The teammate trial: Study design and rationale tacrolimus and everolimus against tacrolimus and MMF in pediatric heart transplantation using the major adverse transplant event (MATE) score.

BACKGROUND: Currently there are no immunosuppression regimens FDA-approved to prevent rejection in pediatric heart transplantation (HT). In recent years, everolimus (EVL) has emerged as a potential alternative to standard tacrolimus (TAC) as the primary immunosuppressant to prevent rejection that may also reduce the risk of cardiac allograft vasculopathy (CAV), chronic kidney disease (CKD) and cytomegalovirus (CMV) infection. However, the 2 regimens have never been compared head-to-head in a randomized trial. The study design and rationale are reviewed in light of the challenges inherent in rare disease research. METHODS: The TEAMMATE trial (IND 127980) is the first multicenter randomized clinical trial (RCT) in pediatric HT. The primary purpose is to evaluate the safety and efficacy of EVL and low-dose TAC (LD-TAC) compared to standard-dose TAC and mycophenolate mofetil (MMF). Children aged <21 years at HT were randomized (1:1 ratio) at 6 months post-HT to either regimen, and followed for 30 months. Children with recurrent rejection, multi-organ transplant recipients, and those with an estimated glomerular filtration rate (eGFR) <30 mL/min/1.73m2 were excluded. The primary efficacy hypothesis is that, compared to TAC/MMF, EVL/LD-TAC is more effective in preventing 3 MATEs: acute cellular rejection (ACR), CKD and CAV. The primary safety hypothesis is that EVL/LD-TAC does not have a higher cumulative burden of 6 MATEs (antibody mediated rejection [AMR], infection, and post-transplant lymphoproliferative disorder [PTLD] in addition to the 3 above). The primary endpoint is the MATE score, a composite, ordinal surrogate endpoint reflecting the frequency and severity of MATEs that is validated against graft loss. The study had a target sample size of 210 patients across 25 sites and is powered to demonstrate superior efficacy of EVL/LD-TAC. Trial enrollment is complete and participant follow-up will be completed in 2023. CONCLUSION: The TEAMMATE trial is the first multicenter RCT in pediatric HT. It is anticipated that the study will provide important information about the safety and efficacy of everolimus vs tacrolimus-based regimens and will provide valuable lessons into the design and conduct of future trials in pediatric HT.

Supplemental nutrition, feeding disorders, and renourishment in pediatric heart failure through transplantation.

BACKGROUND: Tube feeds are used commonly in children listed for heart transplant; however, rates of renourishment and development of feeding disorders are not sufficiently characterized. METHODS: Retrospective review of pediatric heart transplant recipients from January 1, 2014, to January 3, 2021. Demographics, anthropometric, and nutritional data were collected from heart transplant listing through 3 years post-transplant. Renourishment rates, presence of a feeding disorder, and need for a gastric feeding tube were analyzed. Multivariable analysis was conducted to identify risks for poor nutritional outcomes. RESULTS: Of 104 patients, 35 (34%) and 36 (35%) were malnourished at heart transplant listing and transplant, respectively, persisting in 21/91 (23%) 1 year postheart transplant. Forty (38%) received tube feeds at listing, 42 (40%) at heart transplant, and 18/90 (20%) 1 year post-transplant. Rates of feeding disorders fell from 23% at transplantation to 10% 1 year post-transplant. Feeding disorders were associated with younger age at heart transplant (p < .001) and congenital heart disease (p = .03). Forty-six percent of infants required a gastric feeding tube. Renourishment occurred in 20% during listing and was associated with ventricular assist device support (p = .03) and noncalorically dense feeds (p = .03). Malnutrition at transplant was associated with inferior post-transplant survival (6/36 (17%) vs. 2/68 (3%); p = .02). CONCLUSIONS: Malnourishment requiring tube feeds is common in pediatric heart transplant candidates; however, most patients who eventually survive to transplant remain malnourished at time of transplantation and 1 year later. While some children develop feeding disorders, they generally resolve by 1 year post-transplant.

Major Adverse Dystrophinopathy Events (MADE) Score as Marker of Cumulative Morbidity and Risk for Mortality in Boys with Duchenne Muscular Dystrophy.

Background: Overlapping symptoms from cardiomyopathy, respiratory insufficiency, and skeletal myopathy confound assessment of heart failure in Duchenne Muscular Dystrophy. We developed an ordinal scale of multiorgan clinical variables that reflect cumulative disease burden-the Major Adverse Dystrophinopathy Event (MADE) Score. We hypothesized that a higher MADE score would be associated with increased mortality in boys with Duchenne Muscular Dystrophy. The Cooperative International Neuromuscular Research Group Duchenne Natural History Study dataset was utilized for validation. Methods: Duchenne Natural History Study variables were selected based on clinical relevance to prespecified domains: Cardiac, Pulmonary, Myopathy, Nutrition. Severity points (0-4) were assigned and summed for study visits. MADE score for cohorts defined by age, ambulatory status, and survival were compared at enrollment and longitudinally.Associations between MADE score and mortality were examined. Results: Duchenne Natural History Study enrolled 440 males, 12.6 ±6.1 years old, with 3,559 visits over 4.6 ±2.8 years, 45 deaths. MADE score increased with age and nonambulatory status. Mean MADE score per visit was 19 ±10 for those who died vs. 9.8 ±9.3 in survivors p=0.03. Baseline MADE score >12 predicted mortality independent of age (78% sensitivity, CPE.70). Rising MADE score trajectory was associated with mortality in models adjusted for enrollment age, follow-up time, and ambulatory status, all p<.001. Conclusion: A multiorgan severity score, MADE, was developed to track cumulative morbidities that impact heart failure in Duchenne muscular dystrophy. MADE score predicted Duchenne Natural History Study mortality. MADE score can be used for serial heart failure assessment in males and may serve as an endpoint for Duchenne muscular dystrophy clinical research.

Establishing Baseline Metrics of Heart Failure Medication Use in Children: A Collaborative Effort from the ACTION Network.

Heart failure metrics specific to the pediatric population are required to successfully implement quality improvement initiatives in children with heart failure. Medication use at the time of discharge following admission for decompensated heart failure has been identified as a potential quality metric in this population. This study aimed to report medication use at discharge in the current era for children admitted with acute decompensated heart failure. All patients < 21 years of age with an index admission (1/1/2011-12/31/2019) for acute heart failure and a coexisting diagnosis of cardiomyopathy were identified from the Pediatric Health Information System. Medication use patterns were described and compared across age groups and centers. A total of 2288 patients were identified for inclusion. An angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker (ACEi/ARB) was prescribed in 1479 (64.6%), beta blocker in 1132 (49.5%), and mineralocorticoid receptor antagonist (MRA) in 864 (37.8%) patients at discharge. The use of ACEi/ARB at discharge has decreased over time (64.6% vs. 69.6%, p = 0.001) and the use of beta blockers has increased (49.5% vs. 36.8%, p < 0.001) compared to a historical cohort (2001-2010). There is considerable variability in medication use across centers with an overall increase in beta blocker and decrease in ACEi/ARB use over time. Collaborative efforts are needed to standardize care and define quality metrics to identify best practices in the management of pediatric heart failure.

Growth stunting in single ventricle patients after heart transplantation.

BACKGROUND: Malnutrition is common among children with single ventricle (SV) congenital heart disease (CHD). The impact of heart transplantation (HT) on nutritional status in SV patients is understudied. Our aim was to evaluate anthropometric changes in SV patients after HT, compared with those transplanted for cardiomyopathy (CM). METHODS: We performed a single-center retrospective chart review of SV and CM patients < 18 years who underwent HT from January 01, 2010 to December 05, 2017. Wasting and stunting were defined as z-scores for weight-for-age or height-for-age ≤-2, respectively. Changes in these indices between HT and 3 years post-HT were analyzed. RESULTS: Of 86 eligible patients, 28 (33%) had SV CHD and 58 (67%) had CM. Data were available at 3 years post-HT for 57 patients. At transplant, wasting was equally present in SV versus CM patients (7/28, 25% vs. 9/58, 16%, P = .22), which remained true at 3 years post-HT (2/16, 13% vs. 3/41, 7%, P = .61). At transplant, stunting was more common in SV than CM patients (17/28, 61% vs. 8/58, 14%, P < .001). At 3 years post-HT, 6 of 16 (38%) SV patients and 3 of 41 (7%) CM patients remained stunted (P = .01). Among all patients, wasting decreased from transplant to end-point (19% vs. 9%, P = .05), but stunting did not (29% vs. 16%, P = .2), such that wasting and stunting were associated at transplant (P < .001) but not at end-point (P = .17). CONCLUSIONS: Longitudinal growth remains impaired for several years after HT in SV patients, even when weight gain is achieved, suggesting that some factors contributing to growth impairment persist despite resolution of SV physiology.

Significant mortality, morbidity and resource utilization associated with advanced heart failure in congenital heart disease in children and young adults.

BACKGROUND: Children with congenital heart disease (CHD) are at risk for advanced heart failure (AHF). We sought to define the mortality and resource utilization in CHD-related AHF in children and young adults. METHODS: All hospitalizations in the Pediatric Health Information System database involving patients ≤21 years old with a CHD diagnosis and heart failure requiring at least 7 days of continuous inotropic support between 2004 and 2015 were included. Hospitalizations including CHD surgery were excluded. RESULTS: Of 465,482 CHD hospitalizations, AHF was present in 2,712 (0.6%) [58% infant, 55% male, 30% single ventricle]. AHF therapies frequently used included extracorporeal membrane oxygenation (ECMO) (15%) and cardiac transplant (16%). Ventricular assist device (VAD) support was rare (3%), although VAD use significantly increased from 2004 to 2015 (P < .0010). Hospital mortality in CHD with AHF was 26%, with higher mortality associated with single ventricle heart disease (OR 1.64, 95% CI 1.23-2.19; P = .0009), infancy (OR 1.71, 95% CI 1.17-2.5; P = .0057), non-white race (OR 1.28, 95% CI 1.04-1.59; p=0.0234), and chronic complex comorbidities (OR 1.76, 95% CI 1.34-2.30; P < .0001). Over the 11-year study period, despite the significant increase in CHD-related AHF hospitalizations (P < .0001), hospital mortality improved (P = .0011). Median hospital costs were $252,000, a 6-fold increase above those without AHF, and was primarily driven by hospital length of stay (P < .0001). CONCLUSION: AHF in children with CHD in uncommon but increasing and is associated with significant morbidity, mortality and resource utilization. Approximately 1 in 5 children do not survive to hospital discharge. Many risk factors for mortality may not be modifiable, and further study is needed to identify modifiable risk factors and improve care for this complex population.

Long-term surveillance biopsy: Is it necessary after pediatric heart transplant?

Due to limited and conflicting data in pediatric patients, long-term routine surveillance endomyocardial biopsy (RSB) in pediatric heart transplant (HT) remains controversial. We sought to characterize the rate of positive RSB and determine factors associated with RSB-detected rejection. Records of patients transplanted at a single institution from 1995 to 2015 with >2 year of post-HT biopsy data were reviewed for RSB-detected rejections occurring >2 year post-HT. We illustrated the trajectory of significant rejections (ISHLT Grade ≥3A/2R) among total RSB performed over time and used multivariable logistic regression to model the association between time and risk of rejection. We estimated Kaplan-Meier freedom from rejection rates by patient characteristics and used the log-rank test to assess differences in rejection probabilities. We identified the best-fitting Cox proportional hazards regression model. In 140 patients, 86% did not have any episodes of significant RSB-detected rejection >2 year post-HT. The overall empirical rate of RSB-detected rejection >2 year post-HT was 2.9/100 patient-years. The percentage of rejection among 815 RSB was 2.6% and remained stable over time. Years since transplant remained unassociated with rejection risk after adjusting for patient characteristics (OR = 0.98; 95% CI 0.78-1.23; P = 0.86). Older age at HT was the only factor that remained significantly associated with risk of RSB-detected rejection under multivariable Cox analysis (P = 0.008). Most pediatric patients did not have RSB-detected rejection beyond 2 years post-HT, and the majority of those who did were older at time of HT. Indiscriminate long-term RSB in pediatric heart transplant should be reconsidered given the low rate of detected rejection.

Impact of ventricular assist device implantation on the nutritional status of children awaiting heart transplantation.

BACKGROUND: Malnutrition is common in pediatric heart failure and is associated with mortality. The effect of VAD support on malnutrition in children is unknown. We sought to compare the prevalence and severity of malnutrition at HT in children on VAD support vs OMT to inform decisions regarding support strategies. METHODS: Retrospective chart review involving all patients <18 years who underwent HT at Stanford between 1/1/2011 and 3/1/2018. Malnutrition diagnosis and severity were defined by ASPEN guidelines using the lowest age-adjusted z-score for weight (WAZ), height (HAZ), and BMI (BMIZ) when the patient was euvolemic. Changes in z-scores from baseline to HT and across groups were analyzed. RESULTS: A total of 104 patients (52 in each group) were included. Among all patients, WAZ (-0.9 vs 0.3, P < 0.001) and BMIZ (0 vs 0.6, P < 0.001) improved while HAZ (-0.9 vs -0.9, P = 0.4) did not. Compared to children on OMT, children on VAD experienced greater increases in WAZ (0.8 vs 0.3, P < 0.001) and BMIZ (0.7 vs 0.2, P < 0.003) at HT. The prevalence of moderate-to-severe malnutrition decreased in VAD patients (40% to 19%, P < 0.001) and increased in OMT patients (37% to 46%, P < 0.001), leading to a lower prevalence of moderate-to-severe malnutrition at HT (19% vs 46%, P = 0.003). CONCLUSIONS: Malnutrition is common in pediatric HT candidates. Compared to children on OMT, children on VAD support had greater improvement in nutritional status while awaiting HT, and a lower prevalence of malnutrition at HT.

Compassionate deactivation of ventricular assist devices in children: A survey of pediatric ventricular assist device clinicians' perspectives and practices.

OBJECTIVES: This study's objective was to investigate compassionate ventricular assist device deactivation (VADdeact) in children from the perspective of the pediatric heart failure provider. BACKGROUND: Pediatric VAD use is a standard therapy for advanced heart failure. Serious adverse events may affect relative benefit of continued support, leading to consideration of VADdeact. Perspectives and practices regarding VADdeact have been studied in adults but not in children. METHODS: A web-based anonymous survey of clinicians for pediatric VAD patients (<18 years) was sent to list-serves for the ISHLT Pediatric Council, the International Consortium of Circulatory Assist Clinicians Pediatric Taskforce, and the Pediatric Cardiac Intensivist Society. RESULTS: A total of 106 respondents met inclusion criteria of caring for pediatric VAD patients. Annual VAD volume per clinician ranged from <4 (33%) to >9 (20%). Seventy percent of respondents had performed VADdeact of a child. Response varied to VADdeact requests by parent or patient and was influenced by professional degree and region of practice. Except for the scenario of intractable suffering, no consensus on VADdeact appropriateness was reported. Age of child thought capable of making informed requests for VADdeact varied by subspecialty. The majority of respondents (62%) do not feel fully informed of relevant legal issues; 84% reported that professional society supported guidelines for VADdeact in children had utility. CONCLUSION: There is limited consensus regarding indications for VADdeact in children reported by pediatric VAD provider survey respondents. Knowledge gaps related to legal issues are evident; therefore, professional guidelines and educational resources related to pediatric VADdeact are needed.

A Quality Bundle to Support High-Risk Pediatric Ventricular Assist Device Implantation.

Pediatric ventricular assist device (VAD) implantation outcomes are increasingly promising for children with dilated cardiomyopathy and advanced decompensated heart failure (ADHF). VAD placement in patients with clinical features such as complex congenital cardiac anatomy, small body size, or major comorbidities remains problematic. These comorbidities have been traditionally prohibitive for VAD consideration leaving these children as a treatment-orphaned population. Here we describe the quality bundle surrounding these patients with ADHF considered high risk for VAD implantation at our institution. Over a 7-year period, a quality bundle aimed at the peri-operative care for children with high-risk features undergoing VAD implantation was incrementally implemented at a tertiary children's hospital. Patients were considered high risk if they were neonates (< 30 days), had single-ventricle physiology, non-dilated cardiomyopathy, biventricular dysfunction, or significant comorbidities. The quality improvement bundle evolved to include (1) structured team-based peri-operative evaluation, (2) weekly VAD rounds addressing post-operative device performance, (3) standardized anticoagulation strategies, and (4) a multidisciplinary system for management challenges. These measures aimed to improve communication, standardize management, allow for ongoing process improvement, and incorporate principles of a high-reliability organization. Between January 2010 and December 2017, 98 patients underwent VAD implantation, 48 (49%) of which had high-risk comorbidities and a resultant cohort survival-to-transplant rate of 65%. We report on the evolution of a quality improvement program to expand the scope of VAD implantation to patients with high-risk clinical profiles. This quality bundle can serve as a template for future large-scale collaborations to improve outcomes in these treatment-orphaned subgroups.

Impact of Heart Transplantation on the Functional Status of US Children With End-Stage Heart Failure.

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 <21 years of age surviving ≥1 year post-HT from 2005 to 2014 with a functional status score (FSS) available at 3 time points (listing, transplant, ≥1 year post-HT). Logistic regression and generalized estimating equations were used to identify factors associated with abnormal FS (FSS≤8) post-HT. 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.

Pathological antibody-mediated rejection in pediatric heart transplant recipients: Immunologic risk factors, hemodynamic significance, and outcomes.

Biopsy-diagnosed pAMR has been observed in over half of pediatric HT recipients within 6 years of transplantation. We report the incidence and outcomes of pAMR at our center. All endomyocardial biopsies for all HT recipients transplanted between 2010 and 2015 were reviewed and classified using contemporary ISHLT guidelines. Graft dysfunction was defined as a qualitative decrement in systolic function by echocardiogram or an increase of ≥3 mm Hg in atrial filling pressure by direct measurement. Among 96 patients, pAMR2 occurred in 7 (7%) over a median follow-up period of 3.1 years, while no cases of pAMR3 occurred. A history of CHD, DSA at transplant, and elevated filling pressures were associated with pAMR2. Five-sixths (83%) of patients developed new C1q+ DSA at the time of pAMR diagnosis. There was a trend toward reduced survival, with 43% of patients dying within 2.3 years of pAMR diagnosis.

Fluid overload independent of acute kidney injury predicts poor outcomes in neonates following congenital heart surgery.

BACKGROUND: Fluid overload (FO) is common after neonatal congenital heart surgery and may contribute to mortality and morbidity. It is unclear if the effects of FO are independent of acute kidney injury (AKI). METHODS: This was a retrospective cohort study which examined neonates (age < 30 days) who underwent cardiopulmonary bypass in a university-affiliated children's hospital between 20 October 2010 and 31 December 2012. Demographic information, risk adjustment for congenital heart surgery score, surgery type, cardiopulmonary bypass time, cross-clamp time, and vasoactive inotrope score were recorded. FO [(fluid in-out)/pre-operative weight] and AKI defined by Kidney Disease Improving Global Outcomes serum creatinine criteria were calculated. Outcomes were all-cause, in-hospital mortality and median postoperative hospital and intensive care unit lengths of stay. RESULTS: Overall, 167 neonates underwent cardiac surgery using cardiopulmonary bypass in the study period, of whom 117 met the inclusion criteria. Of the 117 neonates included in the study, 76 (65%) patients developed significant FO (>10%), and 25 (21%) developed AKI ≥ Stage 2. When analyzed as FO cohorts (< 10%,10-20%, > 20% FO), patients with greater FO were more likely to have AKI (9.8 vs. 18.2 vs. 52.4%, respectively, with AKI ≥ stage 2; p = 0.013) and a higher vasoactive-inotrope score, and be premature. In the multivariable regression analyses of patients without AKI, FO was independently associated with hospital and intensive care unit lengths of stay [0.322 extra days (p = 0.029) and 0.468 extra days (p < 0.001), respectively, per 1% FO increase). In all patients, FO was also associated with mortality [odds ratio 1.058 (5.8% greater odds of mortality per 1% FO increase); 95% confidence interval 1.008,1.125;p = 0.032]. CONCLUSIONS: Fluid overload is an important independent contributor to outcomes in neonates following congenital heart surgery. Careful fluid management after cardiac surgery in neonates with and without AKI is warranted.

Haemodynamic profiles of children with end-stage heart failure.

AIMS: To evaluate associations between haemodynamic profiles and symptoms, end-organ function and outcome in children listed for heart transplantation. METHODS AND RESULTS: Children <18 years listed for heart transplant between 1993 and 2013 with cardiac catheterization data [pulmonary capillary wedge pressure (PCWP), right atrial pressure (RAP), and cardiac index (CI)] in the Pediatric Heart Transplant Study database were included. Outcomes were New York Heart Association (NYHA)/Ross classification, renal and hepatic dysfunction, and death or clinical deterioration while on waitlist. Among 1059 children analysed, median age was 6.9 years and 46% had dilated cardiomyopathy. Overall, 58% had congestion (PCWP >15 mmHg), 28% had severe congestion (PCWP >22 mmHg), and 22% low cardiac output (CI < 2.2 L/min/m2). Twenty-one per cent met the primary outcome of death (9%) or clinical deterioration (12%). In multivariable analysis, worse NYHA/Ross classification was associated with increased PCWP [odds ratio (OR) 1.03, 95% confidence interval (95% CI) 1.01-1.07, P = 0.01], renal dysfunction with increased RAP (OR 1.04, 95% CI 1.01-1.08, P = 0.007), and hepatic dysfunction with both increased PCWP (OR 1.03, 95% CI 1.01-1.06, P < 0.001) and increased RAP (OR 1.09, 95% CI 1.06-1.12, P < 0.001). There were no associations with low output. Death or clinical deterioration was associated with severe congestion (OR 1.6, 95% CI 1.2-2.2, P = 0.002), but not with CI alone. However, children with both low output and severe congestion were at highest risk (OR 1.9, 95% CI 1.1-3.5, P = 0.03). CONCLUSION: Congestion is more common than low cardiac output in children with end-stage heart failure and correlates with NYHA/Ross classification and end-organ dysfunction. Children with both congestion and low output have the highest risk of death or clinical deterioration.

Safety and Efficacy of Warfarin Therapy in Kawasaki Disease.

OBJECTIVE: To describe the safety and efficacy of warfarin for patients with Kawasaki disease and giant coronary artery aneurysms (CAAs, ≥8 mm). Giant aneurysms are managed with combined anticoagulation and antiplatelet therapies, heightening risk of bleeding complications. STUDY DESIGN: We reviewed the time in therapeutic range; percentage of international normalization ratios (INRs) in range (%); bleeding events, clotting events; INRs ≥6; INRs ≥5 and <6; and INRs <1.5. RESULTS: In 9 patients (5 male), median age 14.4 years (range 7.1-22.8 years), INR testing was prescribed weekly to monthly and was done by home monitor (n = 5) or laboratory (n = 3) or combined (1). Median length of warfarin therapy was 7.2 years (2.3-13.3 years). Goal INR was 2.0-3.0 (n = 6) or 2.5-3.5 (n = 3), based on CAA size and history of CAA thrombosis. All patients were treated with aspirin; 1 was on dual antiplatelet therapy and warfarin. The median time in therapeutic range was 59% (37%-85%), and median percentage of INRs in range was 68% (52%-87%). INR >6 occurred in 3 patients (4 events); INRs ≥5 <6 in 7 patients (12 events); and INR <1.5 in 5 patients (28 events). The incidence of major bleeding events and clinically relevant nonmajor bleeding events were each 4.3 per 100 patient-years (95% CI 0.9-12.6). New asymptomatic coronary thrombosis was detected by imaging in 2 patients. CONCLUSIONS: Bleeding and clotting complications are common in patients with Kawasaki disease on warfarin and aspirin, with INRs in range only two-thirds of the time. Future studies should evaluate the use of direct oral anticoagulants in children as an alternative to warfarin.

A multicenter study of the impella device for mechanical support of the systemic circulation in pediatric and adolescent patients.

OBJECTIVES: The objective was to review the use of Impella devices (Abiomed Inc, Danvers, MA) for temporary circulatory support in pediatric and adolescent patients (age ≤ 21 yrs). BACKGROUND: Options for minimally invasive circulatory support in children are limited, and published data are confined to case reports and small case series. METHODS: This was a retrospective, multicenter review of Impella implants in pediatric and adolescent patients from 2009-15, using standardized data collection and INTERMACS definitions. RESULTS: A total of 39 implants were performed in 38 patients from 16 centers. Median age and weight were 16 yrs (4-21 yrs) and 62 kg (15-134 kg). The primary indication for implant was cardiogenic shock in 28 patients (72%). Cardiac allograft rejection, myocarditis, or cardiomyopathy were the underlying diagnosis in 23 patients (59%); 11 patients had congenital heart disease. The median duration of support was 45 hr (1-1224 hr). Indications for explant included ventricular recovery in 16 patients, transition to another device in 12, death in 5, and transplant in 1. Survival was 85% at 7 days and 68% at 30 days. Major adverse events occurred in 8 patients: hemolysis in 3, bleeding in 2, stroke in 1 (unclear if related to Impella), sepsis in 1, and critical leg ischemia in 1. An increase in aortic regurgitation was noted in three patients, with no evidence of valve injury. CONCLUSION: Temporary circulatory support with Impella devices is feasible in pediatric and adolescent patients, with acceptable risk profiles. More experience and follow up is needed to improve technical performance and patient selection. © 2017 Wiley Periodicals, Inc.

Rehospitalization after pediatric heart transplantation: Incidence, indications, and outcomes.

We report the patterns of rehospitalization after pediatric heart transplant (Htx) at a single center. Retrospective review of 107 consecutive pediatric Htx recipients between January 22, 2007, and August 28, 2014, who survived their initial transplant hospitalization. The frequency, duration, and indications for all hospitalizations between transplant hospitalization discharge and September 30, 2015, were analyzed. A total of 444 hospitalization episodes occurred in 90 of 107 (84%) patients. The median time to first rehospitalization was 59.5 (range 1-1526) days, and the median length of stay was 2.5 (range 0-81) days. There were an average of two hospitalizations per patient in the first year following transplant hospitalization, declining to about 0.8 per patient per year starting at 3 years post-transplant. Admissions for viral infections were most common, occurring in 93 of 386 (24%), followed by rule out sepsis in 61 of 386 (16%). Admissions for suspected or confirmed rejection were less frequent, accounting for 41 of 386 (11%) and 31 of 386 (8%) of all admissions, respectively. Survival to discharge after rehospitalization was 97%. Hospitalization is common after pediatric Htx, particularly in the first post-transplant year, with the most frequent indications for hospitalization being viral illness and rule out sepsis. After the first post-transplant year, the risk for readmission falls significantly but remains constant for several years.

Prospective trial of a pediatric ventricular assist device.

BACKGROUND: Options for mechanical circulatory support as a bridge to heart transplantation in children with severe heart failure are limited. METHODS: We conducted a prospective, single-group trial of a ventricular assist device designed specifically for children as a bridge to heart transplantation. Patients 16 years of age or younger were divided into two cohorts according to body-surface area (cohort 1, <0.7 m(2); cohort 2, 0.7 to <1.5 m(2)), with 24 patients in each group. Survival in the two cohorts receiving mechanical support (with data censored at the time of transplantation or weaning from the device owing to recovery) was compared with survival in two propensity-score-matched historical control groups (one for each cohort) undergoing extracorporeal membrane oxygenation (ECMO). RESULTS: For participants in cohort 1, the median survival time had not been reached at 174 days, whereas in the matched ECMO group, the median survival was 13 days (P<0.001 by the log-rank test). For participants in cohort 2 and the matched ECMO group, the median survival was 144 days and 10 days, respectively (P<0.001 by the log-rank test). Serious adverse events in cohort 1 and cohort 2 included major bleeding (in 42% and 50% of patients, respectively), infection (in 63% and 50%), and stroke (in 29% and 29%). CONCLUSIONS: Our trial showed that survival rates were significantly higher with the ventricular assist device than with ECMO. Serious adverse events, including infection, stroke, and bleeding, occurred in a majority of study participants. (Funded by Berlin Heart and the Food and Drug Administration Office of Orphan Product Development; ClinicalTrials.gov number, NCT00583661.).

Utility of a dedicated pediatric cardiac anticoagulation program: the Boston Children's Hospital experience.

Congenital heart disease is the leading cause of stroke in children. Warfarin therapy can be difficult to manage safely in this population because of its narrow therapeutic index, multiple drug and dietary interactions, small patient size, high-risk cardiac indications, and lack of data to support anticoagulation recommendations. We sought to describe our institution's effort to develop a dedicated cardiac anticoagulation service to address the special needs of this population and to review the literature. In 2009, in response to Joint Commission National Patient Safety Goals for Anticoagulation, Boston Children's Hospital created a dedicated pediatric Cardiac Anticoagulation Monitoring Program (CAMP). The primary purpose was to provide centralized management of outpatient anticoagulation to cardiac patients, to serve as a disease-specific resource to families and providers, and to devise strategies to evolve clinical care with rapidly emerging trends in anticoagulation care. Over 5 years the CAMP Service, staffed by a primary pediatric cardiology attending, a full-time nurse practitioner, and administrative assistant with dedicated support from pharmacy and nutrition, has enrolled over 240 patients ranging in age from 5 months to 55 years. The most common indications include a prosthetic valve (34 %), Fontan prophylaxis (20 %), atrial arrhythmias (11 %), cardiomyopathy (10 %), Kawasaki disease (7 %), and a ventricular assist device (2 %). A patient-centered multi-disciplinary cardiac anticoagulation clinic was created in 2012. Overall program international normalized ratio (INR) time in therapeutic range (TTR) is favorable at 67 % (81 % with a 0.2 margin) and has improved steadily over 5 years. Pediatric-specific guidelines for VKOR1 and CYP2C9 pharmacogenomics testing, procedural bridging with enoxaparin, novel anticoagulant use, and quality metrics have been developed. Program satisfaction is rated highly among families and providers. A dedicated pediatric cardiac anticoagulation program offers a safe and effective strategy to standardize anticoagulation care for pediatric cardiology patients, is associated with high patient and provider satisfaction, and is capable of evolving care strategies with emerging trends in anticoagulation.

Post-transplant outcomes of children bridged to transplant with the Berlin Heart EXCOR Pediatric ventricular assist device.

BACKGROUND: Recent data suggest that Berlin Heart EXCOR Pediatric (EXCOR) ventricular assist device improves waiting list survival for pediatric heart transplant candidates. Little is known about their post-transplant outcomes. The aim of this analysis was to determine whether there was a difference in early survival for children bridged to transplant with EXCOR versus status 1A pediatric heart transplant patients not transplanted with ventricular assist device support. METHODS AND RESULTS: Pediatric heart transplant patients (n=106) bridged to transplantation with EXCOR were compared with a similarly aged cohort (n=1021) within the Organ Procurement and Transplant Network (OPTN) database (both cohorts from May 2007 to December 2010). In the EXCOR group, 12-month post-transplant survival (88.7%) was similar to OPTN patients listed status 1A who were not on ventricular assist device support at transplant (89.3%; P=0.85) and significantly better than 12-month survival in OPTN patients on extracorporeal membrane oxygenation at transplant (60.3%; P<0.001). Rejection (50%) was a significantly (P=0.005) higher cause of 12-month post-transplant mortality in the EXCOR compared with the OPTN group. Death after transplant was also higher in EXCOR patients with congenital heart disease compared with those with cardiomyopathy (26.1% versus 7.2%; P=0.02). Post-transplant survival was similar in EXCOR patients with ≥1 serious adverse event during ventricular assist device support as those without an event during support. CONCLUSIONS: The 12-month post-transplant survival with EXCOR is comparable with overall pediatric heart transplant survival and superior to survival after extracorporeal membrane oxygenation. Neither adverse events during support nor factors associated with mortality during support influence post-transplant survival. Rejection was a significantly greater cause of post-transplant mortality in EXCOR than in OPTN patients.