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Ann Thorac Surg 1999;68:527-530
© 1999 The Society of Thoracic Surgeons

Original Articles

Current results with pediatric heart transplantation

Kirk R. Kanter, MDa, Vincent K.H. Tam, MDa, Robert N. Vincent, MDb, Angel R. Cuadrado, MDb, Anthony A. Raviele, MDb, Alexandria M. Berg, MSNa

a Division of Cardio-Thoracic Surgery, Department of Surgery, Emory University School of Medicine, Atlanta, Georgia, USA
b The Children’s Heart Center, Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, USA

Address reprint requests to Dr Kanter, Division of Cardio-Thoracic Surgery, Emory University School of Medicine, 1365 Clifton Rd, Atlanta, GA 30322
e-mail: kkanter{at}emory.org

Presented at the Forty-fifth Annual Meeting of the Southern Thoracic Surgical Association, Orlando, FL, Nov 12–14, 1998.


   Abstract
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 Abstract
Introduction
 Material and methods
 Results
 Comments
 References
 
Background. Cardiac transplantation is an accepted treatment for children with end-stage heart failure or complex or inoperable congenital defects.

Methods. Since 1988, 95 transplants have been performed in 89 children aged 4 days to 18 years (median 6.9 years, 42 patients 0–5 years). Fifty-eight (61%) had congenital or acquired heart disease, 31 (33%) had idiopathic cardiomyopathy, and 6 (6%) were retransplants. Fifty-seven of the patients had prior cardiac surgery with a range of one to eight procedures (mean 3.4 procedures/patient). At the time of transplantation, 53 (56%) were United Network for Organ Sharing (UNOS) status I, including 23 children on mechanical ventilation and 4 with mechanical circulatory support.

Results. Thirty-day survival in this group was 96%. Posttransplant results showed a median time of ventilation of 1 day (mean 3.0 ± 5.7 days), median duration of inotropic support of 2 days (mean 2.7 ± 2.3 days), median intensive care unit (ICU) stay of 4 days (mean 6.9 ± 9.6 days), and median hospitalization of 9 days (mean 14.3 ± 13.9 days). Follow-up from 1 month to 10.3 years (mean 3.1 years) has demonstrated a 1-year actuarial survival of 79% and a 5-year actuarial survival of 69%. Rejection, both acute and chronic, accounted for the vast majority of deaths.

Conclusions. Pediatric heart transplantation can be accomplished with excellent early survival despite multiple prior cardiac operations and relative severity of illness. Parameters such as postoperative ventilation, inotropic support, ICU stay, and hospitalization can be kept at reasonable levels with acceptable long-term results, although rejection remains a serious problem.


   Introduction
Top
 Abstract
 Introduction
Material and methods
 Results
 Comments
 References
 
Pediatric heart transplantation has become an accepted treatment option for children with end-stage heart failure or inoperable or complex congenital heart disease, with over 3,000 pediatric transplants reported to the Registry of the International Society for Heart and Lung Transplantation in its 1998 report [1]. As this procedure becomes applied more widely, it is important to review results on an ongoing basis at individual centers with moderate experience to determine the efficacy of this procedure in hopes of improving techniques and outcomes. With this in mind, we reviewed the results of 95 consecutive heart transplants in 89 children at our institution.


   Material and methods
Top
 Abstract
 Introduction
 Material and methods
Results
 Comments
 References
 
Since 1988, 95 heart transplants have been performed in 89 children at Egleston Children’s Hospital at Emory University. Ages ranged from 4 days to 18 years, with a mean age of 7.5 ± 6.0 years, and a median age of 6.9 years (Fig 1). Forty-two (44%) were less than 5 years old, and 22 (23%) were under the age of 1 year (12 younger than 3 months).



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  		Fig 1. Age distribution at time of transplantation stratified by diagnostic category (ReTx = retransplantation).

 
The indication for transplantation was idiopathic cardiomyopathy in 31 (33%), congenital heart disease in 50 (53%), acquired heart disease in 8 (8%), and retransplantation in 6 (6%). The number of transplants performed per year categorized by indication for transplant is shown in Figure 2. The most common diagnoses in the congenital category (Table 1) were children who had single ventricle physiology accounting for 33 (67%) of these transplants. Fifteen of these had a previous Fontan procedure.



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  		Fig 2. Number of transplants per calendar year stratified by diagnostic category (ReTx = retransplantation).

 

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  		Table 1. Diagnosis of Children Undergoing Transplantation With Congenital Heart Disease

 
Since the emphasis at our institution is staged surgical palliation for hypoplastic left heart syndrome (the Norwood procedure), only 5 infants with hypoplastic left heart syndrome were transplanted. Of the 8 children with acquired cardiomyopathy, 4 had acquired valvular heart disease, 3 had myocarditis, and 1 had a restrictive cardiomyopathy.

At the time of transplantation, 53 (56%) patients were UNOS (United Network for Organ Sharing) status I, including 23 (24%) on the ventilator, and 4 with mechanical circulatory assistance (one intraaortic balloon, one left ventricular assist device, and two on extracorporeal membrane oxygenation, [ECMO]).

Fifty-seven (61%) of these children had an average of 3.4 ± 2.1 previous cardiac operations (range one to eight operations per patient) including a mean of 1.9 ± 1.5 previous sternotomies per patient (range zero to six). It was necessary to reconstruct the pulmonary arteries at the time of transplantation in 33 patients (35%). Sixty-two patients (65%) had standard atrial anastomoses, whereas the other 33 patients (35%) had separate bicaval anastomoses, including 2 patients with situs inversus.

Postoperatively, all children received triple-drug maintenance immunosuppression (cyclosporine, azathioprine, and steroids) without induction immunotherapy. Efforts were made to wean off steroids within 3 months of transplantation. Routine immune surveillance was performed using scheduled periodic endomyocardial biopsies with rejection episodes treated with pulsed steroids. Only resistant, recurrent, or hemodynamically significant rejection episodes were treated with monoclonal antibodies. Annual coronary arteriography was routine but intravascular ultrasound was not used routinely.


   Results
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 Abstract
 Introduction
 Material and methods
 Results
Comments
 References
 
There were four deaths within 30 days of transplantation (30-day survival 96%) with only one 30-day mortality in the last 76 transplants. Two of these four deaths were in children who were essentially moribund when a donor became available; another was in a child with underestimated gram-negative pneumonia and sepsis. In retrospect, these children were not suitable candidates for transplantation. One of the moribund children was the one with a left ventricular assist device; the other 3 children who required mechanical circulatory assistance pretransplant did well. The fourth 30-day death was at 22 days due to an arrhythmia. Postmortem examination showed unrecognized acute cellular rejection.

Postoperative values for duration of ventilation, inotropic support, intensive care unit (ICU) stay, and posttransplant hospital stay for the hospital survivors are shown in Table 2. Ninety percent of the hospital survivors were weaned from the ventilator within one week of transplantation and 97% were weaned off inotropic support within 1 week. Seventy-six percent of the hospital survivors stayed in the ICU 1 week or less; 92% stayed less than 2 weeks. Two patients stayed as long as 8 weeks in the ICU. The median hospital stay was 9 days, with 84% being discharged within 3 weeks of transplantation, although 2 patients stayed 12 weeks posttransplant.


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  		Table 2. Posttransplant Variables in Hospital Survivors

 
A Kaplan-Meier actuarial survival curve is shown in Figure 3. The 1-year actuarial survival was 79%, and the 5-year actuarial survival was 69%. There were no statistically significant differences in survival at 1 or 5 years among the different groups (congenital, idiopathic, acquired, and retransplant). Excluding the four 30-day mortalities discussed previously, there were 22 deaths in this series, of which 14 were in the first year. Of those 14 children (Table 3), 5 died of sepsis related to their poor pretransplant condition and prolonged ICU stay. One patient died 93 days postoperatively surprisingly of disseminated posttransplant lymphoproliferative disease. The remaining 8 patients dying in the first year succumbed to proven or presumed rejection. Three had transplant coronary artery disease by angiographic or postmortem examination, 3 had autopsy proven acute coronary vasculitis, and 2 died suddenly at home, presumably of rejection.



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  		Fig 3. Kaplan-Meier actuarial survival curve for all transplant recipients. One-year actuarial survival is 79% and 5-year actuarial survival is 69%. Numbers in parentheses represent number of patients at risk for the given time.

 

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  		Table 3. Cause of Death 30–365 Days Posttransplant

 
Except for 1 patient who died 1.5 years posttransplant of trauma sustained in a motor vehicle accident, all seven of the other deaths after 1 year were due to transplant coronary artery disease occurring from 1.2 to 7.6 years (mean 4.5 years) after transplantation. At the time of death, 2 of these patients were awaiting retransplantation, 3 had been turned down for retransplantation due to medical noncompliance, and 2 died unexpectedly and were found to have significant coronary artery disease at autopsy. Also, transplant coronary artery disease was present in all 6 children who underwent late retransplantation a mean of 4.8 years (range 3.1–9.6 years) after their initial transplant.


   Comments
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comments
References
 
Much progress has been made in the field of pediatric heart transplantation since the first unsuccessful effort by Kantrowitz and associates in 1967 [2]. Early reports of children undergoing cardiac transplantation showed alarmingly high perioperative morality rates of 25%–60%, with the diagnosis of congenital heart disease representing a particularly high-risk subset compared with those with cardiomyopathy [3–5]. Presumably, many of these early failures were related to poor patient selection and surgical problems of a technical nature. More recently, however, with more refined surgical techniques and better defined patient selection criteria, results have improved considerably [6–8].

This report shows a very low 30-day mortality of 4%. Although both the Pediatric Heart Transplant Study [9] and the Registry of the International Society for Heart and Lung Transplantation [1] identified age less than 5 years as a risk factor for early death, 42 (44%) of the transplants in this series were in children younger than 5 years, with 22 less than 1 year of age. Furthermore, the severity of illness in this series was moderately acute because 56% of the transplants were in patients who were UNOS status I, with 43% of these on the ventilator at time of transplantation. In contrast to the findings of others [5, 10, 11], we did not find a difference in survival comparing the groups with cardiomyopathy versus those with congenital heart disease, despite the fact that 61% of our series had previous cardiac surgery. Recent reports from Columbia University [12] and the Texas Heart Institute [8] also found no significant early survival difference between these categories. One can infer, therefore, that many of the technical pitfalls seen in earlier experiences with pediatric transplantation involving patient and donor selection, surgical techniques, and early postoperative care largely have been surmounted.

We have shown in this series that these children, despite the severity of their illness and the complexity of their surgical procedure, can recover very quickly after successful transplantation. This is borne out in Table 2, which shows for the hospital survivors after transplantation a median time of ventilation of 1 day (32 children were extubated the day of transplant), median time for inotropic support of 2 days, median ICU stay of 4 days, and median hospitalization of 9 days. Although this hardly can be referred to as "fast track transplantation," the implication is that children, largely due to their resilience, can recover amazingly quickly despite being quite ill before transplantation.

The 1-year actuarial survival rate of 79% and the 5-year actuarial survival rate of 69% in our series compares favorably with survival rates in other reports [9, 10, 12–14], which have 1-year actuarial survival rates from 70% to 82% and 5-year actuarial survival rates from 60% to 64%. As with other series, the dominant cause of death in the first year after transplantation was related to rejection (Table 3). This is despite our policy of routinely scheduled surveillance endomyocardial biopsies in addition to frequent echocardiograms searching for evidence of acute rejection. Disturbingly, 3 of the children who died early had acute coronary vasculitis on postmortem examination with no evidence of acute cellular rejection that could have been detected with endomyocardial biopsy. Other causes of death seen in other reports were low or absent in our patients. There was only one death from posttransplant lymphoproliferative disease and none from opportunistic infection after the initial transplant hospitalization.

All of the deaths after 1 year were due to transplant coronary artery disease, except for the 1 child who died in a motor vehicle accident. When one adds in the 6 children who underwent late retransplantation for transplant coronary artery disease, this means that the incidence of significant graft coronary artery disease resulting in death or retransplantation was 21% of the children who have been followed for more than 1 year (mean follow-up 4.0 ± 2.4 years). Our experience is not different from other studies. Pahl and associates [15] reported a multicenter trial that identified 58 children (out of 815 transplants) who developed transplant coronary artery disease diagnosed by coronary arteriography or autopsy on average 2.2 years after transplantation. Forty-nine of these children died, including 5 of 10 who underwent retransplantation, in contrast to our series in which there were no deaths after retransplantation. Similarly, Vouhe and associates [5] reported a 22% incidence of transplant coronary artery disease in hospital survivors despite a relatively short follow-up period. Gajarski and associates [14] reported a 34% incidence of coronary artery disease on mean follow-up of 4.2 years. The Stanford group also showed a 15% actuarial incidence of transplant coronary artery disease at 5 years [13]. On the other hand, Radley-Smith and Yacoub suggest that this complication can be eliminated by avoiding the use of steroids [10].

At any rate, in our experience, transplant coronary artery disease is the most significant late problem in children after cardiac transplantation. Because our institution has a very low incidence of lethal opportunistic infection yet an ongoing incidence of life-threatening rejection and coronary artery disease, one could argue that our immunosuppressive protocol is inadequate. Partially for this reason, since January 1998, we have changed from cyclosporine to FK 506 (tacrolimus) as the mainstay of immunosuppression in hopes of reducing the incidence of rejection-related deaths [16].

In summary, this series demonstrates that pediatric heart transplantation can be accomplished with excellent early survival despite multiple prior cardiac operations and relative severity of illness. Parameters such as postoperative ventilation, inotropic support, ICU stay, and hospitalization can be kept at reasonable levels with acceptable long-term results. Rejection remains a serious problem and warrants investigation into different and hopefully more effective immunosuppressive protocols.


   References
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comments
 References
 

  1. Hosenpud J.D., Bennett L.E., Keck B.M., Fiol B., Boucek M.M., Novick R.J. The registry of the International Society for Heart and Lung Transplantation. J Heart Lung Transplant 1998;17:656-668.[Medline]
  2. Kantrowitz A., Haller J.D., Joos H., Cerruti M.M., Carstensen H.E. Transplantation of the heart in an infant and an adult. Am J Cardiol 1968;22:782-790.[Medline]
  3. Trento A., Griffith B.P., Fricker F.J., Kormos R.L., Armitage J., Hardesty R.L. Lessons learned in pediatric heart transplantation. Ann Thorac Surg 1989;48:617-623.[Abstract/Free Full Text]
  4. Heck C.F., Shumway S.J., Kaye M.P. The registry of the International Society for Heart Transplantation. J Heart Transplant 1989;8:271-276.[Medline]
  5. Vouhé P.R., Tamisier D., Le Bidois J., et al. Pediatric cardiac transplantation for congenital heart defects. Ann Thorac Surg 1993;56:1239-1247.[Medline]
  6. Kanter K.R., Vincent R.N., Miller B.E., McFadden C. Heart transplantation in children who have undergone previous heart surgery. J Heart Lung Transplant 1993;12:S218-S224.[Medline]
  7. Fullerton D.A., Campbell D.N., Jones S.D., et al. Heart transplantation in children and young adults. Ann Thorac Surg 1995;59:804-812.[Abstract/Free Full Text]
  8. Shaffer K.M., Denfield S.W., Schowengerdt K.O., et al. Cardiac transplantation for pediatric patients with inoperable congenital heart disease. Tex Heart Inst J 1998;25:57-63.[Medline]
  9. Shaddy R.E., Naftel D.C., Kirklin J.K., et al. Outcome of cardiac transplantation in children. Survival in a contemporary multi-institutional experience. Circulation 1996;94(suppl II):69-73.
  10. Radley-Smith R.C., Yacoub M.H. Long-term results of pediatric heart transplantation. J Heart Lung Transplant 1992;11:S277-S281.[Medline]
  11. Webber S.A., Fricker F.J., Michaels M., et al. Orthotopic heart transplantation in children with congenital heart disease. Ann Thorac Surg 1994;58:1664-1669.[Abstract/Free Full Text]
  12. Hsu D.T., Quaegebeur J.M., Michler R.E., et al. Heart transplantation in children with congenital heart disease. J Am Coll Cardiol 1995;26:743-749.[Abstract]
  13. Sarris G.E., Smith J.A., Bernstein D., et al. Pediatric cardiac transplantation. The Stanford experience. Circulation 1994;90(Suppl 2):51-55.
  14. Gajarski R.J., Smith E.O., Denfield S.W., et al. Long-term results of triple-drug-based immunosuppression in nonneonatal pediatric heart transplant recipients. Transplantation 1998;65:1470-1476.[Medline]
  15. Pahl E., Zales V.R., Fricker F.J., Addonizio L.J. Posttransplant coronary artery disease in children. A multicenter national survey. Circulation 1994;90(Suppl 2):56-60.
  16. Armitage J.M., Fricker F.J., del Nido P., Starzl T.E., Hardesty R.L., Griffith B.P. A decade (1982 to 1992) of pediatric cardiac transplantation and the impact of FK 506 immunosuppression. J Thorac Cardiovasc Surg 1993;105:464-473.[Abstract]



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