Ann Thorac Surg 2007;84:1640-1644. doi:10.1016/j.athoracsur.2007.05.070
© 2007 The Society of Thoracic Surgeons
Original Articles: Cardiovascular
Heart Transplantation in Children: Clinical Outcomes in a Single Center
Yanto Sandy Tjang, MD, DSca,*,
Ute Blanz, MDa,
Lech Hornik, MDa,
Gero Tenderich, MDa,
Michiel Morshuis, MDa,
Hans Stenlund, PhDb,
Andreas Bairaktaris, MDa,
Reiner Körfer, MD, PhDa
a Department of Thoracic and Cardiovascular Surgery, Heart and Diabetes Center, North Rhine Westphalia/University Hospital of Bochum, Bad Oeynhausen, Germany
b Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden
Accepted for publication May 29, 2007.
* Address correspondence to Dr Tjang, Wielandstrasse 11, Bad Oeynhausen, 32545, Germany (Email: ystjang{at}hotmail.com).
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Abstract
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Background: Despite being accepted as the best treatment for end-stage heart diseases, the long-term benefit of heart transplantation in children remains a matter of controversial debate. This study aimed to evaluate our clinical experience with heart transplantation in children.
Methods: From March 1989 to December 1999, 93 consecutive orthotopic heart transplantations in children (less than 18 years of age) were performed at the Department of Thoracic and Cardiovascular Surgery, Heart and Diabetes Center NRW in Bad Oeynhausen, Germany. Clinical data were retrieved from a computerized database. Follow-up information was 100% completed.
Results: The main indications for heart transplantation were dilated cardiomyopathy (68%) and congenital heart disease (31%). Early mortality risk was 14% ± 3.6%. Primary graft failure (39%) was the main cause of early death. Total follow-up time was 694 patient-years (mean, 104.1 ± 42.8 months). Twenty-three patients died during follow-up, resulting in 33 of 1,000 patient-years of late mortality rate. Acute rejection (43%) and allograft vasculopathy (26%) were attributed to late mortality. The 1-, 5-, 10-, and 15-year survival was 83%, 74%, 63%, and 50%, respectively. Recipient age less than one year (p = 0.02) and ischemia time greater than 300 minutes (p = 0.04) were associated with decreased survival. Social activities at the end of follow-up were school (69%), working (19%), and at home (12%).
Conclusions: Heart transplantation is a rational and durable treatment option for children with end-stage heart diseases. The long-term outcomes and quality of life after heart transplantation in children are encouraging.
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Introduction
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Introduced by Kantrowitz and colleagues [1], heart transplantation (HTx) has been accepted as the best treatment option for children with end-stage heart diseases. So far, nearly 6,000 procedures have been performed worldwide. More than 3,600 of them have been reported during the last decade [2]. In contrast to earlier studies showing perioperative mortality risk of 25% to 60% [3–5], recent studies revealed encouraging short-term and medium-term survival after HTx in children [6, 7]. Even so, long-term follow-up studies with sufficient patients are scant; therefore, the benefit of HTx in children remains a matter of controversial debates. This study aimed to evaluate our clinical experiences of HTx in children.
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Patients and Methods
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Study Population
From March 1989 to December 1999, 1,030 consecutive orthotopic HTx were performed at the Department of Thoracic and Cardiovascular Surgery, the Heart and Diabetes Center North Rhine Westphalia in Bad Oeynhausen, Germany. Nine percent (93 of 1,030) of them were in children (less than 18 years of age) and are included in our analysis. This study was approved by our Ethics Committee and the need for individual informed consent was waived. Recipient selection criteria included existing end-stage heart failure without other feasible medical or surgical treatment option, absence of systemic diseases, infection, stroke or recent pulmonary infarction, stabile family history, compliance, and evidence of strong motivation. Donor and recipient were matched for ABO blood-type compatibility and body weight. A donor heart was obtained from a beating-heart, brain death individual through cooperation with the Eurotransplant organization. Donor assessment was based on complete clinical-laboratory evaluation and echocardiography. An older donor was accepted if coronary atherosclerotic lesions could be excluded. A donor with HIV, hepatitis B/C, or nonprimary brain cancer was rejected.
Surgical Procedures
Donor heart retrieval occurred as part of a multiorgan procurement effort. The heart was decompressed during harvesting to avoid coronary air embolization. Just prior to stopping the ventilation, both caval veins were ligated and divided to empty the right heart. The left atrial appendage was opened to empty the left heart. After ascending aortic cross-clamping, 30 to 40 mL/kg cardioplegia solution was administered to arrest and cool the heart. After dividing the ascending aorta and pulmonary artery, the heart was explanted by transecting both caval veins and the four pulmonary veins preserving the sinus node, its artery, and sinoatrial pathways. In cases where reconstructive procedure was planned, graft harvesting included the entire aortic arch and descending aorta, pulmonary artery bifurcation and main pulmonary arteries, superior vena cava, and pulmonary veins. Graft preservation was achieved through a combination of topical hypothermia and cold crystalloid cardioplegia solution. During transportation, temperature was kept between 4° and 5°C. Procurement and recipient surgical teams were in frequent communication to accurately coordinate the arrival of the donor heart and the explantation of the recipient heart. Implantation of the donor heart was orthotopically performed, using the biatrial technique [8].
Postoperative Management
nitial immunosuppressive regimen was based on 3 to 4 mg/kg azathioprine (adjusted to renal and hepatic function), 0.25 mg/kg cyclosporine A, and 125 mg methyl-prednisolone (all intravenous). Shortly before releasing the aortic cross-clamping, 125 mg methylprednisolone was administered. In the absence of renal failure or severe circulatory deterioration, 0.1 to 0.2 mg/kg/d cyclosporine A (intravenous) was continuously infused to achieve and maintain a serum level of 300 to 400 µg/L. One to four mg/kg/d azathioprine and 3 x 125 mg/d methylprednisolone were also given. On the third postoperative day, oral application of all drugs was preferred. Long-term immunosuppressive regimen consisted of 4 to 6 mg/kg/d cyclosporine A and 0 to 2 mg/kg/d azathioprine (dosage was adjusted to maintain a white blood cell count of > 4,000 g/L). An acute rejection episode was diagnosed by echocardiography and cytoimmunologic monitoring (if necessary, endomyocardial biopsy). Severe acute rejection was treated with 1 to 7 mg/kg methylprednisolone (bolus therapy). In case of mild rejection, 0.1 to 0.3 mg/kg prednisone was administered or a target trough level of cyclosporine A was increased. If acute rejection occurred under normal trough levels, cyclosporine A was switched to tacrolimus. The T-cell antibodies were used only if therapy resistant acute rejection episodes occurred. Persistent rejection was managed with antithymocyte globulin or methotrexate. Allograft vasculopathy was assessed by routine or dobutamine-stress echocardiography and confirmed by coronary angiography. Arterial hypertension and hypercholesteremia were treated with angiotensin-converting enzyme inhibitors, calcium antagonists, and statins to prevent cardiac allograft vasculopathy. Dermatologic examination was done annually to detect malignancy. Epstein Barr virus was annually monitored and different white cell count was done monthly. All patients underwent psychoneurological examination.
Data Collection and Follow-Up
Preoperative and perioperative data have been recorded ad hoc in a computerized database. Donor, recipient, and perioperative characteristics were retrieved for analysis. Autopsies were obtained for the majority of hospital and late deaths. Follow-up information was collected through outpatient’s clinic reports or by telephone interview with patients, their relatives, and (or) referring physician and were 100% complete. Early mortality was defined as death within 30 days after HTx regardless of a patient’s geographic location. Death after this period was defined as late mortality.
Statistical Analysis
Data were analyzed by means of the Statistical Package for the Social Sciences (SPSS) software, version 12.0 (SPSS Inc, Chicago, IL). Results were expressed as mean and standard deviation (SD) or median and interquartile range for continuous variables and count (%) for categoric variables. Actuarial survival curves were constructed by using the Kaplan-Meier method. Differences between subgroups were assessed by the log-rank test. Results were considered significant where the p value was less than or equal to 0.05.
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Results
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Clinical Characteristics
Age distribution by transplant year is displayed in Figure 1.
Table 1
presents the clinical characteristics. Recipient mean age was 6.5 ± 6.1 years; most were between one and ten years old. There were 68% (63 of 93) male and 31% (29 of 93) female recipients. The main indications for HTx were dilated cardiomyopathy (68%) and congenital heart disease (31%). Twenty-five percent (23 of 93) of the recipients underwent prior cardiac surgery; four of them had more than one. Most of the recipients had blood group A (47%) and O (39%). Most of the HTx were performed electively. Six percent (6 of 93) of the recipients required a ventricular assist device as bridging to HTx, notably the following; Novacor (Baxter Healthcare, Oakland, CA) left ventricular assist device ((LVAD; n = 1, support time: 140 days); Thoratec (Thoratec Laboratories Corp, Pleasanton, CA) LVAD (n = 2, support time: 22 and 24 days) and Thoratec biventricular assist device (n = 3, support time: 8, 107, 110 days). Most of the donors were between one and ten years old; eight of them were older than 20 years. Sex distribution was nearly equal. Most of the donors had blood group A (39%) and O (52%). Histidine-buffered tryptophane-ketoglutarate cardioplegia solution (Bretschneider-Custodiol; Kohler Chemie, Alsbach-Hahnlein, Germany) was used in 91 donors and University of Wisconsin cardioplegia solution (ViaSpan; DuPont, Bad Homburg, Germany) was used in two donors. Donor cause of death was mainly due to head trauma (54%). Mean ischemia time was 213.9 ± 50.3 minutes; 6% (6 of 93) of them had ischemia time greater than 300 minutes.
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Fig 1. Age distribution of heart transplantation in children by transplant year. (Black bar = < one year; grey bar = one to 10 years; white bar = > ten years).
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Perioperative Outcomes
Thirteen recipients died within 30 days after HTx in 62% (8 of 13) males and 38% (5 of 13) females, giving an overall early mortality risk of 14 ± 3.6% (95% confidence interval [CI]: 6.9% to 21.1%). Eight recipients died immediately after HTx or on the first postoperative day due to primary graft failure (n = 5), technical issues (n = 2), and right heart failure (n = 1). Early death occurred in 54% (7 of 13) recipients younger than one year, 31% (4 of 13) recipients between one and ten years, and 15% (2 of 13) recipients older than ten years. The reasons for HTx in these recipients were congenital heart disease (62%) and dilated cardiomyopathy (38%). Eighty-five percent (11 of 13) donor hearts were from females. The detailed causes of death are presented in Table 2.
Long-Term Outcomes
The overall follow-up times were 695 patient-years (mean, 89.6 ± 53.7 months). Excluding all early deaths, mean follow-up time was 104.1 ± 42.8 months (total, 694 patient-years). Twenty-three recipients died during the follow-up period, resulting in 33 of 1,000 patient-years of late mortality rate. Death of these recipients occurred at an average posttransplant survival of 71.6 ± 45.0 months; most were due to acute rejection (43%) and graft vasculopathy (26%). The 1-, 5-, 10-, and 15-year survival was 83%, 74%, 63%, and 50%, respectively (Fig 2). Recipient age less than one year (p = 0.02) and ischemia time greater than 300 minutes (p = 0.04) were associated with decreased survival (Figs 3;
4). Social activities at the end of follow-up were school (69%), working (19%), and at home (12%) (Fig 5).
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Comment
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This study has evaluated our clinical experiences of HTx in children with a follow-up period of over 15 years. Our results demonstrate that children with end-stage heart diseases derive great benefit in life expectancy after HTx, because most of the children were not expected to live longer than six months without HTx. The most important issues of HTx in children are related to patient selection (particularly as it pertains to pulmonary vascular resistance), and long-term issues such as immunosuppression, the role of accelerated allograft vasculopathy, body growth-development, and quality of life [9].
The indication for HTx in neonates has been hypoplastic left heart syndrome [10]. The Norwood procedure is another alternative option [11]. In older children with end-stage heart failure there is generally no other alternative to HTx. In our study, dilated cardiomyopathy and congenital heart disease were the main indications for HTx. We have demonstrated that outcome of HTx in children by indication of dilated cardiomyopathy is better than congenital heart disease [12]. An understanding of early mortality and causes of death is essential for improving long-term survival. Our early mortality risk is 14%, comparable with other studies [4, 6, 7, 9] Most early death was due to primary graft failure. As noted by Bailey [13], the key to avoiding this event is the objectivity in recipient evaluation. Heart transplant recipient should have normal or surgically correctable pulmonary artery anatomy and low pulmonary vascular resistance. Trento and colleagues [4] found that the response of donor right ventricle to increased pulmonary vascular resistance is unpredictable. They proposed not to perform HTx in children with an indexed pulmonary vascular resistance of greater than 6 Wood units/m2 or a transpulmonary gradient of greater than 15 mm Hg. In contrast to the International Society for Heart and Lung Transplantation (ISHLT) registry [2], demonstrating graft failure as the primary cause of early death, acute rejection is the cause of death in most series and most likely occurs in the first month after HTx. Death from acute rejection more likely occurs after late rejection episodes, especially in those associated with severe hemodynamic compromise [14]. Death from rejection may be reduced by improving rejection surveillance and treatment. Improved treatment of rejection may also reduce the incidence and severity of graft vasculopathy. In the infant group, graft failure remains the main cause of early death [2, 15].
Regarding late mortality, deaths are mostly due to rejection [2]; therefore, immunosuppressive regimen plays a big role. Most centers advocate a classic triple-drug immunosuppressive regimen [4, 9, 16–19], others prefer to avoid the routine use of steroids [20, 21]. A triple-drug immunosuppressive regimen demonstrated acceptable rejection and infection rates [9, 16, 22] but a cyclosporine-based immunosuppressive regimen also provided low rejection rates [20, 21], particularly in patients less than ten years old [21]. Optimal immunosuppressive protocol is still undefined. Recent new immunosuppressive regimens are of great current research interest. Accelerated allograft vasculopathy represents the other main cause of late mortality after HTx in children. Its incidence is reported at around 20% to 40%. The exact incidence may be underestimated because coronary angiography is difficult to perform in small children and is probably not sensitive enough to detect early subtle coronary abnormalities [5]. Sixteen percent (6 of 36) of our overall mortality were attributed to allograft vasculopathy. Prophylactic and aggressive treatment of hypertension and hypercholesterolemia may lower its incidence and development [23], and have been implemented in our patients.
Despite disappointing early results, recent survival of HTx in children has been steadily improving. In 1994, the Stanford group [24] reported the 1-, 5-, and 10-year survival of 75%, 60%, and 50%, respectively. In 2002, Scheule and colleagues [25] showed improved 1- and 5-year survival of 84% and 70%, respectively. The recent data from ISHLT [2] demonstrated the 1, 5-, and 10-year survival of 82%, 69%, and 57%, respectively. Our study represents a relatively large study population. The actuarial survival was 83%, 74%, 63%, and 50% at 1, 5, 10, and 15 years, respectively. After HTx, most of our patients experience good quality of life. Nearly 90% of them return to their normal activities (school or working).
In conclusion, HTx is a rational and durable treatment option for children with end-stage heart diseases. The long-term outcomes and quality of life after HTx in children are encouraging. Accumulated experiences with a larger study population over a much longer follow-up time are necessary to determine the independent risk factors of mortality and ultimate fate of children after HTx.
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References
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Abstract
Introduction
