Charles E. Canter

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.).

Berlin Heart EXCOR Pediatric Ventricular Assist Device for Bridge to Heart Transplantation in US Children

Background— Recent data suggest that the Berlin Heart EXCOR Pediatric ventricular assist device is superior to extracorporeal membrane oxygenation for bridge to heart transplantation. Published data are limited to 1 in 4 children who received the device as part of the US clinical trial. We analyzed outcomes for all US children who received the EXCOR to characterize device outcomes in an unselected cohort and to identify risk factors for mortality to facilitate patient selection. Methods and Results— This multicenter, prospective cohort study involved all children implanted with the Berlin Heart EXCOR Pediatric ventricular assist device at 47 centers from May 2007 through December 2010. Multiphase nonproportional hazards modeling was used to identify risk factors for early (<2 months) and late mortality. Of 204 children supported with the EXCOR, the median duration of support was 40 days (range, 1–435 days). Survival at 12 months was 75%, including 64% who reached transplantation, 6% who recovered, and 5% who were alive on the device. Multivariable analysis identified lower weight, biventricular assist device support, and elevated bilirubin as risk factors for early mortality and bilirubin extremes and renal dysfunction as risk factors for late mortality. Neurological dysfunction occurred in 29% and was the leading cause of death. Conclusions— Use of the Berlin Heart EXCOR has risen dramatically over the past decade. The EXCOR has emerged as a new treatment standard in the United States for pediatric bridge to transplantation. Three-quarters of children survived to transplantation or recovery; an important fraction experienced neurological dysfunction. Smaller patient size, renal dysfunction, hepatic dysfunction, and biventricular assist device use were associated with mortality, whereas extracorporeal membrane oxygenation before implantation and congenital heart disease were not.

The 2016 International Society for Heart Lung Transplantation listing criteria for heart transplantation: A 10-year update

Mandeep R. Mehra, MD (Chair), Charles E. Canter, MD, Margaret M. Hannan, MD, Marc J. Semigran, MD, Patricia A. Uber, PharmD, David A. Baran, MD, Lara Danziger-Isakov, MD, MPH, James K. Kirklin, MD, Richard Kirk, MD, Sudhir S. Kushwaha, MD, Lars H. Lund, MD, PhD, Luciano Potena, MD, PhD, Heather J. Ross, MD, David O. Taylor, MD, Erik A.M. Verschuuren, MD, PhD, Andreas Zuckermann, MD and on behalf of the International Society for Heart Lung Transplantation (ISHLT) Infectious Diseases, Pediatric and Heart Failure and Transplantation Councils

Bridging children of all sizes to cardiac transplantation: The initial multicenter North American experience with the Berlin Heart EXCOR ventricular assist device

BACKGROUND Beginning in 2000 and accelerating in 2004, the Berlin Heart EXCOR (Berlin Heart Inc Woodlands, TX) became the first pediatric-specific ventricular assist device (VAD) applied throughout North America for children of all sizes. This retrospective study analyzed the initial Berlin Heart EXCOR pediatric experience as a bridge to transplantation. METHODS Between June 2000 and May 2007, 97 EXCOR VADs were implanted in North America at 29 different institutions. The analysis is limited to 73 patients (75%) from 17 institutions, for which retrospective data were available. RESULTS Median age and weight at VAD implant were 2.1 years (range, 12 days-17.8 years) and 11 kg (range, 3-87.6 kg), respectively. The primary diagnoses were dilated cardiomyopathy in 42 (58%), congenital heart disease in 19 (26%), myocarditis in 7 (10%), and other cardiomyopathies in 5 (7%). Pre-implant clinical condition was critical cardiogenic shock in 38 (52%), progressive decline in 33 (45%), or other in 2 (3%). Extracorporeal membrane oxygenation was used as a bridge to EXCOR in 22 patients (30%). Device selection was left VAD (LVAD) in 42 (57%) and biventricular assist devices (BiVAD) in 31 (43%). The EXCOR bridged 51 patients (70%) to transplant and 5 (7%) to recovery. Mortality on the EXCOR was 23% (n = 17) overall, including 35% (11 of 31) in BiVAD vs 14% (6 of 42) in LVAD patients (p = 0.003). Multivariate analysis showed younger age and BiVAD support were significant risk factors for death while on the EXCOR. CONCLUSIONS This limited but large preliminary North American experience with the Berlin Heart EXCOR VAD as a bridge to cardiac transplantation for children of all ages and sizes points to the feasibility of this approach. The prospective investigational device evaluation trial presently underway will further characterize the safety and efficacy of the EXCOR as a bridge to pediatric cardiac transplantation.

Outcome of Listing for Cardiac Transplantation for Failed Fontan A Multi-Institutional Study

Background— The Fontan procedure is a successful palliation for children with single-ventricle physiology; however, many will eventually require heart transplantation. The purpose of this study was to determine risk factors for death awaiting transplantation and to examine results after transplantation in Fontan patients. Methods and Results— A retrospective, multi-institutional review was performed of 97 Fontan patients <18 years of age listed at 17 Pediatric Heart Transplant Study centers from 1993 to 2001. Mean age at listing was 9.7 years (0.5 to 17.9 years); 25% were <4 years old; 53% were United Network for Organ Sharing status 1; 18% required ventilator support. Pretransplantation survival was 78% at 6 months and 74% at 12 months and was similar to 243 children with other congenital heart disease (CHD) and 747 children without congenital heart disease (No-CHD), who were also awaiting transplantation. Patients who were younger, status 1, had shorter interval since Fontan, or were on a ventilator were more likely to die while waiting. At 6 months, the probability of receiving a transplant was similar for status 1 and 2 (65% versus 68%); however, the probability of death was higher for status 1 (22% versus 5%). Seventy patients underwent transplantation. Survival was 76% at 1 year, 70% at 3 years, and 68% at 5 years, slightly less than CHD and No-CHD patients. Causes of death included infection (30%), graft failure (17%), rejection (13%), sudden death (13%), and graft coronary artery disease (9%). Protein-losing enteropathy (present in 34 patients) resolved in all who survived >30 days after transplantation. Conclusions— Heart transplantation is an effective therapy for pediatric patients with a failed Fontan. Although early posttransplantation survival is slightly lower than other patients with CHD, long-term results are encouraging, and protein-losing enteropathy can be expected to resolve.

Lymphoproliferative disorders after paediatric heart transplantation: a multi-institutional study

BACKGROUND Post-transplant lymphoproliferative disorders (PTLD) are an important cause of morbidity and mortality after organ transplantation. We sought to better define the prevalence, pathology, current therapeutic approaches, and outcomes of PTLD in a large group of children who had received heart transplants. METHODS We assessed data on patients followed up at 19 centres in the Pediatric Heart Transplant Study (PHTS) from 1993 to 2002. Probability of freedom from PTLD was assessed along with details of presentation, pathology, treatment, and outcomes. Risk factors for survival and event-free survival were investigated. FINDINGS Of 1184 primary transplant recipients, 56 (5%) developed PTLD. Probability of freedom from PTLD was 98% at 1 year, 94% at 3 years, and 92% at 5 years. Mean time to PTLD was 23.8 months. Most common sites of disease were gastrointestinal tract (n=22, 39%) and respiratory system (n=14, 25%). Histology was polymorphic in 35 (65%) and monomorphic in 19 (35%). 47 of 48 cases were of B-cell origin, 39 of 45 (87%) were Epstein-Barr virus positive. Probability of survival was 75% at 1 year, 68% at 3 years, and 67% at 5 years after diagnosis. Death from graft loss was as frequent as death from PTLD. INTERPRETATION About 5% of paediatric heart-transplant recipients develop PTLD, almost always of B-cell lineage and driven by Epstein-Barr virus. Although many achieve satisfactory outcomes, mortality remains substantial with death due to progressive disease and allograft loss. Advances in management should focus on strategies to protect the allograft as well as improved therapies for PTLD.

Cardiac troponin I in pediatrics: Normal values and potential use in the assessment of cardiac injury

OBJECTIVE To establish normal values and determine the impact of congenital or acquired heart disease on serum cardiac troponin I (cTnI). METHODS Concentrations of cTnI were measured in two groups of children. Group A represented ambulatory pediatric patients with no apparent cardiac disease (n = 120) and patients in stable condition with known congenital or acquired cardiac abnormalities (n = 96); group B was composed of patients admitted to intensive care units with normal echocardiograms (n = 16), with abnormal echocardiograms (n = 36), and those with blunt chest trauma who were thought to have cardiac contusions (n = 7). RESULTS The cTnI concentrations were generally less than 2.0 ng/ml in group A and frequently below the level of detection for the assay (1.5 ng/ml). There was no statistical difference between the two outpatient subgroups (p = 0.66). Nine intensive care patients had cTnI values greater than 2.0 ng/ml. Six of these patients, all with abnormal echocardiograms, had values less than 7.7 ng/ml. All improved and had subsequent normal cTnI concentrations. None of the three remaining patients (two with systemic illness (trauma and sepsis) and one with severe pulmonary hypertension), all with values greater than 8.0 ng/ml, survived. Three of the four patients with high likelihood of cardiac contusion had cTnI concentrations greater than 2.0 ng/ml (including one patient who died). CONCLUSIONS Cardiac troponin-I values are generally not elevated in children with stable cardiac disease or general pediatric conditions. In the context of severe acute illness, significant elevation of cTnI may be an indicator of poor outcome. Elevation of cTnI may also have diagnostic value in cases when cardiac contusion is suspected.

Increased stiffness and persistent narrowing of the aorta after successful repair of coarctation of the aorta: relationship to left ventricular mass and blood pressure at rest and with exercise.

Fifteen children and adolescents who had repair of coarctation of the aorta before age 15, who were not hypertensive at rest, and who had resting arm-leg blood pressure gradients of less than 20 mm Hg underwent noninvasive evaluation of left ventricular structure and function, aortic stiffness, and residual coarctation as well as bicycle exercise testing. These results were compared with those in 15 age- and sex-matched control subjects. The mean resting age-related systolic blood pressure percentiles (63% versus 46%), transverse aortic stiffness measured by the elastic modulus (Ep) (42.1 versus 23.2 kPa), stiffness index beta (beta) (3.66 versus 2.17), echocardiographic left ventricular fractional shortening (0.42 versus 0.36), left ventricular mass index (99.3 versus 81.0 gm/m2), maximum exercise right arm systolic blood pressure (173 versus 156 mm Hg), and exercise arm-leg blood pressure gradient (35 versus 6 mm Hg) were significantly increased in the coarctectomy patients compared with controls. Univariate correlations in the coarctectomy group showed significant relationships of residual aortic narrowing with left ventricular mass index (r = 0.68, p less than 0.01) and resting systolic blood pressure percentile for age (r = 0.55, p less than 0.05). Residual aortic narrowing did not significantly correlate with aortic stiffness, resting blood pressure gradient, or exercise blood pressure gradient. Neither left ventricular mass index nor resting systolic blood pressure percentile significantly correlated with age of repair or years after repair. These results demonstrate persistent abnormalities in aortic stiffness and left ventricular mass and function after successful repair of coarctation of the aorta in childhood and adolescence.(ABSTRACT TRUNCATED AT 250 WORDS)

The Pediatric Cardiomyopathy Registry and Heart Failure: Key Results from the First 15 Years

Cardiomyopathy is a serious disorder of the heart muscle and, although rare, is a common cause of heart failure in children and the most common cause for heart transplantation in children older than 1 year of age. Funded by the National Heart Lung and Blood Institute since 1994, the Pediatric Cardiomyopathy Registry (PCMR) has followed more than 3500 North American children with cardiomyopathy. Early analyses determined estimates for the incidence of pediatric cardiomyopathy (1.13 cases per 100,000 children per year), risk factors for cardiomyopathy (age <1 year, male sex, black race, and living in New England as opposed to the central southwestern states), the prevalence of heart failure at diagnosis (6%-84% depending on cause), and 10-year survival (29%-94% depending on cause). More recent analyses explored cause-specific functional status, survival and transplant outcomes, and risk factors in greater detail. For many topics these analyses are based on the largest and best-documented samples of children with disease such as the muscular dystrophies, mitochondrial disorders, and Noonan syndrome. Data from the PCMR continue to provide valuable information that guides clinical management and the use of life-saving therapies, such as cardiac transplantation and approaches to treating heart failure, and prepares children, their families, and their caregivers to deal with this serious condition.

Survival and risk factors for death after cardiac transplantation in infants: A multi-institutional study

BACKGROUND Despite the increasing application of cardiac transplantation in infants, reported survival rates vary, and risk factors for death are poorly understood. METHODS AND RESULTS To examine early survival and risk factors for death in infants (< 1 year of age) undergoing cardiac transplantation, 141 infants (36 < 1 months of age) underwent primary cardiac transplantation between January 1, 1993, and January 1, 1995, at 23 centers in the Pediatric Heart Transplant Study (PHTS). Diagnoses were hypoplastic left heart syndrome (66%), other congenital heart disease (17%), cardiomyopathy (14%), and other (3%). Actuarial survival after cardiac transplantation was 84% at 1 month, 70% at 1 year, and 69% at 2 years, with the greatest hazard for death within the first 3 months. The principal cause of death was early graft failure in 20 patients (52% of deaths), infection in 10 (26% of deaths), and rejection in 4 (10%). On the basis of multivariate analysis, risk factors for early mortality were history of previous sternotomy (P = .0003), nonidentical blood type donor (P = .01), recipient non-blood group A (P = .02), and donor cause of death other than closed head trauma (P = .04). Diagnosis at listing, waiting time (mean, 1.3 months), graft ischemic time (mean, 228 minutes; range, 68 to 479 minutes), and recipient ventilatory or inotropic support at listing were not predictive for mortality after transplant. CONCLUSIONS The higher mortality rate observed with infant heart transplantation is due to a higher mortality within the first month after transplantation as a result of early graft failure. Strategies to improve donor heart function at implantation would have the greatest impact on survival after infant cardiac transplantation.