Ranae L. Larsen

Transplantation as a primary treatment for hypoplastic left heart syndrome: intermediate-term results.

BACKGROUND Hypoplastic left heart syndrome is a lethal malformation. For the last 10 years, orthotopic cardiac transplantation has been our preferred treatment for infants with hypoplastic left heart syndrome. METHODS One hundred seventy-six infants with hypoplastic left heart syndrome were entered into a cardiac transplant protocol between November 1985 and November 1995. Interventional procedures to stent the ductus arteriosus or enlarge the interatrial communication were performed in 8 and 35 patients, respectively. Thirty-four patients (19%) died during the waiting period, and 142 infants underwent cardiac transplantation. Age at cardiac transplantation ranged from 1.5 hours to 6 months (median, 29 days). The majority of grafts were oversized, and the median graft ischemic time was 273 minutes (range, 60 to 576 minutes). The implantation procedure used a period of hypothermic circulatory arrest ranging from 23 to 110 minutes (median, 53 minutes). Repair of other significant defects included interrupted aortic arch and total or partial anomalous pulmonary venous connection. RESULTS There were 13 early and 22 late deaths. Patient actuarial survival at 1 month and at 1, 5 and 7 years was 91%, 84%, 76%, and 70% respectively. Half of the late deaths were due to rejection. Severe graft vasculopathy was confirmed in 8 patients. Retransplantation was performed in 5 patients for graft vasculopathy 4 and rejection 1. Lymphoblastic leukemia developed in 1 patient 3 years after cardiac transplantation. CONCLUSIONS Cardiac transplantation can be performed in infants with hypoplastic left heart syndrome with good operative and intermediate-term results. Improved survival can be achieved with increased donor availability, better management of rejection, and control of graft vasculopathy.

Electrocardiographic changes and arrhythmias after cancer therapy in children and young adults

Transient electrocardiographic changes and arrhythmias are known to be acute manifestations of cardiotoxicity secondary to cancer therapy with anthracyclines or cardiac irradiation. However, despite the known risk of late cardiac dysfunction in survivors of childhood cancer therapy, the risk of clinically important electrocardiographic abnormalities and arrhythmias after treatment is unknown. Standard 12-lead and 24-hour ambulatory electrocardiograms were recorded in 73 patients who received anthracyclines alone, 24 who received cardiac irradiation alone, and 27 who received both anthracyclines and cardiac irradiation. The mean age of the patients was 15 years. Mean cumulative anthracycline dose was 282 mg/m2 in patients who received anthracyclines alone and 244 mg/m2 in patients who received both anthracyclines and cardiac irradiation. Analysis of the 12-lead and 24-hour electrocardiograms demonstrated increased frequency of QTc prolongation, supraventricular premature complexes, supraventricular tachycardia, ventricular premature complexes, couplets and ventricular tachycardia (all p less than 0.001) when compared with an age-matched healthy population. Most patients had abnormalities limited to single supraventricular or ventricular premature complexes; however, potentially serious ventricular ectopy, including ventricular pairs and ventricular tachycardia, were noted in patients with cumulative doses greater than 200 mg/m2. Electrocardiographic abnormalities and arrhythmias are not limited to the acute phase of treatment with anthracyclines and cardiac irradiation. Survivors of childhood malignancy who received anthracyclines or cardiac irradiation, or both, probably should undergo ambulatory electrocardiographic monitoring as part of their follow-up to detect potentially life-threatening arrhythmias.

Dobutamine stress echocardiography for assessing coronary artery disease after transplantation in children

OBJECTIVES The purpose of this study was to determine the feasibility, safety and diagnostic accuracy of dobutamine stress echocardiography (DSE) for evaluating posttransplant coronary artery disease (TxCAD) in children, and to determine the frequency of selected cardiac events after normal or abnormal DSE. BACKGROUND Posttransplant coronary artery disease is the most common cause of graft loss (late death or retransplantation) after cardiac transplantation (CTx) in children. Coronary angiography, routinely performed to screen for TxCAD, is an invasive procedure with limited sensitivity. The efficacy of DSE for detecting atherosclerotic coronary artery disease is established, but is unknown in children after CTx. METHODS Of the 78 children (median age 5.7 years, range 3 to 18) entered into the study, 72 (92%) underwent diagnostic DSE by means of a standard protocol, 4.6 +/- 1.9 years after CTx. The results of coronary angiography performed in 70 patients were compared with DSE findings. After DSE, subjects were monitored for TxCAD-related cardiac events, including death, retransplantation and new angiographic diagnosis of TxCAD. RESULTS No major complications occurred. Minor complications, most often hypertension, occurred in 11% of the 72 subjects. The sensitivity and specificity of DSE were 72% and 80%, respectively, when compared with coronary angiography. At follow-up (21 +/- 8 months), TxCAD-related cardiac events occurred in 2 of 50 children (4%) with negative DSE, versus 6 of 22 children (27%) with positive DSE (p < 0.01). CONCLUSIONS DSE is a feasible, safe and accurate screening method for TxCAD in children. Positive DSE identifies patients at increased risk of TxCAD-related cardiac events. Negative DSE predicts short-term freedom from such events.

The Medium-Term Findings in Coronary Arteries by Intravascular Ultrasound in Infants and Children After Heart Transplantation

OBJECTIVES The study purposes were to determine 1) whether intravascular ultrasound (IVUS) was more sensitive than angiography for the detection of post-transplant coronary artery disease (PTCAD) in pediatric patients; and 2) whether those transplanted as neonates reacted differently than older patients. BACKGROUND Experience with IVUS for the diagnosis of PTCAD in children is limited. METHODS Patients were divided into two groups: those transplanted as neonates (early group) and those transplanted in infancy or childhood (late group). Morphometric analysis was performed, including maximal intimal thickness (MIT) and intimal index (II). Stanford classification was used to grade lesion severity. Acute rejection and cytomegalovirus (CMV) status were correlated with MIT and II. RESULTS Thirty children were studied (early group, n = 13; late group, n = 17). All segments studied were angiographically normal. Mean MIT and mean II were significantly greater in the late group (0.26 +/- 0.14 vs. 0.13 +/- 0.04 mm, p < 0.001 and 0.11 +/- 0.07 vs. 0.07 +/- 0.03 mm, p = 0.04, respectively). There was a significant correlation between MIT and II in those who had acute rejection in the late group. Patients in the late group who were CMV-positive had a significantly higher MIT compared with those in the late group with negative serology (p = 0.04). CONCLUSIONS Intravascular ultrasound was more sensitive than angiography in detecting PTCAD after pediatric heart transplantation. There is a possible role for acute rejection and CMV in the development of PTCAD.

Early Predictors of Survival to and After Heart Transplantation in Children With Dilated Cardiomyopathy

Background— The importance of clinical presentation and pretransplantation course on outcome in children with dilated cardiomyopathy listed for heart transplantation is not well defined. Methods and Results— The impact of age, duration of illness, sex, race, ventricular geometry, and diagnosis of myocarditis on outcome in 261 children with dilated cardiomyopathy enrolled in the Pediatric Cardiomyopathy Registry and Pediatric Heart Transplant Study was studied. End points included listing as United Network for Organ Sharing status 1, death while waiting, and death after transplantation. The median age at the time of diagnosis was 3.4 years, and the mean time from diagnosis to listing was 0.62±1.3 years. Risk factors associated with death while waiting were ventilator use and older age at listing in patients not mechanically ventilated (P=0.0006 and P=0.03, respectively). Shorter duration of illness (P=0.04) was associated with listing as United Network for Organ Sharing status 1. Death after transplantation was associated with myocarditis at presentation (P=0.009), nonwhite race (P<0.0001), and a lower left ventricular end-diastolic dimension z score at presentation (P=0.04). In the myocarditis group, 17% (4 of 23) died of acute rejection after transplantation. Conclusions— Mechanical ventilator use and older age at listing predicted death while waiting, whereas nonwhite race, smaller left ventricular dimension, and myocarditis were associated with death after transplantation. Although 97% of children with clinically or biopsy-diagnosed myocarditis at presentation survived to transplantation, they had significantly higher posttransplantation mortality compared with children without myocarditis, raising the possibility that preexisting viral infection or inflammation adversely affects graft survival.

Pediatric cardiac retransplantation: Intermediate-term results

BACKGROUND Cardiac retransplantation (re-CTx) in children is a controversial therapy, yet it remains the best treatment option to recipients with failing grafts. Our objective was to determine the incidence of re-CTx in a large pediatric population of recipients and evaluate the outcome of such therapy. METHODS Between November 1985 and November 1999, 347 children underwent cardiac transplantation at the Loma Linda University Medical Center. Of these, 32 children were listed for re-CTx. Ten patients died while waiting, and 22 recipients underwent re-CTx. Median age at re-CTx was 7.1 years (range, 52 days to 20.1 years). RESULTS Indications for re-CTx were allograft vasculopathy (n = 16), primary graft failure (n = 5), and acute rejection (n = 1). Two patients with primary graft failure underwent retransplantation within 24 hours of the first transplantation procedure while on extracorporeal membrane oxygenation support. Median time interval to re-CTx for the others was 7.2 years (range, 32 days to 9.4 years). Operative mortality for all cardiac re-CTx procedures was 13.6%. Causes of hospital mortality were pulmonary hypertension with graft failure (n = 2) and multiorgan failure (n = 1). Median hospital stay after re-CTx was 14.1 days (range, 6 to 45 days). There was one late death from severe rejection. Actuarial survival at 3 years for re-CTx was 81.9% +/- 8.9% compared with 77.3% +/- 2.6% for primary cardiac transplantation recipients (p = 0.70). CONCLUSIONS Elective re-CTx can be performed with acceptable mortality. Although the number of patients undergoing retransplantation in this report is small and their long-term outcome is unknown, the intermediate-term survival after re-CTx is similar to that of children undergoing primary cardiac transplantation.

Effect of a selection and postoperative care protocol on survival of infants with hypoplastic left heart syndrome

BACKGROUND We report the development and implementation of a program designed to assign patients preoperatively to either transplant or Norwood procedure based on a score derived from known risk factors and to enhance postoperative care of infants undergoing the Norwood procedure. METHODS A weighted score for each of six variables comprised the scoring system: ventricular function, tricuspid regurgitation, ascending aortic diameter, atrial septal defect blood flow characteristics, blood type, and age. The scoring system was used to prospectively assign mortality risk and lead to recommendation of either Norwood procedure or transplantation. RESULTS Survival following the Norwood procedure significantly improved after the management program was implemented (88% versus 40% at 48 hours, 57% versus 10% at 30 days, and 50% versus 10% at 1 year, p < 0.0001 at each time point). The survival of the group that received a score of 7 or less (high risk) who underwent the Norwood procedure was 78% at 48 hours, 44% at 30 days, and 33% at 1 year; survival rates among patients considered lower risk (greater than 7) were 100% at 48 hours and 80% at 30 days and 1 year. Transplant outcomes remained unchanged. CONCLUSIONS We report improved survival following the Norwood procedure after the implementation of an institutional management approach aimed at improving the outcome of infants with hypoplastic left heart syndrome and may help neutralize historical biases toward Norwood procedure or transplantation.

Usefulness of cardiac transplantation in children with visceral heterotaxy (asplenic and polysplenic syndromes and single right-sided spleen with levocardia) and comparison of results with cardiac transplantation in children with dilated cardiomyopathy

Surgical mortality is high in children with visceral heterotaxy (VH), particularly if atrioventricular valve insufficiency, ventricular dysfunction, or aortic atresia is present. This study reviews the outcome of cardiac transplantation (CT) in infants and children with VH and congenital heart disease who are at high risk for standard palliative or corrective surgery. We reviewed CT outcomes in 29 children with VH, congenital heart disease, atrioventricular valve insufficiency, ventricular dysfunction, and/or aortic atresia. Median age at CT was 3.1 years. Cardiac surgery had been performed in 20 patients (69%) before CT. Follow-up since CT has been 8.5 ± 2.2 years. Outcomes were compared with 45 children who underwent transplantation for dilated cardiomyopathy. Actuarial graft survival in the VH group at 30 days and 1, 5, and 10 years was 100%, 86%, 68%, and 50%, respectively, compared with 100%, 96%, 83%, and 68% in children who underwent transplantation for dilated cardiomyopathy (p = 0.12). Splenic status, cardiac position, age at CT, number of prior cardiac surgeries, or systemic venous anomalies were not predictors of mortality after CT. Cardiopulmonary bypass and graft ischemic times were longer in the VH group; time on the ventilator after CT, length of hospitalization, and rejection, infection, post-transplant lymphoproliferative disease, and transplant coronary artery disease rates were equal. Thus, CT is a viable alternative therapy for high-risk patients with VH, possibly offering improved survival over standard surgical management.

Moderate acute rejection detected during annual catheterization in pediatric heart transplant recipients.

BACKGROUND Acute rejection commonly occurs within the first year after heart transplantation, and then decreases in frequency with time. Recently, the long-term utility of endomyocardial biopsy during routine annual catheterization has been questioned. The purpose of this study was to retrospectively review the prevalence of biopsy-proven rejection during routine annual catheterization in our patient population, determine whether biopsies late after transplant are useful, and identify factors that correlate with late unsuspected rejection. METHODS Biopsy results from the annual catheterization were evaluated from 1986 to August 2000. The prevalence of moderate rejection was evaluated and compared with the patients immunosuppressive regimen; the prevalence of late rejection; and how late rejection correlated with recipient age, number of first-year rejections and presence of sub-therapeutic cyclosporine. RESULTS A total of 1108 biopsies were performed in 269 children with a mean follow-up of 5 +/- 3 years (median 5 years, range 1 to 11 years). Three-drug immunosuppressive therapy, including steroids, was used in 93 patients. There was a persistent 8% to 10% prevalence of moderate rejection at up to 10 years post-transplantation. Moderate rejection was more likely in patients: (1). on 3-drug immunosuppressive therapy; (2). with a recipient age >1 year; and (3). with a relatively lower cyclosporine level. CONCLUSIONS These data suggest that continued surveillance of pediatric transplant patients for acute rejection is indicated for long-term follow-up.

Pretransplant Risk Factors and Causes of Death or Graft Loss After Heart Transplantation During Early Infancy

BACKGROUND This study was performed to report causes of death or graft loss and to identify possible pretransplant risk factors for death or graft loss in infants after heart transplantation. METHODS AND RESULTS Pretransplant risk factors were compared for 153 infants registered for heart transplantation within 90 days of life and transplanted from November 1985 to June 1994. Factors assessed were diagnosis, age at transplantation, race, weight, blood type, sex, donor/recipient blood type match, sex match, weight ratio, fetal registration, locale of pretransplant waiting period, mechanical ventilation, ischemic time, and the need for atrial septostomy or septectomy pretransplantation. No factor was associated with death or graft loss at 1 month or 1 year. Causes of death or graft loss were determined using clinical course and pathology data when available. Death or grafts lost at 1 month, 1 year, and > 1 year were 14, 13, and 15, respectively. Causes of death or graft loss expressed as a percent (at 1 month, 1 year, and > 1 year, respectively) were acute rejection (14, 23, 27), chronic rejection and posttransplant coronary disease (0, 8, 47), infectious causes (21, 15, 13), early graft failure (21, 0, 0), technical issues (21, 23, 0), chronic graft dysfunction (0, 15, 0), and miscellaneous (21, 15, 13). The graft loss rate at 1 year was significantly correlated (linear regression, r2 = .66; P < .05) with the year of transplantation. Actuarial survival in this population was 91% at 1 month, 81% at 1 year, and 73% at 3 years. CONCLUSIONS Heart transplantation in the young infant can be performed with acceptable short-term and midterm results. Causes of death or graft loss and survival are similar to adult data. No pretransplant risk factors were identified. The experience level of the transplant team members affects survival. The diagnosis and management of rejection remain a major challenge.