Cardiac

Transplantation Linda

c

in the Pediatric J. Addonizio

ARDIAC transplantation is an accepted therapy for end-stage heart disease in the adult patient. The International Heart Transplantation Registry has recorded that over 6,800 patients have received cardiac transplants as of March 15, 1988, with 2,200, being performed in 1987 alone.’ The almost exponential rise in procedures is directly related to the improved outlook and survival for transplantation patients as a result of the introduction of cyclosporine immunosuppression. The 5-year survival rate for patients on triple drug immunosuppression is 84%; the IO-year survival rate is 72% (61 patients).* However accepted transplantation is in the adult population, it is still considered by many as only a desperation therapy for children with end-stage heart disease. The first reported infant cardiac transplantation occurred in 1967, when Kantrowitz et al* transplanted the heart from an anencephalic infant into a 2-week-old infant with tricuspid atresia. The child survived only a few hours. Then in 1968, Cooley et al3 performed a heartlung transplant in a 2-month-old child with an atrioventricular (AV) septal defect who died hours after the operation with pulmonary insufficiency. A review of the data from the Heart Transplantation Registry showed that prior to 1980 less than five children received cardiac transplants per year, and the majority of them were adolescents.4 Since that time there has been a rapid increase in the number of procedures in the pediatric age group coinciding with the improved survival and higher quality lifestyle afforded by the use of cyclosporine immunosuppression. In 1984, 37 children received cardiac transplants, with 25% under the age of 10 years.4 The most recent data from The International Heart Transplant Registry shows that now 651 patients under the age of 20 years have undergone transplantation between 1967 and November 1988. The l-year actuarial survival rate for the series was 75%, with a 5-year actuarial survival rate of 7 l%.’ INDICATIONS

Heart transplantation is indicated in children with end-stage heart disease for which no reasonProgress in Cardiovascular

Diseases, Vol XXXIII,

No 1 (July/August),

Patient

able surgical procedure is available or when they are refractory to maximal medical therapy. These patients can be divided into two diagnostic categories, those with acquired heart disease and those with congenital defects (Table 1). Acquired Heart Disease Children with cardiomyopathy comprise the majority of candidates referred for transplantation.4*6 Most patients have idiopathic dilated cardiomyopathy; however, there are a substantial number of children referred with familial cardiomyopathy as well as postviral myopathy. Rarely, patients with acute severe myocarditis cannot be managed medically and become candidates for transplantation. In addition, there are those children with hypertrophic and/or restrictive cardiomyopathies who do not have systolic myocardial dysfunction, but have severe enough diastolic impairment to warrant referral for transplantation. Endocardial fibroelastosis is another type of myocardial disease that can lead to transplantation. In some patients with the contracted type it results in a restrictive picture, and in others it gives a dilated poorly contractile left ventricle (LV) with classic congestive heart failure. Although both types of patients are candidates for transplantation, the former have a higher incidence of pulmonary vascular disease at a relatively young age, and may have to be considered for heart-lung transplantation. The use of adriamycin and other anthracyclines in the treatment of childhood neoplasia has lead to a group of children whose neoplasms have been cured; however, they are left with a severe congestive cardiomyopathy, and irreversible cardiac failure. This is an indication for cardiac transplantation providing the child is felt to be tumor-free. A primary cardiac tumor is another lesion that would be amenable to transplantation From the Department of Pediatrics. Columbia University. College of Physicians and Surgeons, New York, NY. Address reprint requests to Linda J. Addonizio, MD, Columbia University, College of Physicians and Surgeons, 630 W 168th St. New York, NY 10023. 0 1990 by W.B. Saunders Company. 0033-0620/90/3301-0003$5.00/O 1990:

pp 19-34

19

LINDA Table

‘l.

Diagnoses

That

Transplantation

May

Require

Cardiac

in Pediatrics

Acquired heart disease Idiopathic dilated cardiomyopathy Acute myocarditis lschemic cardiomyopathy Restrictive Endocardial Anthracycline Cardiac Congenital

cardiomyopathy fibroelastosis myocardial

tumor heart

toxicity

disease

Ventricular failure following previous repairs Complex defects not amenable to surgery As alternative when there is no definitive surgical dure

proce-

when it is nonmalignant, and cannot be resected. In most cases this is usually a large fibroma involving the ventricular free wall and causing outflow obstruction. Cardiac transplantation for atherosclerosis and ischemic heart disease, although rare in the pediatric age group, has been reported and is usually in the context of familial hypercholesterolemia. Congenital

Heart Disease

Patients with complex congenital heart lesions that cannot be helped by adequate palliative or corrective surgery or who have severe myocardial dysfunction following surgical procedures are candidates for transplantation. It is estimated that perhaps 10% to 20% of children with congenital heart disease might benefit from this therapy during their lifetime.6 Most complex congenital heart lesions are amenable to some type of primary or first stage palliative repair. Patients with univentricular hearts, tricuspid atresia, or pulmonary atresia usually do well after initial surgical interventions. However, a small proportion of these patients cannot have the second more “definitive” repair secondary to chamber size, poor ventricular function, high pulmonary resistance, or other valvar insufficiency. A cardiac transplant procedure is feasible in even the most complex of lesions if the pulmonary arteries are of reasonable size. Pulmonary artery (PA) reconstruction for kinking, or stenoses following systemic to pulmonary shunts, or PA bands can be performed sucessfully at the time of transplantation. Trento et al7 felt, in a recent report, that unfavorable pulmonary anatomy resulted in prohibitive

J. ADDONIZIO

perioperative mortality in patients with congenital heart lesions. Macoviak et al’ described successful repair of the PA in a 22 year old with univentricular heart who received an orthotopic transplant. We have now transplanted four patients with complex anatomy who required extensive pulmonary reconstruction without any added morbidity.9910 One patient, a 17 year old with tricuspid atresia, pulmonary atresia, and a Waterston shunt was referred with aortic insufficiency, mitral insufficiency, poor ventricular function, and severe stenosis of the right PA resulting in diminished flow to the left lung. During the transplant a complete reconstruction of the PA and takedown of the Waterston was performed. A subsequent pulmonary angiogram showed a normal flow pattern (Fig 1). There are several congenital heart defects in which the right ventricle (RV) serves as the systemic ventricle. It is a source of controversy whether the RV can be relied on to perform a normal systemic workload for a lifetime. Patients with D-transposition of the great vessels who have had Mustard or Senning repairs sometimes return with poorly functioning systemic ventricles and/or tricuspid insufficiency, and are referred for transplantation. Patients with corrected or L-transposition of the great vessels become candidates for transplant when associated lesions are repaired, and RV function deteriorates. Most commonly the additional abnormalities include atria1 (ASD) and/or ventricular septal defect (VSD), left AV valve abnormalities, VSD with or without pulmonic stenosis, dextrocardia, or a single ventricle with an outlet chamber with or without pulmonary stenosis. Repair of these lesions can be more difficult because of the unusual position of the ventricles and conduction system, and progressive tricuspid (left AV) valve insufficiency may occur. In infants with hypoplastic left heart syndrome, there has been no definitive repair available that does not carry a high morbidity and mortality. Cardiac transplantation has become an option for these patients. Bailey et al have reported on the successful transplantation of 14 infants with hypoplastic left heart syndrome with 78% survival, and no morbidity.” Mavroudis et all2 have also reported on five infants transplanted with this lesion with four survivors. It seems clear that transplantation is a viable thera-

CARDIAC

TRANSPLANTATION

IN CHILDREN

Fig 1. (A) Pulmonary angiogram in a patient with pulmonary atresia status post-Waterston shunt showing filling of only the right pulmonary artery secondary to severe distortion of the proximal right pulmonary artery. (6) Pulmonary angiogram of the same patient following transplantation and repair of the pulmonary arteries showing normal filling of both branch pulmonary arteries.

22

LINDA

peutic modality for this syndrome. However, there is a shortage of donor hearts for this age group, and there are a number of infants who die waiting for transplantation, or who must be removed from the list for end-organ dysfunction. Some people have advocated using the first stage Norwood procedure as a bridge to transplantation, because of the donor shortage. Although feasible, it would add greater morbidity to what might be felt to be a more definitive repair, and would abrogate the immunologic advantage that transplantation affords in the newborn period. Other lesions that may come to transplantation as the primary procedure are severe Ebstein’s malformation or Uhl’s anomaly. The last category of children with congenital heart lesions that are referred for transplantation consists of those patients who have had complete repair of their abnormalities, but return with severe irreversible ventricular dysfunction perhaps from poor myocardial preservation at the time of surgery, or superimposed cardiomyopathy. EVALUATION

Evaluation for possibletransplantation entails a multidisciplinary approach, to determine if there are any other major systemic diseasesor permanent underlying organ dysfunction that would make transplantation dangerous or unfeasible. Another goal of the evaluation is to determine if there are any more “standard” therapeutic options available to the patient. In this institution, the children are examined by members of the transplant team from pediatric cardiology, surgery, nursing, neurology, psychiatry, physical therapy, dentistry, and social service. The cardiac evaluation consistsof two-dimensional echocardiography for anatomy and function, electrocardiogram (ECG), and radionuelide evaluation of ventricular function, when appropriate. A complete cardiac catheterization is performed for hemodynamic evaluation or to rule out operative alternatives depending on the diagnosis. An RV endomyocardial biopsy is performed if myocarditis is suspected. When PA pressuresare elevated and pulmonary vascular resistance (PVR) index is greater than five units, a vasodilator study using a graded nitroprusside infusion is performed to determine reactivity of the pulmonary vascular bed.

J. ADDONIZIO

Other major organ dysfunction or pathology is evaluated by standard blood tests or more specific testing (ie, pulmonary function tests) as indicated. A neurological consultation is obtained for elucidation of prior or impending neurological events as well as for a baseline before transplantation. A dental consult where appropriate is also performed to check for and remedy possible sources of infection and teach proper oral hygiene that will be necessary after transplantation. The infectious diseaseand immunologic evaluation consists of multiple cultures looking for active or occult bacterial, viral, fungal, or parasitic infections, as well as serologies for prior exposure to cytomegalovirus (CMV), toxoplasma, Epstein-Barr virus, hepatitis B, human immunodeficiency virus (HIV), varicella, and herpes viruses. Skin testing for tuberculosis with an anergy panel is performed. If the patient is PPD-positive, then isoniazid prophylaxis will be given. CMV and toxoplasma screeningare important becauseof transmittal via the donor organs and the high morbidity and mortality associated with these infections in new transplant recipients.” Therefore, most institutions attempt to match donors and recipients according to CMV status and to use CMV-negative blood if the recipient is seronegative. Screening for exposure to Epstein-Barr virus is performed becauseit has been associated with the development of lymphoma after transplantation.” Knowledge of the varicella immune status in the pediatric population is necesary becausethey have a high exposure to active cases.Zoster immune globulin is administered for exposure, but we have found that the children tolerate varicella infection easily posttransplant using acyclovir therapy. It is also important to know their immunization status. If they are not on the active donor list, immunizations should be completed, asindicated by age, especially the measles, mumps, rubella vaccine that contains live virus. After transplant, no live viral vaccines are given. However, diptheria, pertussis, tetanus as well as Salk polio vaccine can be given safely. Pneumococcal and Haemophilus injluenzae vaccines may also be given. The remainder of the immunologic workup consists of ABO blood typing for donor matching, human lymphocyte antigen (HLA) typing (for retrospective use), and measurement

CARDIAC

TRANSPLANTATION

IN CHILDREN

of the percent reactive antibody (PRA) against a donor panel. If the PRA is high, attempts will be made to effect a donor/recipient cytotoxic screen prior to transplantation. Psychiatric and social service evaluations are made to not only identify possible problems but to help the patients and family develop coping strategies with the extreme changes in lifestyle transplantation imposes. A physical therapy evaluation is also obtained to design a comprehensive program for posttransplant rehabilitation and to provide immediate help with energy conservation techniques for the donor waiting period. Another integral part of this posttransplant rehabilitation planning is a dietary evaluation with education about a heart-healthy diet. CONTRAINDICATIONS

Through the years a list of absolute contraindications to cardiac transplantation has evolved. Most centers have found, by violating these “rules” that many clinical problems on this list are only relative contraindications, and that successful transplantation can be achieved. Consequently the list of absolute contraindications has been narrowed to in&de oniy those clinical situations where the risks involved with the procedure outweigh the possiblebenefits. A major contraindication to transplantation is active neoplasm. A child with a previous neoplasm that is felt to be cured is a suitable candidate with the understanding that this patient might perhaps have an increased risk for developing another tumor on immunosuppressive therapy. In this serieswe have transplanted two children with previous tumors (acute myeloblastic leukemia and neuroblastoma) without recurrence for 18 and 30 months postoperatively. Another problem that posesa high risk for mortality after transplantation is serious infection. Most children awaiting transplantation who develop infections requiring intravenous (IV) antibiotics are placed on inactive status until the infection is adequately treated. This situation is a constant threat for those patients who are extremely debilitated and dependent on inotropic support in the intensive care setting. Two desperately ill children underwent transplantation in this institution who had been febrile on the day prior to transplantation. Both were subsequently found to have pneumonia and died of septic

23

complications despite appropriate therapy. A related contraindication is a recent or unresolved pulmonary infarction because of the possibility of superimposedinfection and abscessformation. The only anatomical contraindication is inadequate PAS. As previously discussed, PAS of sufficient size that are stenotic or distorted can usually be repaired successfully at the time of transplantation. Abnormal great vessel relationships, dextrocardia, venous drainage anomalies, and abnormal situs, although more difficult to repair, are not felt to be insurmountable surgical problems at this institution. We performed a transplantation in a 12-year-old boy with dextrocardia, L-transposition, following ventricular septal defect (VSD), and conduit repair of pulmonic stenosiswho had poor ventricular function after left AV valve replacement. In addition, there was interruption of the inferior vena cava with azygouscontinuation, and the hepatic veins draining into the right atrium. At surgery the heart was placed in the left side of the chest (Fig 2). Those patients with inadequate PAS can be evaluated for possibleheart-lung transplantation. Severe, fixed high-PVR is a major contraindication because of anticipated donor right heart failure in the operating room or in the early postoperative period. Much has been written about this fatal complication, how to avoid it, and what level of resistance is acceptable.13-‘6 A retrospective analysis on data from 82 transplantation patients in this institution was performed to develop more specific pulmonary resistance criteria for transplantation.17 We compared PVR calculated in Wood units and indexed resistance units (corrected for body surface area [BSA]) to the incidence of right heart failure after transplantation. Indexing resistance units, although not traditionally usedby most centers, is necessaryto allow valid comparisons between patients of widely varying size. This is especially pertinent in the pediatric population but becomes as important in adults whose cardiac outputs are extremely low; therefore, indexing for BSA gives a more correct estimate of resistanceto Bow. Previous accepted criteria allowed transplantation in patients with PVR lessthan 6 Wood units.” We observed four deaths, in this institution, secondary to acute right heart failure (three intraoperative, one postoperative) in adult patients with preoperative PVR lessthan 5 Wood units. In the

24

LINDA

,,, ;r 4 7);

retrospective study it became clear that no patient developed right heart failure with a PVR index less than 6, and that correcting for body size identified a subpopulation of 25 of 73 patients previously felt to have acceptably low PVR by Wood criteria, who were at risk for developing right heart failure. Seven of these patients developed right heart failure, and four died of right heart failure. We also felt that vasodilator studies in the cardiac catheterization laboratory as well as trials of chronic IV vasodilators was helpful in testing the reactivity of the pulmonary bed. Pediatric patients referred for transplantation generally have a higher incidence of elevated PVR whether secondary to inoperative congenital heart lesions or long-term severe congestive heart failure. We reported successful transplantation procedures in six children with markedly elevated PVR (7 to 15 indexed units) when their resistance was at least somewhat responsive to vasodilator therapy. i8 One child with cardiomyopathy who was not a candidate for heart-lung transplantation had fixed PVR of 18 units. He is now 3 years after a successful heterotopic transplantation and leading a normal life (Fig 3). Heterotopic transplantation might prove to be a viable option for this category of patient because the hypertrophied native RV provides the pulmonary blood flow that the thin-walled donor RV could not, whereas the donor LV takes over the systemic workload from the failed native LV (Fig 4).

J. ADDONIZIO

Fig 2. Chest x-rays on a child with dextrocardia, corrected transposition, following ventricular septal defect and conduit repair for pulmonary stenosis, and left atrioventricular valve replacement. On the left (A) is a film pretransplant showing the dextrocardia, and on the right (6) is a film posttransplant with the donor heart now in the left chest.

Irreversible hepatic or renal dysfunction is a contraindication to orthotopic cardiac transplantation because of the necessity for cyclosporine therapy, which is metabolized by the liver and effects renal function. These patients could be considered for possible dual organ transplant (ie, heart and liver or heart and kidney). A child with a renal or genitourinary anomaly could be considered a candidate, especially if the anomaly was reparable and if renal function was normal. Central nervous system disease that is degenerative in nature or so severe that the child could not have a meaningful lifestyle is also a contraindication to transplantation. We have transplanted children with prior strokes or transient ischemic attacks without significant added morbidity. Anticonvulsant therapy for a previous seizure disorder is manageable, although it is difficult to titrate because of the interaction with cyclosporine metabolism. The role of a stable family support system is crucial in pediatric transplantation. Commitment to a transplantation program and lifestyle can be an overwhelming task for an adult with even the most stable of family systems. Therefore, for a small child who is dependent on his caregivers, we require at least one stable family member who will be committed to the child’s health care and well-being. Although this is usually a parent, we have patients whose parents were not capable of handling this responsibility so that an aunt or grandmother took over the

CARDIAC

TRANSPLANTATION

25

IN CHILDREN

Fig 3. (A) Pretransplant chest x-ray of a patient with severe cardiomyopathy Chest x-ray following heterotopic transplant in this same patient showing decreased size of the native left ventricle on the left.

caregiving role. This requirement is really necessary because noncompliance or neglect of the medical regimen can easily result in death. When the patient is an adolescent and for the most part capable of self-care, then we can be more flexible. Most family situations have been found to be workable; however, this comes about by virtue of a large investment of time on the part of the transplant team both preoperatively and postoperatively. OPTIMAL

TIMING

OF TRANSPLANTATION

Despite the success with transplantation in the adult patient, it is still considered by many to be only a desperation therapy for children with similar end-stage heart disease. Thus, most children referred for transplantation have already developed severe pulmonary hypertension and/ or hemodynamic decompensation and inotrope dependency. Although children with extreme debilitation and multiorgan failure can survive and thrive following transplantation, it is clear that these risk factors affect their chance for survival, and their postoperative morbidity.’ In addition, with the unpredictable length of wait for a donor organ, many children die prior to

the

and donor

high pulmonary heart shadow

vascular resistance. in the right chest,

(B) with

transplantation, or develop complications that could put them on the inactive list. A retrospective analysis of our pediatric recipient population showed that only 23% had not developed pulmonary hypertension or hemodynamic decompensation requiring inotropic support at the time of transplantation. A univariate and multivariate analysis was performed examining the effect of nine variables on survival after transplantation, including: pulmonary hypertension, inotrope dependency, age, need for hospitalization, congenital heart disease, need for surgical PA reconstruction, prior stroke, history of cardiac arrest(s), and mechanical ventilator dependence.lg None of the potential risk factors were a statistically significant predictor of risk, although pulmonary hypertension approached significance. However, the combined presence of pulmonary hypertension and inotrope dependency was a highly significant predictor of mortality (relative risk, 4:l; P < .002). One-year actuarial survival of patients with this combination was 30% versus 84% without the combination (Fig 5). The l-year actuarial survival of patients with neither of these risk factors was 100%. Therefore, it is clear that patients referred

LINDA

J. ADDONIZIO

Fig 4. (AI A radionuclide angiogram in the frontal projection of a child status postheterotopic transplant showing the donor left ventricle (dLV) on the right with e tiny nonworking donor right ventricle IdRV). The native LV remains dilated on the left. and the large native RV provides the pulmonary blood flow. [B) Simultaneous electrocardiogrem (ECG) and arterial pressure tracing immediately postheterotopic transplant showing the donor ECG complexes (D) associated with more systemic work load than the native heart (NI. E represents an ectopic native heart complex.

earlier in their disease process have improved survival. However, it is often extremely difficult to predict impending deterioration in these children with severe heart disease, because it is not infrequent that they may have relatively few overt symptoms until they decompensate. Studies in adult patients with idiopathic dilated cardiomyopathy have shown that LV ejection fraction (LVEF) measured by radionuclide techniques was the only significant predictor of short-term mortality, particularly identifying

those patients who were likely to die within 6 months. In a study by Keough et al,” patients with LVEF z--20% had an actuarial survival of approximately 90% at 1 year. In contrast, the patients with LVEF