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The Pediatric Interagency Registry for Mechanical Circulatory Support (Pedimacs), supported by the Society of Thoracic Surgeons, provides detailed information on pediatric patients supported with ventricular assist devices (VADs).From September 19, 2012, to December 31, 2021, there were 1,355 devices in 1,109 patients (19 years) from 42 North American Hospitals.Cardiomyopathy was the most common underlying etiology (58%), followed by congenital heart disease (CHD) (26%) and myocarditis (9%). Regarding device type, implantable continuous (IC) VADs were most common at 40%, followed by paracorporeal pulsatile (PP) (28%), and paracorporeal continuous (PC) (27%). Baseline demographics differed, with the PC cohort being younger, smaller, more complex (ie. CHD), and sicker at implant (P.0001). At six months post-VAD implantation, a favorable outcome (transplant, recovery, or alive on device) was achieved in 84% of patients, which was greatest among those on IC VADs (92%) and least for PC VADs (69%). Adverse events (AEs) were not uncommon, with non-gastrointestinal bleeding (incidence of 14%) and neurological dysfunction (11% [Stroke 4%]), within 2 weeks post implant being the most prevalent. Stroke and bleeding had negative impacts on overall survival (p=0.002 and p0.001, respectively).This Sixth Pedimacs Report demonstrates the continued evolution of the pediatric field. The complexity of cardiac physiologies and anatomical constraint mandates the need for multiple types of devices utilized (PC, PP, IC). Detailed analyses of each device type in this report provide valuable information to further advance the care of this challenging and vulnerable population.

Elevated pulmonary vascular resistance (PVR) in the setting of left heart failure may contribute to poor outcomes after pediatric heart transplant (HTx), but peri-transplant management is variable.We sought to characterize international practice by surveying physicians at pediatric HTx centers.We received 49 complete responses from 39 centers in 16 countries. Most respondents are pediatric cardiologists (90%), practice at centers offering heart (86%) and lung (55%) transplant, and perform pre-HTx acute vasoreactivity testing (AVT, 88%) in patients with elevated PVR. Half (51%) reported defining a PVR cutoff for HTx eligibility as ≤6 WU mManagement of elevated PVR in children awaiting HTx is heterogenous. Evidence-based guidelines are needed to allow for longitudinal determination of optimal outcomes and standardized care.

Most pediatric patients on ventricular assist device (VAD) survive to transplantation. Approximately 15% will die on VAD support, and the circumstances at the end-of-life are not well understood. We, therefore, sought to characterize patient location and invasive interventions used at the time of death.Retrospective database study of a cohort meeting inclusion criteria.Thirty-six centers participating in the Advanced Cardiac Therapies Improving Outcomes Network (ACTION) Registry.Children who died on VAD therapy in the period March 2012 to September 2021.None.Of the 117 of 721 patients (16%) who died on VAD, the median (interquartile range) age was 5 years (1-16 yr) at 43 days (17-91 d) postimplant. Initial goals of therapy were bridge to consideration for candidacy for transplantation in 60 of 117 (51%), bridge to transplantation in 44 of 117 (38%), bridge to recovery 11 of 117 (9%), or destination therapy (i.e., VAD as the endpoint) in two of 117 (2%). The most common cause of death was multiple organ failure in 35 of 117 (30%), followed by infection in 12 of 117 (10%). Eighty-five of 92 (92%) died with a functioning device in place. Most patients were receiving invasive interventions (mechanical ventilation, vasoactive infusions, etc.) at the end of life. Twelve patients (10%) died at home.One-in-six pediatric VAD patients die while receiving device support, with death occurring soon after implant and usually from noncardiac causes. Aggressive interventions are common at the end-of-life. The ACTION Registry data should inform future practices to promote informed patient/family and clinician decision-making to hopefully reduce suffering at the end-of-life.

Infectious complications are a major cause of morbidity and mortality after HT. Fontan patients may be more susceptible to post-HT infections.This was a single-center, retrospective cohort analysis of pediatric patients undergoing HT for FF physiology or DCM, who underwent induction with ATG. The primary endpoint was an infection in the first 180 days post-HT, defined as positive (1) blood/urine/respiratory culture; (2) viral PCR; (3) skin or wound infection; and/or (4) culture-negative infection if ≥5 days of antibiotics were completed. Secondary endpoints included (1) cell counts after ATG; (2) PTLD; and (3) rejection (≥Grade 2R ACR or pAMR2) in the first 180 days post-HT.A total of 59 patients (26 FF, 33 DCM) underwent HT at 14.7 (IQR 10.6, 19.5) and 11.7 (IQR 1.4, 13.6) years of age, respectively. The median total ATG received was 7.4 (IQR 4.9, 7.7) vs 7.5 (IQR 7.3, 7.6) mg/kg (p = NS) for FF and DCM patients, respectively. Twenty-three patients (39%) developed an infection 180 days post-HT, with a higher rate of infection in FF patients (54% vs 27%, p = .03). Adjusted for pre-transplant absolute lymphocyte count, FF patients had a higher risk of infection at 30 days post-HT (OR 7.62, 95% CI 1.13-51.48, p = .04). There was no difference in the incidence of PTLD (12% vs 0%; p = .08) or rejection (12% vs 21%; p = .49).Compared to DCM patients, FF patients have a higher risk of infection. Modifications to induction therapy for FF patients should be considered.

Ventricular assist devices (VADs) are increasingly used in pediatric heart failure as bridges to heart transplantation, although 25% will die with VADs. Family experiences in this population are not well-described. The objective is to understand bereaved families' perspectives on VAD and end-of-life decision-making.Semistructured interviews with bereaved caregivers of pediatric VAD patients.Tertiary children's hospital.Families of six pediatric VAD patients who died from 2014 to 2020.Not available.Applying a grounded theory framework, interviews were coded by two independent readers using qualitative software. Themes were discussed in iterative multidisciplinary meetings. Participants were interviewed at a median 2.4 years after their child died. Three major themes emerged: 1) "lack of regret" for VAD implantation despite the outcome; 2) "caregiver-child accord" (via patient's verbal assent or physical cues) at implantation and end-of-life was important in family decision-making; and 3) development of a "local surrogate family" (medical team and peer families) provided powerful support.Bereaved families' perspectives provide insight into quality decision-making for major interventions and end-of-life care in pediatric patients with chronic illness who face decisions regarding technology dependence.

Single ventricle (SV) patients with pulmonary vascular disease (SV-PVD) are considered poor surgical candidates for Glenn or Fontan palliation. Given limited options for Stage 1 (S1) and Stage 2 (S2) SV patients with SV-PVD, we report on the use of subcutaneous treprostinil (TRE) to treat SV-PVD in this population. This single-center, retrospective cohort study examined SV patients who were not candidates for subsequent surgical palliation due to SV-PVD and were treated with TRE. The primary outcome was ability to progress to the next surgical stage; secondary outcomes included changes in hemodynamics after TRE initiation. Between 3/2014 and 8/2021, 17 SV patients received TRE for SV-PVD: 11 after S1 and 6 after S2 (median PVR 4.1 [IQR 3.2-4.8] WU*m

BACKGROUND Indications for a heart‒liver transplantation (HLT) for Fontan recipients are not well defined. We compared listing characteristics, post-operative complications, and post-transplant outcomes of Fontan recipients who underwent HLT with those of patients who underwent heart-only transplantation (HT). We hypothesized that patients who underwent HLT have increased post-operative complications but superior survival outcomes compared with patients who underwent HT. METHODS We performed a retrospective review of Fontan recipients who underwent HLT or HT at a single institution. Characteristics at the time of listing, including the extent of liver disease determined by laboratory, imaging, and biopsy data, were compared. Post-operative complications were assessed, and the Kaplan‒Meier survival method was used to compare post-transplant survival. Univariate regression analyses were performed to identify the risk factors for increased mortality and morbidity among patients who underwent HT. RESULTS A total of 47 patients (9 for HLT, 38 for HT) were included. Patients who underwent HLT were older, were more likely to be on dual inotrope therapy, and had evidence of worse liver disease. Whereas ischemic time was longer for the group who underwent HLT, post-operative complications were similar. Over a median post-transplant follow-up of 17 (interquartile range: 5–52) months, overall mortality for the cohort was 17%; only 1 patient who underwent HLT died (11%) vs 7 patients who underwent HT (18%) ( p = 0.64). Among patients who underwent HT, cirrhosis on pre-transplant imaging was associated with worse outcomes. CONCLUSIONS Despite greater inotrope need and more severe liver disease at the time of listing, Fontan recipients undergoing HLT have post-transplant outcomes comparable with those of patients undergoing HT. HLT may offer a survival benefit for Fontan recipients with liver disease.

Background Children with Down syndrome (DS) have a high risk of cardiac disease that may prompt consideration for heart transplantation (HTx). However, transplantation in patients with DS is rarely reported. This project aimed to collect and describe waitlist and post– HTx outcomes in children with DS. Methods and Results This is a retrospective case series of children with DS listed for HTx. Pediatric HTx centers were identified by their participation in 2 international registries with centers reporting HTx in a patient with DS providing detailed demographic, medical, surgical, and posttransplant outcome data for analysis. A total of 26 patients with DS were listed for HTx from 1992 to 2020 (median age, 8.5 years; 46% male). High‐risk or failed repair of congenital heart disease was the most common indication for transplant (N=18, 69%). A total of 23 (88%) patients survived to transplant. All transplanted patients survived to hospital discharge with a median posttransplant length of stay of 22 days. At a median posttransplant follow‐up of 2.8 years, 20 (87%) patients were alive, 2 (9%) developed posttransplant lymphoproliferative disorder, and 8 (35%) were hospitalized for infection within the first year. Waitlist and posttransplant outcomes were similar in patients with and without DS ( P =non‐significant for all). Conclusions Waitlist and post‐HTx outcomes in children with DS selected for transplant listing are comparable to pediatric HTx recipients overall. Given acceptable outcomes, the presence of DS alone should not be considered an absolute contraindication to HTx.

Acute kidney injury (AKI) is common following pediatric cardiac transplantation. Since no treatments exist, strategies focus on early identification and prevention. Kinetic glomerular filtration rate (kGFR) was developed to assess renal function in the non-steady state. Although used to predict AKI in adults, kGFR has not been explored in children. Our study examines AKI and the ability of kGFR to identify AKI risk in pediatric heart transplant recipients. One hundred and seventy-five patients under 21 years who underwent cardiac transplantation at Lucile Packard Children’s Hospital between September 2007–December 2017 were included. kGFR1 was calculated using pre-operative and immediate post-operative creatinines; kGFR2 was calculated with the first two post-operative creatinines. The primary outcome was AKI as defined by the Kidney Disease: Improving Global Outcomes criteria. One hundred and thirty-one (75%) and 78 (45%) patients developed AKI and severe AKI, respectively; 5 (2.9%) required dialysis. kGFR was moderately associated with post-operative AKI risk. The adjusted area under the curve (AUC) for kGFR1 was 0.72 (discovery) and 0.65 (validation). The AUC for kGFR2 was 0.72 (discovery) and 0.68 (validation). AKI is pervasive in children undergoing cardiac transplant, particularly in the 24 h after surgery. kGFR moderately identifies AKI risk and may represent a novel risk stratification technique.

Introduction Abulia is defined as a pathological state of amotivation, apathy, and global absence of willpower. It presents with a challenging array of overlapping symptoms, making effective identification and treatment difficult. Case presentation We describe the first known report of an adolescent with a ventricular assist device who developed abulia following a left middle cerebral artery (MCA) stroke who responded successfully to treatment with olanzapine. Discussion The neurobiological etiology of abulia is still unclear but is postulated to be related to deficits in the dopaminergic reward circuitry in the frontal-subcortical-mesolimbic regions. There have been reports of poststroke patients with abulia being treated by modulating this dopamine circuitry and in some cases with short-term low-dose olanzapine. Conclusion Further research is needed to develop a better understanding of the pathophysiology of abulia leading to more effective treatment algorithms including more specific diagnostic tools and effective pharmacological interventions.

Sudden cardiac arrest (SCA) is a prevailing cause of mortality after pediatric heart transplant (HT) but remains understudied. We analyzed the incidence, outcomes, and risk factors for SCA at our center.Retrospective review of all pediatric HT patients at our center from January 1, 2009 to January 1, 2021. SCA was defined as an abrupt loss of cardiac function requiring cardiopulmonary resuscitation and/or mechanical circulatory support (MCS). Events that occurred in the setting of limited resuscitative wishes, or while on MCS were excluded. Patient characteristics and risk factors were analyzed.Fourteen of 254 (6%) experienced SCA at a median of 3 (1, 4) years post-HT. Seven (50%) events occurred out-of-hospital. Eleven (79%) died from their initial event, 2 (18%) after failure to separate from extracorporeal membrane (ECMO). In univariate analysis, black race, younger donor age, prior acute cellular rejection (ACR) episode, pacemaker and/or ICD in place, and pre-mortem diagnosis of allograft vasculopathy were associated with SCA (P = .003-0.02). In multivariable analysis, history of ACR, younger donor age, and black race retained significance. [OR = 6.3, 95% CI: 1.6-25.4, P = .01], [OR = 0.9, 95% CI: 0.8-1, P = .04], and [OR = 7.3, 95% CI: 1.1-49.9, P = .04], respectively. SCA occurred in 3 patients with a functioning ICD or pacemaker, which failed to restore a perfusing rhythm.SCA occurs relatively early after pediatric HT and is usually fatal. Half of events happen at home. Those who received younger donors, have a history of ACR, or are of black race are at increased risk. ICDs/pacemakers may offer limited protection.

Background Although mortality has decreased considerably in pediatric heart transplantation, waitlist and post-transplant death rates remain notable. End-of-life focused research in this population, however, is very limited. This Pediatric Heart Transplant Society study aimed to describe the circumstances surrounding death of pediatric heart transplant patients. Methods A retrospective analysis of the multi-institutional, international, Pediatric Heart Transplant Society registry was conducted. Descriptive statistics and univariate analyses were performed to 1) describe end-of-life in pediatric pre- and post-heart transplant patients and 2) examine associations between location of death and technological interventions at end-of-life with demographic and disease factors. Results Of 9217 patients (0-18 years) enrolled in the registry between 1993 and 2018, 2804 (30%) deaths occurred; 1310 while awaiting heart transplant and 1494 post-heart transplant. The majority of waitlist deaths (89%) occurred in the hospital, primarily in ICU (74%) with most receiving mechanical ventilation (77%). Fewer post-transplant deaths occurred in the hospital (22%). Out-of-hospital death was associated with older patient age (p Conclusions ICU deaths with high use of technological interventions at end-of-life were common, particularly in patients awaiting heart transplant. In this high mortality population, findings raise challenging considerations for clinicians, families, and policy makers on how to balance quality of life amidst high risk for hospital-based death.

Acute kidney injury (AKI) is common after pediatric heart transplantation (HT) and is associated with inferior patient outcomes. Hemodynamic risk factors for pediatric heart transplant recipients who experience AKI are not well described. We performed a retrospective review of 99 pediatric heart transplant patients at Lucile Packard Children's Hospital Stanford from January 1, 2015, to December 31, 2019, in which clinical and demographic characteristics, intraoperative perfusion data, and hemodynamic measurements in the first 48 postoperative hours were analyzed as risk factors for severe AKI (Kidney Disease: Improving Global Outcomes [KDIGO] stage ≥ 2). Univariate analysis was conducted using Fisher's exact test, Chi-square test, and the Wilcoxon rank-sum test, as appropriate. Multivariable analysis was conducted using logistic regression. Thirty-five patients (35%) experienced severe AKI which was associated with lower intraoperative cardiac index (p = 0.001), higher hematocrit (p 12 mm Hg (odds ratio [OR] = 4.27; 95% confidence interval [CI]: 1.48–12.3, p = 0.007) and MAP

The Pediatric Interagency Registry for Mechanical Circulatory Support (Pedimacs) provides detailed information on pediatric patients supported with ventricular assist devices (VADs).From September 19, 2012, to December 31, 2020, 1229 devices in 1011 patients were reported to the registry from 47 North American Hospitals in patients aged younger than 19 years.Cardiomyopathy was the most common underlying etiology (58%), followed by congenital heart disease (CHD; 25%) and myocarditis (10%). The most common devices implanted were implantable continuous (IC; 419 [41%]), followed by paracorporeal pulsatile (PP; 269 [27%]), paracorporeal continuous (PC; 263 [26%]), and percutaneous (53 [5%]). Overall, at 6 months after VAD implantation, 83% had a positive outcome (transplant, explant, or alive on device). The freedom from stroke at 3 months was highest in IC VADs (93%), compared with PP VADs (84%) and with PC VADs (75%). There were differences in survival by device type, with patients on IC VADs having the best overall survival and those on PC having the lowest overall survival, though the patient populations being supported by each VAD type differed significantly from each other.This Fifth Pedimacs Report demonstrates the continued robust growth of VADs in the pediatric community, now with more than 1000 patients reported to the registry. The multiple available device types (PC, PP, IC) serve different populations with different pre-VAD risk profiles, which may account for differences in survival and adverse events between device types.

Background To evaluate the impact of a clinical pathway on the incidence and severity of acute kidney injury in patients undergoing heart transplant. Methods This was a 2.5-year retrospective evaluation using 3 years of historical controls within a cardiac intensive care unit in an academic children's hospital. Patients undergoing heart transplant between May 27, 2014, and April 5, 2017 (pre-pathway) and May 1, 2017, and November 30, 2019 (pathway) were included. The clinical pathway focused on supporting renal perfusion through hemodynamic management, avoiding or delaying nephrotoxic medications, and providing pharmacoprophylaxis against AKI. Results There were 57 consecutive patients included. There was an unadjusted 20% reduction in incidence of any acute kidney injury (p = .05) and a 17% reduction in Stage 2/3 acute kidney injury (p = .09). In multivariable adjusted analysis, avoidance of Stage 2/3 acute kidney injury was independently associated with the clinical pathway era (AOR -1.3 [95% CI -2.5 to -0.2]; p = .03), achieving a central venous pressure of or less than 12 mmHg (AOR -1.3 [95% CI -2.4 to -0.2]; p = .03) and mean arterial pressure above 60 mmHg (AOR -1.6 [95% CI -3.1 to -0.01]; p = .05) in the first 48 h post-transplant, and older age at transplant (AOR - 0.2 [95% CI -0.2 to -0.06]; p = .002). Conclusions This report describes a renal protection clinical pathway associated with a reduction in perioperative acute kidney injury in patients undergoing heart transplant and highlights the importance of normalizing perioperative central venous pressure and mean arterial blood pressure to support optimal renal perfusion.

BACKGROUND: Young adult heart transplant (HT) recipients transferring to adult care are at risk for poor health outcomes. We conducted a pilot randomized controlled trial to determine feasibility and test a transition intervention for young adults who underwent HT as children and transferred to adult care. METHODS: Participants were randomized to the transition intervention (4 months long, focused on HT knowledge, self-care, self-advocacy, and social support) or usual care. Self-report questionnaires and medical records data were collected at baseline and 3 and 6 months after the initial adult clinic visit. Longitudinal analyses comparing outcomes over time were performed using generalized estimating equations and linear mixed models. RESULTS: Transfer to adult care was successful and feasible (i.e., excellent participation rates). The average patient standard deviation of mean tacrolimus levels was similar over time in both study arms and < 2.5, indicating adequate adherence. There were no between group and within group differences in percent of tacrolimus bioassays within target range (>50%). Average overall adherence to treatment was similarly good for both groups. Rates of appointment keeping through 6 months after transfer declined over time in both groups. CONCLUSIONS: Feasibility of the study was demonstrated. Our transition intervention did not improve outcomes.

Objective To determine the association between continuous flow ventricular assist devices and the incidence of vasoplegia following orthotopic heart transplant in children. Moreover, to propose a novel clinical definition of vasoplegia for use in pediatric populations. Methods This is a single-center, retrospective cohort study set in the cardiovascular intensive care unit of a tertiary children's hospital. All patients aged 3 years and older who underwent orthotopic heart transplant at Stanford University between April 1, 2014, and July 31, 2017, were included. Vasoplegia was defined by the use of vasoconstrictive medication, diastolic hypotension, preserved systolic heart function, and absence of infection or right atrial pressure or central venous pressure Results Of 44 eligible patients, 21 were supported using a continuous flow ventricular assist device. Following heart transplant, 14 patients (32%) developed vasoplegia by the study definition. Development of vasoplegia was associated with pretransplant use of a continuous flow ventricular assist device (52% vs 13%) with a relative risk of 4.02 (95% confidence interval, 1.30-12.45; P = .009). No other variables were predictive of vasoplegia in univariable analysis. Presence of vasoplegia was not associated with adverse outcomes, although there were trends towards higher incidence of acute kidney injury and increased length of hospital stays. Conclusions Children receiving continuous flow ventricular assist device support are at increased risk for vasoplegia following orthotopic heart transplant, using a novel definition of vasoplegia. Anticipation of this complication will allow for prompt intervention, thereby minimizing hemodynamic instability and impact on patient outcomes.

Hypertrophic cardiomyopathy (HCM) has historically been diagnosed phenotypically. Through genetic testing, identification of a molecular diagnosis (MolDx) is increasingly common but the impact on pediatric patients is unknown. This was a retrospective study of next-generation sequencing data for 602 pediatric patients with a clinician-reported history of HCM. Diagnostic yield was stratified by gene and self-reported race/ethnicity. A MolDx of HCM was identified in 242 (40%) individuals. Sarcomeric genes were the highest yielding, but pathogenic and/or likely pathogenic (P/LP) variants in syndromic genes were found in 36% of individuals with a MolDx, often in patients without documented clinical suspicion for a genetic syndrome. Among all MolDx, 73% were in genes with established clinical management recommendations and 2.9% were in genes that conferred eligibility for clinical trial enrollment. Black patients were the least likely to receive a MolDx. In the current era, genetic testing can impact management of HCM, beyond diagnostics or prognostics, through disease-specific guidelines or clinical trial eligibility. Genetic testing frequently can help identify syndromes in patients for whom syndromes may not be suspected. These findings highlight the importance of pursuing broad genetic testing, independent of suspicion based on phenotype. Lower rates of MolDx in Black patients may contribute to health inequities. Further research is needed evaluating the genetics of HCM in underrepresented/underserved populations. Additionally, research related to the impact of genetic testing on clinical management of other diseases is warranted. Supplementary Information The online version contains supplementary material available at 10.1007/s00246-021-02764-1.

BACKGROUND Routine surveillance biopsy (RSB) is performed to detect asymptomatic acute rejection (AR) after heart transplantation (HT). Variation in pediatric RSB across institutions is high. We examined center-based variation in RSB and its relationship to graft loss, AR, coronary artery vasculopathy (CAV), and cost of care during the first year post-HT. METHODS We linked the Pediatric Health Information System (PHIS) and Scientific Registry of Transplant Recipients (SRTR, 2002-2016), including all primary-HT aged 0-21 years. We characterized centers by RSB frequency (defined as median biopsies performed among recipients aged ≥12 months without rejection in the first year). We adjusted for potential confounders and center effects with mixed-effects regression analysis. RESULTS We analyzed 2867 patients at 29 centers. After adjusting for patient and center differences, increasing RSB frequency was associated with diagnosed AR (OR 1.15 p = 0.004), a trend toward treated AR (OR 1.09 p = 0.083), and higher hospital-based cost (US$390 315 vs. $313 248, p

Context Compassionate deactivation (CD) of ventricular assist device (VAD) support is a recognized option for children when the burden of therapy outweighs the benefits. Objectives To describe the prevalence, indications, and outcomes of CD of children supported by VADs at the end of life. Methods Review of cases of CD at our institution between 2011 and 2020. To distinguish CD from other situations where VAD support is discontinued, patients were excluded from the study if they died during resuscitation (including extracorporeal membrane oxygenation), experienced brain or circulatory death prior to deactivation, or experienced a non-survivable brain injury likely to result in imminent death regardless of VAD status. Results Of 24 deaths on VAD, 14 (58%) were CD. Median age was 5.7 (interquartile range (IQR) 0.6, 11.6) years; 6 (43%) had congenital heart disease; 4 (29%) were on a device that can be used outside of the hospital. CD occurred after 40 (IQR: 26, 75) days of support; none while active transplant candidates. CD discussions were initiated by the caregiver in 6 (43%) cases, with the remainder initiated by a medical provider. Reasons for CD were multifactorial, including end-organ injury, infection, and stroke. CD occurred with endotracheal extubation and/or discontinuation of inotropes in 12 (86%) cases, and death occurred within 10 (IQR: 4, 23) minutes of CD. Conclusion CD is the mode of death in more than half of our VAD non-survivors and is pursued for reasons primarily related to noncardiac events. Caregivers and providers both initiate CD discussions. Ventilatory and inotropic support is often withdrawn at time of CD with ensuing death.

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.

Introduction: Recent studies have suggested a relationship between mortality and center volume in pediatric heart transplantation; however, these studies utilize databases that lack granularity to assess patient risk profiles. Hypothesis: Utilizing the Pediatric Heart Transplant Society (PHTS) database, we hypothesized that there would be a difference in outcomes among centers based on yearly transplant volume, and that the patient’s clinical profiles would differ by center volume. Methods: We performed a retrospective analysis of the PHTS dataset from all pediatric (≤ 18 years of age) cases from 2009-2018. Centers were stratified into 5 groups based on annual volume: ≤ 4, 4-6, 6-9, 9-14, and > 14 transplants. We evaluated specific variables, including those identified as significant risk factors in previous PHTS studies including mechanical ventilation, PRA > 10%, high BUN, gender, and Fontan completion, within each group. We used Kaplan Meier for survival, contingency tables with Pearson Chi-square test for association, and analysis-of-variance to compare means. P< 0.05 was considered statistically significant. Results: There were 6800 cases among 55 centers. Table 1 demonstrates that there was no significant difference in one-year post transplant survival among the groups, and the patient variables showing statistically significant differences followed no specific pattern among the center volume groups. It also demonstrates that there is no clear association between cumulative risk factors within individual patients and center volume. Conclusions: One-year post transplant survival is similar within the PHTS for all centers regardless of case volume. These group differences were different for different variables and did not segregate consistently between lower volume and higher volume groups suggesting there exists a complicated relationship among risk factors and center volume.

Outcomes in pediatric patients with ventricular assist devices (VADs) for advanced heart failure (HF) are improving, but the risk of associated morbidity and mortality remains substantial. Few data exist on the involvement of pediatric palliative care (PPC) in this high-risk patient population. We aimed to characterize the extent of palliative care involvement in the care of patients requiring VAD placement at our institution. Single-center retrospective chart review analyzing all VAD patients at a large pediatric center over a 4 year period. Timing and extent of palliative care subspecialty involvement were analyzed. Between January 2014 and December 2017, 55 HF patients underwent VAD implantation at our institution. Pediatric palliative care utilization steadily increased over consecutive years (2014

The number of children needing heart transplantation continues to rise. Although improvements in heart failure therapy, particularly durable mechanical support, have reduced waitlist mortality, the number of children who die while waiting for a suitable donor organ remains unacceptably high. Roughly, 13% of children and 25% of infants on the heart transplant waitlist will not survive to transplantation. With this in mind, the Advanced Cardiac Therapies Improving Outcomes Collaborative Learning Network (ACTION), through its Waitlist Outcomes Committee, convened a 2-day symposium in Ann Arbor, Michigan, from 2-3 November 2019, to better understand the factors that contribute to pediatric heart transplant waitlist mortality and to focus future efforts on improving the organ allocation rates for children needing heart transplantation. Using improvement science methodology, the heart failure-transplant trajectory was broken down into six key steps, after which modes of failure and opportunities for improvement at each step were discussed. As a result, several projects aimed at reducing waitlist mortality were initiated.

Acute kidney injury (AKI) is common following pediatric cardiac transplantation. Since no treatments exist, strategies focus on early identification and prevention. Kinetic glomerular filtration rate (kGFR) was developed to assess renal function in the non-steady state. Although used to predict AKI in adults, kGFR has not been explored in children. Our study examines AKI and the ability of kGFR to identify AKI risk in pediatric heart transplant recipients.One hundred and seventy-five patients under 21 years who underwent cardiac transplantation at Lucile Packard Children's Hospital between September 2007-December 2017 were included. kGFROne hundred and thirty-one (75%) and 78 (45%) patients developed AKI and severe AKI, respectively; 5 (2.9%) required dialysis. kGFR was moderately associated with post-operative AKI risk. The adjusted area under the curve (AUC) for kGFRAKI is pervasive in children undergoing cardiac transplant, particularly in the 24 h after surgery. kGFR moderately identifies AKI risk and may represent a novel risk stratification technique.Our research suggests that kGFR, a dynamic assessment of renal function that uses readily available laboratory values, can moderately identify AKI risk in children undergoing cardiac transplantation. Current published studies on kGFR are in adult populations; this study represents the first formal study of kGFR in a pediatric population. kGFR may serve as an early AKI indicator, allowing providers to implement preventative strategies sooner in a patient's clinical course.

BACKGROUND Currently, there are no simple tools to evaluate the acute heart failure (HF) symptom severity in children hospitalized with acute decompensated HF (ADHF). We sought to develop an inpatient HF score (HFS) that could be used as a clinical tool and for clinical trials. METHODS Pediatric HF clinicians at Stanford reviewed the limitations of existing HFSs, which include lack of calibration to the inpatient setting, omission of gastrointestinal symptoms, need for multiple age-based tools, and scores that prioritize treatment intensity over patient symptoms. To address these, we developed an acute HFS corresponding to the 3 cardinal symptoms of HF: difficulty with breathing, feeding, and activity. The score was iteratively improved over a 3-year pilot phase until no further changes were made. The inter-rater reliability (IRR) across a range of providers was assessed using the final version. Peak HFSs were analyzed against mortality and length of stay (LOS) for all pediatric HF discharges between July and October 2019. RESULTS The final HFS was a 4-point ordinal severity score for each of the 3 symptom domains (total score 0-12). Among clinicians who scored 12 inpatients with ADHF simultaneously, the intraclass correlation (ICC) was 0.94 (respiratory ICC = 0.89, feeding ICC = 0.85, and activity ICC = 0.80). Score trajectory reflected our clinical impression of patient response to HF therapies across a range of HF syndromes including 1- and 2-ventricle heart disease and reduced or preserved ejection fraction. Among the 28 patients hospitalized during a 3-months period (N = 28), quartiles of peak score were associated with LOS (p < 0.01) and in-hospital mortality (p < 0.01): HFS 0 to 3 (median LOS of 5 days and mortality of 0%), HFS 4 to 6 (median LOS of 18 days and mortality of 0%), HFS 5 to 9 (median LOS of 29 days and mortality of 23%), and HFS 10 to 12 (median LOS of 121 days and mortality of 50%). CONCLUSION This simple acute HFS may be a useful tool to quantify and monitor day-to-day HF symptoms in children hospitalized with ADHF regardless of etiology or age group. The score has excellent IRR across provider levels and is associated with major hospital outcomes supporting its clinical validity. Validation in a multicenter cohort is warranted.

Background Despite the routine use of hemodynamic assessment in pediatric heart transplant (HT) patients, expected intracardiac pressure measurements in patients free of significant complications are incompletely described. A better understanding of the range of intracardiac pressures in these HT patients is important for the clinical interpretation of these indices and consequent management of patients. Methods We conducted a retrospective chart review of pediatric HT recipients who had undergone HT between January 2010 and December 2015 at Lucile Packard Children's Hospital. We analyzed intracardiac pressures measured in the first 12 mo after HT. We excluded those with rejection, graft coronary artery disease, mechanical support, or hemodialysis. We used a longitudinal general additive model with bootstrapping technique to generate age and donor-recipient size-specific curves to characterize filling pressures through 1-y post-HT. Results Pressure measurements from the right atrium, pulmonary artery, and pulmonary capillary wedge pressure were obtained in 85 patients during a total of 829 catheterizations. All pressure measurements were elevated in the immediate post-HT period and decreased to a stable level by post-HT day 90. Pressure measurements were not affected by age group, donor-recipient size differences, or ischemic time. Conclusions Intracardiac pressures are elevated in the early post-HT period and decrease to levels typical of the native heart by 90 d. Age, donor-to-recipient size differences, and ischemic time do not contribute to differences in expected intracardiac pressures in the first year post-HT.

Background There is inadequate power to perform a valid clinical trial in pediatric heart transplantation (HT) using a conventional end-point, because the disease is rare and hard end-points, such as death or graft loss, are infrequent. We sought to develop and validate a surrogate end-point involving the cumulative burden of post-transplant complications to predict death/graft loss to power a randomized clinical trial of maintenance immunosuppression in pediatric HT. Methods Pediatric Heart Transplant Study (PHTS) data were used to identify all children who underwent an isolated orthotopic HT between 2005 and 2014 who survived to 6 months post-HT. A time-varying Cox model was used to develop and evaluate a surrogate end-point comprised of 6 major adverse transplant events (MATEs) (acute cellular rejection [ACR], antibody-mediated rejection [AMR], infection, cardiac allograft vasculopathy [CAV], post-transplant lymphoproliferative disease [PTLD] and chronic kidney disease [CKD]) occurring between 6 and 36 months, where individual events were defined according to international guidelines. Two thirds of the study cohort was used for score development, and one third of the cohort was used to test the score. Results Among 2,118 children, 6.4% underwent graft loss between 6 and 36 months post-HT, whereas 39% developed CKD, 34% ACR, 34% infection, 9% AMR, 4% CAV and 2% PTLD. The best predictive score involved a simple MATE score sum, yielding a concordance probability estimate (CPE) statistic of 0.74. Whereas the power to detect non-inferiority (NI), assuming the NI hazard ratio of 1.45 in graft survival was 10% (assuming 200 subjects and 6% graft loss rate), the power to detect NI assuming a 2-point non-inferiority margin was >85% using the MATE score. Conclusion The MATE score reflects the cumulative burden of MATEs and has acceptable prediction characteristics for death/graft loss post-HT. The MATE score may be useful as a surrogate end-point to power a clinical trial in pediatric HT.

Purpose Routine surveillance biopsy (RSB) is performed to detect asymptomatic acute rejection (AR) after heart transplantation (HT). Variation in pediatric RSB across institutions is high. We examined center-based variation in RSB use and its relationship to graft loss, AR, coronary artery vasculopathy (CAV), and cost of care during the first year post-HT. Methods We linked the Pediatric Health Information System (PHIS) and Scientific Registry of Transplant Recipients (SRTR, 2002-2016), including all primary-HT aged 0-21. We scored institutional RSB strategy by the median number of first-year biopsies in recipients aged ≥12 months without rejection. Mixed effects regression analysis was used to adjust for potential confounders and center effects. Results Of 2,867 patients at 29 centers, we identified an inflection at the top-tertile of centers (834 patients at 10 centers with RSB-score≥4). Higher-RSB centers (i.e. those in the top-tertile) had more patients on pre-HT ventilator/ECMO (23% vs 18% p=0.04) and fewer with a positive crossmatch (13% vs 17% p=0.007). After adjusting for patient and center differences, higher RSB frequency was associated with diagnosed AR (OR 1.15 p=0.004), a trend toward treated AR (OR 1.09 p=0.083) and higher cost (US$450,708 vs 342,170, p Conclusion Higher RSB frequency is associated with increased diagnosis, but not treatment, of AR one-year post-HT. Graft survival and CAV appear unchanged at medium term follow-up. De-intensification at high-frequency institutions may be safe and reduce costs, but further study of differences in treated rejections are necessary.

Purpose Studies suggest that pediatric heart transplant (HT) waitlist mortality has declined. The impact of factors like refinements to the heart allocation system, patient selection, greater ABO incompatible (ABO-I) HT and VAD support are unknown. We examined the 20-year trend in waitlist mortality to identify factors associated with declining mortality and whether allocational inefficiencies persist. Methods All children Results Overall 11,374 patients met inclusion criteria (3,248 in Era 1; 5,378 in Era 2; 2,748 in Era 3). Waitlist mortality declined significantly across eras (21%, 17%, 13%, P Conclusion Pediatric HT waitlist mortality has declined significantly over the past 20 years. There is evidence to suggest that greater VAD use, revisions to organ allocation, refinements in patient selection and ABO-I transplant may all contribute. Organ allocation inefficiencies persist under the current allocation system suggesting opportunities for allocation improvement may still exist.

Purpose There are limited data reporting outcomes of children with trisomy 21 undergoing heart transplantation (HTx). This project reports the waitlist and post-HTx outcomes of children with trisomy 21. Methods This is a retrospective cohort study of children with trisomy 21 listed for or who underwent HTx at 11 centers within North America and internationally. Demographic, medical, surgical, and post-HTx outcome data were collected and described. Results Twenty-one patients with trisomy 21 were listed for HTx from 1992 through 2019 (median age 8.5y, 43% male, 52% white). High-risk or failed repair of congenital heart disease was the indication for transplant in 16 (76%) patients with atrioventricular septal defect being the most common (N=12). Other diagnoses included dilated cardiomyopathy in 4 patients (secondary to anthracyclines in 2) and myocarditis in 1 patient. A total of 18 (86%) patients survived to transplant. Of this group, support at the time of transplant included inotropes (N=10, 56%), ventricular assist device (N=7, 39%), and mechanical ventilation (N=2, 11%). No patients required post-operative extracorporeal membrane oxygenation or dialysis. All centers reported the use of standard immunosuppression without alterations secondary to trisomy 21. All transplanted patients survived to hospital discharge with a median post-HTx length of stay of 19d. With a median follow-up of 2.9y, 16 (89%) patients were alive, 5 (28%) had rejection within the 1st year post-HTx, 2 (11%) developed post-transplant lymphoproliferative disorder (PTLD), and 7 (39%) were hospitalized for infection within the 1st year post-HTx. For the two post-HTx mortalities, the causes of death were 1) coronary allograft vasculopathy at 22y post-HTx and 2) multiple episodes of rejection and PTLD at 1.5y post-HTx (Figure). Conclusion Waitlist and intermediate post-HTx outcomes are acceptable in children with trisomy 21. The presence of trisomy 21 should not be an absolute contraindication to heart transplantation in the appropriate clinical setting.

Purpose Compassionate deactivation (CD) of ventricular assist device (VAD) support is a recognized option for children when the burden of ongoing therapy outweighs the benefits. The circumstances, indications, and outcomes of CD in pediatric VAD patients are insufficiently described. Methods Review of all cases of CD at our institution between 2011-2020. To distinguish CD of VAD from other situations where VAD support is discontinued, deactivations occurring after myocardial recovery, brain or cardiac death or while also on ECMO, were excluded. Results are presented descriptively. Results Of 24 deaths on VAD, 14 (58%) were CD. Median age was 5.7 (0.6, 11.6) years; 7 (50%) had congenital heart disease; 4 (29%) were on a “dischargeable” device. CD occurred after 40 (IQR: 26, 75) days of support, none while active transplant candidates. CD discussions were initiated by the patient/parent/caregiver in 6 (43%) cases, the remainder by a medical provider ( Table ). Reasons for CD were multifactorial, and included stroke, end-organ injury, and loss of transplant candidacy. ( Figure ). CD occurred with endotracheal extubation in 12(86%) cases, and death occurred within 10 (IQR: 4, 23) minutes of CD. Conclusion CD is the mode of death in more than half of our VAD non-survivors, and is chosen for reasons mainly related to noncardiac events. Patients, caregivers, and providers may initiate CD discussions. Ventilatory support is often withdrawn at time of CD with ensuing death.

We are currently utilizing a technique of heart transplantation in situs inversus/dextrocardia that maintains dextrocardia after implantation. Concerns may be technical difficulty and long-term complications. We have therefore obtained follow-up in our cohort up to 10 years. Between July 2007 and February 2017, we performed heart transplantation in five patients with situs inversus and dextrocardia. All had bilateral superior venae cavae (SVC). In all, the recipient left SVC was anastomosed to the donor SVC, and the recipient right SVC was anastomosed to the donor right atrial appendage. The normal donor heart was rotated 120° to the right to maintain a position of dextrocardia in the recipient. Three patients are alive and well to this date. One patient, who also had a pneumonectomy for recurrent infections at the time of transplant, died early postoperatively from a disseminated fungal infection. Another patient did well initially, however died from post-transplant lymphoproliferative disease 4 years posttransplantation. A third patient required stent implantation 4 years postoperatively to treat stenosis of the right SVC to right atrial anastomosis. There were no other complications related to the surgical technique and no other reinterventions. This technique maintains excellent long-term outcomes. It uses the existing pericardial cavity most effectively. It avoids pericardial resection, lung compression, or right ventricular compromise. Anastomotic obstruction of the SVC connection to the right atrium may occur, which is amenable to transcutaneous stenting.

The development of ventricular assist devices to sustain the circulation represents one of the great achievements in the treatment of heart failure. Though early (1st generation) pulsatile devices required that patients remain hospitalized while on support, newer 2nd and 3rd generation continuous-flow (CF) devices have allowed for hospital discharge, expanding their use beyond bridge to transplantation to include permanent support. This indication, referred to as “destination therapy” is emerging as a viable alternative to heart transplantation in adults, and more recently, children. Though no formal indications exist for destination therapy in children, it may be considered in lieu of transplantation in patients with non-cardiac life-limiting comorbidities, severe pulmonary hypertension, obesity (BMI > 35 kg/m 2 ), recurrent malignancy, or if it is their preference. One group for whom DT may be most appropriate is those with advanced dystrophinopathies for whom post-transplant outcomes remain poor. Outpatient management of the pediatric destination therapy patient requires close monitoring by a multidisciplinary team of physicians, nurses, pharmacists, social workers, nutritionists, and psychologists. Because destination therapy in children remains quite rare, little is known about long-term outcomes in this population, though studies of children supported as outpatients as a bridge to transplantation suggest that survival is excellent and functional status improves post-implantation. As ventricular assist devices continue to develop, the future will not only include application of this technology to a more diverse group of patients, but the additional challenge of supporting patients for increasingly longer durations, managing late complications, and facilitating improvements in quality of life.

Background Patients listed for heart transplant after their 18 th birthday purportedly wait longer to receive a donor heart compared to patients listed before their 18 th birthday. It is unclear whether there is an actual difference in wait times and whether any difference in wait time is associated with lower likelihood of transplant and/or higher risk of mortality. Methods Organ procurement and transplant network data were used to identify all patients listed for heart transplant between 2006 and 2014 within a one year period before and after their 18 th birthday. The primary study endpoint was the waiting time to receive a donor heart. Secondary endpoints included the probability of transplant and waitlist mortality. Regression discontinuity analysis was used to analyze the effect of age on either side of the sharp cut-off value of age 18 years (6,574 days of life), when allocation of donor hearts transitions from the pediatric to adult allocation system. Results A total of 360 patients met the study inclusion criteria, including 207 (57.5%) listed during the 12-month period prior to the 18 th birthday under the pediatric allocation system, and 153 (42.5%) listed during the 12 months after the 18 th birthday under the adult allocation system. The pediatric cohort was more likely to be listed status 1A. Otherwise, the two groups shared similar baseline characteristics. Overall, patients listed after the 18 th birthday waited 8.5 months longer to receive a transplant than adolescents listed before the 18 th birthday (P=0.01), had a 47% lower probability of receiving a transplant (P=0.001) but no difference in waitlist mortality (P=0.37). Conclusion Patients listed for heart transplant shortly after their 18 th birthday have significantly longer wait-times compared to patients listed shortly before their 18 th birthday, a lower probability of transplant but no significant difference in waitlist mortality. For medically fragile adolescents at high risk of death, birth date may be one factor to be aware of in timing of heart transplant listing.

As survival with pediatric left ventricular assist devices (LVADs) has improved, decisions regarding the optimal support strategy may depend more on quality of life and functional status (FS) rather than mortality alone. Limited data are available regarding the FS of children supported with LVADs. We sought to compare the FS of children supported with LVADs vs vasoactive infusions to inform decision making around support strategies.Organ Procurement and Transplant Network data were used to identify all United States children aged between 1 and 21 years at heart transplant (HT) between 2006 and 2015 for dilated cardiomyopathy and supported with an LVAD or vasoactive infusions alone at HT. FS was measured using the 10-point Karnofsky and Lansky scale.Of 701 children who met the inclusion criteria, 430 (61%) were supported with vasoactive infusions, and 271 (39%) were supported with an LVAD at HT. Children in the LVAD group had higher median FS scores at HT than children in the vasoactive infusion group (6 vs 5, p0.001) but lower FS scores at listing (4 vs 6, p0.001). The effect persisted regardless of patient location at HT (home, hospital, intensive care) or device type. Discharge by HT occurred in 46% of children in the LVAD group compared with 26% of children in the vasoactive infusion cohort (p = 0.001). Stroke was reported at HT in 3% of children in the LVAD cohort and in 1% in the vasoactive infusion cohort (p = 0.04).Among children with dilated cardiomyopathy undergoing HT, children supported with LVADs at HT have higher FS than children supported with vasoactive infusions at HT, regardless of device type or hospitalization status. Children supported with LVADs at HT were more likely to be discharged from the hospital but had a higher prevalence of stroke at HT.

Context Despite advances in therapies, many pediatric heart transplant (Htx) recipients will die prematurely. We characterized the circumstances surrounding death in this cohort, including location of death and interventions performed in the final 24 hours. Methods We reviewed all patients who underwent Htx at Lucile Packard Children's Hospital, Stanford, survived hospital discharge, and subsequently died between July 19, 2007 and September 13, 2015. The primary outcome studied was location of death, characterized as inpatient, outpatient, or emergency department. Circumstances of death (withdrawal of life-sustaining treatment, death during resuscitation, or death without resuscitation with/without do not resuscitate) and interventions performed in the last 24 hours of life were also analyzed. Results Twenty-three patients met the entry criteria. The median age at death was 12 (range 2–20) years, and the median time between transplant and death was 2.8 (range 0.8–11) years. Four (17%) died at home, and three (13%) died in the emergency department. Sixteen (70%) patients died in the hospital, 14 of 16 (88%) of whom died in an intensive care unit. Five of 23 (22%) patients experienced attempted resuscitation. Interventions performed in the last 24 hours of life included intubation (74%), mechanical support (30%), and dialysis (22%). Most patients had a recent outpatient clinical encounter with normal graft function within 60 days of dying. Conclusions/Lessons Learned Death in children after Htx often occurs in the inpatient setting, particularly the intensive care unit. Medical interventions, including attempted resuscitation, are common at the end of life. Given the difficulty in anticipating life-threatening events, earlier discussions with patients regarding end-of-life wishes are appropriate, even in those with normal graft function.

Background: There are limited data describing the functional status (FS) of children after heart transplant (HT). We sought to describe the FS of children surviving at least 1 year after HT, to evaluate the impact of HT on FS, and to identify factors associated with abnormal FS post-HT. Methods: Organ Procurement and Transplantation Network data were used to identify all US children Results: A total of 1633 children met study criteria. At the 1-year assessment, 64% were “fully active/no limitations” (FSS=10), 21% had “minor limitations with strenuous activity” (FSS=9); and 15% scored ≤8. In comparison with listing FS, FS at 1 year post-HT increased in 91% and declined/remained unchanged in 9%. A stepwise regression procedure selected the following variables for association with abnormal FS at 1 year post-HT: ≥18 years of age (odds ratio [OR], 1.8; 95% confidence interval [CI], 1.2–2.7), black race (OR, 1.5; 95% CI, 1.1–2.0), support with ≥inotropes at HT (OR, 1.7; 95% CI, 1.2–2.5), hospitalization status at HT (OR, 1.5; 95% CI, 1.0–2.19), chronic steroid use at HT (OR, 1.5; 95% CI, 1.0–2.2), and treatment for early rejection (OR, 2.0; 95% CI, 1.5–2.7). Conclusion: Among US children who survive at least 1 year after HT, FS is excellent for the majority of patients. HT is associated with substantial improvement in FS for most children. Early rejection, older age, black race, chronic steroid use, hemodynamic support at HT, and being hospitalized at HT are associated with abnormal FS post-HT.

Purpose Currently there are no-FDA approved immunosuppressants specific to pediatric heart transplantation (HT). In recent years, everolimus (EVL) has emerged as an alternative to tacrolimus (TAC) as a primary immunosuppressant to prevent rejection that may also prevent kidney and coronary disease. However, the two regimens have never been evaluated systematically. Methods The TEAMMATE Trial (IND 127980) is designed to evaluate the safety and efficacy of EVL and low-dose (LD-TAC) compared to standard-therapy TAC and mycophenolate mofetil (MMF). The study design and rationale are reviewed in light of challenges inherent in rare disease research. Results The TEAMMATE trial is the first multicenter randomized clinical trial (RCT) in pediatric HT. The primary purpose is to evaluate the risk-benefit profile of the two regimens to prevent major adverse transplant events (MATE), and to support FDA approval of 1 or both regimens for pediatric HT. Children Conclusion The TEAMMATE trial is the first RCT in pediatric HT. It is anticipated that the study will provide important information about the safety and effectiveness of EVL and TAC and provide valuable lessons into the design and conduct of future trials in pediatric HT.

Purpose Infectious complications are a major cause of morbidity & mortality after heart transplantation (HT). Patients who have undergone Fontan palliation may have a higher susceptibility to post HT infections given thymectomy in infancy and known depletions of T-cell subsets. Methods This was a single-center, retrospective cohort analysis of pediatric patients undergoing HT for dilated cardiomyopathy (DCM) or failing Fontan physiology, who underwent post HT induction with anti-thymoglobulin (ATG). Repeat HTs and multi organ transplants were excluded. The primary endpoint was infection in the first 180 days post HT, defined as 1) positive blood, urine, or respiratory culture; 2) positive viral PCR (excluding CMV and EBV); 3) skin or wound infection; or 4) culture-negative infection if a full antibiotic course (≥ 5 days) was completed. Secondary endpoints included sensitivity to ATG as defined by 1) absolute lymphocyte (ALC) and CD3 counts after 5 doses; 2) the incidence of post transplant lymphoproliferative disorder (PTLD); and 3) rejection (>/= Grade 2R ACR or pAMR2) in the first 180 days post HT. Results From 1/2014 to 9/2019, 63 patients (30 Fontan, 33 DCM) underwent HT at a median of 15.4 (IQR 10.8, 20.1) and 11.7 (IQR 1.4, 13.6) years, respectively. The median total ATG received was 7.5 (IQR 6.7, 8.2) mg/kg vs 7.2 (IQR 4.7, 9.2) mg/kg (p=NS), respectively. The median CD3 [9 (IQR 3,14) vs 12 (IQR 6, 26); p=0.04, Figure 1A] and lymphocyte counts [172 (IQR 98, 354) vs 427 (IQR 205, 662); p=0.02] after ATG were lower in Fontan vs DCM patients. 28 patients (41%) developed at least one infection within 180 days after HT, with a higher rate of infection in Fontan patients (60% vs 24%, p=0.005; Figure 1B). There was no difference in the incidence of PTLD (10% vs 0%; p=0.1) or rejection (17% vs 27%; p=0.31) between Fontan vs DCM patients, respectively. Conclusion Compared to DCM patients, Fontan patients have a more pronounced suppression of CD3 counts after induction, as well as a higher risk of infection.