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Cardiac transplantation in children and adolescents
Cardiac transplantation in children and adolescents Linda J. A d d o n i z i o , MD, a n d Eric A. Rose, MD From the Departments of Pediatrics and Surgery, College of Physicians and Surgeons of Columbia University, New York
Between June 1984 and October 1986, we evaluated 22 children for possible cardiac transplantation at Columbia-Presbyterian Medical Center. Four children died awaiting donor organs. Fifteen children received transplants; eight had cardiomyopathy, and seven had congenital heart dlsease. One child received a heterotopic transplant because of extremely high pulmonary vascular resistance. Irnnrnunosuppressive therapy consisted of 4 to 40 m g / k g / d cyclosporine and 0.2 to 0.5 rng/kg/d prednisone. Rejection was detected by the presence of myocyte necrosis in surveillance endomyocardial biopsy specimens. There were one intraoperative and three early deaths, two from infection and one rejection. The 11 survivors are observed from a few weeks to more than 2 years after transplantation, and all are in excellent clinical health and participate in age-appropriate activitles. These data corroborate the experience of other institutions that cardiac transplantation is a valid treatment in children. (J PEDIATR1987;111(6, part 2):1034-8)
Cardiac transplantation is becoming an increasingly accepted form of therapy for end-stage cardiac disease. Improved results of this treatment have been attributed to the use of cyclosporine immunosuppression. 1 The International Heart Transplantation Registry has recorded more than 2500 heart transplantations since 1976, of which 960 were performed in 1985 alone. The registry reported an 80% 1-year and 77% 5-year survival rate using cyclosporine immunosuppression, compared with 60% 1-year and 42% 4-year survival with conventional azathioprine therapy.2 Centers increasingly began to offer transplantation to the pediatric population, with the result that as of July 1986, 186 cardiac transplantations had been performed in patients younger than 19 years of age. 2 With this improved expectation for extended survival, a heart transplantation program for children was initiated at the ColumbiaPresbyterian Medical Center in June 1984. INDICATIONS
AND CONTRAINDICATIONS
Heart transplantation is indicated in children with end-stage or terminal heart disease for which no reason-
Reprint requests: Linda J. Addonizio, MD, Babies Hospital (102A), 3959 Broadway, New York, NY 10032.
1034
able surgical or medical therapy is available. Children with end-stage cardiomyopathy comprise the majority of candidates referred for transplantation. Although most congenital heart lesions are potentially correctable, perhaps 10% to 20% of patients have lesions for which there is no adequate "corrective" procedure and who could benefit from this treatment? Heart transplantation is also a reasonable alternative in patients with congenital cardiac disease and end-stage myocardial dysfunction, which sometimes occurs after palliative surgery. In patients with CMV
Cytomegalovirus
[
hypoplastic left-heart syndrome, an anatomic lesion for which no definitive repair is available, cardiac transplantation has become an option as well? Evaluation for possible transplantation entails a multidisciplinary approach, to determine if there are any other major systemic diseases or permanent underlying organ dysfunction that would make transplantation dangerous. In our institution, the children are examined by members of our transplant team from pediatric cardiology, surgery, neurology, psychiatry, physical therapy, dentistry, and social service.
Volume 111 Number 6, part 2
Major contraindications to transplantation include active neoplasm or serious infection, recent or unresolved pulmonary infarction, anatomically inadequate pulmonary arteries, and severe, fixed high pulmonary vascular resistance. The last contraindication relates to anticipated donor right-sided heart failure in the operating room when a normal, thin-walled right ventricle would be forced to work against an abnormally high resistance. Pediatric patients referred for transplantation generally have a higher incidence of elevated pulmonary vascular resistance, whether secondary to inoperative congenital heart lesions or long-term severe congestive heart failure. All children must have had a recent cardiac catheterization to evaluate this factor. We have recently reported that many children with high pulmonary vascular resistance are able to have successful transplants when the resistance can be lowered using intravenous vasodilator therapy, either in the catheterization laboratory or after a 1- to 2-week trial in the intensive care unit. 5 Patients are also screened for prior exposure to cytomegalovirus, toxoplasma, Epstein-Barr virus, tuberculosis, and varicella. Screening for Epstein-Barr virus is performed because it has been associated with the development of lymphoma after transplantation. 6 CMV and toxoplasma can be transmitted via the donor organs, and the morbidity and mortality associated with these infections in transplant recipients has been high. 7 Most institutions therefore attempt to match donors and recipients according to CMV status, and for toxoplasma status, if possible. Donors and recipients are primarily matched by ABO blood type and body size. If the recipient has pulmonary hypertension or elevated pulmonary resistance, a larger donor heart is sought. In contrast to donor matching in renal transplantation, H L A typing is performed only retrospectively, because of time constraints and donor heart viability. At present, the donor heart must be implanted within 4 to 5 hours after cross-clamping the aorta. The retrospective H L A data have shown that antigenic mismatches have not correlated with early graft loss. PATIENT
POPULATION
From June 1984 through October 1986, we evaluated 22 children for possible cardiac transplantation at Columbia University. Of these, 19 were accepted into the program. Four children died awaiting transplantation, one during the evaluation period. This 20% loss of patients on the waiting list is indicative of the need for more organ donation and earlier referrals of recipients.~before obligatory intravenous inotropic medications and intensive care support. Two patients were denied entry into the program, one with a residual intracardiac lesion that was amenable to surgery, the other patient with severe fixed pulmonary
Cardiac transplantation
10 3 5
T a b l e I. Age of children with cardiad transplants
Age (yr)
Patients
Survivors"
0-5 6-10 11-15 16-19 Total
4 1 6 ~ 15
2 1 5 _~3 11 (73%)
*Three early deaths: Two infection(2 weeks, 2Vzmonths),one rejection (6~,5weeks). One intraoperativedeath.
hypertension and a chronically infected thoracotomy site. Of the 22 children evaluated thus far, 15 have undergone cardiac transplantation and one child is still waiting. The children ranged in age from 4 days to 18 years (Table I) at the time of transplantation. Eight patients had cardiomyopathy, five dilated and three of the restrictive type. The remaining seven patients had congenital heart defects; some of these had undergone previous surgery with subsequent poor myocardial function (Table II). Seven of the 15 patients had significant elevation of pulmonary vascular resistance. Despite this, 14 of the patients received orthotopic cardiac transplants, that is, replacement of the native heart with the donor organ. One child with end-stage cardiomyopathy and severe fixed pulmonary vascular resistance received a heterotopic cardiac transplant. This patient was not a candidate for heart-lung transplantation because of previous surgery, and he was not a candidate for a transplant in the orthotopic position because of vascular disease; therefore, a second heart (donor) was anastomosed in parallel with his own heart, in the heterotopic position. In this patient, the donor left ventricle provided the systemic cardiac output that his own left ventricle could not. In contrast, the native right ventricle, which was hypertrophied and accustomed to working against high pulmonary resistance, continued to provide the pulmonary blood flow that the thin-walled donor right ventricle could not. Twelve of the 15 patients were dependent on intravenous inotropic support at the time of surgery, six were on respirators, and four had had cardiac arrests prior to surgery. Early mortality and morbidity seemed to be related in part to this degree of pretransplant debilitation. CLINICAL
COURSE AND MANAGEMENT
In the early postoperative period, the cardiac output is to a large extent heart-rate dependent. Although the patients are hemodynamicaUy stable, the donor heart is denervated, and therefore low doses of isoproterenol are usually required for regulation of heart rate in the first 24 to 48 hours.
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Addonizio and Rose
The Journal of Pediatrics December 1987
T a b l e II. Preoperative diagnoses in children with cardiac transplants No. of patients
Cardiomyopathy Restrictive Dilated Congenital defects Hypoplastic left heart Tetralogy of Fallot, s/p repair Single ventricle, transposition of great vessels, mitral atresia, s/p banding Corrected transposition of great vessels, pulmonic stenosis, ventricular septal defect, mitral valve replacement Multiple ventricular septal defects, s/p repair Atrioventricular canal, pulmonic stenosis, s/p shunt Corrected transposition of great vessels, ventricular septal defect, mitral valve replacement
8 3 5 7
Age
4-18 yr 4 d-16 yr
The immunosuppressive regimen begins preoperatively with an orally administered dose of 3 to 6 mg/kg cyclosporine, depending on the renal function. In the operating room methylprednisolone 10 mg/kg is administered intravenously and continued at 3 mg/kg for three postoperative doses. After surgery, cyclosporine in doses ranging from 4 to 40 m g / k g / d is given in two to three divided doses to maintain a serum trough level of 150 to 200 ng/mL (by radioimmunoassay). We have found that the metabolism of cyclosporine is much faster in children than in adults; therefore a more frequent dosing schedule maintains optimal trough levels at a lower total daily dose. On the second postoperative day, prednisone 0.5 mg/kg is given in two divided doses and is then tapered after the first month after transplant to a low of 2.5 to 10 rag/d, depending on the patient's size. Endomyocardial biopsy is used to diagnose rejection, because most episodes are clinically silent. The biopsies are performed on an outpatient basis, initially every week for the first 3 weeks, then every 10 days for a month, every 3 weeks, then monthly for the first year. Cardiac rejection is diagnosed by the presence of myocyte necrosis on the biopsy specimen. Most patients have an average of two rejection episodes, the majority occurring within 3 months of transplantation. 8 Standard therapy for acute rejection at
our institution consists of an orally administered boost of prednisone for 3 days, with a rapid taper of dosage over 1 week to the previous maintenance dose. Intravenous steroids or anti-thymocyte globulin are reserved for resistant rejection, g There was one intraoperative death due to donor heart failure in a 16-year-old patient with corrected transposition of the great vessels. In addition, there were three early deaths. The single neonate with hypoplastic left-heart syndrome died from overwhelming Pseudomonas infection, and a 15-year-old patient who had been receiving massive amounts of steroids preoperatively for myocarditis also died from infection at 10 weeks with CMV pneumonia and multibacterial sepsis. The third death postoperatively was in a 3-year-old child who died of acute rejection at 6 weeks, associated with an undetectable serum cyclosporine level. The 11 survivors range in age from 2 to 18 years and are currently from a few weeks to more than 2 years after transplantation; two have been followed up for longer than 2 years, six for more than 1 year, and the three most recent recipients for less than 1 year. All are in excellent clinical health, and except for the child who just received a transplant, all of the children have returned to school and are active in sports (some for the first time) or ageappropriate activities. The average duration of hospitalization after transplant was approximately 3 weeks, but ranged from 8 days to several months. Complications in our pediatric transplant patients have been primarily related to immunosuppressive therapy. Three children experienced seizures early postoperatively, which were thought to be secondary to high cyclosporine levels in two patients and cyclosporine in combination with metabolic abnormalities in the third. These were selflimited and had no permanent neurologic effects. Hypertension, which is almost universal in the adult transplant population, has occurred in only three children, and has been easily controlled with/~-adrenergic blockade or calcium channel blockers. Renal dysfunction secondary to cyclosporine therapy in these patients has been mild; transient perioperative rises in BUN and creatinine concentration generally have been seen only in those children with the most compromised preoperative hemodynamics. One child has steroid-induced diabetes mellitus. The infectious complications in our survivors have included varicella, which was well tolerated in one, clinical pneumonia thought to be viral in one, recrudescence of oral herpes simplex in one patient, and warts in two. There has been no long-term morbidity from these infections. Although the follow-up in our children has extended to only 289 years, they have been growing and developing normally despite daily steroid therapy.
Volume 111 Number 6, part 2
DISCUSSION Heart transplantation is no longer considered experimental. The report of the U.S. Department of Health and Human Services Task Force stated that the "Public Health Service now recommends that if the institution and patient selection criteria are applied, cardiac transplantation is deemed not only safe, effective and widely accepted, but also reasonable and necessary. ''9 Using cyclosporine immunosuppression, there is now an 80% chance for survival at 1 year, and 70% at 5 years. 2 It is only natural for this life-saving therapy to be offered to children with end-stage cardiac disease. However, some clinicians believe that cardiac transplantation is still experimental in children because there are unanswered questions as to the ultimate long-range survival and side effects of the medications? 0-~2 The results of transplantation in our population of 15 children are similar to the adult experience for the short term (21A years). Other transplant centers have published similar results with longer follow-up. Starnes et al? 3 at Stanford reported an 82% survival at 5 years in the 22 children and adolescents in their series; Fricker ~4 at Pittsburgh reported experience with 10 pediatric transplant recipients observed for up to 3 years postoperatively. It must not be forgotten that the children in these three series had no chance for survival before transplantation. The two major causes of mortality in all series were rejection and infection. The International Registry reported that rejection was the cause of 28% of the deaths in children after transplantation? 5 Stanford reported the same incidence of rejection in their pediatric population as in their adult patients. In our experience, only one died of transplant rejection, but this was associated with an undetectable cyclosporine level. All children had a least one rejection episode. There has been considerable improvement in immunosuppressive techniques over the years as experience has grown, and the "optimal" regimen is constantly changing. It is hoped that continuing research and further experience will lead to the ideal combination of immunosuppressive medications. The detection of rejection still requires invasive procedures. There is no adequate noninvasive test at present for routine rejection surveillance. However, the children, even the toddlers, tolerate the repeated catheterizations well, and the number of biopsies diminish progressively postoperatively. Research into noninvasive techniques for monitoring, such as labeled antibodies and lymphocyte testing, is being actively pursued at many centers? 6' 17 There is a balance to be maintained with immunosuppression in these patients. With enough medication to suppress rejection entirely, the incidence of infection increases dramatically. Cyclosporine is responsible for a
Cardiac transplantation
10 3 7
marked decrease in infectious complications in the transplant population. 1~With azathioprine immunosuppression, the death rate from infection in children was 26% whereas the infectious mortality for cyclosporine was only 9%. 15 In addition, the deaths in most series, including our own, usually occurred in the early postoperative period in those patients who were extremely debilitated before transplantation. The surviving children in our series seem to handle common childhood illnesses, and have had their share of viral upper and lower respiratory tract infections without complications. CMV remains a life-threatening pathogen in seronegative recipients. The development of a vaccine and drug therapy for this virus will be invaluable, because it is not always possible to assess the CMV status of donors or blood products. 19 Because it is unclear whether an immunosuppressed patient can respond adequately to routine vaccinations, some authors believe that incompletely immunized children should not receive transplants? ~ In our series, one child who contracted varicella 2 years after transplantation recovered without complications, and is not immune to varicella by serologic testing. Our children receive scheduled immunizations with the exception of live viral vaccines (Salk vaccine is substituted for oral polio vaccine). The issue of growth retardation secondary to long-term use of corticosteroids remains unanswered at present. Unlike children with collagen vascular diseases, in whom this process has been well documented, transplant patients receive very small maintenance doses of prednisone. Cooley et al. 2~ reported an 8-month-old transplant recipient receiving cyclosporine and prednisone immunosuppression whose growth has followed the normal growth curves for more than 18 months after transplant. 2~ It is not known whether these children will attain their full growth potential; however, other factors that affect growth must be considered. Many of the children referred for transplantation have some growth retardation on the basis of severe complex congenital heart disease or cachexia and debilitation from long-term congestive heart failure. The group of children who will be most affected, not only by possible growth failure but also by the unknown effects of long-term immunosuppression, are the neonates, most of whom have hypoplastic left-heart syndrome. Bailey et al. 4 have reported a series of infants who are now reaching normal developmental milestones, more than 1 year after transplantation? Transplantation in this group of infants seems to be a reasonable alternative to other palliative procedures; however, the long-range outcome, as with any new treatment, is not known. Complications from the use of cyclosporine include hypertension, particularly nocturnal, which was not significant in our pediatric population, unlike the experience in
10 3 g
Addonizio and Rose
other centers. This may be related to differences in cyclosporine dosing. Similarly, the progressive decrease in renal function originally reported in the early experience with cyclosporine appears to be dose related. 21 Accelerated coronary atherosclerosis can occur in the donor heart, but the incidence is small. The cause is unclear, but may be related to a chronic immune injury to the vessels. In patients in whom this becomes severe, retransplantation can be performed. The single largest problem in transplant programs is the lack of donors. Twenty percent to 30% of patients waiting for organs will die before donors can be found. It is not simply a lack of suitable donors; m a n y patients who qualify as donors are not identified. Greater public and health professional awareness and education and a more coordinated system for donor procurement are necessary. OUTLOOK
FOR THE FUTURE
The lifestyle of these children after transplantation is relatively normal. They have traded end-stage heart failure for a new set of problems, in a sense another disease process. However, cardiac transplantation allows them to participate fully in most normal activities of life, which they would never have been able to do. Although the smaller children in whom we have performed transplantation are growing, it is too early to assess the long-range effects of chronic immunosuppression on the growth of the young child, and the development of lymphoproliferative disorders. The field of cardiac transplantation is not static. Continued new developments should improve the longterm outlook for the transplant recipient. We believe that cardiac transplantation is an acceptable therapeutic alternative for the child, as well as the adult, with terminal heart disease. REFERENCES
1. Oyer PE, Stinson EB, Jamieson SW, et al. Cyclosporine in cardiac transplantation: 289 year follow up. Transplant Proc 1983;15:2546. 2. Solis E, Kaye MP. The registry of the International Society for Heart Transplantation: third official report--June 1986. J Heart Transplant 1986;5:2. 3. Penkoske PA, Freedom RM, Rowe RD, Trusler GA. The future of heart and heart-lung transplantation in children. Heart Transplant 1984;3:233.
The Journal of Pediatrics December 1987
4. Bailey LL, Nehlsen-Cannarella SL, Doroshow RW, Jacobson JG, et al. Cardiac allotransplantation in newborns as therapy for hypoplastic left heart syndrome. N Engl J Med 1986; 315:949. 5. Addonizio L J, Rose EA, Gersony WM, Cardiac transplantation in children with elevated pulmonary vascular resistance. Am Heart J 1986;112:647. 6. Hanto DW, Sakamoto K, Purtilo DT, et al. The Epstein-Barr virus in the pathogenesis of post transplant lymphoproliferative disorders. Surgery 1981;90:204. 7. Hakim M, Wregnitt TG, English TAH, et al. Significance of donor transmitted disease in cardiac transplantation. Heart Transplant 1985;4:302. 8. Michler RE, Smith CR, Drusin RE, et al. Reversal of cardiac transplant rejection without massive immunosuppression. Circulation 1986 (in press). 9. Haddow CM. Oct. 9, 1985, memorandum to the Secretary. Subject: Heart transplantation decision memorandum and report-action. Washington, D.C.: Health Care Financing Administration, 1985. 10. Allen HD. Is cardiac transplantation in children an experimental procedure? Am J Dis Child 1986;140:1105. 11. Baum D, Stinson EB, Shumway NE. The place for heart transplantation in children. Pediatr Cardiol 1981;4:743. 12. English TAH. Is cardiac transplantation suitable for children? Cardiology 1983;4:57. 13. Starnes VA, Stinson EB, Oyer PE, et al. Cardiac transplantation in children and adolescents [Abstract]. Circulation 1986;74(suppl 2):11-218. 14. Fricker FJ. Experience with heart transplantation in children. In: Pediatric cardiology. New York: Springer-Verlag, 1985: 616. 15. Pennington D, Sarafian J, Swartz M. Heart transplantation in children. Heart Transplant 1985;4:441. 16. Addonizio L J, Michler RE, Marboe C, et al. Detection of cardiac aUograft rejection using indium labeled antimyosin Fab. J Am Coil Cardiol 1987;9:555. 17. Ertel W, Reichenspurner H, Lersch C, et al. Cyto-immunological monitoring in acute rejection and viral, bacterial or fungal infection following transplantation. Heart Transplant 1985;4:390. 18. Dresdale A, Drusin RE, Lamb J, Rose EA. Reduced infection in cardiac transplant recipients. Circulation 1985;72(suppl 2):11-237. 19. Marker SC, Simmons RL, Balfour HH. Cytomegalovirus vaccine in renal allograft recipients. Transplant Proc 1981; 13:117. 20. Cooley DA, Frazier OH, Van Buren T, et al. Cardiac transplantation in an 8 month old female infant with subendocardial fibroelastosis. JAMA 1986;256:1326. 21. Myers BD, Ross J, Newton L, et al. Cyclosporine associated chronic nephropathy. N Engl J Med 1984;311:699.
Between June 1984 and October 1986, we evaluated 22 children for possible cardiac transplantation at Columbia-Presbyterian Medical Center. Four children died awaiting donor organs. Fifteen children received transplants; eight had cardiomyopathy, and seven had congenital heart dlsease. One child received a heterotopic transplant because of extremely high pulmonary vascular resistance. Irnnrnunosuppressive therapy consisted of 4 to 40 m g / k g / d cyclosporine and 0.2 to 0.5 rng/kg/d prednisone. Rejection was detected by the presence of myocyte necrosis in surveillance endomyocardial biopsy specimens. There were one intraoperative and three early deaths, two from infection and one rejection. The 11 survivors are observed from a few weeks to more than 2 years after transplantation, and all are in excellent clinical health and participate in age-appropriate activitles. These data corroborate the experience of other institutions that cardiac transplantation is a valid treatment in children. (J PEDIATR1987;111(6, part 2):1034-8)
Cardiac transplantation is becoming an increasingly accepted form of therapy for end-stage cardiac disease. Improved results of this treatment have been attributed to the use of cyclosporine immunosuppression. 1 The International Heart Transplantation Registry has recorded more than 2500 heart transplantations since 1976, of which 960 were performed in 1985 alone. The registry reported an 80% 1-year and 77% 5-year survival rate using cyclosporine immunosuppression, compared with 60% 1-year and 42% 4-year survival with conventional azathioprine therapy.2 Centers increasingly began to offer transplantation to the pediatric population, with the result that as of July 1986, 186 cardiac transplantations had been performed in patients younger than 19 years of age. 2 With this improved expectation for extended survival, a heart transplantation program for children was initiated at the ColumbiaPresbyterian Medical Center in June 1984. INDICATIONS
AND CONTRAINDICATIONS
Heart transplantation is indicated in children with end-stage or terminal heart disease for which no reason-
Reprint requests: Linda J. Addonizio, MD, Babies Hospital (102A), 3959 Broadway, New York, NY 10032.
1034
able surgical or medical therapy is available. Children with end-stage cardiomyopathy comprise the majority of candidates referred for transplantation. Although most congenital heart lesions are potentially correctable, perhaps 10% to 20% of patients have lesions for which there is no adequate "corrective" procedure and who could benefit from this treatment? Heart transplantation is also a reasonable alternative in patients with congenital cardiac disease and end-stage myocardial dysfunction, which sometimes occurs after palliative surgery. In patients with CMV
Cytomegalovirus
[
hypoplastic left-heart syndrome, an anatomic lesion for which no definitive repair is available, cardiac transplantation has become an option as well? Evaluation for possible transplantation entails a multidisciplinary approach, to determine if there are any other major systemic diseases or permanent underlying organ dysfunction that would make transplantation dangerous. In our institution, the children are examined by members of our transplant team from pediatric cardiology, surgery, neurology, psychiatry, physical therapy, dentistry, and social service.
Volume 111 Number 6, part 2
Major contraindications to transplantation include active neoplasm or serious infection, recent or unresolved pulmonary infarction, anatomically inadequate pulmonary arteries, and severe, fixed high pulmonary vascular resistance. The last contraindication relates to anticipated donor right-sided heart failure in the operating room when a normal, thin-walled right ventricle would be forced to work against an abnormally high resistance. Pediatric patients referred for transplantation generally have a higher incidence of elevated pulmonary vascular resistance, whether secondary to inoperative congenital heart lesions or long-term severe congestive heart failure. All children must have had a recent cardiac catheterization to evaluate this factor. We have recently reported that many children with high pulmonary vascular resistance are able to have successful transplants when the resistance can be lowered using intravenous vasodilator therapy, either in the catheterization laboratory or after a 1- to 2-week trial in the intensive care unit. 5 Patients are also screened for prior exposure to cytomegalovirus, toxoplasma, Epstein-Barr virus, tuberculosis, and varicella. Screening for Epstein-Barr virus is performed because it has been associated with the development of lymphoma after transplantation. 6 CMV and toxoplasma can be transmitted via the donor organs, and the morbidity and mortality associated with these infections in transplant recipients has been high. 7 Most institutions therefore attempt to match donors and recipients according to CMV status, and for toxoplasma status, if possible. Donors and recipients are primarily matched by ABO blood type and body size. If the recipient has pulmonary hypertension or elevated pulmonary resistance, a larger donor heart is sought. In contrast to donor matching in renal transplantation, H L A typing is performed only retrospectively, because of time constraints and donor heart viability. At present, the donor heart must be implanted within 4 to 5 hours after cross-clamping the aorta. The retrospective H L A data have shown that antigenic mismatches have not correlated with early graft loss. PATIENT
POPULATION
From June 1984 through October 1986, we evaluated 22 children for possible cardiac transplantation at Columbia University. Of these, 19 were accepted into the program. Four children died awaiting transplantation, one during the evaluation period. This 20% loss of patients on the waiting list is indicative of the need for more organ donation and earlier referrals of recipients.~before obligatory intravenous inotropic medications and intensive care support. Two patients were denied entry into the program, one with a residual intracardiac lesion that was amenable to surgery, the other patient with severe fixed pulmonary
Cardiac transplantation
10 3 5
T a b l e I. Age of children with cardiad transplants
Age (yr)
Patients
Survivors"
0-5 6-10 11-15 16-19 Total
4 1 6 ~ 15
2 1 5 _~3 11 (73%)
*Three early deaths: Two infection(2 weeks, 2Vzmonths),one rejection (6~,5weeks). One intraoperativedeath.
hypertension and a chronically infected thoracotomy site. Of the 22 children evaluated thus far, 15 have undergone cardiac transplantation and one child is still waiting. The children ranged in age from 4 days to 18 years (Table I) at the time of transplantation. Eight patients had cardiomyopathy, five dilated and three of the restrictive type. The remaining seven patients had congenital heart defects; some of these had undergone previous surgery with subsequent poor myocardial function (Table II). Seven of the 15 patients had significant elevation of pulmonary vascular resistance. Despite this, 14 of the patients received orthotopic cardiac transplants, that is, replacement of the native heart with the donor organ. One child with end-stage cardiomyopathy and severe fixed pulmonary vascular resistance received a heterotopic cardiac transplant. This patient was not a candidate for heart-lung transplantation because of previous surgery, and he was not a candidate for a transplant in the orthotopic position because of vascular disease; therefore, a second heart (donor) was anastomosed in parallel with his own heart, in the heterotopic position. In this patient, the donor left ventricle provided the systemic cardiac output that his own left ventricle could not. In contrast, the native right ventricle, which was hypertrophied and accustomed to working against high pulmonary resistance, continued to provide the pulmonary blood flow that the thin-walled donor right ventricle could not. Twelve of the 15 patients were dependent on intravenous inotropic support at the time of surgery, six were on respirators, and four had had cardiac arrests prior to surgery. Early mortality and morbidity seemed to be related in part to this degree of pretransplant debilitation. CLINICAL
COURSE AND MANAGEMENT
In the early postoperative period, the cardiac output is to a large extent heart-rate dependent. Although the patients are hemodynamicaUy stable, the donor heart is denervated, and therefore low doses of isoproterenol are usually required for regulation of heart rate in the first 24 to 48 hours.
10 3 6
Addonizio and Rose
The Journal of Pediatrics December 1987
T a b l e II. Preoperative diagnoses in children with cardiac transplants No. of patients
Cardiomyopathy Restrictive Dilated Congenital defects Hypoplastic left heart Tetralogy of Fallot, s/p repair Single ventricle, transposition of great vessels, mitral atresia, s/p banding Corrected transposition of great vessels, pulmonic stenosis, ventricular septal defect, mitral valve replacement Multiple ventricular septal defects, s/p repair Atrioventricular canal, pulmonic stenosis, s/p shunt Corrected transposition of great vessels, ventricular septal defect, mitral valve replacement
8 3 5 7
Age
4-18 yr 4 d-16 yr
The immunosuppressive regimen begins preoperatively with an orally administered dose of 3 to 6 mg/kg cyclosporine, depending on the renal function. In the operating room methylprednisolone 10 mg/kg is administered intravenously and continued at 3 mg/kg for three postoperative doses. After surgery, cyclosporine in doses ranging from 4 to 40 m g / k g / d is given in two to three divided doses to maintain a serum trough level of 150 to 200 ng/mL (by radioimmunoassay). We have found that the metabolism of cyclosporine is much faster in children than in adults; therefore a more frequent dosing schedule maintains optimal trough levels at a lower total daily dose. On the second postoperative day, prednisone 0.5 mg/kg is given in two divided doses and is then tapered after the first month after transplant to a low of 2.5 to 10 rag/d, depending on the patient's size. Endomyocardial biopsy is used to diagnose rejection, because most episodes are clinically silent. The biopsies are performed on an outpatient basis, initially every week for the first 3 weeks, then every 10 days for a month, every 3 weeks, then monthly for the first year. Cardiac rejection is diagnosed by the presence of myocyte necrosis on the biopsy specimen. Most patients have an average of two rejection episodes, the majority occurring within 3 months of transplantation. 8 Standard therapy for acute rejection at
our institution consists of an orally administered boost of prednisone for 3 days, with a rapid taper of dosage over 1 week to the previous maintenance dose. Intravenous steroids or anti-thymocyte globulin are reserved for resistant rejection, g There was one intraoperative death due to donor heart failure in a 16-year-old patient with corrected transposition of the great vessels. In addition, there were three early deaths. The single neonate with hypoplastic left-heart syndrome died from overwhelming Pseudomonas infection, and a 15-year-old patient who had been receiving massive amounts of steroids preoperatively for myocarditis also died from infection at 10 weeks with CMV pneumonia and multibacterial sepsis. The third death postoperatively was in a 3-year-old child who died of acute rejection at 6 weeks, associated with an undetectable serum cyclosporine level. The 11 survivors range in age from 2 to 18 years and are currently from a few weeks to more than 2 years after transplantation; two have been followed up for longer than 2 years, six for more than 1 year, and the three most recent recipients for less than 1 year. All are in excellent clinical health, and except for the child who just received a transplant, all of the children have returned to school and are active in sports (some for the first time) or ageappropriate activities. The average duration of hospitalization after transplant was approximately 3 weeks, but ranged from 8 days to several months. Complications in our pediatric transplant patients have been primarily related to immunosuppressive therapy. Three children experienced seizures early postoperatively, which were thought to be secondary to high cyclosporine levels in two patients and cyclosporine in combination with metabolic abnormalities in the third. These were selflimited and had no permanent neurologic effects. Hypertension, which is almost universal in the adult transplant population, has occurred in only three children, and has been easily controlled with/~-adrenergic blockade or calcium channel blockers. Renal dysfunction secondary to cyclosporine therapy in these patients has been mild; transient perioperative rises in BUN and creatinine concentration generally have been seen only in those children with the most compromised preoperative hemodynamics. One child has steroid-induced diabetes mellitus. The infectious complications in our survivors have included varicella, which was well tolerated in one, clinical pneumonia thought to be viral in one, recrudescence of oral herpes simplex in one patient, and warts in two. There has been no long-term morbidity from these infections. Although the follow-up in our children has extended to only 289 years, they have been growing and developing normally despite daily steroid therapy.
Volume 111 Number 6, part 2
DISCUSSION Heart transplantation is no longer considered experimental. The report of the U.S. Department of Health and Human Services Task Force stated that the "Public Health Service now recommends that if the institution and patient selection criteria are applied, cardiac transplantation is deemed not only safe, effective and widely accepted, but also reasonable and necessary. ''9 Using cyclosporine immunosuppression, there is now an 80% chance for survival at 1 year, and 70% at 5 years. 2 It is only natural for this life-saving therapy to be offered to children with end-stage cardiac disease. However, some clinicians believe that cardiac transplantation is still experimental in children because there are unanswered questions as to the ultimate long-range survival and side effects of the medications? 0-~2 The results of transplantation in our population of 15 children are similar to the adult experience for the short term (21A years). Other transplant centers have published similar results with longer follow-up. Starnes et al? 3 at Stanford reported an 82% survival at 5 years in the 22 children and adolescents in their series; Fricker ~4 at Pittsburgh reported experience with 10 pediatric transplant recipients observed for up to 3 years postoperatively. It must not be forgotten that the children in these three series had no chance for survival before transplantation. The two major causes of mortality in all series were rejection and infection. The International Registry reported that rejection was the cause of 28% of the deaths in children after transplantation? 5 Stanford reported the same incidence of rejection in their pediatric population as in their adult patients. In our experience, only one died of transplant rejection, but this was associated with an undetectable cyclosporine level. All children had a least one rejection episode. There has been considerable improvement in immunosuppressive techniques over the years as experience has grown, and the "optimal" regimen is constantly changing. It is hoped that continuing research and further experience will lead to the ideal combination of immunosuppressive medications. The detection of rejection still requires invasive procedures. There is no adequate noninvasive test at present for routine rejection surveillance. However, the children, even the toddlers, tolerate the repeated catheterizations well, and the number of biopsies diminish progressively postoperatively. Research into noninvasive techniques for monitoring, such as labeled antibodies and lymphocyte testing, is being actively pursued at many centers? 6' 17 There is a balance to be maintained with immunosuppression in these patients. With enough medication to suppress rejection entirely, the incidence of infection increases dramatically. Cyclosporine is responsible for a
Cardiac transplantation
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marked decrease in infectious complications in the transplant population. 1~With azathioprine immunosuppression, the death rate from infection in children was 26% whereas the infectious mortality for cyclosporine was only 9%. 15 In addition, the deaths in most series, including our own, usually occurred in the early postoperative period in those patients who were extremely debilitated before transplantation. The surviving children in our series seem to handle common childhood illnesses, and have had their share of viral upper and lower respiratory tract infections without complications. CMV remains a life-threatening pathogen in seronegative recipients. The development of a vaccine and drug therapy for this virus will be invaluable, because it is not always possible to assess the CMV status of donors or blood products. 19 Because it is unclear whether an immunosuppressed patient can respond adequately to routine vaccinations, some authors believe that incompletely immunized children should not receive transplants? ~ In our series, one child who contracted varicella 2 years after transplantation recovered without complications, and is not immune to varicella by serologic testing. Our children receive scheduled immunizations with the exception of live viral vaccines (Salk vaccine is substituted for oral polio vaccine). The issue of growth retardation secondary to long-term use of corticosteroids remains unanswered at present. Unlike children with collagen vascular diseases, in whom this process has been well documented, transplant patients receive very small maintenance doses of prednisone. Cooley et al. 2~ reported an 8-month-old transplant recipient receiving cyclosporine and prednisone immunosuppression whose growth has followed the normal growth curves for more than 18 months after transplant. 2~ It is not known whether these children will attain their full growth potential; however, other factors that affect growth must be considered. Many of the children referred for transplantation have some growth retardation on the basis of severe complex congenital heart disease or cachexia and debilitation from long-term congestive heart failure. The group of children who will be most affected, not only by possible growth failure but also by the unknown effects of long-term immunosuppression, are the neonates, most of whom have hypoplastic left-heart syndrome. Bailey et al. 4 have reported a series of infants who are now reaching normal developmental milestones, more than 1 year after transplantation? Transplantation in this group of infants seems to be a reasonable alternative to other palliative procedures; however, the long-range outcome, as with any new treatment, is not known. Complications from the use of cyclosporine include hypertension, particularly nocturnal, which was not significant in our pediatric population, unlike the experience in
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Addonizio and Rose
other centers. This may be related to differences in cyclosporine dosing. Similarly, the progressive decrease in renal function originally reported in the early experience with cyclosporine appears to be dose related. 21 Accelerated coronary atherosclerosis can occur in the donor heart, but the incidence is small. The cause is unclear, but may be related to a chronic immune injury to the vessels. In patients in whom this becomes severe, retransplantation can be performed. The single largest problem in transplant programs is the lack of donors. Twenty percent to 30% of patients waiting for organs will die before donors can be found. It is not simply a lack of suitable donors; m a n y patients who qualify as donors are not identified. Greater public and health professional awareness and education and a more coordinated system for donor procurement are necessary. OUTLOOK
FOR THE FUTURE
The lifestyle of these children after transplantation is relatively normal. They have traded end-stage heart failure for a new set of problems, in a sense another disease process. However, cardiac transplantation allows them to participate fully in most normal activities of life, which they would never have been able to do. Although the smaller children in whom we have performed transplantation are growing, it is too early to assess the long-range effects of chronic immunosuppression on the growth of the young child, and the development of lymphoproliferative disorders. The field of cardiac transplantation is not static. Continued new developments should improve the longterm outlook for the transplant recipient. We believe that cardiac transplantation is an acceptable therapeutic alternative for the child, as well as the adult, with terminal heart disease. REFERENCES
1. Oyer PE, Stinson EB, Jamieson SW, et al. Cyclosporine in cardiac transplantation: 289 year follow up. Transplant Proc 1983;15:2546. 2. Solis E, Kaye MP. The registry of the International Society for Heart Transplantation: third official report--June 1986. J Heart Transplant 1986;5:2. 3. Penkoske PA, Freedom RM, Rowe RD, Trusler GA. The future of heart and heart-lung transplantation in children. Heart Transplant 1984;3:233.
The Journal of Pediatrics December 1987
4. Bailey LL, Nehlsen-Cannarella SL, Doroshow RW, Jacobson JG, et al. Cardiac allotransplantation in newborns as therapy for hypoplastic left heart syndrome. N Engl J Med 1986; 315:949. 5. Addonizio L J, Rose EA, Gersony WM, Cardiac transplantation in children with elevated pulmonary vascular resistance. Am Heart J 1986;112:647. 6. Hanto DW, Sakamoto K, Purtilo DT, et al. The Epstein-Barr virus in the pathogenesis of post transplant lymphoproliferative disorders. Surgery 1981;90:204. 7. Hakim M, Wregnitt TG, English TAH, et al. Significance of donor transmitted disease in cardiac transplantation. Heart Transplant 1985;4:302. 8. Michler RE, Smith CR, Drusin RE, et al. Reversal of cardiac transplant rejection without massive immunosuppression. Circulation 1986 (in press). 9. Haddow CM. Oct. 9, 1985, memorandum to the Secretary. Subject: Heart transplantation decision memorandum and report-action. Washington, D.C.: Health Care Financing Administration, 1985. 10. Allen HD. Is cardiac transplantation in children an experimental procedure? Am J Dis Child 1986;140:1105. 11. Baum D, Stinson EB, Shumway NE. The place for heart transplantation in children. Pediatr Cardiol 1981;4:743. 12. English TAH. Is cardiac transplantation suitable for children? Cardiology 1983;4:57. 13. Starnes VA, Stinson EB, Oyer PE, et al. Cardiac transplantation in children and adolescents [Abstract]. Circulation 1986;74(suppl 2):11-218. 14. Fricker FJ. Experience with heart transplantation in children. In: Pediatric cardiology. New York: Springer-Verlag, 1985: 616. 15. Pennington D, Sarafian J, Swartz M. Heart transplantation in children. Heart Transplant 1985;4:441. 16. Addonizio L J, Michler RE, Marboe C, et al. Detection of cardiac aUograft rejection using indium labeled antimyosin Fab. J Am Coil Cardiol 1987;9:555. 17. Ertel W, Reichenspurner H, Lersch C, et al. Cyto-immunological monitoring in acute rejection and viral, bacterial or fungal infection following transplantation. Heart Transplant 1985;4:390. 18. Dresdale A, Drusin RE, Lamb J, Rose EA. Reduced infection in cardiac transplant recipients. Circulation 1985;72(suppl 2):11-237. 19. Marker SC, Simmons RL, Balfour HH. Cytomegalovirus vaccine in renal allograft recipients. Transplant Proc 1981; 13:117. 20. Cooley DA, Frazier OH, Van Buren T, et al. Cardiac transplantation in an 8 month old female infant with subendocardial fibroelastosis. JAMA 1986;256:1326. 21. Myers BD, Ross J, Newton L, et al. Cyclosporine associated chronic nephropathy. N Engl J Med 1984;311:699.