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Background- Extracorporeal membrane oxygenation (ECMO) has served for >2 decades as the standard of care for US children requiring mechanical support as a bridge to heart transplantation. Objective data on the safety and efficacy of ECMO for this indication are limited. We describe the outcomes of ECMO as a bridge to heart transplantation to serve as performance benchmarks for emerging miniaturized assist devices intended to replace ECMO. Methods and Results- Data from the Extracorporeal Life Support Organization Registry and the Organ Procurement Transplant Network database were merged to identify children supported with ECMO and listed for heart transplantation from 1994 to 2009. Independent predictors of wait-list and posttransplantation in-hospital mortality were identified. Objective performance goals for ECMO were developed. Of 773 children, the median age was 6 months (interquartile range, 1 to 44 months); 28% had cardiomyopathy; and in 38%, a bridge to transplantation was intended at ECMO initiation. Overall, 45% of subjects reached transplantation, although one third of those transplanted died before discharge; overall survival to hospital discharge was 47%. Wait-list mortality was independently associated with congenital heart disease, cardiopulmonary resuscitation before ECMO, and renal dysfunction. Posttransplantation mortality was associated with congenital heart disease, renal dysfunction, ECMO duration of >14 days, and initial ECMO indication as a bridge to recovery. In the objective performance goal cohort (n=485), patients with cardiomyopathy had the highest survival to hospital discharge (63%), followed by patients with myocarditis (59%), 2-ventricle congenital heart disease (44%) and 1-ventricle congenital heart disease (33%). Conclusion- Although ECMO is effective for short-term circulatory support, it is not reliable for the long-term circulatory support necessary for children awaiting heart transplantation. Fewer than half of patients bridged with ECMO survive to hospital discharge. More effective modalities for chronic circulatory support in children are urgently needed. [ABSTRACT FROM AUTHOR]

Adverse events (AEs) experienced by children and adults with congenital heart disease (CHD) on ventricular assist devices (VADs) are sometimes unique to these populations. The Advanced Cardiac Therapies Improving Outcomes Network (ACTION) and the Academic Research Consortium (ARC) aimed to harmonize definitions of pediatric and CHD AEs for use in clinical trials, registries, and regulatory evaluation. Data from the ACTION registry and adjudication committee were used to adapt general mechanical circulatory support ARC definitions. This ACTION-ARC international expert panel of trialists, clinicians, patients, families, statisticians, biomedical engineers, device developers, and regulatory agencies drafted and iterated definitions harmonized to ACTION data and existing literature during sessions conducted between December 2022 and May 2023, followed by dissemination across clinical/research audiences and professional organizations and further revision. Both email-linked, internet-based surveys and in-person discussions were used as a modified Delphi process. Nineteen AE types were identified and defined, including seven new event types and six event types that were deleted and will no longer be collected, achieving consensus. ACTION-ARC paired rigorous development with methodical stakeholder involvement and dissemination to define pediatric VAD AEs to facilitate assimilation of data across future clinical trials and evaluation of devices for VAD-supported children and adults with CHD., Competing Interests: Disclosure: A.L. is a consultant for Bayer, Abbott, Abiomed, Berlin Heart, and Syncardia and is the primary investigator for the Berlin ACTIVE driver trial. I.A. is a consultant for Abbott, Abiomed, Bivacor, and Berlin Heart. P.M.A.A. is Treasurer of the Board of Directors of the Extracorporeal Life Support Organization (ELSO) and immediate past-chair of PediECMO, a research collaborative between ELSO and the Pediatric Acute Lung Injury and Sepsis Investigators. P. Alexander’s institution received funding from the National Institutes of Health (NICHD R13HD104432) and the U.S. Department of Defense (U.S. DoD PRMRP Clinical Trial Award #W81XWH2210301). R.P.B. reports grants from the National Institutes of Health (NIH) R01 HL153519 and is a member of the Extracorporeal Life Support Organization (ELSO) Board of Directors. S.B. is a full-time employee of Abiomed, Inc. a part of Johnson and Johnson. K.B. is an Abbott employee. J.C. receives an unrestricted education grant—from Abbott and is a medical monitor for Pumpkin Trial. R.R.D. is a paid consultant for Abbott, Inc. and Abiomed, Inc. R.L.K. is an employee at Abbott, Inc. R.K. is an employee at Berlin Heart Inc. M.K. is involved in Grants & Consulting for Medtronic, Abbott Vascular, Johnson & Johnson, Boston Scientific, and Getinge. J.L. is a consultant for Abbott. D.L.S.M. is a consultant for Abbott Inc., Syncardia Inc., and Berlin Heart Inc. R.A.N. uses Berlin Heart of North America travel funds to attend the annual user’s group meeting. F.D.P. is a non-compensated ad-hoc scientific advisor for Abbott, BrioHealth Solutions, FineHeart, and Medtronic, a non-compensated medical monitor for Abiomed, a member—Data Safety Monitoring Board for Carmat, receives grant funding from the National Heart, Lung, and Blood Institute and the Agency for Healthcare Research and Quality, and receives partial salary support from Blue Cross/Blue Shield of Michigan as Associate Director of the Michigan Society of Thoracic and Cardiovascular Surgeons Quality Collaborative. D.M.P. is on the Data Safety Monitoring Board for the Berlin Active Driver Trial. D.R. is associated with ACTION, DSMB for Parexel (unrelated to topic of AE manuscript), and Medicolegal consultation (unrelated to topic of AE manuscript). J.W.R. is a consultant for American Regent, AskBio, BioMarin, Bayer, Merck, Bristol Myers Squibb, and Enzyvant. E.S. reports institutional contracts for which he receives no direct compensation with Boston Scientific, Cardiawave, Edwards Lifesciences, Medtronic, Shanghai Microport Medical Co. Ltd., NVT GmBH, Pie Medical Imaging, Siemens Healthcare GmBH. M.E.S. is involved in a Medtronic educational contract, Octapharma advisory panel, and NIH DSMB for PumpKIN trial (completed). J.M.T. is a Berlin Heart CEC member. C.V. is on the Merck scientific advisory committee and a consultant for Abiomed. C.R.V. is a consultant for PTC therapeutics (previous), Antisense (current), and Capricor (current). The other authors have no conflicts of interest to report., (Copyright © ASAIO 2024.)

The OpenOximetry Repository is a structured database storing clinical and lab pulse oximetry data, serving as a centralized repository and data model for pulse oximetry initiatives. It supports measurements of arterial oxygen saturation (SaO2) by arterial blood gas co-oximetry and pulse oximetry (SpO2), alongside processed and unprocessed photoplethysmography (PPG) data and other metadata. This includes skin color measurements, finger diameter, vital signs (e.g., arterial blood pressure, end-tidal carbon dioxide), and arterial blood gas parameters (e.g., acid-base balance, hemoglobin concentration). Data contributions are encouraged. All data, from desaturation studies to clinical trials, are collected prospectively to ensure accuracy. A common data model and standardized protocols for consistent archival and interpretation ensure consistent data archival and interpretation. The dataset aims to facilitate research on pulse oximeter performance across diverse human characteristics, addressing performance issues and promoting accurate pulse oximeters. The initial release includes controlled lab desaturation studies (CLDS), with ongoing updates planned as further data from clinical trials and CLDS become available., Competing Interests: Competing Interests The UCSF Hypoxia Research Laboratory receives funding from pulse oximeter manufacturers/sponsors to test the sponsors’ devices for the purposes of product development and regulatory performance testing. Data submitted by the UCSF Hypoxia Lab for this repository do not include Hypoxia Lab sponsors’ study devices unless the sponsor provides consent to include these data. Otherwise, all UCSF Hypoxia Lab data are collected from devices procured by the Hypoxia Lab for the purposes of independent research. At the time of this publication, no pulse oximeter company provides direct funding for the Open Oximetry Project, participates in study design or analysis, or is involved in the creation of this data repository. None of the investigators who maintain this database own stock or equity interests in any pulse oximeter device companies. AIW holds equity and management roles in Ataia Medical. Atia Medical was not involved in study design, funding, or any portion of the study. There are no other conflicts of interest to declare.

Background: In 2016, the United Network for Organ Sharing revised its pediatric heart transplant (HT) allocation policy., Objectives: This study sought to determine whether the 2016 revisions are associated with reduced waitlist mortality and capture patient-specific risks., Methods: Children listed for HT from 1999 to 2023 were identified using Organ Procurement and Transplantation Network data and grouped into 3 eras (era 1: 1999-2006; era 2: 2006-2016; era 3: 2016-2023) based on when the United Network for Organ Sharing implemented allocation changes. Fine-Gray competing risks modeling was used to identify factors associated with death or delisting for deterioration. Fixed-effects analysis was used to determine whether allocation changes were associated with mortality., Results: Waitlist mortality declined 8 percentage points (PP) across eras (21%, 17%, and 13%, respectively; P < 0.01). At listing, era 3 children were less sick than era 1 children, with 6 PP less ECMO use (P < 0.01), 11 PP less ventilator use (P < 0.01), and 1 PP less dialysis use (P < 0.01). Ventricular assist device (VAD) use was 13 PP higher, and VAD mortality decreased 9 PP (P < 0.01). Non-White mortality declined 10 PP (P < 0.01). ABO-incompatible listings increased 27 PP, and blood group O infant mortality decreased 13 PP (P < 0.01). In multivariable analyses, the 2016 revisions were not associated with lower waitlist mortality, whereas VAD use (in era 3), ABO-incompatible transplant, improved patient selection, and narrowing racial disparities were. Match-run analyses demonstrated poor correlation between individual waitlist mortality risk and the match-run order., Conclusions: The 2016 allocation revisions were not independently associated with the decline in pediatric HT waitlist mortality. The 3-tier classification system fails to adequately capture patient-specific risks. A more flexible allocation system that accurately reflects patient-specific risks and considers transplant benefit is urgently needed., Competing Interests: Funding Support and Author Disclosures The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024. Published by Elsevier Inc.)

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

Background: Pediatric heart transplant (HT) candidates experience high waitlist mortality due to a limited donor pool that is constrained in part by anti-HLA sensitization. We evaluated the impact of CDC and Flow donor-specific crossmatch (XM) results on pediatric HT outcomes., Methods: All pediatric HTs between 1999 and 2019 in the OPTN database were included. Donor-specific XM results were sub-categorized based on CDC and Flow results. Primary outcomes were treated rejection in the first year and time to death or allograft loss. Propensity scores were utilized to adjust for differences in baseline characteristics., Results: A total of 4,695 pediatric HT patients with T-cell XM data were included. After propensity score adjustment, a positive T-cell CDC-XM was associated with 2 times higher odds of treated rejection (OR 2.29 (1.56, 3.37)) and shorter time to death/allograft loss (HR 1.50 (1.19, 1.88)) compared to a negative Flow-XM. HT recipients who were Flow-XM positive with negative/unknown CDC-XM did not have higher odds of rejection or shorter time to death/allograft loss. An isolated positive B-cell XM was also not associated with worse outcomes. Over the study period XM testing shifted from CDC- to Flow-based assays., Conclusions: A positive donor-specific T-cell CDC-XM was associated with rejection and death/allograft loss following pediatric HT. This association was not observed with a positive T-cell Flow-XM or B-cell XM result alone. The shift away from performing the CDC-XM may result in loss of important prognostic information unless the clinical relevance of quantitative Flow-XM results on heart transplant outcomes is systematically studied., (Copyright © 2024 International Society for the Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Evidence for the efficacy of cardiac resynchronization therapy (CRT) in pediatric and congenital heart disease (CHD) has been limited to surrogate outcomes., Objectives: This study aimed to assess the impact of CRT upon the risk of transplantation or death in a retrospective, high-risk, controlled cohort at 5 quaternary referral centers., Methods: Both CRT patients and control patients were <21 years of age or had CHD; had systemic ventricular ejection fraction <45%; symptomatic heart failure; and significant electrical dyssynchrony (QRS duration z score >3 or single-site ventricular pacing >40%) at enrollment. Patients with CRT were matched with control patients via 1:1 propensity score matching. CRT patients were enrolled at CRT implantation; control patients were enrolled at the outpatient clinical encounter where inclusion criteria were first met. The primary endpoint was transplantation or death., Results: In total, 324 control patients and 167 CRT recipients were identified. Mean follow-up was 4.2 ± 3.7 years. Upon propensity score matching, 139 closely matched pairs were identified (20 baseline indices). Of the 139 matched pairs, 52 (37.0%) control patients and 31 (22.0%) CRT recipients reached the primary endpoint. On both unadjusted and multivariable Cox regression analysis, the risk reduction associated with CRT for the primary endpoint was significant (HR: 0.40; 95% CI: 0.25-0.64; P < 0.001; and HR: 0.44; 95% CI: 0.28-0.71; P = 0.001, respectively). On longitudinal assessment, the CRT group had significantly improved systemic ventricular ejection fraction (P < 0.001) and shorter QRS duration (P = 0.015), sustained to 5 years., Conclusions: In pediatric and CHD patients with symptomatic systolic heart failure and electrical dyssynchrony, CRT was associated with improved heart transplantation-free survival., Competing Interests: Funding Support and Author Disclosures Dr Shah has served as a consultant for Medtronic. Dr McElhinney has served as a proctor and consultant for Medtronic Inc. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

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., (© 2023 Wiley Periodicals LLC.)

Background: Functional status predicts waitlist survival in adult heart transplantation and is an independent predictor of outcomes in pediatric liver transplantation. This has not been studied in pediatric heart transplantation. Study aims were to determine the association of: (1) functional status at listing with waitlist and post-transplant outcomes, and (2) functional status at transplant with post-transplant outcomes in pediatric heart transplantation., Methods: Retrospective United Network of Organ Sharing database study of pediatric patients listed for heart transplant between 2005 and 2019 with Lansky Play Performance Scale (LPPS) scores at listing. Standard statistical methods were used to assess relationships between LPPS and outcomes (waitlist and post-transplant). Negative waitlist outcome was defined as death or removal from waitlist due to clinical deterioration., Results: There were 4,169 patients identified, including 1,080 with LPPS 80-100 (normal activity), 1,603 with LPPS 50-70 (mild limitations), and 1,486 with LPPS 10-40 (severe limitations). LPPS 10-40 correlated with negative waitlist outcomes (HR 1.69, CI 1.59-1.80, p < 0.0001). While LLPS at listing had no association with post-transplant survival, those with LPPS 10-40 at transplant had inferior 1-year post-transplant survival compared to those with LPPS ≥50 (92% vs 95%-96%, p = 0.0011). Functional status was an independent predictor of post-transplant outcomes in patients with cardiomyopathy. A functional improvement of ≥20 points between listing and transplant (N = 770, 24%) was associated with higher 1-year post-transplant survival (HR 1.63, 95% CI: 1.10-2.41, p = 0.018)., Conclusions: Functional status is associated with waitlist and post-transplant outcomes. Interventions targeting functional impairment may improve pediatric heart transplantation outcomes., (Copyright © 2023 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

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/1.73m 2 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., Competing Interests: Conflict of interest The authors have no relevant financial disclosures. This study does discuss the use of off-label medications for pediatric heart transplantation., (Copyright © 2023 Elsevier Inc. All rights reserved.)

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 M ajor A dverse D ystrophinopathy E vent (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.

Mechanical circulatory support (MCS), including ventricular assist device (VAD) support, is a leading cause of stroke in children; however, existing pediatric stroke recommendations do not apply to many pediatric VAD patients. We sought to develop a multidisciplinary pathway to improve timely and effective acute stroke care and examine the early performance of the pathway in expediting stroke care. Stakeholders from pediatric heart failure, cardiac intensive care, neurology, interventional radiology, neuroradiology, neurosurgery, pharmacy, and adult VAD care convened at Stanford University in August 2017 to discuss the challenges of providing high-quality acute stroke care to children on VAD support, and to develop multidisciplinary acute stroke pathways. Stakeholders identified multiple barriers to providing timely acute stroke care to pediatric VAD patients. These include delayed recognition of stroke, and lack of clarity related to the optimal imaging technique, when to emergently reverse antithrombotic therapy (AT), pediatric indications for thrombectomy and cranial decompression, and strategies to avoid unnecessary serial CTS. Four stroke pathways were created including evaluation and management of the pediatric patient with (1) an acute neurologic change before an imaging diagnosis; (2) an arterial ischemic stroke (AIS); (3) an intracerebral hemorrhage (ICH); and (4) a subdural hematoma (SDH). With the implementation of the stroke pathway, the median time-to-first-CT image decreased by 43 minutes from 66 to 23 minutes ( P < 0.001) while the proportion with a CT within 30 minutes increased from 0% to 67% ( P < 0.001). Despite a variety of challenges, multidisciplinary consensus can be achieved on a rapid stroke management pathway for children on VAD support that addresses important barriers to timely stroke care. Although too few stoke events occurred to differentiate clinical outcomes, the time-to-first-CT image was significantly shorter after pathway implementation., Competing Interests: Disclosure: The authors have no conflicts of interest., (Copyright © ASAIO 2023.)

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

Stroke, thromboembolism, and bleeding are the most recognized complications associated with pediatric ventricular assist devices (VADs) and the leading cause of death and disability on VAD support. Recently, newer antithrombotic strategies like bivalirudin have emerged that appear to be associated with a reduction in the neurologic event rates, especially for smaller pediatric-specific VADs like the Berlin Heart and PediMag/CentriMag systems where the risk of stroke is the highest. While contemporary antithrombotic therapies have likely contributed to lowering adverse event rates, we speculate that clotting and bleeding adverse events may have dropped because of a variety of other seemingly small changes to antithrombotic management that are independent of the antithrombotic agents used. This view is supported by recent reports documenting low stroke rates with anticoagulants other than bivalirudin, a drug that may have a wider therapeutic window but is not available in all locations throughout the world. The primary purpose of this report is 1) to summarize contemporary antithrombotic regimens used for smaller pediatric VADs today associated with low event rates in the United States and abroad and () to review 10 practical lessons learned and pitfalls to avoid that we believe to be important to reducing bleeding and clotting events based on our collective experience managing pediatric VADs over the past 20 years irrespective of the antithrombotic agents used., Competing Interests: Disclosure: Ms. Murray and Dr. Almond have received travel support to Advanced Cardiac Therapies Improving Outcomes Network (ACTION) meetings, which is supported by Berlin Heart, Inc and Abbott, Inc. Dr. Almond served as principle investigator (PI) on the US Food and Drug Administration (FDA) Orphan Product Development grant supporting the Berlin Heart Investigational Device Exemption (IDE) Trial (RO1 FDA 00033577) and currently serves as Medical PI of the NHLBI contract supporting the PumpKIN Trial (HHS N268201200001I). The other authors have no conflicts of interest to report., (Copyright © ASAIO 2022.)

Children on ventricular assist device (VAD) support can present several unique challenges, including small patient size, univentricular or biventricular congenital heart disease (1V- or 2V-CHD) and need for biventricular VAD (BiVAD) support. While cardiac catheterization can provide valuable information, it is an invasive procedure with inherent risks. We sought to evaluate the safety of catheterization in pediatric patients on VAD support. We performed a retrospective review of patients on VAD support who underwent catheterization at Lucile Packard Children's Hospital between January 1, 2014 and September 1, 2019. Using definitions adapted from Pedimacs, adverse events (AEs) after catheterization were identified, including arrhythmia; major bleeding or acute kidney injury within 24 hours; respiratory failure persisting at 24 hours; and stroke, pericardial effusion, device malfunction, bacteremia or death within 7 days. AEs were categorized as related or unrelated to catheterization. Sixty procedures were performed on 39 patients. Underlying diagnoses were dilated cardiomyopathy (48%), 1V-CHD (35%), 2V-CHD (8%), and other (8%). Devices were implantable continuous flow (72%), paracorporeal pulsatile (18%) and paracorporeal continuous flow (10%). Catheterizations were performed on patients in the ICU (60%), on inotropic support (42%), with deteriorating clinical status (37%) and on BiVAD support (12%). There were 9 AEs possibly related to catheterization including 6 episodes of respiratory failure, 2 major bleeding events, and 1 procedural arrhythmia. AE occurrence was associated with ICU status ( P = 0.01), BiVAD support ( P = 0.04) and procedural indication to evaluate worsening clinical status ( P = 0.04). Despite high medical acuity, catheterization can be performed with an acceptable AE profile in children on VAD support., Competing Interests: Disclosure: There are no conflicts of interest to report, (Copyright © ASAIO 2021.)

Background: Research evaluating hemostatic agents for the treatment of clinically significant bleeding has been hampered by inconsistency and lack of standardized primary clinical trial outcomes. Clinical trials of hemostatic agents in both cardiac surgery and mechanical circulatory support, such as extracorporeal membrane oxygenation and ventricular assist devices, are examples of studies that lack implementation of universally accepted outcomes., Methods: A subgroup of experts convened by the National Heart, Lung, and Blood Institute and the US Department of Defense developed consensus recommendations for primary outcomes in cardiac surgery and mechanical circulatory support., Results: For cardiac surgery the primary efficacy endpoint of total allogeneic blood products (units vs mL/kg for pediatric patients) administered intraoperatively and postoperatively through day 5 or hospital discharge is recommended. For mechanical circulatory support outside the perioperative period the recommended primary outcome for extracorporeal membrane oxygenation is a 5-point ordinal score of thrombosis and bleeding severity adapted from the Common Terminology Criteria for Adverse Events version 5.0. The recommended primary endpoint for ventricular assist device is freedom from disabling stroke (Common Terminology Criteria for Adverse Events AE ≥ grade 3) through day 180., Conclusions: The proposed composite risk scores could impact the design of upcoming clinical trials and enable comparability of future investigations. Harmonizing and disseminating global consensus definitions and management guidelines can also reduce patient heterogeneity that would confound standardized primary outcomes in future research., (Copyright © 2022 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Aim: To describe the clinical and hemodynamic characteristics of Fontan failure in children listed for heart transplant., Methods: In a nested study of the Pediatric Heart Transplant Society, 16 centers contributed information on Fontan patients listed for heart transplant between 2005and 2013. Patients were classified into four mutually exclusive phenotypes: Fontan with abnormal lymphatics (FAL), Fontan with reduced systolic function (FRF), Fontan with preserved systolic function (FPF), and Fontan with "normal" hearts (FNH). Primary outcome was waitlist and post-transplant mortality., Results: 177 children listed for transplant were followed over a median 13 (IQR 4-31) months, 84 (47%) were FAL, 57 (32%) FRF, 22 (12%) FNH, and 14 (8%) FPF. Hemodynamic characteristics differed between the 4 groups: Fontan pressure (FP) was most elevated with FPF (median 22, IQR 18-23, mmHg) and lowest with FAL (16, 14-20, mmHg); cardiac index (CI) was lowest with FRF (2.8, 2.3-3.4, L/min/m 2 ). In the entire cohort, 66% had FP >15 mmHg, 21% had FP >20 mmHg, and 10% had CI <2.2 L/min/m 2 . FRF had the highest risk of waitlist mortality (21%) and FNH had the highest risk of post-transplant mortality (36%)., Conclusions: Elevated Fontan pressure is more common than low cardiac output in pediatric failing Fontan patients listed for transplant. Subtle hemodynamic differences exist between the various phenotypes of pediatric Fontan failure. Waitlist and post-transplant mortality risks differ by phenotype., Competing Interests: Disclosure Statement This study complies with the Declaration of Helsinki and the research was approved by Stanford University Institutional Review Board. Participating centers contributed supplemental data to the Pediatric Heart Transplant Society under Institutional Review Board approval or waiver of consent where applicable., (Copyright © 2021 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Abstract: High-quality evidence guiding optimal transfusion and other supportive therapies to reduce bleeding is needed to improve outcomes for patients with either severe bleeding or hemostatic disorders that are associated with poor outcomes. Alongside challenges in performing high-quality clinical trials in patient populations who are at risk of bleeding or who are actively bleeding, the interpretation of research evaluating hemostatic agents has been limited by inconsistency in the choice of primary trial outcomes. This lack of standardization of primary endpoints or outcomes decreases the ability of clinicians to assess the validity of endpoints and compare research results across studies, impairs meta-analytic efforts, and, ultimately, delays the translation of research results into clinical practice. To address this challenge, an international panel of experts was convened by the National Heart Lung and Blood Institute and the US Department of Defense on September 23 and 24, 2019, to develop expert opinion, consensus-based recommendations for primary clinical trial outcomes for pivotal trials in pediatric and adult patients with six categories in various clinical settings. This publication documents the conference proceedings from the workshop funded by the National Heart Lung and Blood Institute and the US Department of Defense that consolidated expert opinion regarding clinically meaningful outcomes across a wide range of disciplines to provide guidance for outcomes of future trials of hemostatic products and agents for patients with active bleeding., Competing Interests: A complete list of conflicts of interest and working group members is provided in Supplementary Appendix., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

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.

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., (Copyright © 2020. Published by Elsevier Inc.)

Background: Given poor outcomes, strategies to improve ventricular assist devices (VADs) for single-ventricle patients with bidirectional Glenn (BDG) palliation are needed., Methods: This retrospective review describes an institutional experience with VAD support for patients with BDG from April 2011 to January 2019. Surgical strategies, complications, and causes of death are described. Survival to heart transplantation for various strategies are compared., Results: A total of 7 patients with BDG (weights, 5.6 to 28.8 kg; ages, 7 months to 11 years) underwent VAD implantation. Three patients underwent implantation of Berlin Heart EXCOR devices (Berlin Heart, Inc, Spring, TX), 2 had HeartWare HVADs (Medtronic, Minneapolis, MN) implanted, and 2 patients underwent implantation of paracorporeal continuous flow devices. Four patients underwent ventricular inflow cannulation, and 3 underwent atrial inflow cannulation. At the time of VAD implantation, the BDG was left intact in 3 patients, taken down in 3 patients, and created de novo in 1 patient. Over a total of 420 VAD support days, 2 patients survived to heart transplantation, 1 patient with HeartWare ventricular cannulation and intact BDG (after 174 days) and another with Berlin Heart atrial cannulation and BDG take-down (after 72 days). There were 3 deaths within 2 weeks of VAD implantation (2 from respiratory failure, 1 from infection) and 2 deaths after 30 days as a result of strokes., Conclusions: The surgical strategy and postoperative management of VAD with BDG are still evolving. Successful support can be achieved with (1) both pulsatile and continuous flow pumps, (2) atrial or ventricular cannulation, and (3) with or without BDG take-down. Surgical strategy should be determined by individual patient anatomy, physiology, and condition., (Copyright © 2020 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

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.

Improving the outcomes of pediatric patients with congenital heart disease with end-stage heart failure depends on the collaboration of all stakeholders; this includes providers, patients and families, and industry representatives. Because of the rarity of this condition and the heterogeneity of heart failure etiologies that occur at pediatric centers, learnings must be shared between institutions and all disciplines to move the field forward. To foster collaboration, excel discovery, and bring data to the bedside, a new, collaborative quality improvement science network-ACTION (Advanced Cardiac Therapies Improving Outcomes Network)-was developed to meet the needs of the field. Existing gaps in care and the methods of improvement that will be used are described, along with the mission and vision, utility of real-world data for regulatory purposes, and the organizational structure of ACTION is described.

Background: Cardiac resynchronization therapy (CRT) studies in pediatric or congenital heart disease patients have shown an improvement in ejection fraction and heart failure symptoms. However, a survival benefit of CRT in this population has not been established. This study aimed to evaluate the impact of CRT upon heart transplant-free survival in pediatric and congenital heart disease patients, using a propensity score-matched (PSM) analysis., Methods: This single-center study compared CRT patients (implant date, 2004-2017) and controls, matched by 1:1 PSM using 21 comprehensive baseline indices for risk stratification. CRT patients were <21 years of age or had congenital heart disease, had systemic ventricular ejection fraction <45%, symptomatic heart failure, and had significant electrical dyssynchrony, all before CRT implant. Controls were screened from nonselective imaging and ECG databases. Controls were retrospectively enrolled when they achieved the same inclusion criteria at an outpatient clinical encounter, within the same time period., Results: Of 133 patients who received CRT during the study period, 84 met all study inclusion criteria. One hundred thirty-three controls met all criteria at an outpatient encounter. Following PSM, 63 matched CRT-control pairs were identified with no significant difference between groups across all baseline indices. Heart transplant or death occurred in 12 (19%) PSM-CRT subjects and 37 (59%) PSM-controls with a median follow-up of 2.7 years (quartiles, 0.8-6.1 years). CRT was associated with markedly reduced risk of heart transplant or death (hazard ratio, 0.24 [95% CI, 0.12-0.46]; P <0.001). There was no CRT procedural mortality and 1 system infection at 54 months post-implant., Conclusions: In pediatric and congenital heart disease patients with symptomatic systolic heart failure and electrical dyssynchrony, CRT was associated with improved heart transplant-free survival. Visual Overview: A visual overview is available for this article.

Ventricular assist device (VAD) support for children with single ventricle (SV) heart disease remains challenging. We performed a single-center retrospective review of SV patients on VAD support and examined survival to transplant using the Kaplan-Meier method. Patients transplanted were compared with those who died on support. Between 2009 and 2017, there were 14 SV patients with 1,112 patient-days of VAD support. Stages of palliation included pre-Glenn (n = 5), Glenn (n = 5), and Fontan (n = 4). Eight patients (57%) were successfully bridged to transplant at a median 107 days. Deaths occurred early (n = 6, median 16 days) and in smaller patients (10.1 vs. 28.3 kg, P = 0.04). All Fontan patients survived to transplant, whereas only 20% of Glenn patients survived to transplant. Adverse events occurred in 79% (n = 11). Five patients met hospital discharge criteria, with two patients (one pre-Glenn, one Glenn) discharged and transplanted after 219 and 174 days of VAD support. All transplanted patients were discharged at a median 21 days posttransplant. SV patients in various stages of palliation can be successfully bridged to transplant with VAD support. With use of intracorporeal continuous-flow devices, longer-term support and hospital discharge are possible.

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., (© 2019 Wiley Periodicals, Inc.)

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.

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 <5 mm Hg., 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., (Copyright © 2019 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Infections in adult ventricular assist device patients increase subsequent mortality and stroke risk. Less is known about outcomes after infections in younger patients, where diabetes and obesity, risk factors associated with poor outcomes, are less prevalent. The purpose of this study was to examine outcomes after infections in adolescents and young adults with continuous-flow left ventricular assist devices (VAD) bridged to transplant. From Pediatric Interagency Registry for Mechanically Assisted Circulatory Support and Interagency Registry for Mechanical Circulatory Support registries, we identified patients aged 12-29 years with continuous-flow VADs implanted as bridged to transplant from September 2012 to March 2016. The primary predictor variable was first reported infection. The primary outcome was death on VAD support; secondary outcome was clinical stroke. Kaplan-Meier and Cox proportional hazard methods were used to compare outcomes between patients before or without infection and patients after infection. Ninety-two adolescents (12-18 years of age) and 224 young adults (19-29 years of age) with 3,748 patient-months of follow-up were included. Adolescents were smaller (body surface area 1.7 vs. 2.0 m, p < 0.01) and implanted at higher Interagency Registry for Mechanical Circulatory Support profiles (p = 0.005); there were no differences in diabetes and obesity, and survival on VAD was similar (p = 0.22). Among adolescents but not young adults, mortality increased after infection (hazard ratio 8.2, 95% confidence interval 1.6-42.6, p = 0.01). In contrast, stroke risk increased after infection in young adults (hazard ratio 3.1, 95% confidence interval 1.3-7.6, p = 0.01) but not in adolescents. Despite similar underlying risk factors, adolescents have increased mortality after infections, whereas young adults have increased strokes after infections. Both pre- and postimplant factors likely contribute to the discrepancy in outcomes between the two age cohorts.

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., (© 2019 Wiley Periodicals, Inc.)

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., (© 2019 Wiley Periodicals, Inc.)

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., (Copyright © 2018 Elsevier Inc. All rights reserved.)

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., (© 2018 Wiley Periodicals, Inc.)

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., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

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., (Copyright © 2018. Published by Elsevier Inc.)

Background: In this study we sought to quantify hazards associated with various donor factors into a cumulative risk scoring system (the Pediatric Heart Donor Assessment Tool, or PH-DAT) to predict 1-year mortality after pediatric heart transplantation (PHT)., Methods: PHT data with complete donor information (5,732) were randomly divided into a derivation cohort and a validation cohort (3:1). From the derivation cohort, donor-specific variables associated with 1-year mortality (exploratory p-value < 0.2) were incorporated into a multivariate logistic regression model. Scores were assigned to independent predictors (p < 0.05) based on relative odds ratios (ORs)., Results: The final model had an acceptable predictive value (c-statistic = 0.62). The significant 5 variables (ischemic time, stroke as the cause of death, donor-to-recipient height ratio, donor left ventricular ejection fraction, glomerular filtration rate) were used for the scoring system. The validation cohort demonstrated a strong correlation between the observed and expected rates of 1-year mortality (r = 0.87). The risk of 1-year mortality increases by 11% (OR 1.11 [1.08 to 1.14]; p < 0.001) in the derivation cohort and 9% (OR 1.09 [1.04 to 1.14]; p = 0.001) in the validation cohort with an increase of 1-point in score. Mortality risk increased 5 times from the lowest to the highest donor score in this cohort. Based on this model, a donor score range of 10 to 28 predicted 1-year recipient mortality of 11% to 31%., Conclusion: This novel pediatric-specific, donor risk scoring system appears capable of predicting post-transplant mortality. Although the PH-DAT may benefit organ allocation and assessment of recipient risk while controlling for donor risk, prospective validation of this model is warranted., (Copyright © 2018 International Society for the Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

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.

Ventricular assist devices (VADs) have been placed as destination therapy in adults for more than 20 years, but have only recently been considered an option in a subset of pediatric patients. A 2016 report from the Pediatric Interagency Registry for Mechanical Circulatory Support revealed only eight pediatric patients implanted with a VAD as destination therapy. Herein, we report the case of an adolescent male with Becker muscular dystrophy who underwent VAD placement in 2011 as bridge to candidacy. He subsequently decided to remain as destination therapy and so far has accrued more than 2100 days on VAD support, the longest duration of pediatric VAD support reported in the literature to date.

Background: Management of mechanical circulatory support in children with congenital heart disease (CHD) is challenging due to physiologic variations and anatomic limitations to device placement. In this study we examine the use of Berlin Heart EXCOR in CHD patients., Methods: CHD patients were identified from the EXCOR Pediatric Study data set (2007 to 2010). Mortality and serious adverse events were compared between CHD and non-CHD cohorts, and predictors of poor outcomes in the CHD cohort were identified., Results: CHD was present in 29% (n = 59, 18 with 1-ventricle physiology) of all EXCOR patients (N = 204). Successful bridge (transplant or wean) was less likely in CHD patients compared with non-CHD patients (48% vs 80%; p < 0.01). Among CHD patients, no neonates, 25% of infants (30 days to 1 year) and 65% of children (>1 year) were successfully bridged. Pre-implant congenital heart surgery (CHS) and extracorporeal membrane oxygenation (ECMO) on the same admission occurred in 60% of children ≤1 year of age (83% of neonates, 50% of infants), with 8% survival. Regardless of age, patients who did not have CHS and ECMO had 61% survival. Smaller pump, pre-implant bilirubin >1.2 mg/dl and renal dysfunction were independently associated with mortality., Conclusions: End-organ function at implant reliably predicts adverse outcomes and should be considered when making implant decisions. EXCOR use in neonates and infants with CHD should be approached cautiously. If patients have undergone pre-implant CHS and ECMO, EXCOR support may not provide any survival benefit. EXCOR support in non-infants with CHD is challenging but can be consistently successful with appropriate patient selection., (Copyright © 2017 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Patients listed for heart transplant after their 18th birthday purportedly wait longer to receive a donor heart compared with patients listed before their 18th 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 1-year period before and after their 18th birthday. The primary study end-point was the waiting time to receive a donor heart. Secondary end-points 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 before their 18th birthday under the pediatric allocation system, and 153 (42.5%) listed during the 12 months after their 18th birthday under the adult allocation system. The pediatric cohort was more likely to be listed Status 1A. Otherwise, the 2 groups shared similar baseline characteristics. Overall, patients listed after their 18th birthday waited 8.5 months longer to receive a transplant than adolescents listed before their 18th birthday (p = 0.01) and had a 47% lower probability of receiving a transplant (p = 0.001), but there was no difference in waitlist mortality (p = 0.37)., Conclusions: Patients listed for heart transplant shortly after their 18th birthday have significantly longer wait-times compared with patients listed shortly before their 18th birthday and 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 a relevant factor in the timing of heart transplant listing., (Copyright © 2017. Published by Elsevier Inc.)

Background: Stroke is the most feared complication associated with the Berlin Heart EXCOR pediatric ventricular assist device (VAD), the most commonly used VAD in children, and affects 1 in 3 children. We sought to determine whether a modified anti-thrombotic guideline, involving more intense platelet inhibition and less reliance on platelet function testing, is associated with a lower incidence of stroke., Methods: All children supported with the EXCOR at Stanford from 2009 to 2014 were divided into 2 cohorts based on the primary anti-thrombotic guideline used to prevent pump thrombosis: (1) the Edmonton Anti-thrombotic Guideline (EG) cohort, which included children implanted before September 2012 when dual anti-platelet therapy was used with doses titrated to Thromboelastrography/PlateletMapping (TEG/PM); and (2) the Stanford Modified Anti-thrombotic Guideline (SG) cohort, which included children implanted on or after September 2012 when triple anti-platelet therapy was used routinely and where doses were uptitrated to high, weight-based dosing targets, with low-dose steroids administered as needed for inflammation., Results: At baseline, the EG (N = 16) and SG (N = 11) cohorts were similar. The incidence rate of stroke in the SG cohort was 84% lower than in the EG cohort (0.8 vs 4.9 events per 1,000 days of support, p = 0.031), and 86% lower than in the previous Investigational Device Exemption trial (p = 0.006). The bleeding rate was also lower in the SG cohort (p = 0.015). Target doses of aspirin, clopidogrel and dipyridamole were higher (all p < 0.003), with less dosing variability in the SG cohort than in the EG cohort. There was no difference in adenosine diphosphate inhibition by TEG/PM, but arachidonic acid inhibition was higher in the SG cohort (median 75% vs 39%, p = 0.008)., Conclusions: Stroke was significantly less common in pediatric patients supported with the Berlin Heart EXCOR VAD using a triple anti-platelet regimen uptitrated to high, weight-based dosing targets as compared with the dual anti-platelet regimen titrated to PM, and without a higher risk of bleeding. Larger studies are needed to confirm these findings., (Copyright © 2017 International Society for the Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Extracorporeal membrane oxygenation (ECMO) has long served as the standard of care for short-term mechanical circulatory support in pediatrics. It is unknown whether newer-generation temporary circulatory support (TCS) devices afford children a meaningful survival advantage over ECMO., Objectives: This study sought to determine whether bridge-to-heart transplant survival with a TCS device is superior to ECMO after adjusting for patient differences., Methods: All children ≤21 years of age listed for heart transplant from 2011 to 2015 who received a TCS device or ECMO as a bridge to transplant were identified using Organ Procurement and Transplantation Network data. Children supported with a TCS device were compared with a propensity score (PS)-matched cohort of children supported with ECMO as a bridge to transplant. The primary endpoint was Kaplan-Meier survival to transplant., Results: The number of TCS devices implanted in children increased from ≤3 per year before 2011 to 50 in 2015. Overall, 93 patients implanted with TCS devices were included for analysis (59% left ventricular assist devices, 23% right ventricular assist devices, 18% biventricular assist devices). The most commonly used device was the CentriMag-PediMag system (65%), followed by TandemHeart (18%), Rotaflow (6%), and Impella (5%). Among 164 PS-matched patients, support duration was longer for the TCS cohort (median 19 days vs. 6 days; p < 0.001), and was longest for the CentriMag-PediMag (24 days vs. 6 days; p < 0.001) with 27% supported for >60 days. Compared with the ECMO cohort, the PS-matched TCS cohort had longer survival to transplant (hazard ratio: 0.49; 95% confidence interval: 0.30 to 0.79) and longer overall survival (hazard ratio: 0.61; 95% confidence interval: 0.39 to 0.96), with 90-day mortality before transplant that was modestly reduced (from 45% with ECMO to 39% with TCS)., Conclusions: The use of TCS devices in children as a bridge to transplant has risen rapidly in recent years, led by the growth of magnetically levitated centrifugal flow pumps. Compared with conventional ECMO, TCS durations are longer, and more importantly, patient survival is superior., (Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)