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Ann Thorac Surg 2005;79:53-60
© 2005 The Society of Thoracic Surgeons
a Department of Cardiac Surgery, Munich, Germany
b Department of Pediatric Cardiology, Ludwig Maximilians University Hospital Munich-Grosshadern, Munich, Germany
Accepted for publication December 10, 2003.
* Address reprint requests to Dr Groetzner, Department of Cardiothoracic and Vascular Surgery, Friedrich Schiller University Jena, D-07747 Jena, Germany
jan.groetzner{at}med.uni-jena.de
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Abstract |
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METHODS: Since 1988, 50 heart transplants were performed in 47 patients (30 with dilated cardiomyopathy, 17 with congenital heart disease). Mean age was 9.4 ± 6.9 years (range, 4 days to 17.9 years). Twenty-three patients had a total of 36 previous operations. Clinical outcome was evaluated retrospectively.
RESULTS: Perioperative mortality was 6% due to primary graft failure. Late mortality (12%) was caused by acute rejection (n = 2), pneumonia (n = 2), intracranial hemorrhage (n = 1), and suicide (n = 1). Mean follow-up was 5.24 ± 3.6 years. Actuarial 1, 5, and 10 year survival was 86%, 86%, and 80% and improved significantly after 1995 (92% [1 year]; 92% [5 years]). There was no significant difference between patients with dilated or congenital heart disease (1 year: 86% vs 82%; 5 years: 83% vs 74%; 10 years 83% vs 74%; p = 0.62). Three patients with therapy resistant acute or chronic rejection and assisted circulation underwent retransplantation and are alive. Freedom from acute rejection after 5 years was 40% with primary cyclosporine immunosuppression regime and 56% with tacrolimus. Since the introduction of mycophenolate mofetil, freedom from acute rejection increased to 62%. All survivors are at home and in good cardiac condition.
CONCLUSIONS: Pediatric heart transplantation is the treatment of choice for end-stage dilated cardiomyopathy as for congenital heart disease with excellent clinical midterm results. It is a valid alternative to reconstructive surgery in borderline patients. However, further follow-up is necessary to evaluate the long-term side effects of immunosuppressants.
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Introduction |
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Material and Methods |
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TopAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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Indication for transplantation was end-stage heart failure of any origin without any other feasible medical or surgical treatment option. Preoperative diagnosis was either cardiomyopathy (n = 30) or congenital heart disease (n = 17). Three patients underwent retransplantation. Twenty-three patients had 36 surgical interventions before heart transplantation (HTx) (Table 1). All patients were in New York Heart Association (NYHA) Class III-IV or IV preoperatively and received anticongestive medication; ten had ventricular arrhythmias, 11 were intubated, and 20 stayed on the intensive care unit (ICU) before transplantation. In five patients a ventricular assist device (VAD) and in one patient an extracorporeal membrane oxygenation (ECMO) were implanted as bridge to transplant or to retransplant. These patients and 12 others were listed as high urgent. Congestive heart disease (CHD) patients were younger and had less commonly mechanical circulatory support than dilated cardiomyopathy (DCM) patients. Preoperative data are listed in Table 2.
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Bretschneider's cardioplegia was used for perfusion of the donor graft until 1991; in 1992 we changed to University of Wisconsin solution due to better long-term results in animal studies [2]. In 1996, inhalative nitric oxide (NO) was introduced for patients with high pulmonary vascular resistance to prevent postoperative right ventricular failure.
Immunosuppression Regime
The immunosuppressive protocol at our institution changed during the study period: In the beginning we used a triple regimen consisting of cyclosporine, corticosteroids, and azathioprine. In 1994, tacrolimus was introduced for immunosuppression regimen in a child after retransplantation and was used thereafter. Mycophenolate mofetil (MMF) was combined with cyclosporine in 1995 for the first time. Since then the immunosuppressive regimen consisted of cyclosporine in combination with trough level adjusted MMF and corticosteroids.
Methylprednisolone (500 mg) was started intraoperatively at the end of cardiopulmonary bypass and tapered down (to 2 to 4 mg/kg/8 hours) postoperatively until oral administration of prednisone was possible; it was further tapered down to a minimum of 0.1 mg/kg within 2 weeks and completely stopped after six months. Intravenous cyclosporine or tacrolimus therapy was started immediately after surgery on arrival in the ICU (cyclosporine: 1 to 3 mg/kg/d; tacrolimus: 0.01 to 0.03 mg/kg/d) and subsequently continued orally as soon as oral intake was well established. Mycophenolate mofetil was given intravenously (250 mg/d) on the first postoperative days and continued orally after extubation. Cyclosporine, tacrolimus, and MMF were administered trough level adjusted. Trough levels were targeted higher in the first year after transplantation. Target trough levels were 250 to 350 ng/mL for cyclosporine, 11 to 15 ng/mL for tacrolimus, and 2 to 4 µg/mL for mycophenolic acid in the first year. Postoperatively, 1 to 2 mg · kg · d azathioprine was given intravenously and later adjusted orally to maintain a white blood cell count of more than 4,000 g/L.
Severe acute rejection was treated with methylprednisolone bolus therapy (1 to 7 mg/kg). In case of mild rejection diagnosed by cytoimmunology, echocardiography, endomyocardial biopsy, and clinical appearance, prednisone was administered (0.1 to 0.3 mg/kg) or target trough levels of the calcineurin inhibitor were increased. If acute rejection occurred in patients with cyclosporine-based immunosuppression regimen under normal trough levels, the immunosuppressive regimen was switched from cyclosporine to tacrolimus.
The T-cell antibodies were not used routinely, but were administered if therapy resistant acute rejection episodes occurred. Persistent rejection, despite corticosteroid bolus therapy, was managed in four cases with antithymocyte globulin and in one case in 1992 with methotrexate. Recently, Interleukin2 antibodies were given in seven patients as de-novo immunosuppression regime, allowing lower calcineurin-inhibitor trough levels to prevent renal failure.
Since 1994, ganciclovir prophylaxis against cytomegalic virus (CMV) infection was administered in 12 CMV-IgG negative recipients with CMV-IgG positive donors. Amphotericin was given routinely as an oral solution to prevent thrush (upper airway fungal infections) in the first four postoperative weeks. Lifelong pneumocystis carinii prophylaxis consisted of sulfamethoxazol and trimethoprim (Cotrim-Sandoz, Sandoz Pharmaceuticals GmbH, Ismaning, Germany) twice a week.
Follow-Up
Routine follow-up examination for detection of acute or chronic rejection or infectious complications included echocardiography, chest roentgenogram, electrocardiogram, routine laboratory values, evaluation of immunosuppressive trough levels, and CMV clonab. Acute rejection episodes were diagnosed in infants and children by echocardiography and cytoimmunological monitoring [3] and, if necessary, confirmed by endomyocardial biopsy. Adolescents underwent routine biopsies at least every 6 to 8 weeks in the first year by a jugular approach. Graft vessel disease was assessed by routine echocardiography or dobutamine-stress-echocardiography and confirmed by coronary angiography. Routine coronary angiography was restricted to older adolescents and was performed every two years. Arterial hypertension and hypercholesteremia were treated aggressively with angiotensin-converting enzyme (ACE) inhibitors, calcium antagonists, and statins to prevent graft vessel disease.
To detect tumors as early as possible, all patients were checked annually by a dermatologist; Epstein Barr virus (EBV) was monitored at least annually and different white cell count was done monthly. Since the mid 1990s all patients underwent annual psychoneurologic follow-up. In case of personal, educational, or family problems psychological support was given and, if necessary, psychological therapy was initiated.
For statistical analysis, the Student's t test was used to calculate differences between parametric data (presented as means ± standard deviation [SD]). Differences between categorical variables were calculated using the 
2 test. Differences were considered significant at p less than 0.05. All statistics were calculated using SPSS software (SPSS Inc., Chicago, IL).
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Results |
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Survival
There were six late deaths due to acute rejection after 2 and 4 months (n = 2), CMV pneumonia (n = 1), pneumonia after anesthesia for central venous line placement (n = 1), intracranial hemorrhage (n = 1), and suicide (n = 1). Actuarial 1, 5, and 10 year survival was 86%, 80%, and 80%. There was no significant difference between patients with DCM and patients with CHD (survival at 1 year: 86% vs 82% [p = 0.71]; at 5 years: 83% vs 74% [p = 0.68]; at 10 years: 83% vs 74% [p = 0.62] (Fig 1)). Age was no predictive factor for survival. Retransplantation was performed in three patients: two patients suffered from therapy resistant acute rejection (AR) within the first postoperative month with severe heart failure necessitating mechanical circulatory support as a bridge to retransplantation. The third patient developed severe coronary artery disease four years after primary transplantation. All three patients are alive. Ventricular assist device or ECMO implantation before transplantation was not a risk factor for long-term survival (VAD/ECMO patients vs non-VAD/ECMO patients: 5 year survival: 75% vs 82%; p = 0.82). The actuarial survival has improved significantly since 1995: 1 year: 92% vs 78%; p = 0.09; 5 years: 92% vs 68%; p = 0.04 (Fig 2).
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Acute rejection was one of four serious complications following pediatric cardiac transplantation (in addition to infection, graft vessel disease, and neoplasms) and had the highest incidence in the first year after transplantation. Overall, 53 AR episodes were detected, representing a freedom of acute rejection of 45% in the first year. The incidence of AR/100 patients' days was 0.001. Two patients died because of ARs, in two others AR was the indication for urgent retransplantation.
In cyclosporine (CsA) treated patients, freedom from acute rejection (FfAR) tended to be lower than in tacrolimus treated patients, although the difference did not reach statistical significance (FfAR after 1 year CsA, 40% vs Tac, 56%; p = 0.17). All life threatening ARs were seen with cyclosporine therapy and 5 therapy resistant rejection episodes were successfully treated by switching to tacrolimus. Mycophenolate mofetil in combination with calcineurin inhibitors (started in 1995) lead to a significantly higher freedom from AR compared to calcineurin inhibitors combined with azathioprine or steroids (Fig 3). However, MMF was associated with severe gastrointestinal side effects in four patients necessitating a switch to azathioprine. Other adverse effects such as gingival hyperplasia (6 patients) and hirsutism (8 patients) occurred in cyclosporine treated patients and resolved after switching to tacrolimus.
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Graft Function–Graft Vessel Disease
Echocardiographic fractional shortening at the most recent clinical follow-up was 36.2% ± 5.6% (range, 18% to 42%). Mild tricuspid regurgitation (< 2 degrees) was seen in 5 of 50 patients (4 with atrioatrial anastomoses) and was not progressive during the follow-up period. No case of severe tricuspid regurgitation was detected. All but 9 patients were on antihypertensive medication. Rhythm disturbances were treated in 4 patients (2 pacemaker implantations for sinus arrest, 2 cardioversions for atrial flutter). Right bundle branch block occurred in 12 patients, two of whom suffered from graft vessel disease.
Graft vessel disease was detected in three male patients after 11.1, 9.1, and 3.8 years postoperatively. Overall, graft survival was 87%, 85%, and 76% after 1, 5, and 10 years. All patients were on a cyclosporine-azathioprine immunosuppressive regimen. Age at transplantation was 9.2, 12.2, and 17.3 years. One patient was successfully retransplanted, one underwent coronary artery bypass graft (CABG) surgery and one, who additionally suffered from a lymphoma, was treated medically.
Neoplastic Disorders
In two (4.3%) patients a malignant lymphoma occurred 7.9 and 12.1 years after transplantation. Both patients were on cyclosporine-based immunosuppression regimen, which was tapered down to a minimum after diagnosis. Minimizing immunosuppressive therapy was limited by severe acute rejection episode in one patient. Lymphoma treatment consisted of radiation and chemotherapy in both patients and bone marrow transplantation in one. Both patients are currently in remission.
Renal Failure
Severe chronic renal failure (creatinine > 2.5 mg/dL or hemodialysis) was not observed in our patients. Although serum creatinine was elevated preoperatively and perioperatively and renal failure necessitating hemodialysis occurred intermittently in 20 cases postoperatively, serum-creatinine levels were neither elevated at discharge nor at recent follow-up (Fig 5). There was no difference in renal function between patients on tacrolimus or cyclosporine-based immunosuppression regimens.
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Comment |
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TopAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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Our data represent a 15 year experience in pediatric cardiac transplantation of a "small" pediatric transplant center with a mean clinical follow-up time of more than 5 years. The actuarial survival at 1, 5, and 10 years was 86%, 80%, and 80% with a significant improvement of 1 year survival from 78% to 92% after 1995.
Survival did not differ significantly between cardiomyopathy and CHD patients, although CHD patients were younger, had longer cardiopulmonary bypass times, and had had more surgical procedures before transplantation. This finding is in contradiction to Boucek and colleagues [5] who identified CHD as a risk factor for poor outcome. However, our cohort did not include proportionally as many hypoplastic left heart syndrome patients as the ISHLT registry. Additionally, we started our pHTx program with DCM patients, so that children with CHD transplanted later may not have undergone the same learning curve.
In our series the most common cause of early death in the first years of our program was primary graft failure. Growing experience in donor organ protection and perioperative management, and the availability of NO application, reduced the incidence of primary graft failure. Optimized perioperative bridging techniques became available in the early 1990s (eg, MEDOS-assist device; MEDOS GmbH, Aachen, Germany) and added to this improvement.
In the long-term follow-up, acute rejection and infection were the most common causes of death. Significant changes in the use of new immunosuppressive drugs play the key role in the prevention of AR and life threatening infections. Calcineurin inhibitors, particularly tacrolimus, seem to be most effective in the prevention of AR in the pediatric population as has previously been reported in adults [9]. However, others demonstrated excellent results in the prevention of AR with cyclosporine-based immunosuppression regimes [10]. In our cohort, tacrolimus stopped AR in several cyclosporine resistant AR episodes. This effect was not seen vice versa. All life threatening ARs occurred under cyclosporine-based immunosuppression regimes. Therefore, and because of some minor advantages with respect to side effects such as hirsutism, gingival hyperplasia and pharmacokinetics [9, 11], tacrolimus may be used primarily as a basic immunosuppressant in pediatric patients. In our study, freedom from AR improved significantly when calcineurin inhibitors were administered in combination with MMF as a secondary immunosuppressant. The relatively small number of fatal rejections in our series compared to Bauer and colleagues [13], who reported 40% rejection related deaths, may be due to the combination of tacrolimus and MMF used in our patients since the mid 1990s. In our series, infection was not associated with one particular immunosuppressive regimen. Incidence was most frequent in the high-risk phase for AR and the associated higher immunosuppression regimes in the first postoperative year. The management of infection prophylaxis was adjusted to our adult HTx program. The decrease of the number of AR episodes with consecutive AR treatment over the years resulted in a corresponding decrease of infections after AR treatment and, therefore, with a decrease of the overall incidence of infections. This may also be due to the use of more effective antibiotics and prophylactic agents (eg, ganciclovir) and to the avoidance of long-term steroid use leading to an overall reduction of severe infections during the study period. However, the inadequate limitation of immunosuppressive therapy is seen in the occurrence of severe adverse effects. Neoplastic disorders occurred in 4.3% of our patients; the incidence was lower than in most studies [7, 8, 12, 13] with even shorter follow-up reporting an incidence between 6.9% [7] and 12% [5]. Neoplasms occurred late, indicating that the incidence increases with follow-up time, necessitating close follow-up and early screening standards. The lowering of immunosuppressive therapy under strict supervision and the avoidance of potentially cancerogenetic agents such as OKT3 [14] are prophylactic tools to reduce the incidence of neoplasms. In patients with a malignancy and graft vessel disease (GVD), the adaptation of immunosuppressive therapy is problematic. In patients with GVD, higher immunosuppressive trough levels improve clinical outcome [15], whereas the opposite is true for patients with cancer requiring reduced immunosuppression regimes [14]. In the future, the introduction of rapamycin as basic immunosuppressant in pHTx patients may be an alternative therapeutic option because of its strong antiproliferative effect. Clinical studies showed that rapamycin reduced intima proliferation in adult heart transplant recipients [6] and also inhibits, effectively, growth of human cancer metastases [17].
To date, one of the keys to successful treatment of both neoplasms and GVD is early diagnosis. Early radiologic and serologic detection of neoplasms (eg, EBV-antibody), and early detection of GVD by intravascular ultrasound or noninvasively by stress echocardiography, have a decisive impact on patients' outcome [8, 18]. The low incidence of neoplasms and GVD in our series compared to other pediatric [7, 12, 13] and adult transplant studies [14], is possibly a result of the strict time schedule of recurrent routine checkups in a specialized institution. Although stress echocardiography only detects GVD in an advanced state safely, it is the only noninvasive examination for routine detection of GVD in children.
Prophylactic and aggressive treatment of hypertension and hypercholesterolemia lower the incidence and development of GVD in adults [19] and children as well [20] and was implemented at our institution in 1996. Cardiac retransplantation, although performed successfully at our institution in all cases, can only be the final treatment option for GVD. Overall, the early introduction of prophylactic statin treatment, the sufficient immunosuppressive therapy with decreasing AR numbers, CMV prophylaxis, the steroid-free long-term immunosuppression regimen, and the strict routine assessment of GVD may explain the low incidence of GVD in our study and the improvements in recent years.
In contrast to our adult transplant candidates [9], renal function was not impaired in our pediatric transplant patients or in other pediatric series [13] independent of the immunosuppressive regimen. However, longer follow-up is necessary to assess the clinical significance of this calcineurin-inhibitor associated side effect especially in neonates. Fortunately, so far renal impairment does not play a major role in diminishing quality of life as it does for adults [21].
Psychological care, preoperative evaluation of psychiatric disorders, and personal compliance are considered major issues for clinical outcome especially in pediatric transplant patients [22, 23]. Although we implemented strict preoperative evaluation and initiated a psychological care program, one of our patients developed a severe psychiatric disorder and committed suicide.
Quality of life was experienced as not limited by the majority of our pediatric patients and most of them participate in normal educational programs. Nevertheless, it has been demonstrated that extended psychological care helps optimize compliance and acceptance of demanding clinical follow-up examinations (eg, detection of GVD by coronary angiography) resulting in enhanced quality of life and improved overall clinical outcome [22, 24].
The number of transplantations in pediatric patients at our institution is limited by donor organ shortage. This is reflected in higher mortality rates on the waiting list compared to adult cardiac transplant recipients [3]. Therefore, and because of the unknown side effects of lifelong immunosuppressive medication, pediatric cardiac transplantation is restricted to patients with medically and surgically untreatable heart failure without any other therapeutic option.
In summary, cardiac transplantation is an effective treatment for pediatric patients with congenital or acquired end-stage heart failure and can be performed with excellent intermediate-term results. These results can be achieved in experienced centers with excellent interdisciplinary cooperation. [16]
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TopAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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