

Background: Acute decompensated heart failure (ADHF) is a highly morbid condition among adults. Little is known about outcomes in children with ADHF. We analyzed the Pediatric Cardiac Critical Care Consortium registry to determine the epidemiology, contemporary treatments, and predictors of mortality in critically ill children with ADHF. Methods: Cardiac intensive care unit (CICU) patients ≤18 years of age meeting Pediatric Cardiac Critical Care Consortium criteria for ADHF were included. ADHF was defined as systolic or diastolic dysfunction requiring continuous vasoactive or diuretic infusion, respiratory support, or mechanical circulatory support. Demographics, diagnosis, therapies, complications, and mortality are described for the cohort. Predictors of CICU mortality were identified using logistic regression. Results: Among 26 294 consecutive admissions (23 centers), 1494 (6%) met criteria for analysis. Median age was 0.93 years (interquartile range, 0.1–9.3 years). Patients with congenital heart disease (CHD) comprised 57% of the cohort. Common therapies included the following: vasoactive infusions (88%), central venous catheters (86%), mechanical ventilation (59%), and high flow nasal cannula (46%). Common complications were arrhythmias (19%), cardiac arrest (10%), sepsis (7%), and acute renal failure requiring dialysis (3%). Median length of CICU stay was 7.9 days (interquartile range, 3–18 days) and the CICU readmission rate was 22%. Overall, CICU mortality was 15% although higher for patients with CHD versus non-CHD (19% versus 11%; P Conclusions: ADHF in children is characterized by comorbidities, high mortality rates, and frequent readmission, especially among patients with CHD. Opportunities exist to determine best practices around appropriate use of mechanical support, cardiac arrest prevention, and optimal heart transplantation candidacy to improve outcomes for these patients.

Introduction: Patient factors leading to cardiac arrest (CA) in the pediatric cardiac critical care unit (CICU) are well understood, but may be unmodifiable. Our understanding of the impact of CICU organizational factors (OFs) such as staffing models, health care provider education, and CICU bed management is limited. The association between these potentially modifiable CICU OFs on CA prevention and rescue outcomes is unknown. Hypothesis: CICU OFs associate with CA prevention and rescue. Methods: Retrospective analysis of Pediatric Cardiac Critical Care Consortium (PC4) clinical registry including data for all patients admitted to CICUs from August 2014 to March 2019. Prevention was defined as the prevalence of subjects not suffering CA. Rescue was defined as survival after CA. CICU OFs were captured via questionnaire distributed to PC4 participants in 2017 (100% response). Stratified, multivariable regression was used to evaluate associations between OFs and outcome in medical and surgical admission subgroups: competing time-to-events framework (to assess prevention) and multinomial regression (to assess rescue), accounting for clustering of patients within hospitals. Results: We analyzed 54,521 CICU admissions (59% surgical, 41% medical) from 29 hospitals with 1398 CA events (2.5%). We studied 12 OFs that varied across centers after accounting for collinearity. For both surgical and medical admissions, lower average daily occupancy (2 years experience, increased proportion of nurses with critical care certification, % of full-time intensivists, % of intensivists with critical care training, dedicated respiratory therapists, quality/safety resources, and annual CICU admission volume were not associated with improved prevention or rescue. Conclusion: Our multi-institutional analysis suggests that lower average CICU occupancy was the only consistent OF evaluated that was associated with CA prevention and rescue. CICUs that have average daily occupancy >80% may need specific strategies to mitigate the risks of CA.

Background— Pediatric data on the impact of pre–heart transplantation (HTx) risk factors on early post-HTx outcomes remain inconclusive. Thus, among patients with previous congenital heart disease or cardiomyopathy, disease-specific risk models for graft loss were developed with the use pre-HTx recipient and donor characteristics. Methods and Results— Patients enrolled in the Pediatric Heart Transplant Study (PHTS) from 1996 to 2006 were stratified by pre-HTx diagnosis into cardiomyopathy and congenital heart disease cohorts. Logistic regression identified independent, pre-HTx risk factors. Risk models were constructed for 1-year post-HTx graft loss. Donor factors were added for model refinement. The models were validated with the use of patients transplanted from 2007 to 2009. Risk factors for graft loss were identified in patients with cardiomyopathy (n=896) and congenital heart disease (n=965). For cardiomyopathy, independent risk factors were earlier year of transplantation, nonwhite race, female sex, diagnosis other than dilated cardiomyopathy, higher blood urea nitrogen, and panel reactive antibody >10%. The recipient characteristic risk model had good accuracy in the validation cohort, with predicted versus actual survival of 97.5% versus 95.3% (C statistic, 0.73). For patients with congenital heart disease, independent risk factors were nonwhite race, history of Fontan, ventilator dependence, higher blood urea nitrogen, panel reactive antibody >10%, and lower body surface area. The risk model was less accurate, with 86.6% predicted versus 92.4% actual survival, in the validation cohort (C statistic, 0.63). Donor characteristics did not enhance model precision. Conclusions— Risk factors for 1-year post-HTx graft loss differ on the basis of pre-HTx cardiac diagnosis. Modeling effectively stratifies the risk of graft loss in patients with cardiomyopathy and may be an adjunctive tool in allocation policies and center performance metrics.

Although the dramatically improved survival of children with single‐ventricle heart disease with Fontan circulation in the recent era is a tremendous accomplishment in pediatric cardiology and cardiac surgery, it has been accompanied by a growing realization that Fontan circulation is largely a

Background The onset of plastic bronchitis ( PB ) can be debilitating in survivors of Fontan surgery. The rarity of this complication makes designing studies to understand risk factors for PB challenging. This 2‐center case‐control study aimed to describe patient outcomes and to assess the association of antecedent patient factors with PB development. Methods and Results Using center registries, PB patients (n=25) were matched 1:2 to non‐ PB Fontans (n=43) by date of Fontan surgery and center. The groups were compared for baseline characteristics. Association of patient characteristics with PB was assessed using logistic regression and of potential risk factors with onset of PB using time‐to‐event analyses. The median time from Fontan to PB diagnosis was 2.5 years. Overall, 12/25 PB patients died or underwent heart transplant; the median transplant‐free survival was 8.3 years after diagnosis. Factors associated with developing PB included post‐surgical chylothorax (44% PB versus 10% control; odds ratio [ OR ] 7.3; P =0.003), chest tube ( CT ) duration at stage 2 ( P =0.04) and Fontan ( P =0.004), and postoperative ascites (36% PB versus 12% control; OR 4.2; P =0.003). CT drainage >13 days at Fontan was associated with earlier PB onset ( P =0.04). Early‐onset PB was associated with an increased risk of death ( OR 5.0; P =0.002). Conclusions PB is a life‐threatening disorder. A longer duration of CT drainage after surgery, chylothorax, and development of ascites are all associated with developing PB . Understanding the pathophysiology of peri‐operative complications in individual patients and using targeted interventions may delay the onset of the PB phenotype.