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Congenital heart disease is one of the major diagnoses in pediatric heart transplantation recipients of all age groups. Assessment of pulmonary vascular resistance in these patients prior to transplantation is crucial to determine their candidacy, however, it is frequently inaccurate because of their abnormal anatomy and physiology. This problem places them at significant risk for pulmonary hypertension and right ventricular failure post transplantation. The pathophysiology of pulmonary vascular disease in children with congenital heart disease depends on their pulmonary blood flow patterns, systemic ventricle function, as well as semilunar valves and atrioventricular valves structure and function. In our review we analyze the pathophysiology of pulmonary vascular disease in children with congenital heart disease and end-stage heart failure, and outline the state of the art pre-transplantation medical and surgical management to achieve reverse remodeling of the pulmonary vasculature by using pulmonary vasodilators and mechanical circulatory support.

Background: Variable rates of malignancy and early infection have previously been reported in heart transplant (HTx) recipients who received induction therapy. This study hypothesized that induced pediatric patients would have an increased risk of these events compared with non-induced patients., Methods: Data from a prospective, multicenter event-driven registry of outcomes after HTx listing in patients aged < 18 years was used to analyze risks of infection and malignancy and their association with induction between January 1993 and December 2007., Results: Of 2,374 patients, 1,258 (53%) received induction and more frequently from 1999 to 2008 compared with 1993 to 1998 (70.8% vs 57.5%, p < 0.001). At HTx, induced patients were more likely to have congenital heart disease (56.9% vs 48.1%, p < 0.001) but no more likely to be positive for Epstein-Barr virus (50.3% vs 51.4%, p = 0.67). Post-transplant lymphoproliferative disease (PTLD) was the most common malignancy (n = 92) within 5 years of HTx. Patients who received induction had a lower risk for PTLD (hazard ratio [HR], 0.5; 95% confidence interval [CI], 0.3-0.84; p = 0.009) and early fungal infections (HR, 0.60; 91% CI, 0.40-0.91; p = 0.016). Among induction agents used, OKT3 was associated with lowest freedom from PTLD and fungal/cytomegalovirus infection., Conclusions: Induction use has increased since 1999 and has not been associated with an increased risk of malignancy (predominantly PTLD) or overall infection. Because these adverse events occurred with higher rates in non-induced patients, it is likely that induction alone is not the primary risk determinant for PTLD and infection., (Copyright © 2011 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Survival after pediatric heart transplant has improved over time, as has the incidence of overall rejection. We studied the effect of era on the occurrence and outcome of rejection with hemodynamic compromise (HC)., Methods: Data from 2227 patients who received allografts between 1993 and 2006 at 36 centers in the Pediatric Heart Transplant Study were analyzed to determine incidence, outcome, and risk factors for rejection with HC in early (1993-1999) and recent (2000-2006) eras. Rejection with HC was classified as severe (RSHC) when inotropes were used for circulatory support and mild (RMHC) when inotropes were not used., Results: Of 1217 patients with any episode of rejection, 541 had rejection with HC. Freedom from RMHC improved at 1 year (81% vs 90%, p < 0.001) and at 5 years (74% vs 85%, p < 0.001) in the early vs recent eras, but freedom from RSHC was similar between eras (93% vs 95% at 1 year and 85% vs 87% at 5 years, p = 0.24). Survival after RSHC (63% at 1 year and 49% at 5 years) was worse than after RMHC (87% at 1 year and 72% at 5 years, p < 0.001) and did not change over time. Risk factors for RSHC were non-white race (hazard ratio [HR], 1.73; 95% confidence interval [CI], 1.29-2.32, p < 0.01), older age (HR, 2.85; 95% CI, 1.24-6.53; p = 0.01), and non-A blood type (HR, 1.51;, 95% CI, 1.11-2.04,; p = 0.01), but the only risk factor for RMHC was earlier era of transplant (HR, 1.94; 95% CI, 1.56-2.41; p < 0.001)., Conclusions: The incidence of RMHC has declined over time but the same era effect has not occurred with RSHC. Close follow-up after RSHC is crucial because mortality is so high., (Copyright © 2011 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

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., (Copyright © 2011 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Myocarditis is a cause of a new-onset dilated cardiomyopathy phenotype in children, with small studies reporting high rates of recovery of left ventricular (LV) function., Methods and Results: The presenting characteristics and outcomes of children with myocarditis diagnosed clinically and with biopsy confirmation (n=119) or with probable myocarditis diagnosed clinically or by biopsy alone (n=253) were compared with children with idiopathic dilated cardiomyopathy (n=1123). Characteristics at presentation were assessed as possible predictors of outcomes. The distributions of time to death, transplantation, and echocardiographic normalization in the biopsy-confirmed myocarditis and probable myocarditis groups did not differ (P≥0.5), but both groups differed significantly from the idiopathic dilated cardiomyopathy group (all P≤0.003). In children with myocarditis, lower LV fractional shortening z-score at presentation predicted greater mortality (hazard ratio, 0.85; 95% confidence interval, 0.73 to 0.98; P=0.03) and greater LV posterior wall thickness predicted transplantation (hazard ratio, 1.17; 95% confidence interval, 1.02 to 1.35; P=0.03). In those with decreased LV fractional shortening at presentation, independent predictors of echocardiographic normalization were presentation with an LV end-diastolic dimension z-score >2 (hazard ratio, 0.36; 95% confidence interval, 0.22 to 0.58; P<0.001) and greater septal wall thickness (hazard ratio, 1.16; 95% confidence interval, 1.01 to 1.34; P=0.04)., Conclusions: Children with biopsy-confirmed or probable myocarditis had similar proportions of death, transplantation, and echocardiographic normalization 3 years after presentation and better outcomes than those of children with idiopathic dilated cardiomyopathy. In children with myocarditis who had impaired LV ejection at presentation, rates of echocardiographic normalization were greater in those without LV dilation and in those with greater septal wall thickness at presentation. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00005391.

Background: Uncertainty exists whether hearts from infants who have died of sudden infant death syndrome (SIDS) are acceptable for transplantation because the mechanism of death in SIDS remains unclear. We analyzed post-transplant outcomes in infants who received a heart from a donor where SIDS was the primary cause of brain death., Methods: This retrospective multicenter cohort study used data from the Organ Procurement and Transplant Network (OPTN). All infants aged < 12 months undergoing heart transplant between 1994 and 2008 were included. A Cox proportional hazards model was used to determine whether donor SIDS was independently associated with post-transplant graft loss (death or retransplant)., Results: During the study period, 66 of 1033 infants (6.4%) who underwent heart transplant received an allograft from a SIDS donor. These infants were similar to the remaining infants with respect to age, diagnosis, blood type, and invasive support. In multivariable analysis, graft loss was associated with congenital heart disease (hazard ratio [HR], 1.6; 95% confidence interval [CI], 1.2-2.1), ventilator (HR, 1.4; 95% CI, 1.1-1.9), and extracorporeal membrane oxygenation support (HR, 3.0; 95% CI, 2.2-4.3), but not donor SIDS (HR, 1.0; 95% CI, 0.6-1.5), suggesting graft survival in SIDS-donor heart recipients was similar to the remaining infants. Primary causes of post-transplant death in infants receiving SIDS-donor hearts and the remaining infants were similar., Conclusions: Graft survival was similar in infants who received SIDS-donor hearts compared with those who received hearts from donors who died of other causes. There was no increase in incidence of non-rejection-related cardiac deaths after transplant in these children., (Copyright © 2010 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

This article describes the causes and outcomes of dilated cardiomyopathy in children. Genetic, infectious, metabolic, and acquired causes of dilated cardiomyopathy are discussed. The predictors for better and worse outcomes are reviewed. Guidelines for the use of medical and surgical therapies to treat heart failure in children are summarized., (Copyright © 2010 Elsevier Inc. All rights reserved.)

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., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Background: Rejection is a major cause of morbidity and mortality after pediatric heart transplantation (HTx). Survival after pediatric HTx has improved over time, but whether there has been an era-related improvement in the occurrence of allograft rejection is unknown., Methods: The Pediatric Heart Transplant Study (PHTS) database was queried for patients who underwent HTx from January 1993 to December 2005 to determine the incidence of rejection and identify factors associated with the first episode of rejection in the first year after HTx., Results: Data were reviewed in 1,852 patients from 36 centers. The incidence of rejection declined over 13 years at a rate of -2.58 +/- 0.41 (p < 0.001) from approximately 60% to 40% (p < 0.001). The mean number of episodes of rejection also significantly fell at a rate of -0.05 +/- 0.01 per patient/year from 1.19 to 0.66 (p < 0.001). The incidence of rejection with hemodynamic compromise and death from rejection did not change. Multivariate analysis for the risk of a first rejection episode demonstrated decreased risk of rejection with later year of HTx (odds ratio [OR], 0.88; 95% confidence interval [CI], 0.85-0.91; p < 0.001) and use of mechanical support (OR, 0.65; 95% CI, 0.42-0.99; p = 0.046). Increased risk of rejection was associated with positive donor-specific crossmatch (OR, 1.85; 95% CI, 1.18-2.88; p = 0.007) and older recipient age (OR, 1.05; 95% CI, 1.02-1.07; p < 0.001)., Conclusions: Although the overall incidence and prevalence of rejection has substantially decreased over time in pediatric HTx recipients in the first year after HTx, the rate of rejection with hemodynamic compromise or death from rejection remains unchanged., (Copyright 2010 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Tachyarrhythmias in pediatric post-heart transplant patients are not well defined. In this study we sought to further characterize these arrhythmias in terms of presentation, course, and outcome., Methods: This investigation was a retrospective review of heart transplant recipients at St. Louis Children's Hospital during the period of 1991 to 2006. Patients were excluded if they were >18 years at transplantation or if follow-up information was unavailable. Patients with tachyarrhythmias beyond the first 2 weeks post-transplant were identified., Results: Twenty-eight tachyarrhythmias occurred in 25 of 237 heart transplant recipients. Freedom from arrhythmia was 92% at 1-year post-transplant and 86% at 15 years post-transplant. Intra-atrial reentry tachycardia (12 patients) and ectopic atrial tachycardia (10 patients) were the most common arrhythmias. Rejection was found in 3 (12%) and previously unrecognized coronary disease was found in another 2 (8%) at the time of presentation with arrhythmia. Fifteen of 25 (60%) were asymptomatic at presentation, but 4 of 25 (16%) presented with heart failure, including 3 without evidence of rejection. No risk factors for developing arrhythmia were identified. Twenty-one arrhythmias resolved with brief pharmacologic or no therapy. Only 3 had a recurrence after the initial arrhythmia. Five patients underwent catheter ablation., Conclusions: Our experience suggests that the presence of tachyarrhythmias after pediatric heart transplantation is not rare and usually not associated with rejection. Pediatric heart transplant recipients have a higher incidence of ectopic atrial tachycardia (EAT) than their adult counterparts. Most tachyarrhythmias resolve after a relatively brief period of medical treatment and recurrence is uncommon.

Background: Pediatric heart transplant recipients with a positive complement-dependent cytotoxic (CDC) donor-recipient crossmatch are at high risk for rejection. We sought to correlate the pattern of C3d and C4d myocardial capillary deposition and pericapillary macrophage infiltration, possible markers of antibody-mediated rejection, to clinical evidence of rejection in these patients., Methods: Were studied 15 pre-sensitized pediatric patients who had 21 rejection episodes, as defined by International Society for Heart and Lung Transplantation (ISHLT) biopsy Grade >or=2R and/or the development of abnormal left ventricular (LV) function at >1 week after transplant. Archived paraffin-embedded endomyocardial biopsies (n = 74) from these patients were subjected to immunoperoxidase staining for C3d, C4d and CD68 in duplicate. Positive and negative controls were included for each assay., Results: C3d deposition was present in 74 of 74 (100%) specimens. C4d deposition was present in 6 of 74 (8%) biopsies from 4 patients. Biopsies with C4d deposition had ISHLT Grade >or=2R cellular infiltration in 5 of 6 specimens. Pericapillary macrophage infiltration, defined as positive staining for CD68, was found in 34 of 74 (46%) biopsies, and was associated with ISHLT Grade >or=2R in 10 of 34 (29%)., Conclusions: C3d deposition was universally present after heart transplantation with a CDC(+) donor/recipient crossmatch. C4d deposition and pericapillary macrophage infiltration were found with some, but not all, episodes of rejection. Further study is needed to understand the significance of the presence of complement fragments and pericapillary macrophage infiltration in these endomyocardial biopsies.

We report a fatal device-device interaction between a wearable automated defibrillator (WAD; LifeVest - LifeCor, Inc., Pittsburgh, PA, USA) and a unipolar pacemaker that occurred in an 18-year-old patient listed for cardiac transplantation due to his failing Fontan. The patient developed ventricular tachycardia that was initially detected by the WAD. However, large unipolar pacing artifacts and specific WAD arrhythmia detection algorithms caused the WAD to revert to nonrecognition of the arrhythmia, which lead to the patient's death. We identify likely causes of the failure and suggest methods of preventing such occurrences in the future.

Objective: To review clinical courses of pediatric heart transplant survivors after 5 years from transplantation for infections, lymphoproliferative, and autoimmune diseases., Study Design: A total of 71 patients were examined in 2 groups, infant recipients (underwent transplant <1 year of age, n = 38) and older recipients (underwent transplant >1 year, n = 33). All patients received comparable immunosuppression. Calculated occurrence rates were reported as means per 10 years of follow-up with SEs. Differences were examined by using Poisson regression., Results: Infant recipients had significantly higher (P < .001) occurrence rates of severe (mean, 2.04 +/- 0.5) and chronic infections (mean, 4.58 +/- 0.67) compared with older recipients (means, 0.37 +/- 0.19 and 1.87 +/- 0.70, respectively). Types of infections were similar to those in the general population with extremely rare opportunistic infections; however, they were more severe and resistant to treatment. Autoimmune disorders occurred at a frequency comparable with lymphoproliferative diseases and were observed in 7 of 38 infants (18%). Most common were autoimmune cytopenias., Conclusions: Infant heart transplant recipients who survive in the long term have higher occurrence rates of infections compared with older recipients. Autoimmune disorders are a previously unrecognized morbidity in pediatric heart transplantation.

Management of chronic heart failure in pediatrics has been altered by the adult literature showing improvements in mortality and hospitalization rates with the use of beta-adrenoceptor antagonists (beta-blockers) for routine therapy of all classes of ischemic and non-ischemic heart failure. Many pediatric heart failure specialists have incorporated these agents into their routine management of pediatric heart failure related to dilated cardiomyopathy or ventricular dysfunction in association with congenital heart disease. Retrospective and small prospective case series have shown encouraging improvements in cardiac function and symptoms, but interpretation has been complicated by the high rate of spontaneous recovery in pediatric patients. A recently completed pediatric double-blind, randomized, placebo-controlled clinical trial showed no difference between placebo and two doses of carvedilol over a 6-month period of follow-up, with significant improvement of all three groups over the course of evaluation. Experience with adults has suggested that only certain beta-blockers, including carvedilol, bisoprolol, nebivolol, and metoprolol succinate, should be used in the treatment of heart failure and that patients with high-grade heart failure may derive the most benefit. Other studies surmise that early or prophylactic use of these medications may alter the risk of disease progression in some high-risk subsets, such as patients receiving anthracyclines or those with muscular dystrophy. This article reviews these topics using experience as well as data from all the recent pediatric studies on the use of beta-blockers to treat congestive heart failure, especially when related to systolic ventricular dysfunction.

Background: The difficulty in obtaining a prospective negative donor/recipient crossmatch limits the ability to successfully transplant pediatric heart transplant candidates who show evidence of antibodies to multiple human leukocyte antigens (pre-sensitized patients)., Methods: We utilized a protocol that included peri-operative plasmapheresis, thymoglobulin and cyclophosphamide in 17 pre-sensitized (panel-reactive antibodies [PRA] >10%) pediatric patients to accept donors for these patients without a prospective crossmatch between 1995 and 2005. A retrospective review of survival, rejection and infection was performed, comparing the frequency of rejection and infection in our patients who were transplanted with a complement-dependent cytotoxic (CDC)-positive donor/recipient crossmatch to those patients transplanted with a negative crossmatch., Results: Thirteen of 17 patients were found to have a CDC-positive crossmatch. Actuarial survival after transplantation was 85% at 1 year and 73% at 3 years. Twelve of 13 (92%) of these patients experienced rejection, and 5 of 13 (38%) had recurrent rejection, generally in the first 2 months after transplantation. Rejection was associated with hemodynamic compromise in 58% of first rejection episodes and 67% of episodes of recurrent rejection. The frequency of rejection in these patients was significantly greater than the frequency in patients with a negative crossmatch in the first 6 months after transplantation, but not afterward. The frequency of infection episodes was not significantly different between the groups., Conclusions: Heart transplantation in pre-sensitized pediatric recipients with a CDC-positive donor/recipient crossmatch may result in reasonable short-term survival, but with a high frequency of early rejection, often with hemodynamic compromise.

Retransplants comprise only a small minority (3-4%) of heart transplants, however outcome following retransplantation is compromised. Risk factors for a poor outcome following retransplantation include retransplantation early (<6 months) after primary transplant, retransplantation for acute rejection or early allograft failure, and retransplantation in an earlier era. The incidence of rejection and infection is similar following primary transplant and retransplantation. The compromised outcomes and risk factors for a poor outcome are similar in adult and pediatric heart retransplantation. However, due to the short half-life of the transplanted heart, it is an expectation that patients transplanted in childhood may require retransplantation. Based on the data available and the opinion of the working group, indications for heart retransplantation are (i) chronic severe cardiac allograft vasculopathy with symptoms of ischemia or heart failure (should be considered) or asymptomatic moderate or severe left ventricular dysfunction (may be considered) or (ii) chronic graft dysfunction with symptoms of progressive heart failure in the absence of active rejection. Patients with graft failure due to acute rejection with hemodynamic compromise, especially <6 months post-transplant, are inappropriate candidates for retransplantation. In addition, guidelines established for primary transplant candidacy should be strictly followed.

Objectives: The goal of this study is to determine the incidence of sudden cardiac death in children with cardiomyopathy prior to pediatric heart transplantation., Background: Recent primary prevention trials of implantable cardiac defibrillator (ICD) therapy in adults with ischemic and non-ischemic cardiomyopathy have shown a survival benefit. The incidence of sudden death, and thus the likelihood of improved survival with ICD therapy, in children with cardiomyopathy is currently unknown., Methods: The Pediatric Heart Transplant Study (PHTS) database was retrospectively queried for patients < or =18 years of age who died from any cause after listing for but prior to heart transplantation. Patients having arrhythmic or sudden death were included for study. Clinical and demographic variables were examined to identify higher-risk sub-groups., Results: Of the 2,392 patients in the PHTS database, 420 (17.6%) died prior to heart transplantation. Only 32 deaths (1.3% of total listed, 7.6% of total deaths) were sudden or arrhythmic in nature. Patients with ischemic cardiomyopathy had an increased risk of sudden death (relative risk = 6.92). Presence of congenital heart disease and United Network for Organ Sharing (UNOS) status at listing were not associated with an increased risk of sudden death., Conclusions: The overall incidence of sudden death in children awaiting heart transplantation is low; therefore, uniform implantation of ICDs for the primary prevention of sudden death is unlikely to improve survival in this population. Children with ischemic cardiomyopathy appear to have a higher risk of sudden death and may benefit from ICD therapy.

Background: Since the initial utilization of heart transplantation as therapy for end-stage pediatric heart disease, improvements have occurred in outcomes with heart transplantation and surgical therapies for congenital heart disease along with the application of medical therapies to pediatric heart failure that have improved outcomes in adults. These events justify a reevaluation of the indications for heart transplantation in congenital heart disease and other causes of pediatric heart failure., Methods and Results: A working group was commissioned to review accumulated experience with pediatric heart transplantation and its use in patients with unrepaired and/or previously repaired or palliated congenital heart disease (children and adults), in patients with pediatric cardiomyopathies, and in pediatric patients with prior heart transplantation. Evidence-based guidelines for the indications for heart transplantation or retransplantation for these conditions were developed., Conclusions: This evaluation has led to the development and refinement of indications for heart transplantation for patients with congenital heart disease and pediatric cardiomyopathies in addition to indications for pediatric heart retransplantation.

Background: Many uncertainties regarding the fate of children undergoing heart transplantation as infants were present when we and others embarked on this program. Although no truly long-term results are available, a significant cohort of children has now reached preteen and early teenage status. We reviewed our group of infants transplanted more than 10 years ago to assess survival and quality of life as they approach their teenage years., Methods: We retrospectively reviewed the medical records of all infant (younger than 6 months of age) heart transplant recipients, transplanted between 1988 and 1995, to ascertain survival statistics, incidence of complications, and current health status., Results: A total of 42 patients were identified. The majority of these underwent transplantation for hypoplastic left heart syndrome. Eleven patients have died, 4 early and 7 late. The actual survival at 10 years is 76%. Twenty-seven of the 31 long-term survivors attend regular school; 4 are in special education classes owing to developmental delay. Five patients take medication for attention-deficit disorder. Malignancies have been discovered in 5, and 1 died secondary to this. Six patients have significant renal insufficiency, 1 of whom has undergone renal transplantation. One patient has undergone retransplantation for coronary artery disease. One patient required reoperation for supravalvar aortic stenosis. Other general medical problems that are being treated include sleep apnea (n = 1), hypertension (n = 5), and recurrent pneumonias (n = 1)., Conclusions: Although these children require ongoing medical attention, including daily medications and regular follow-up visits, most have a satisfactory quality of life and behave much like normal children.

Background: Transplant coronary arteriopathy (TCAD) limits graft survival after heart transplantation in adult and pediatric heart transplant recipients. Intravascular ultrasound (IVUS) provides a highly sensitive technique to detect TCAD. However, its use to determine factors associated with TCAD in pediatric recipients has been limited and its utility in surveillance for symptomatic TCAD in this population is uncertain., Methods: One hundred fifty-eight IVUS studies from 66 patients (27 <1 year and 39 >1 year at time of transplant) were performed 12 to 144 months after transplantation within the routine surveillance for TCAD. Maximal intimal thickness (MIT) and intimal index (II) were measured, and the Stanford classification was utilized to grade overall severity of disease. Mixed repeated-measures linear regression models were used to investigate the main and interaction effects of age at transplant, age at time of study, time since transplant and rejection events., Results: Age at catheterization (p = 0.0002), transplantation at age >12 months (p = 0.014), increasing time after transplantation (p = 0.021) and the combination of late rejection and hemodynamic compromising rejection (p = 0.05) were significantly associated with increasing MIT. Age at catheterization (p = 0.0149), transplantation at age >12 months (p = 0.016), time from transplantation (p = 0.0076) and rejection with hemodynamic compromise (p = 0.01) were significantly associated with increased II. Nine patients developed evidence of severe (Stanford Class 4) TCAD by IVUS, but only 2 (22%) developed symptomatic TCAD, with a median follow-up of 44 months. Four of the 7 patients who developed symptomatic TCAD had no or minimal TCAD (Stanford Class 0 or 1) on a surveillance examination within 18 months of the onset of symptoms., Conclusions: Increasing time after transplantation, recipient age and age at transplantation as well as rejection history, especially rejection with hemodynamic compromise, are associated with the development of TCAD as detected by IVUS in pediatric heart transplant recipients. Severe TCAD detected by IVUS does not often rapidly progress to symptomatic TCAD. Symptomatic TCAD may develop rapidly even in patients with little or no TCAD detected by IVUS.

The Pediatric Heart Transplant Study (PHTS) group was founded in 1991 as a voluntary, collaborative effort dedicated to the advancement of the science and treatment of children following listing for heart transplantation. Since 1993, the PHTS has collected data in an international, prospective, event-driven database that examines risk factors for outcome events following listing for transplantation. The events include transplantation, death, rejection, infection, malignancy, graft vasculopathy, and retransplantation. Over its 12 years of existence, the PHTS has made major contributions to the field of pediatric heart transplantation, especially in the areas of outcome analysis and risk factor assessment for death and other major morbidities after listing and after transplantation. The new challenges facing the PHTS include how to implement the practice of evidence-based medicine in the field of pediatric heart transplantation and how to support ongoing data collection and analysis to provide long-term outcomes as the PHTS subjects enter their second decade after transplantation.

The objective of this study was to evaluate the safety and efficacy of carvedilol in pediatric patients with stable moderate heart failure. We performed a single-arm prospective drug trial at three academic medical centers and the results were compared to historical controls. Patients were 3 months to 17 years old with an ejection fraction <40% in the systemic ventricle for at least 3 months on maximal medical therapy including ACE inhibitors. Treated patients were started on 0.1 mg/kg/day and uptitrated to 0.8 mg/kg/day or the maximal tolerated dose. Echocardiographic parameters of function were prospectively measured at entry and at 6 months. Two composite endpoints were recorded: severe decline in status and significant clinical change. Adverse events were reviewed by a safety committee. Data were also collected from untreated controls with dilated cardiomyopathy meeting entry criteria, assessed over a similar time frame. Twenty patients [12 dilated cardiomyopathy (DCM) and 8 congenital] with a median age of 8.4 years (range, 8 months to 17.8 years) were treated with carvedilol. Three patients discontinued the drug during the study. At entry, there was no statistical difference in age, weight, or ejection fraction between the treated group and controls. The ejection fraction of the treated DCM group improved significantly from entry to 6 months (median, 31 to 40%, p = 0.04), with no significant change in ejection fraction in the control group [median, 29 to 27%, p = not significant (NS)]. The median increase in ejection fraction was larger for the treated DCM group than for the untreated DCM controls (7 vs 0%, p = 0.05). By Kaplan-Meier analysis, time to death or transplant tended to be longer in treated patients (p = 0.07). The difference in the proportion of patients with severe decline in status or significant clinical change in the treated group was not significant compared to the controls (5 vs 12%, p = NS). We conclude that in this prospective protocol of pediatric patients, the use of adjunct carvedilol in the DCM group improved ejection fraction compared to untreated controls and trended toward delaying time to transplant or death.

Objective: To identify the otolaryngological manifestations of posttransplant lymphoproliferative disorder (PTLD) in pediatric heart and lung transplant recipients., Methods: A 14-year retrospective case series review (1990-2003) of children less than 18 years of age presenting with PTLD after receiving orthotopic heart and lung transplants at St. Louis Children's hospital (St. Louis, MO, USA)., Results: One hundred ninety seven cardiac and 246 pulmonary transplant patients were included in this review. Thirteen heart transplant patients developed PTLD with 39% (5/13) presenting in the head and neck. Thirty-two lung transplant patients developed PTLD with 25% (8/32) presenting in the head and neck. PTLD in cardiac transplants most often presented as adenotonsillar hypertrophy or cervical lymphadenopathy. The sinonasal cavity was the most common site of head and neck PTLD in pulmonary transplants patients., Conclusions: This study suggests that head and neck involvement is more common than currently reported in the literature. As thoracic organ transplants become more frequent in children, otolaryngologists caring for this population should maintain a high index of suspicion for any suggestive findings. Evaluation must include tissue biopsy, as histopathologic examination is required for diagnosis.

Pediatric myocarditis is most often associated with the acute or subacute onset of congestive heart failure in a previously healthy child. Myocarditis presenting with acute, severe symptomatology, termed fulminant myocarditis, has a high rate of recovery. Aggressive supportive care is indicated in fulminant myocarditis, including mechanical circulatory support. For subacute heart failure, supportive care remains the mainstay of therapy for myocarditis. A number of uncontrolled pediatric studies using both immunosuppressive therapy and/or immunomodulating therapy with intravenous gamma globulin have suggested these therapies are safe and useful in treating pediatric myocarditis. However, translating these results into recommended, routine therapy for pediatric myocarditis is complicated by the high rate of spontaneous improvement of myocarditis with supportive care, and the lack of demonstrable benefit for immunosuppressive and immunomodulating therapies in blinded, randomized, placebo-controlled trials in adult myocarditis. Heart transplantation remains the final therapeutic option for children with myocarditis and intractable severe heart failure.

Background: Transplant coronary artery disease (TCAD) limits survival in heart transplant recipients; however, its incidence in children is unknown. The purpose of this study was to determine the angiographic incidence of TCAD, potential risk factors, and outcomes in a large pediatric cohort., Methods: From January 1993 to December 1, a total of 1,222 children, aged newborn to 17 years, underwent primary cardiac transplantation at 20 institutions. A total of 2,049 coronary angiograms were performed in 751 patients. All angiograms were graded for coronary disease and results were submitted to the Pediatric Heart Transplant Study database. We analyzed time-related freedom from graded severity and events from coronary disease, and we examined risk factors., Results: The incidence of angiographic abnormalities at 1, 3, and 5 years was 2%, 9%, and 17%, respectively; however, moderate-to-severe disease occurred in only 6% at 5 years, compared with 15% in the adult transplant database (p <0.0001). The major risk factors were older recipient and donor age. Two or more episodes of rejection in the 1st year correlated with coronary disease (p = 0.05). Overall freedom from graft loss caused by primary TCAD was 99%, 96%, and 91% at 1, 5, and 9 years after heart transplantation, respectively. Death or graft loss occurred within 2 years of diagnosis in patients with severe disease; 24% of patients with any coronary disease died within 2 years., Conclusions: The incidence of TCAD in children is smaller than the incidence in adults, but increases with age. Graft loss is infrequent in children; however, severe coronary disease correlates with poor prognosis.

Background: Infants with hypoplastic left heart syndrome (HLHS) commonly undergo cardiac transplantation as primary management., Methods: We examined outcomes of primary transplantation for unpalliated HLHS. We analyzed data from the 20 institutions of the Pediatric Heart Transplant Study Group, from January 1, 1993, through December 31, 1998, using actuarial and parametric survival analysis and competing outcomes analysis., Results: During the 6 years studied, 1,234 patients were listed for cardiac transplantation; 262 patients (21.2%) had unpalliated HLHS. The number (and percentage) of patients with HLHS decreased from 58 (27% of patients listed) in 1993 to 30 (14%) in 1998. Overall, 25% of infants with HLHS died while waiting; primary cause of death was cardiac failure (50%). Of the remaining patients awaiting transplantation, 23 (9%) underwent Norwood/Fontan-type surgeries as interim palliation: 52% died. Ultimately, 175 patients underwent cardiac transplantation (67%); 50% received organs by 2 months after listing. Post-transplant actuarial survival was 72% at 5 years, with 76% of deaths (35/46) occurring within 3 months; early mortality was caused primarily by graft failure within the first 30 days after transplantation (in 54%). Among 1-month survivors, survival at 1 and at 5 years was 92% and 85%, respectively. Of the 262 patients listed with unpalliated HLHS, overall survival, taking into account mortality after listing and after transplantation, was 68% at 3 months and 54% at 5 years., Conclusions: Cardiac transplantation offers good intermediate survival for infants with unpalliated HLHS.

Background: Although anthracycline therapy is invaluable for treating neoplastic disorders, morbidity includes severe cardiomyopathy that leads to heart transplantation. This multicenter study describes the course of children who experienced anthracycline cardiomyopathy (ACM) and who subsequently required heart transplantation., Methods: We reviewed transplant databases/registries at 4 pediatric heart transplant centers to identify children with ACM who were listed for heart transplantation. We reviewed medical records to determine cancer therapy, clinical course, and outcome., Results: Eighteen patients were listed, and 17 underwent transplantation. Mean age at cancer diagnosis was 6.0 years (SD, 3.7). The mean anthracycline dose was 361 mg/m2 (SD, 110). The median time from cancer diagnosis to listing for heart transplantation was 9.2 years (range, 0.4-15.2 years). Six transplantations were performed in patients who had disease-free intervals of <5 years. Two patients were lost to follow-up, and 8 are alive at 4.9 years (SD, 2.0; range, 1.3-7.4 years) after transplantation. Seven patients died at 4.7 years (SD, 2.0; range, 1.2-7.1 years) after transplantation. One patient had recurrent cancer. One-, 2- and 5-year survivals were 100%, 92%, and 60%, respectively., Conclusions: Cardiomyopathy that progresses to the need for heart transplantation occurs in patients receiving a wide range of cumulative anthracycline doses. The time from chemotherapy to ACM varies. Outcomes after transplantation are acceptable, and cancer recurrence is rare. Reconsideration of the 5-year disease-free wait period is warranted.

Objectives: We studied the outcomes of pediatric patients diagnosed with dilated cardiomyopathy (DCM) and their relation to epidemiologic and echocardiographic variables at the time of presentation., Background: The outcome of pediatric DCM patients ranges from recovery to a 50% to 60% chance of death within five years of diagnosis. The impact of heart transplantation and other emerging therapies on the outcomes of pediatric DCM patients is uncertain., Methods: We performed a retrospective study of the outcomes in 91 pediatric patients diagnosed with DCM from 1990 to 1999. Routine therapy included use of digoxin, diuretics, angiotensin-converting enzyme inhibitors, and heart transplantation., Results: At the time of last follow-up, 11 patients (12%) had died without transplantation; 20 (22%) underwent transplantation; 27 (30%) had persistent cardiomyopathy; and 33 (36%) had recovery of left ventricular systolic function. Overall actuarial one-year survival was 90%, and five-year survival was 83%. However, actuarial freedom from "heart death" (death or transplantation) was only 70% at one year and 58% at five years. Multivariate analysis found age <1 year (hazard ratio 7.1), age >12 years (hazard ratio 4.5), and female gender (hazard ratio 3.0) to be significantly associated with a greater risk of death or transplantation and a higher left ventricular shortening fraction at presentation (hazard ratio 0.92), with a slightly decreased risk of death or transplantation., Conclusions: Pediatric DCM patients continue to have multiple outcomes, with recovery of left ventricular systolic function occurring most frequently. Utilization of heart transplantation has led to improved survival after the diagnosis of pediatric DCM.

Background: Primary graft failure, or circulatory insufficiency immediately after transplantation, frequently occurs after pediatric cardiac transplantation and is the most common cause of death after infant transplantation. Risk factors for pediatric primary graft failure are poorly defined., Methods: We retrospectively reviewed donor, procedural and recipient characteristics for primary graft failure in 165 pediatric cardiac transplant recipients (median age at transplant 1.1 years) by multivariatle logistic regression. Primary graft failure was defined as the need for mechanical circulatory support or use of multiple intravenous inotrope/pressors, including epinephrine, for circulatory support within the first 24 hours after transplantation., Results: Primary graft failure occurred in 54 patients (33%); 24 patients (15%) required mechanical support for their graft failure; and primary graft failure was the cause of death or graft loss in 10 patients. Recipient risk factors associated with an increased risk of primary graft failure included diagnosis of congenital heart disease and a need for mechanical support before transplantation. Ventilator support before transplantation and maximal pulmonary vascular resistance index were risk factors for the development of isolated right ventricular graft failure. Donor risk factors associated with an increased risk for primary graft failure included increasing donor recipient weight and body surface area ratios; increasing donor ischemic time; anoxia as a cause of death; and increasing cardiopulmonary resuscitation time. Donor blood type O+ and hyperdynamic donor systolic function were associated with a decreased risk of primary graft failure., Conclusions: Multiple donor, recipient and procedural risk factors, including the type and severity of heart disease in the recipient before transplantation, are associated with primary graft failure after pediatric cardiac transplantation. Avoidance of matching high-risk donors to high-risk recipients may improve morbidity and mortality after transplantation.

Background: Acquired left ventricular dysfunction after pediatric cardiac transplantation is associated with a high mortality rate. It often occurs without biopsy evidence of cellular rejection or severe transplant coronary arteriopathy., Methods: We employed a protocol for treatment of acquired, non-ischemic left ventricular dysfunction utilizing plasmapheresis, monoclonal anti-T-cell antibody (OKT3), cyclophosphamide and steroids, regardless of the results of endomyocardial biopsy. Left ventricular dysfunction was defined as an echocardiographic shortening fraction of <29% and/or symptoms of congestive heart failure requiring inotropic support. Transplant coronary arteriopathy was excluded by coronary angiography in all cases., Results: Ten pediatric heart transplant recipients were treated for 13 episodes of non-ischemic left ventricular dysfunction. Biopsy scores were low grade (ISHLT Grade 1A or 1B) in 8 episodes. Eight of 10 patients had a history of non-compliance in regularly taking immunosuppressant medications. Inotropic support was required in 9 of 13 cases, with a median duration of 5 days. Median left ventricular shortening fraction was 17% at time of presentation. Normalization of shortening fraction occurred a median of 40 days from the start of treatment. Survival to hospital discharge occurred in 11 of 13 (85%) patients. Long-term patient survival, however, was only 50% at 24 months after presentation with a first episode of acquired left ventricular dysfunction., Conclusions: Use of plasmapheresis, OKT3, cyclophosphamide and steroids resulted in successful short-term reversal of non-ischemic left ventricular dysfunction in pediatric heart transplant patients, but long-term survival remained poor.

Background: The purpose of this study was to assess the feasibility and limitation of multi-detector row computed tomographic (MDCT) imaging for evaluating coronary arteries in pediatric heart transplant patients., Methods: Coronary MDCT angiography was performed in eight pediatric heart transplant recipients. The presence of coronary calcification was evaluated. Luminal changes of the visualized coronary segments on MDCT images were compared with catheter angiographic findings and intravascular ultrasound., Results: Coronary calcification was present in one patient who had severe coronary arteriopathy documented by intravascular ultrasound. In 48 coronary segments visualized on MDCT images, 33, 7, and 4 segments each had normal, luminal irregularities, and moderate stenoses, respectively, which were confirmed by catheter angiography. Twelve coronary segments could not be assessed because of severe motion artifacts. Image quality degradation was more pronounced in patients with higher heart rates., Conclusions: Noninvasive MDCT angiography is promising but requires further technical improvement to evaluate coronary arteries in pediatric heart transplant patients.

We sought to document morbidities and growth for patients with hypoplastic left heart syndrome (HLHS) to inform the initial surgical decision and understand healthcare needs. Data were obtained on 137 patients with HLHS, born between 1989 and 1994, who survived staged surgery ( n = 62) or transplantation ( n = 75) and had follow-up information available from four pediatric cardiac surgical centers. In patients with HLHS older than 1 year of age at follow-up, 93% experienced at least one major postsurgical morbidity. Morbidities depended on the surgery received. Hypertension, renal compromise, and abnormal infections were more common in transplanted patients than staged surgery patients. Staged surgery patients used more anticongestive medications and experienced more morbidities requiring interventional catheterization than did transplanted patients. Rejection was common for transplanted patients. On average these children spent 23 days per year in the hospital. Patients with HLHS were small for their age; 43% of staged surgery patients weighed below the third percentile at last information, compared to 19% of transplanted patients ( p = 0.003). The median height percentile was the 10th in both groups. Normal activity level was reported in more transplanted patients (90%) than staged surgery patients (49%; p < 0.001). Trade-offs between mortality and morbidity outcomes can help inform the initial surgical decision.

Background: Because of the poor prognosis of pediatric restrictive cardiomyopathy, transplantation has been proposed as the treatment of choice for this disease., Methods: We reviewed our experience with the presentation, evaluation, and short-term outcome in 8 pediatric patients with restrictive cardiomyopathy referred for transplantation. Potential reversibility of elevation in pulmonary vascular resistance was tested before transplantation with nitroprusside and nitric oxide, with follow-up cardiac catheterization performed 6 to 12 months after transplantation., Results: The mean age of diagnosis of restrictive cardiomyopathy was 6.3 years and the mean interval from diagnosis to referral for transplantation was 3.6 years. Elevation of pulmonary vascular resistance was common and tended to progress with longer follow-up. Three of the 8 patients had pulmonary vascular resistance indices greater than 10 Woods unit/m(2) and transpulmonary gradients greater than 20 mm Hg. The administration of nitroprusside and nitric oxide reversed elevated pulmonary resistance and transpulmonary gradients in all patients. Nitric oxide successfully reversed pulmonary vascular resistance in patients unresponsive to nitroprusside. All patients underwent successful transplantation and follow-up catheterization revealed normal pulmonary hemodynamics in each patient., Conclusions: Pediatric restrictive cardiomyopathy can be associated with marked elevation in the pulmonary vascular resistance, which may contribute to the poor prognosis in these patients and potentially make cardiac transplantation problematic. Orthotopic cardiac transplantation can be successfully performed in patients who demonstrate reversibility of pulmonary vascular resistance. Nitric oxide appears to be the best agent to demonstrate reversibility of pulmonary resistance in these patients.

Background: Infant heart transplant recipients have been reported to have decreased rates of rejection when clinical criteria are used for diagnosis. This study compares the rates of acute episodes of rejection in heart and lung transplant recipients transplanted in the first year of life to those of older recipients utilizing pathologic criteria., Methods: Records of 100 consecutive lung transplant recipients (cystic fibrosis patients excluded) and 107 consecutive heart transplant recipients were reviewed with respect to: time to first rejection; total number; single versus multiple; and early (<90 days) versus late (>180 days) biopsy-proven rejection episodes. Rejection was defined as ISHLT biopsy Grade 3A or A2 for heart and lung transplant recipients, respectively. Biopsy and immunosuppression protocols were similar between groups., Results: Kaplan-Meier analysis for freedom from rejection showed infant heart recipients were more often rejection-free (p = 0.004) as were infant lung recipients (p = 0.0001). Multivariate analysis revealed age at transplant as the most significant factor in predicting time to first rejection (age <1 year: risk ratio 0.19 [0.068-0.54] for lung transplant recipients and risk ratio 0.46 [0.27-0.78] for heart transplant recipients). Early rejection episodes occurred with less frequency in both the infant heart (19 of 63 [30%] versus 24 of 44 [50%]; p = 0.016) and lung (3 of 26 [12%] versus 63 of 74 [85%]; p = 0.001) groups. Late episodes of rejection were also less frequent in infant heart (4 of 53 [8%] versus 10 of 36 [28%], p = 0.016) and lung (0 of 23 [0%] versus 29 of 65 [45%]; p = 0.001) recipients. Multiple (> or =2) rejection episodes occurred less in infant heart (4 of 63 [6%] versus 9 of 41 [22%]; p = 0.037) and lung recipients (0 of 26 [0%] versus 17 of 74 [23%]; p = 0.003)., Conclusions: These results demonstrate that age of <1 at time of thoracic transplantation confers significant protection from early, late and multiple episodes of acute rejection, as well as significantly greater freedom from rejection and time to first rejection.

In multiple clinical trials, beta-blockers have been shown to significantly improve morbidity and mortality in adults with chronic congestive heart failure, but there is little reported experience with their use in children. Heart failure involves activation of the adrenergic nervous system and other neurohumoral systems in order to maintain cardiovascular homeostasis. These compensatory mechanisms have been shown to cause myocardial damage with chronic activation, which has been hypothesized to be a major contributing factor to the clinical deterioration of adults with heart failure. Studies have demonstrated inhibition of this neurohumoral response and concomitant clinical benefits with beta-blockers. Consequently, beta-blockers have evolved to become an important part of comprehensive medical therapy for congestive heart failure in adults. Pediatric heart failure represents an entirely different spectrum of disease, caused more commonly by congenital heart disease than cardiomyopathy. Surgical palliation and correction are important components of pediatric heart failure therapy, and residual, postsurgical cardiac lesions can lead to chronic heart failure. Although neurohumoral activation in children is similar to that in adults with heart failure, there are important differences from adults in physiology and developmental changes that are especially observed in infants. Current published clinical experience with beta-blocker use in children with heart failure is limited to case series with relatively small numbers of patients. Nevertheless, these series show consistent symptomatic improvement, and improvement in ventricular systolic function in patients with cardiomyopathies and congenital heart disease, similar to findings in adults. Adverse effects were common and many patients in these studies had adverse outcomes (death and/or need for transplantation). One study has noted differences in pharmacokinetics in children compared with adults. However, a multicenter, randomized controlled trial to evaluate carvedilol in pediatric heart failure from systolic ventricular dysfunction is currently ongoing and should help to clarify the efficacy and tolerability of carvedilol in children.

Objectives: We sought to identify the optimal treatment strategy for hypoplastic left heart syndrome (HLHS)., Background: Surgical treatment of HLHS involves either transplantation (Tx) or staged palliation of the native heart. Identifying the best treatment for HLHS requires integrating individual patient risk factors and center-specific data., Methods: Decision analysis is a modeling technique used to compare six strategies: staged surgery; Tx; stage 1 surgery as an interim to Tx; and listing for transplant for one, two, or three months before performing staged surgery if a donor is unavailable. Probabilities were derived from current literature and a dataset of 231 patients with HLHS born between 1989 and 1994. The goal was to maximize first-year survival., Results: If a donor is available within one month, Tx is the optimal choice, given baseline probabilities; if no donor is found by the end of one month, stage 1 surgery should be performed. When survival and organ donation probabilities were varied, staged surgery was the optimal choice for centers with organ donation rates < 10% in three months and with stage 1 mortality <20%. Waiting one month on the transplant list optimized survival when the three-month organ donation rate was > or =30%. Performing stage 1 surgery before listing, or performing stage 1 surgery after an unsuccessful two- or three-month wait for transplant, were almost never optimal choices., Conclusions: The best strategy for centers that treat patients with HLHS should be guided by local organ availability, stage 1 surgical mortality and patient risk factors.

Pulmonary hypertension represents a significant risk factor for peri-operative death in patients undergoing cardiac transplantation. Heart-lung transplantation is generally the only procedure available for patients whose pulmonary hypertension can not be reversed by conventional pharmacologic means. We present a pediatric patient with end-stage cardiac disease and refractory pulmonary hypertension who was treated with long-term intravenous prostacyclin. This resulted in a significant enough improvement in her hemodynamics to allow for successful cardiac transplantation alone.

Objective: The objective was to determine the dosing, efficacy, and side effects of the nonselective beta-blocker carvedilol for the management of heart failure in children., Study Design: Carvedilol use in addition to standard medical therapy for pediatric heart failure was reviewed at 6 centers., Results: Children with dilated cardiomyopathy (80%) and congenital heart disease (20%), age 3 months to 19 years (n = 46), were treated with carvedilol. The average initial dose was 0.08 mg/kg, uptitrated over a mean of 11.3 weeks to an average maintenance dose of 0.46 mg/kg. After 3 months on carvedilol, there were improvements in modified New York Heart Association class in 67% of patients (P =.0005, chi2 analysis) and improvement in mean shortening fraction from 16.2% to 19.0% (P =.005, paired t test). Side effects, mainly dizziness, hypotension, and headache, occurred in 54% of patients but were well tolerated. Adverse outcomes (death, cardiac transplantation, and ventricular-assist device placement) occurred in 30% of patients., Conclusions: Carvedilol as an adjunct to standard therapy for pediatric heart failure improves symptoms and left ventricular function. Side effects are common but well tolerated. Further prospective study is required to determine the effect of carvedilol on survival and to clearly define its role in pediatric heart failure therapy.

Background: Rejection with severe hemodynamic compromise results in high mortality in adult transplant patients. This study determines the incidence, outcome and risk factors for rejection with severe hemodynamic compromise in a multi-institutional study of pediatric heart transplant recipients., Methods: Data from 847 patients transplanted between 1/1/93 and 12/31/98 at 18 centers in the Pediatric Heart Transplant Study were analyzed. Rejection with severe hemodynamic compromise was defined as a clinical event occurring beyond 1 week postoperatively, which led to augmentation of immunosuppression and use of inotropic therapy. Actuarial freedom from such rejection and death after rejection were determined and risk factors sought., Results: Among 1,033 rejection episodes in 532 patients, 113 (11%) episodes were associated with severe hemodynamic compromise in 95 patients. The highest risk for severe rejection was in the first year. Risk factors were older recipient age (p >.05) and non-white race (p >.001). Survival after an episode was poor (60%), and biopsy score did not affect outcome. Deaths were due to rejection (n = 14), other cardiac causes (n = 17), infection (n = 5), lymphoma (n = 2), pulmonary causes (n = 2), and thrombosis (n = 1)., Conclusions: Rejection with severe hemodynamic compromise occurs in 11% of pediatric patients, irrespective of age, sex or biopsy score, and mortality is high. Non-white race and older recipient age are independent risk factors for rejection with severe hemodynamic compromise. Aggressive treatment and close surveillance should be crucial components of protocols aimed at reducing the high mortality.

Objectives: We compared survival in treatment strategies and determined risk factors for one-year mortality for hypoplastic left heart syndrome (HLHS) using intention-to-treat analysis., Background: Staged revision of the native heart and transplantation as treatments for HLHS have been compared in treatment-received analyses, which can bias results., Methods: Data on 231 infants with HLHS, born between 1989 and 1994 and intended for surgery, were collected from four pediatric cardiac surgical centers. Status at last contact for survival analysis and mortality at one year for risk factor analysis were the outcome measures., Results: Survival curves showed improved survival for patients intended for transplantation over patients intended for staged surgery. One-year survival was 61% for transplantation and 42% for staged surgery (p < 0.01); five-year survival was 55% and 38%, respectively (p < 0.01). Survival curves adjusted for preoperative differences were also significantly different (p < 0.001). Waiting-list mortality accounted for 63% of first-year deaths in the transplantation group. Mortality with stage 1 surgery accounted for 86% of that strategy's first-year mortality. Birth weight <3 kg (odds ratio [OR] 2.4), highest creatinine > or =2 mg/dL (OR 4.7), restrictive atrial septal defect (OR 2.7) and, in staged surgery, atresia of one (OR 4.2) or both (OR 11.0) left-sided valves produced a higher risk for one-year mortality., Conclusions: Transplantation produced significantly higher survival at all ages up to seven years. Patients with atresia of one or both valves do poorly in staged surgery and have significantly higher survival with transplantation. This information may be useful in directing patients to the better strategy for them.

The period of preoperative management of the pediatric cardiac transplant patient can be divided into three phases: determination of transplant feasibility, listing, and medical management. Chronic infection, irreversible elevation of pulmonary vascular resistance, and intractable disease in other organ systems may all be contraindications for transplantation. The United Network for Organ Sharing has recently changed its listing guidelines. Adolescent donors are now preferentially, to some extent, allocated to adolescent recipients. Management of pediatric patients awaiting cardiac transplantation encompasses optimization of cardiac output through the use of vasodilators and oral and intravenous inotropic agents. For those patients listed for transplantation who have single ventricle lesions, such as hypoplastic left heart syndrome, management of heart failure also includes balancing systemic and pulmonary blood flows. Mechanical support of the circulation with extracorporeal membrane oxygenation or ventricular assist devices can be used as a bridge to transplant in pediatric patients.

Selective coronary angiography (SCA) is an important diagnostic tool in pediatric cardiology; however, there are few reports on its feasibility and safety in young patients. We reviewed our experience with SCA from July 1, 1993 to December 31, 1997. There were 158 cardiac catheterizations that included SCA in patients whose ages ranged from 2 days to 46 years (median, 5.3 years). The most common indication was surveillance for coronary vasculopathy after heart transplantation. A retrograde approach was used in all patients through the femoral artery (n = 157) or umbilical artery (n = 1). Preformed coronary catheters were used and the Judkins left (JL) and Judkins right (JR) were the most common catheters, with the catheter curve size correlating with patient height (R(2) =.76 for JL, R(2) =. 673 for JR). Complications during SCA included brief ST-T wave changes (11%), bradycardia (2.5%), and ventricular fibrillation (0. 6%). Complications of vascular access were transient pulse loss (6%), hematoma (5%), and rebleeding (0.6%). Only one case of femoral artery occlusion was encountered on subsequent cath. In conclusion, complications of SCA were infrequent and serious complications were rare. SCA can be safely performed in pediatric patients at any age including neonates.

Objectives: This study analyzed the relationship of variability in routine trough cyclosporine (CSA) levels to morbidity after pediatric cardiac transplantation., Background: Due to high interindividual variation between dosage and blood concentrations, trough surveillance CSA levels are routinely performed after cardiac transplantation to adjust dosages. In addition, trough CSA levels have been used as a measure of patient compliance in transplant recipients. Recent investigations have demonstrated a relationship between late rejection and mistimed CSA dosing intervals, which could also lead to CSA levels that are incorrectly presumed to be trough levels., Methods: Trough surveillance whole-blood CSA levels were retrospectively reviewed in 49 pediatric heart transplant recipients who had a median follow-up of 42 months (range 6 to 138 months). All patients received the same immunosuppression regimen (CSA, azathioprine, and steroids), the same CSA-level surveillance protocol, and the same stabilization of CSA dose and level in the therapeutic range (150 to 300 ng/ml) prior to hospital discharge. CSA levels drawn because of coexisting phenomena (drug interaction, gastroenteritis) that could cause CSA-level fluctuation were excluded from analysis. Cyclosporine variability was measured as the percentage of CSA levels that were considered sub-therapeutic (< or = 100 ng/ml), toxic (> or = 450 ng/ml), or both. Cyclosporine-level variability was then analyzed in respect to demographic and outcome variables., Results: For the group, the median percentage of sub-therapeutic levels was 3% (range, 0% to 16%); the median percentage of toxic levels was 5% (range, 0% to 36%); the median of the combination of sub-therapeutic and toxic levels was 10% (0% to 38%). Eight of the 49 patients (16%) has a high (>20%) percentage of sub-therapeutic + toxic levels or high CSA variability. High CSA variability was significantly associated with recipients > 12 months of age (p = 0.028), and recipients with a history of non-compliance (p < 0.001). Patients with high CSA variability had a significantly higher median number of hospitalized days per year of follow-up (p = 0.036), higher rate of recurrent rejection (> or = 2 episodes; p = 0.0003), and higher death rate more than 6 months after transplant (p = 0.01)., Conclusions: Although this study could not determine cause, high variability in trough CSA levels was a marker for pediatric heart transplant recipients at greater risk for recurrent rejection and hospitalization after transplantation.