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Heart Transplantation in Children With a Fontan Procedure
Kirk R. Kanter, MD, William T. Mahle, MD, Robert N. Vincent, MD, Alexandria M. Berg, MSN, Brian E. Kogon, MD, and Paul M. Kirshbom, MD Division of Cardiothoracic Surgery, Department of Surgery, Emory University School of Medicine, and Children’s Healthcare of Atlanta at Egleston, Division of Pediatric Cardiology, Emory University School of Medicine, Atlanta, Georgia
Background. Previous studies have reported that children with a prior Fontan procedure have decreased survival after heart transplantation. We examined 190 primary pediatric heart transplants. Methods. Since 1988, 27 (14.2%) of 190 children less than 18 years old undergoing primary heart transplantation had a Fontan procedure 3.7 ⴞ 4.3 years before transplantation. Compared with 163 (85.8%) non-Fontan primary transplants, the Fontan patients were similar in age (8.2 ⴞ 5.0 vs 6.5 ⴞ 6.0 years), presensitization, and pretransplant clinical status. More Fontan patients had prior operations (100% vs 50%; p < 0.0001) and needed pulmonary artery reconstruction (100% vs 23.5%; p < 0.0001). Twelve (44%) had protein-losing enteropathy. Results. Donor ischemic times (211 ⴞ 72 vs 170 ⴞ 61 minutes; p ⴝ 0.0018) and cardiopulmonary bypass times (197 ⴞ 91 vs 121 ⴞ 53 minutes; p < 0.0001) were greater in the Fontan group as were durations of ventilator support (4.9 ⴞ 6.6 vs 2.6 ⴞ 3.9 days; p ⴝ 0.018) and hospital stay
(20.2 ⴞ 17.5 vs 14.3 ⴞ 12.4 days; p ⴝ 0.0435). The Fontan group had one 30-day mortality. One-year actuarial survival (81.5% vs 84.6%, Fontan vs non-Fontan) and fiveyear actuarial survival (65.5% vs 66.2%, Fontan vs nonFontan) were similar, as was rejection incidence at one year (2.0 ⴞ 2.0 vs 1.7 ⴞ 1.9 episodes per patient; p ⴝ 0.3972). Five Fontan patients (18.5%) required retransplantation 4.9 ⴞ 3.6 years posttransplant compared with 18 non-Fontan patients (11.0%) retransplanted 5.2 ⴞ 3.4 years posttransplant (p ⴝ 0.3346). Conclusions. Contrary to prior reports, we did not identify any early or midterm disadvantage for children undergoing heart transplantation after a previous Fontan procedure despite more complex transplant operations. We contend that carefully selected children with a failing Fontan circulation can do as well as other children with heart transplantation. (Ann Thorac Surg 2011;91:823–30) © 2011 by The Society of Thoracic Surgeons
T
Furthermore, because all of the patients with a previous Fontan procedure who are considered for transplantation have had prior operations, they may be sensitized with preformed antibodies from exposure to blood products, which would increase the risk of rejection after transplantation. Many of these Fontan patients have complex venous or arterial connections, which can make the transplant operation technically challenging. After transplantation, there are many risk factors common in the Fontan patient, including increased risk of bleeding, the presence of systemic artery-to-pulmonary artery collateral arteries, unrecognized or underestimated pulmonary artery hypertension, and decreased resistance to infection, particularly in those patients who are malnourished due to PLE. In view of these challenges and aware of the discouraging results from other centers, we retrospectively examined our experience with 27 children younger than 18 years of age who underwent primary heart transplantation after a Fontan procedure.
he Fontan procedure is commonly employed as longterm palliation of children with single-ventricle physiology. As time goes on, a percentage of these patients will develop refractory heart failure or complications of the Fontan necessitating heart transplantation. Previous studies have shown diminished survival in patients undergoing transplantation after a failed Fontan procedure compared with other patients undergoing transplantation [1– 8]. Various reasons have been proposed for these disappointing results [9]. The pulmonary vascular resistance in patients after a Fontan procedure can be difficult to assess due to the presence of systemic-topulmonary collateral arteries, low cardiac output, and nonpulsatile flow [1, 10, 11]. Many of these patients, particularly those with a short interval from Fontan to need for transplantation, can have significant other morbidities which make them high-risk candidates for transplantation. These comorbidities include protein-losing enteropathy (PLE), hepatic dysfunction, and renal dysfunction.
Accepted for publication Nov 15, 2010. Presented at the Fifty-sixth Annual Meeting of the Southern Thoracic Surgical Association, Marco Island, FL, Nov 4 –7, 2009. Address correspondence to Dr Kanter, Pediatric Cardiac Surgery, Emory University School of Medicine, 1405 Clifton Rd, Atlanta, GA 30322; e-mail: [email protected].
© 2011 by The Society of Thoracic Surgeons Published by Elsevier Inc
Patients and Methods Approval for this retrospective study was obtained from the Emory University School of Medicine Human Inves0003-4975/$36.00 doi:10.1016/j.athoracsur.2010.11.031
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tigation Committee. The need for patient consent was waived.
Patient Population PEDIATRIC CARDIAC
From June 1988 to November 2009, we performed 222 heart transplants at Children’s Healthcare of Atlanta at Egleston, the pediatric hospital affiliated with Emory University in Atlanta. After excluding 29 retransplant operations and three patients older than 18 years of age, there remained 190 primary pediatric heart transplants for analysis. Twenty seven of these patients (14.2%) had a Fontan procedure 3.7 ⫾ 4.3 years before transplantation (range, 2.5 months to 15.3 years). Nine of the 27 patients (33%) were transplanted within one year of their Fontan procedure, of which six children were transplanted within six months of their Fontan procedure. The age of the original Fontan procedure was 4.5 ⫾ 3.3 years (range, 1.5 to 12.4 years of age). Age at transplantation was 8.2 ⫾ 5.0 years for the Fontan patients compared with 6.5 ⫾ 6.0 years for the 163 patients who did not have a Fontan procedure (p ⫽ 0.1781). During the same time, nine additional children with a prior Fontan procedure were evaluated and listed for transplantation but were not transplanted. One was removed from the heart transplant waiting list at the wishes of the parents; the remaining eight died without transplantation, typically due to high levels of preformed antibodies greatly reducing the possibility of a compatible donor or due to an intercurrent infection or clinical deterioration precluding transplantation. During this time, over 500 Fontan procedures were performed at our institution, so this experience reflects a transplantation rate of roughly 5% in Fontan recipients. Children with a previous Fontan procedure were evaluated for transplantation if they had ongoing heart failure symptoms despite optimal medical therapy including maximal afterload reduction and, often, trials of home inotropic support, or if they had PLE refractory to standard medical therapy (including attempts at Fontan baffle refenestration or enlarging an existing fenestration). Patients with significant hepatic dysfunction as determined by impaired synthetic function (especially an elevated protime in the absence of anticoagulation) were excluded from consideration for transplantation. All patients had pretransplant cardiac catheterization to identify any correctable anatomic problems with the Fontan
pathway or with the atrioventricular valves, to assess pulmonary vascular resistance, and to eliminate accessory sources of pulmonary blood flow with aggressive occlusion of systemic-to-pulmonary collateral arteries in the catheterization laboratory [12]. Although many of the patients were listed for cardiac transplantation while clinically stable, most did not receive a transplant until they had deteriorated and required hospital admission, intravenous inotropic support, and, not uncommonly, mechanical ventilation. In this clinical state, their status on the heart transplant waiting list was upgraded to a more urgent UNOS (United Network for Organ Sharing) status I in 67% of the Fontan patients. No Fontan patient was maintained on mechanical circulatory support pretransplant although one required continuous venovenous hemofiltration for renal failure pretransplant. As shown in Table 1, the percentage of patients in both the Fontan and the non-Fontan groups with a panel reactive antibody (PRA) greater than 10% to class I antigens was similar as was the UNOS (United Network for Organ Sharing) status at the time of transplantation. All of the Fontan patients had prior operations compared with 50.3% of the non-Fontan patients. The number of prior operations per patient for those with a Fontan procedure was 4.9 ⫾ 1.9 operations per patient compared with 2.4 ⫾ 1.7 for the 82 patients in the non-Fontan group who had previous operations (p ⬍ 0.0001). Twenty-two percent of the Fontan patients and 26% of the non-Fontan patients required ventilator support at the time of transplantation (Table 1). Twelve of the Fontan children (44%) had protein-losing enteropathy (PLE) as one of the indications for heart transplantation. Twenty-one (78%) of the Fontan patients had decreased ventricular function prior to transplantation (10 with PLE), whereas six Fontan patients had preserved ventricular function (2 with PLE).
Operative Techniques Coordination of the donor and recipient operations was carefully planned so that there would be adequate time for a safe, cautious, and hemostatic reopening of the recipient’s chest. The use of femoral cannulation for cardiopulmonary bypass was atypical. All Fontan patients had bicaval anastomoses for the transplant. Venous, arterial, and situs abnormalities were managed with previously described surgical techniques [13–15].
Table 1. Patient Characteristics Characteristic
Fontan (n ⫽ 27)
Non-Fontan (n ⫽ 163)
p Value
Age at transplant (years, mean ⫾ SD) Class I PRA ⱖ10% (n, %) UNOS status I (n, %) Days on waiting list Prior operation (n, %) Number of prior operations per patient who had a prior operation Ventilated at time of transplant (n, %)
8.2 ⫾ 5.0 5 (18.5%) 18 (67%) 84.1 ⫾ 133 27 (100%) 4.9 ⫾ 1.9 (n ⫽ 27)
6.5 ⫾ 6.0 27 (16.8%) 119 (73%) 64.1 ⫾ 119 82 (50.3%) 2.4 ⫾ 1.7 (n ⫽ 82)
0.1781 0.7858 0.4942 0.4271 ⬍0.0001 ⬍0.0001
6 (22%)
42 (26%)
PRA ⫽ panel reactive antibody;
UNOS ⫽ United Network for Organ Sharing.
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Immunosuppression and Rejection Surveillance Both groups had identical immunotherapy regimens using triple drug immunosuppression. Early in this series the patients were treated with cyclosporine, azathioprine, and a weaning dose of steroids. Efforts were made to wean off steroids entirely within a year of transplantation based on negative endomyocardial biopsies. After 1992, mycophenolate was used routinely in place of azathioprine. Induction immunotherapy was not used until 2005 when we routinely added daclizumab to the standard triple drug therapy. In 2007, tacrolimus was substituted for cyclosporine as the preferred calineurin inhibitor. Periodic surveillance endomyocardial biopsies were performed on all patients, as were routine annual coronary arteriograms. Rejection episodes were treated with pulsed steroids. Only recurrent, refractory or hemodynamically compromising rejection episodes were treated with monoclonal antibodies such as OKT-3. Diagnostic intravascular ultrasound of the coronary arteries was not used routinely.
Statistical Analysis Continuous variables were compared by analysis of variance and are presented as mean ⫾ standard deviation. Nominal variables were compared by 2 analysis with the Fisher exact test. Life-table analysis was done by the Kaplan-Meier survival method with significance determined by log-rank analysis. All statistical tests were considered significant if the p value was less than 0.05.
Results The results for several perioperative variables are shown in Table 2. Pulmonary artery reconstruction, which previously has been identified as a risk factor for unfavorable outcome at the time of transplantation [2], was performed in all of the Fontan patients compared with 22% of the non-Fontan patients (p ⬍ 0.0001). As a surrogate marker for operative complexity, both donor ischemia time and cardiopulmonary bypass time were significantly longer in the Fontan group compared with the non-Fontan group (Table 2). The Fontan patients required significantly longer durations of ventilation and hospital stay. The duration of posttransplant inotropic support and time in the intensive care unit also tended to
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Table 2. Perioperative Variables Variable Pulmonary artery reconstruction (n, %) Donor ischemia time (minutes) Cardiopulmonary bypass time (minutes) Days ventilated posttransplant Days on inotropic support posttransplant Days in intensive care unit posttransplant Days in hospital posttransplant
Fontan (n ⫽ 27)
Non-Fontan (n ⫽ 163)
p Value
27 (100%)
36 (22.1%)
⬍0.0001
211 ⫾ 72
170 ⫾ 61
0.0018
197 ⫾ 91
121 ⫾ 53
⬍0.0001
4.9 ⫾ 6.6
2.6 ⫾ 3.9
0.018
5.2 ⫾ 3.8
4.5 ⫾ 6.2
0.6231
11.5 ⫾ 12.9
7.7 ⫾ 9.8
0.099
20.2 ⫾ 17.5
14.3 ⫾ 12.4
0.0435
be longer in the Fontan group, but these differences did not achieve statistical significance (Table 2). There was one 30-day mortality in the Fontan group giving a 30-day survival of 96.3% compared with a 30-day survival of 95.6% in the non-Fontan group. This patient was a 2.8-year-old boy with heterotaxy syndrome who had a fenestrated lateral tunnel Fontan procedure ten months before transplantation followed by a common atrioventricular valve repair 3.5 months later. He developed severe heart failure and was listed for cardiac transplantation. He deteriorated and at the time of transplantation he was intubated in the intensive care unit in renal failure requiring dialysis. After transplantation, he remained anuric. A renal ultrasound revealed renal vein thrombosis. He succumbed to Candida sepsis and disseminated intravascular coagulopathy ten days after transplantation. The Kaplan-Meier estimate for patient survival is shown in Figure 1. The results are not statistically different for the Fontan patients compared with the non-Fontan patients with a one-year actuarial survival of 81.5% for the Fontan patients and 84.6% for the non-Fontan patients. The five-year actuarial survival for the Fontan patients was 65.5% compared with 66.2% for the non-Fontan patients. Note that there is a cluster of deaths in the first six months after transplantation in the Fontan patients, but by five years the two curves seem to converge (Fig 1). In contrast to the recent report from Boston [16] that identified pretransplant preserved ventricular function in Fontan patients as a risk factor for one-year mortality after heart transplantation, in our series there was one death within one year in the six patients (17% one-year mortality) who had preserved pretransplant ventricular function, compared with four deaths within one year in the 21 patients (19% one-year mortality) who had impaired ventricular function pretransplant. These early mortality rates were not statistically different. Furthermore, comparing the six Fontan patients who had cardiac transplantation within six months of their Fontan procedure to the other Fontan patients, one-year survival rates were similar (83% vs 81%).
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Excessive pulmonary venous return was a common problem during the transplant operation due to systemic-topulmonary collateral arteries. It often was necessary to reduce cardiopulmonary bypass flow during the pulmonary artery anastomosis to aid visualization. A generous amount of donor pulmonary artery was procured to allow for extensive patching of the native pulmonary arteries including the site of the previous Glenn anastomosis, if present. To prevent right ventricular distention in the transplanted heart, a left atrial vent was always used and often an additional vent was placed in the pulmonary artery during rewarming. Commonly, the heart from a donor larger than the recipient was used and prolonged donor travel times were avoided as much as possible to reduce donor ischemic time.
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Fig 1. Kaplan-Meier actuarial freedom from death stratified by patients who had a previous Fontan procedure () and those who did not (X). The survival estimates are not statistically different (p ⫽ 0.4975).
Of the twelve patients with PLE, ten survived more than six months after transplantation; all ten had complete resolution of the PLE. The presence of PLE did not affect one-year survival after transplantation (83%) compared with those Fontan recipients who did not have PLE (one-year survival 80%). The incidence of acute rejection at 30 days was statistically significantly more frequent in the Fontan patients (Fig 2) even though the percentage of patients with elevated levels of preformed antibodies as measured by PRA greater than 10% was comparable between the two groups (Table 1). By one year, the incidence of acute rejection was similar between the two groups (Fig 2).
Fig 2. Incidence of rejection episodes per patient at thirty days and one year after transplantation. (Fontan [black]; non-Fontan [horizontal striped].)
On average follow-up of 6.7 ⫾ 5.2 years, cardiac retransplantation was performed in five (18.5%) of the Fontan patients an average of 4.9 ⫾ 3.6 years after initial transplantation. One 4.3-year-old Fontan patient required acute retransplantation for acute right heart failure due to uncontrolled systemic-to-pulmonary artery collateral arteries. The child required support with ECMO (extracorporeal membrane oxygenation) after transplantation. While on ECMO, she had coil occlusion of multiple large systemic-to-pulmonary collateral arteries in the Cardiac Catheterization Laboratory. She was listed for retransplantation. A suitable donor became available two days after her initial transplant and she underwent successful retransplantation and did well (after a prolonged hospitalization) for seven years more until she developed transplant vasculopathy. The other four retransplant operations in the Fontan group were more than one year after the initial transplant procedure and were for transplant coronary artery disease or for nonspecific graft dysfunction with poor diastolic compliance of the transplanted heart. On follow-up of 6.1 ⫾ 5.7 years, the incidence of retransplantation in the nonFontan patients was 18 of 163 (11.0%) , which was not significantly statistically different from the Fontan patients. Freedom from retransplantation and death for the two groups is shown in Figure 3. The two groups are statistically not different.
Comment Early reports showed poor survival after transplantation in patients who have had a previous Fontan procedure
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Fig 3. Kaplan-Meier actuarial freedom from death or retransplantation (graft survival) comparing Fontan () patients with non-Fontan patients (X) showing no statistical difference in graft survival (p ⫽ 0.4215).
[1– 8]. The group from Columbia University [3, 5] reported a 33% incidence of early death in nine patients who had a Fontan, all within the first week of transplantation. A later report from the Columbia group [2] identified a 37.9% overall mortality in Fontan patients who underwent transplantation (11 deaths in 29 patients). Other institutions reported similar discouraging results with transplantation after the Fontan procedure. The group from Newcastle in England [1] identified three operative deaths in nine patients with a Fontan procedure (both adults and children) with no late deaths on follow-up. Michielon and colleagues [6, 7] in Rome reported a 67% perioperative mortality rate with four deaths out of six patients with a Fontan procedure. A more recent paper by Jayakumar and colleagues from Columbia [4] identified nine deaths within two months of transplantation in 24 adults and children undergoing transplantation after a Fontan procedure, resulting in a 62.5% one-year survival with a 57% five-year survival. Similarly, Petko and colleagues [8] from the Children’s Hospital of Philadelphia reported four perioperative deaths in nine patients transplanted after a Fontan procedure with an additional two late deaths. The 2009 pediatric report of the International Society of Heart and Lung Transplantation [17] reaffirms that for pediatric heart transplantation, the basic diagnosis of congenital heart disease is a risk factor for poor survival at one and five years. A recent multiinstitutional study [18] combining results from the Pediatric Heart Transplant Study Group and the Cardiac Transplant Research Database identified 107 adults and children with a Fontan procedure who underwent transplantation at a mean age of 15 years. The relative risk for death was 8.6 for Fontan patients compared with non-Fontan patients who had a
congenital diagnosis. The one-year survival was 71%. These authors identified younger recipient (recipient age between 6 and 12 years) as a risk factor, with 28% more deaths in this group. This continued to be a risk factor for death even after the early posttransplant period. Analyzing only pediatric patients, Bernstein and colleagues and the Pediatric Heart Transplant Study Group [19] identified 97 patients younger than 18 years of age listed for heart transplantation after a Fontan procedure. The mean age was 10.7 ⫾ 5.4 years at transplant. Seventy of these 97 patients were transplanted with a one-year survival of 76% and a five-year survival of 68%. There are, however, isolated single-institution reports demonstrating reasonable survival after heart transplantation in patients with a Fontan procedure. Mitchell and colleagues from Denver [10, 20] described 14 patients undergoing heart transplantation after a Fontan procedure. The average age at transplant was 11.6 years. There was only one death at six months posttransplant giving an actuarial graft survival of 93% at three years and 82% at five years. The group from Bergamo, Italy [21] also showed reasonable survival after heart transplantation for adults and children after the Fontan procedure. They identified fourteen patients (half less than 18 years old) with an average age at transplantation of 17.2 ⫾ 6.3 years. The one-year and five-year actuarial survival was 86% and 77%, respectively. In the current series, the twenty-seven children with a Fontan procedure undergoing heart transplantation were younger (mean age 8.2 ⫾ 5.0 years) compared with most series in which the average age at transplantation is in the mid-to-late teens. These patients were clearly complex with an average number of previous operations of 4.9 ⫾ 1.9 operations per patient. Two-thirds of the pa-
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tients were UNOS status I and 22% on the ventilator at the time of transplantation. A total of 18.5% of the patients were presensitized with a class I PRA greater than 10% (Table 1). Despite the high complexity of the operative procedure, including pulmonary reconstruction in all patients (which previously has been identified as a risk factor for transplantation [2]), the early perioperative results were similar compared with the non-Fontan patients. The only early death in the Fontan group was in a patient who was essentially moribund at the time of transplantation with anuric renal failure, ventilator dependence, and severe heart failure. Using donor ischemic time and cardiopulmonary bypass time as surrogates for operative complexity, the Fontan patients had significantly more complex transplant operations. Accordingly, their time in the intensive care unit and time in the hospital after transplantation were significantly longer compared with the non-Fontan transplant patients (Table 2). Despite this, the actuarial survival out to five years (Fig 1) was not different from those patients who had not had a Fontan procedure. Although nine of the Fontan transplanted patients had their Fontan procedure within one year of transplant (six ⬍6 months), we did not find that these patients fared any worse than those Fontan patients undergoing transplantation more than one year after their transplant procedure. This is in contrast to the report by Bernstein and colleagues [19] which showed that patients who are transplanted as UNOS status I or who were less than 6 months from their Fontan procedure at the time of transplant had a poor outcome. Twelve of the 27 Fontan transplant patients (44%) had PLE. All ten of these 12 patients who survived more than six months after transplant had complete resolution of their PLE. This confirms the observations of other groups who have also noted resolution of PLE after transplantation [4, 10, 19, 21–24]. The degree of pretransplant sensitization in our patient population did not differ between the patients who had previously undergone a Fontan procedure compared with those who did not (Table 1). Intuitively, compared with the non-Fontan patients one would have expected the Fontan patients to have a higher incidence of preformed antibodies due to exposure to blood products during prior operations. A partial explanation for this inconsistency would be that the truly highly sensitized Fontan patients listed for transplantation died before transplantation while waiting for a suitable donor with a negative prospective crossmatch. Nonetheless, the multiinstitutional review from the Pediatric Heart Transplant Study Group [19] identified only 16.5% of their Fontan patients as having an elevated PRA (defined as ⬎20% in their study). Although the incidence of acute rejection was higher within 30 days of transplant in the Fontan patients, there was no statistically significant difference at one year of age (Fig 2). This is in contrast to the report by Gamba and colleagues from Bergamo, Italy [21] that suggested that rejection episodes were less common in Fontan patients compared with non-Fontan patients.
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In summary, our report suggests that, contrary to multiple previous reports, children undergoing cardiac transplantation after a Fontan procedure can be transplanted with results similar to patients who have not had a prior Fontan procedure. This is despite higher operative complexity and a more difficult postoperative course as suggested by prolonged posttransplant ventilation and longer hospital stays. There is an ongoing incidence of death and retransplantation in these patients (Fig 3). Medium-term follow-up in our series suggests that their outlook is similar to other pediatric heart transplant recipients. Although our series may suffer from small numbers of patients and its retrospective nature, we contend this single-institution report demonstrates that carefully selected children with a failing Fontan procedure can undergo successful cardiac transplantation.
References 1. Carey JA, Hamilton JR, Hilton CJ, et al. Orthotopic cardiac transplantation for the failing Fontan circulation. Eur J Cardiothorac Surg 1998;14:7–13. 2. Chen JM, Davies RR, Mital SR, et al. Trends and outcomes in transplantation for complex congenital heart disease: 1984 to 2004. Ann Thorac Surg 2004;78:1352– 61. 3. Hsu DT, Quaegebeur JM, Michler RE, et al. Heart transplantation in children with congenital heart disease. J Am Coll Cardiol 1995;26:743–9. 4. Jayakumar KA, Addonizio LJ, Kichuk-Chrisant MR, et al. Cardiac transplantation after the Fontan or Glenn procedure. J Am Coll Cardiol 2004;44:2065–72. 5. Lamour JM, Addonizio LJ, Galantowicz ME, et al. Outcome after orthotopic cardiac transplantation in adults with congenital heart disease. Circulation 1999;100(19 Suppl):II200 –5. 6. Michielon G, Parisi F, Di CD, et al. Orthotopic heart transplantation for failing single ventricle physiology. Eur J Cardiothorac Surg 2003;24:502–10. 7. Michielon G, Parisi F, Squitieri C, et al. Orthotopic heart transplantation for congenital heart disease: an alternative for high-risk Fontan candidates? Circulation 2003;108(Suppl 1):II140 –9. 8. Petko M, Myung RJ, Wernovsky G, et al. Surgical reinterventions following the Fontan procedure. Eur J Cardiothorac Surg 2003;24:255–9. 9. Hosseinpour AR, Cullen S, Tsang VT. Transplantation for adults with congenital heart disease. Eur J Cardiothorac Surg 2006;30:508 –14. 10. Mitchell MB, Campbell DN, Ivy D, et al. Evidence of pulmonary vascular disease after heart transplantation for Fontan circulation failure. J Thorac Cardiovasc Surg 2004;128:693– 702. 11. Simmonds J, Burch M, Dawkins H, Tsang V. Heart transplantation after congenital heart surgery: improving results and future goals. Eur J Cardiothorac Surg 2008;34: 313–7. 12. Kanter KR, Vincent RN, Raviele AA. Importance of acquired systemic-to-pulmonary collaterals in the Fontan operation. Ann Thorac Surg 1999;68:969 –74. 13. Doty DB, Renlund DG, Caputo GR, Burton NA, Jones KW. Cardiac transplantation in situs inversus. J Thorac Cardiovasc Surg 1990;99:493–9. 14. Chartrand C, Guerin R, Kangah M, Stanley P. Pediatric heart transplantation: surgical considerations for congenital heart diseases. J Heart Transplant 1990;9:608 –16.
15. Mayer JE Jr, Perry S, O’Brien P, et al. Orthotopic heart transplantation for complex congenital heart disease. J Thorac Cardiovasc Surg 1990;99:484 –91. 16. Griffiths ER, Kaza AK, Wyler von Ballmoos MC, et al. Evaluating failing Fontans for heart transplantation: predictors of death. Ann Thorac Surg 2009;88:558 – 63. 17. Kirk R, Edwards LB, Aurora P, et al. Registry of the International Society for Heart and Lung Transplantation: twelfth official pediatric heart transplantation report-2009. J Heart Lung Transplant 2009;28:993–1006. 18. Lamour JM, Kanter KR, Naftel DC, et al. The effect of age, diagnosis, and previous surgery in children and adults undergoing heart transplantation for congenital heart disease. J Am Coll Cardiol 2009;54:160 –5. 19. Bernstein D, Naftel D, Chin C, et al. Outcome of listing for cardiac transplantation for failed Fontan: a multiinstitutional study. Circulation 2006;114:273– 80.
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20. Mitchell MB, Campbell DN, Boucek MM. Heart transplantation for the failing Fontan circulation. Semin Thorac Cardiovasc Surg Pediatr Card Surg Annu 2004;7:56 – 64. 21. Gamba A, Merlo M, Fiocchi R, et al. Heart transplantation in patients with previous Fontan operations. J Thorac Cardiovasc Surg 2004;127:555– 62. 22. Brancaccio G, Carotti A, D’Argenio P, Michielon G, Parisi F. Protein-losing enteropathy after Fontan surgery: resolution after cardiac transplantation. J Heart Lung Transplant 2003; 22:484 – 6. 23. Holmgren D, Berggren H, Wåhlander H, Hallberg M, Myrdal U. Reversal of protein-losing enteropathy in a child with Fontan circulation is correlated with central venous pressure after heart transplantation. Pediatr Transplant 2001;5:135–7. 24. Mertens LL, Hagler DJ, Canter CE, et al. The outcome of heart transplantation for protein-losing enteropathy after the Fontan operation (abstract). Circulation 1999;100:I-602.
DISCUSSION DR ROBERT JAQUISS (Little Rock, AR): I would like to congratulate Kirk and his colleagues for truly outstanding results in what I think are the riskiest group of pediatric heart transplant patients. And I would say before this paper what I thought I knew about patients who need transplants after Fontan is that they don’t do as well as non-Fontan patients, and Kirk has clearly shown us that doesn’t have to be true. I knew it from a bunch of other reports, particularly a couple from the PHTS [Pediatric Heart Transplant Study], one of which Kirk is an author on, that have examined this fairly closely. One of them, the earlier one from 2006, showed that there is a significant waiting list mortality, and I will ask you about that in a second; as high as 22% depending on status, and then after transplant the survival was worse as well, all of which seems to be, as Kirk has shown, front– end loaded. So the early survival after transplant is where the big difference is. And this was really confirmed in a publication from the PHTS, the one that Kirk was a coauthor on, that showed that Fontan patients have an odds ratio of 8.6 for early death when compared to all other diagnoses. So this is really a tremendous accomplishment to make the survival curves match when they haven’t in other reports. I think this suggests that Kirk and his team have solved the early risk problem, and this is an example of the power of single-center studies to bring excellence to our attention and show us who we need to go to to learn from. So with that backdrop, I have got two questions for you, Kirk. One is that the only difference I could find between your patients and the PHTS patients is that yours are actually statistically significantly younger at the time of transplant after a Fontan. Do you think that you are better at identifying who is going to fail or who is failing, getting them listed, supporting them, and getting them transplanted? My second question has to do with what I talked about a moment ago, which is waiting list attrition. In the PHTS study, that was as high as 22% of kids dying before getting a transplant if they were listed as status 1. Do you have any tips about that or comments about your experience? What do you think about getting these kids into better shape before we transplant them, perhaps the PLE [protein-losing enteropathy] kids, maybe putting a device in them or something like that? Again, I congratulate you on outstanding results. DR KANTER: Our patients did tend to be younger than in other reports; however, if you read the PHTS report carefully, you will see that the age group between two and six had a 28% increased risk of mortality. This 28% increased risk was an ongoing risk
looking at both the acute phase and in the constant phase. There was still an ongoing mortality hazard for children transplanted at two to six years of age even just looking at those patients who survived six months. Since our average age at transplant was about eight years old that means that almost half of our patients were under six at the time of transplant. I can assure you that our cardiologists are not sending these patients to us when they are still healthy as evidenced by the fact that two-thirds of them were UNOS [United Network for Organ Sharing] status I. As you know, at that age they have to be on a ventilator or on inotropic support to be status I. So they were fairly sick at time of transplant, and certainly the 40% who had PLE were quite a challenging group. Regarding attrition on the waiting list, we, too, saw that. During the same time period we had seven Fontan patients who were listed who were not transplanted. One family decided to come take their son off the list. The other six died while waiting. Earlier, I mentioned that I was surprised that the percentage of patients with preformed antibodies was similar in the Fontan and non-Fontan groups. Perhaps the patients who died on the waiting list were highly sensitized so we just couldn’t get a donor in time. If we had transplanted all the patients we had listed for transplant in the Fontan group, I suspect our percentage of presensitized individuals would have been significantly different from the non-Fontan patients. Up until a year ago we would have done a prospective cross match if the PRA [panel reactive antibody] were above 20%. We have now started doing virtual cross matches. Hopefully in the future, those sensitized patients won’t die on the waiting list. DR KIMBERLY L. GANDY (Milwaukee, WI): Dr Kanter, I would like to echo those thoughts. Those are absolutely fantastic results for this patient population. My question for you that you partially answered does relate to the sensitization rate in these patients. Many of us are recently seeing rates as high as 30 to 60% in our transplant population, even the non-Fontan patient population. So my question for you is, are you seeing more of that now? Is this your baseline rate, which is just a very low rate of sensitization, or is part of the reason that some of these patients were excluded beforehand as you just mentioned? DR KANTER: I am surprised that our presensitization rate is under 20% for all of these children who have had an average of almost five operations per patient. Of course, this translates to exposure to many blood products. Because of the timing of the series, many of these patients had their early operations before
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we were even thinking about transplant. At our institution now, we wash the blood in all patients undergoing heart surgery with the thought that they may eventually need a transplant, but in those days you just gave regular blood. So I was really surprised. PEDIATRIC CARDIAC
DR GANDY: So you are not using HLA [human leukocyte antigen]–matched blood or any special tricks for these kids beforehand? DR KANTER: No we are not. DR GANDY: Thank you. DR CONSTANTINE MAVROUDIS (Cleveland, OH): Dr Kanter, your presentation was excellent. Did any of your patients require placement of a ventricular assist device as a bridge to cardiac transplantation? If not and if you were presented with a situation today, would you use a right ventricular assist device, a left ventricular assist device, a biventricular assist device, or a DeBakey rotary ventricular assist device? DR KANTER: None of our patients required a VAD [ventricular assist device] pretransplant. One that I mentioned who required early retransplantation had ECMO [extracorporeal membrane oxygenation] between the two transplants (I suppose you could consider ECMO a form of a VAD). Faced with the need for a VAD pretransplant, I would assume that the pulmonary vascular resistance is reasonably low as evidenced by surviving, albeit somewhat poorly, with a Fontan circulation. So if you can support the systemic ventricle, even if it is a morphologic right ventricle, then they are living on a Fontan circulation and therefore just isolated left heart support should be adequate to
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get them through as a bridge to transplant. Since we have not yet done it, that is just speculation, but, I think, educated speculation. DR MAVROUDIS: I am not sure that would help somebody with protein-losing enteropathy. DR KANTER: The patients with protein-losing enteropathy are quite challenging due to their severe malnutrition and immune compromise pretransplant. If you can get by without a devastating infection, you are lucky. I think we were quite lucky in this series. DR JOHN EDMUND MAYER, JR (Boston, MA): Just one quick comment, and I think all of us should think about this. What we are probably really interested in is impedance in the pulmonary vascular bed rather than resistance, and I think it is pretty clear that when we measure pulmonary vascular resistance we are not exactly measuring what a right ventricle that is actually pumping blood is going to face when it pumps into that Fontan circulation. So we either have to rethink how we assess pulmonary vascular impedance in the normal and then the rest of our congenital heart surgery experience, or at least we need to recognize that what we are measuring in a Fontan circulation is truly pulmonary vascular resistance, because it is pretty nonphasic flow for the most part as opposed to what we measure in all the other circumstances where there is pulsatile flow. DR KANTER: I think Marc De Leval also made the observation that you cannot accurately measure pulmonary vascular resistance in a patient with a Fontan circulation.
Background. Previous studies have reported that children with a prior Fontan procedure have decreased survival after heart transplantation. We examined 190 primary pediatric heart transplants. Methods. Since 1988, 27 (14.2%) of 190 children less than 18 years old undergoing primary heart transplantation had a Fontan procedure 3.7 ⴞ 4.3 years before transplantation. Compared with 163 (85.8%) non-Fontan primary transplants, the Fontan patients were similar in age (8.2 ⴞ 5.0 vs 6.5 ⴞ 6.0 years), presensitization, and pretransplant clinical status. More Fontan patients had prior operations (100% vs 50%; p < 0.0001) and needed pulmonary artery reconstruction (100% vs 23.5%; p < 0.0001). Twelve (44%) had protein-losing enteropathy. Results. Donor ischemic times (211 ⴞ 72 vs 170 ⴞ 61 minutes; p ⴝ 0.0018) and cardiopulmonary bypass times (197 ⴞ 91 vs 121 ⴞ 53 minutes; p < 0.0001) were greater in the Fontan group as were durations of ventilator support (4.9 ⴞ 6.6 vs 2.6 ⴞ 3.9 days; p ⴝ 0.018) and hospital stay
(20.2 ⴞ 17.5 vs 14.3 ⴞ 12.4 days; p ⴝ 0.0435). The Fontan group had one 30-day mortality. One-year actuarial survival (81.5% vs 84.6%, Fontan vs non-Fontan) and fiveyear actuarial survival (65.5% vs 66.2%, Fontan vs nonFontan) were similar, as was rejection incidence at one year (2.0 ⴞ 2.0 vs 1.7 ⴞ 1.9 episodes per patient; p ⴝ 0.3972). Five Fontan patients (18.5%) required retransplantation 4.9 ⴞ 3.6 years posttransplant compared with 18 non-Fontan patients (11.0%) retransplanted 5.2 ⴞ 3.4 years posttransplant (p ⴝ 0.3346). Conclusions. Contrary to prior reports, we did not identify any early or midterm disadvantage for children undergoing heart transplantation after a previous Fontan procedure despite more complex transplant operations. We contend that carefully selected children with a failing Fontan circulation can do as well as other children with heart transplantation. (Ann Thorac Surg 2011;91:823–30) © 2011 by The Society of Thoracic Surgeons
T
Furthermore, because all of the patients with a previous Fontan procedure who are considered for transplantation have had prior operations, they may be sensitized with preformed antibodies from exposure to blood products, which would increase the risk of rejection after transplantation. Many of these Fontan patients have complex venous or arterial connections, which can make the transplant operation technically challenging. After transplantation, there are many risk factors common in the Fontan patient, including increased risk of bleeding, the presence of systemic artery-to-pulmonary artery collateral arteries, unrecognized or underestimated pulmonary artery hypertension, and decreased resistance to infection, particularly in those patients who are malnourished due to PLE. In view of these challenges and aware of the discouraging results from other centers, we retrospectively examined our experience with 27 children younger than 18 years of age who underwent primary heart transplantation after a Fontan procedure.
he Fontan procedure is commonly employed as longterm palliation of children with single-ventricle physiology. As time goes on, a percentage of these patients will develop refractory heart failure or complications of the Fontan necessitating heart transplantation. Previous studies have shown diminished survival in patients undergoing transplantation after a failed Fontan procedure compared with other patients undergoing transplantation [1– 8]. Various reasons have been proposed for these disappointing results [9]. The pulmonary vascular resistance in patients after a Fontan procedure can be difficult to assess due to the presence of systemic-topulmonary collateral arteries, low cardiac output, and nonpulsatile flow [1, 10, 11]. Many of these patients, particularly those with a short interval from Fontan to need for transplantation, can have significant other morbidities which make them high-risk candidates for transplantation. These comorbidities include protein-losing enteropathy (PLE), hepatic dysfunction, and renal dysfunction.
Accepted for publication Nov 15, 2010. Presented at the Fifty-sixth Annual Meeting of the Southern Thoracic Surgical Association, Marco Island, FL, Nov 4 –7, 2009. Address correspondence to Dr Kanter, Pediatric Cardiac Surgery, Emory University School of Medicine, 1405 Clifton Rd, Atlanta, GA 30322; e-mail: [email protected].
© 2011 by The Society of Thoracic Surgeons Published by Elsevier Inc
Patients and Methods Approval for this retrospective study was obtained from the Emory University School of Medicine Human Inves0003-4975/$36.00 doi:10.1016/j.athoracsur.2010.11.031
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tigation Committee. The need for patient consent was waived.
Patient Population PEDIATRIC CARDIAC
From June 1988 to November 2009, we performed 222 heart transplants at Children’s Healthcare of Atlanta at Egleston, the pediatric hospital affiliated with Emory University in Atlanta. After excluding 29 retransplant operations and three patients older than 18 years of age, there remained 190 primary pediatric heart transplants for analysis. Twenty seven of these patients (14.2%) had a Fontan procedure 3.7 ⫾ 4.3 years before transplantation (range, 2.5 months to 15.3 years). Nine of the 27 patients (33%) were transplanted within one year of their Fontan procedure, of which six children were transplanted within six months of their Fontan procedure. The age of the original Fontan procedure was 4.5 ⫾ 3.3 years (range, 1.5 to 12.4 years of age). Age at transplantation was 8.2 ⫾ 5.0 years for the Fontan patients compared with 6.5 ⫾ 6.0 years for the 163 patients who did not have a Fontan procedure (p ⫽ 0.1781). During the same time, nine additional children with a prior Fontan procedure were evaluated and listed for transplantation but were not transplanted. One was removed from the heart transplant waiting list at the wishes of the parents; the remaining eight died without transplantation, typically due to high levels of preformed antibodies greatly reducing the possibility of a compatible donor or due to an intercurrent infection or clinical deterioration precluding transplantation. During this time, over 500 Fontan procedures were performed at our institution, so this experience reflects a transplantation rate of roughly 5% in Fontan recipients. Children with a previous Fontan procedure were evaluated for transplantation if they had ongoing heart failure symptoms despite optimal medical therapy including maximal afterload reduction and, often, trials of home inotropic support, or if they had PLE refractory to standard medical therapy (including attempts at Fontan baffle refenestration or enlarging an existing fenestration). Patients with significant hepatic dysfunction as determined by impaired synthetic function (especially an elevated protime in the absence of anticoagulation) were excluded from consideration for transplantation. All patients had pretransplant cardiac catheterization to identify any correctable anatomic problems with the Fontan
pathway or with the atrioventricular valves, to assess pulmonary vascular resistance, and to eliminate accessory sources of pulmonary blood flow with aggressive occlusion of systemic-to-pulmonary collateral arteries in the catheterization laboratory [12]. Although many of the patients were listed for cardiac transplantation while clinically stable, most did not receive a transplant until they had deteriorated and required hospital admission, intravenous inotropic support, and, not uncommonly, mechanical ventilation. In this clinical state, their status on the heart transplant waiting list was upgraded to a more urgent UNOS (United Network for Organ Sharing) status I in 67% of the Fontan patients. No Fontan patient was maintained on mechanical circulatory support pretransplant although one required continuous venovenous hemofiltration for renal failure pretransplant. As shown in Table 1, the percentage of patients in both the Fontan and the non-Fontan groups with a panel reactive antibody (PRA) greater than 10% to class I antigens was similar as was the UNOS (United Network for Organ Sharing) status at the time of transplantation. All of the Fontan patients had prior operations compared with 50.3% of the non-Fontan patients. The number of prior operations per patient for those with a Fontan procedure was 4.9 ⫾ 1.9 operations per patient compared with 2.4 ⫾ 1.7 for the 82 patients in the non-Fontan group who had previous operations (p ⬍ 0.0001). Twenty-two percent of the Fontan patients and 26% of the non-Fontan patients required ventilator support at the time of transplantation (Table 1). Twelve of the Fontan children (44%) had protein-losing enteropathy (PLE) as one of the indications for heart transplantation. Twenty-one (78%) of the Fontan patients had decreased ventricular function prior to transplantation (10 with PLE), whereas six Fontan patients had preserved ventricular function (2 with PLE).
Operative Techniques Coordination of the donor and recipient operations was carefully planned so that there would be adequate time for a safe, cautious, and hemostatic reopening of the recipient’s chest. The use of femoral cannulation for cardiopulmonary bypass was atypical. All Fontan patients had bicaval anastomoses for the transplant. Venous, arterial, and situs abnormalities were managed with previously described surgical techniques [13–15].
Table 1. Patient Characteristics Characteristic
Fontan (n ⫽ 27)
Non-Fontan (n ⫽ 163)
p Value
Age at transplant (years, mean ⫾ SD) Class I PRA ⱖ10% (n, %) UNOS status I (n, %) Days on waiting list Prior operation (n, %) Number of prior operations per patient who had a prior operation Ventilated at time of transplant (n, %)
8.2 ⫾ 5.0 5 (18.5%) 18 (67%) 84.1 ⫾ 133 27 (100%) 4.9 ⫾ 1.9 (n ⫽ 27)
6.5 ⫾ 6.0 27 (16.8%) 119 (73%) 64.1 ⫾ 119 82 (50.3%) 2.4 ⫾ 1.7 (n ⫽ 82)
0.1781 0.7858 0.4942 0.4271 ⬍0.0001 ⬍0.0001
6 (22%)
42 (26%)
PRA ⫽ panel reactive antibody;
UNOS ⫽ United Network for Organ Sharing.
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Immunosuppression and Rejection Surveillance Both groups had identical immunotherapy regimens using triple drug immunosuppression. Early in this series the patients were treated with cyclosporine, azathioprine, and a weaning dose of steroids. Efforts were made to wean off steroids entirely within a year of transplantation based on negative endomyocardial biopsies. After 1992, mycophenolate was used routinely in place of azathioprine. Induction immunotherapy was not used until 2005 when we routinely added daclizumab to the standard triple drug therapy. In 2007, tacrolimus was substituted for cyclosporine as the preferred calineurin inhibitor. Periodic surveillance endomyocardial biopsies were performed on all patients, as were routine annual coronary arteriograms. Rejection episodes were treated with pulsed steroids. Only recurrent, refractory or hemodynamically compromising rejection episodes were treated with monoclonal antibodies such as OKT-3. Diagnostic intravascular ultrasound of the coronary arteries was not used routinely.
Statistical Analysis Continuous variables were compared by analysis of variance and are presented as mean ⫾ standard deviation. Nominal variables were compared by 2 analysis with the Fisher exact test. Life-table analysis was done by the Kaplan-Meier survival method with significance determined by log-rank analysis. All statistical tests were considered significant if the p value was less than 0.05.
Results The results for several perioperative variables are shown in Table 2. Pulmonary artery reconstruction, which previously has been identified as a risk factor for unfavorable outcome at the time of transplantation [2], was performed in all of the Fontan patients compared with 22% of the non-Fontan patients (p ⬍ 0.0001). As a surrogate marker for operative complexity, both donor ischemia time and cardiopulmonary bypass time were significantly longer in the Fontan group compared with the non-Fontan group (Table 2). The Fontan patients required significantly longer durations of ventilation and hospital stay. The duration of posttransplant inotropic support and time in the intensive care unit also tended to
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Table 2. Perioperative Variables Variable Pulmonary artery reconstruction (n, %) Donor ischemia time (minutes) Cardiopulmonary bypass time (minutes) Days ventilated posttransplant Days on inotropic support posttransplant Days in intensive care unit posttransplant Days in hospital posttransplant
Fontan (n ⫽ 27)
Non-Fontan (n ⫽ 163)
p Value
27 (100%)
36 (22.1%)
⬍0.0001
211 ⫾ 72
170 ⫾ 61
0.0018
197 ⫾ 91
121 ⫾ 53
⬍0.0001
4.9 ⫾ 6.6
2.6 ⫾ 3.9
0.018
5.2 ⫾ 3.8
4.5 ⫾ 6.2
0.6231
11.5 ⫾ 12.9
7.7 ⫾ 9.8
0.099
20.2 ⫾ 17.5
14.3 ⫾ 12.4
0.0435
be longer in the Fontan group, but these differences did not achieve statistical significance (Table 2). There was one 30-day mortality in the Fontan group giving a 30-day survival of 96.3% compared with a 30-day survival of 95.6% in the non-Fontan group. This patient was a 2.8-year-old boy with heterotaxy syndrome who had a fenestrated lateral tunnel Fontan procedure ten months before transplantation followed by a common atrioventricular valve repair 3.5 months later. He developed severe heart failure and was listed for cardiac transplantation. He deteriorated and at the time of transplantation he was intubated in the intensive care unit in renal failure requiring dialysis. After transplantation, he remained anuric. A renal ultrasound revealed renal vein thrombosis. He succumbed to Candida sepsis and disseminated intravascular coagulopathy ten days after transplantation. The Kaplan-Meier estimate for patient survival is shown in Figure 1. The results are not statistically different for the Fontan patients compared with the non-Fontan patients with a one-year actuarial survival of 81.5% for the Fontan patients and 84.6% for the non-Fontan patients. The five-year actuarial survival for the Fontan patients was 65.5% compared with 66.2% for the non-Fontan patients. Note that there is a cluster of deaths in the first six months after transplantation in the Fontan patients, but by five years the two curves seem to converge (Fig 1). In contrast to the recent report from Boston [16] that identified pretransplant preserved ventricular function in Fontan patients as a risk factor for one-year mortality after heart transplantation, in our series there was one death within one year in the six patients (17% one-year mortality) who had preserved pretransplant ventricular function, compared with four deaths within one year in the 21 patients (19% one-year mortality) who had impaired ventricular function pretransplant. These early mortality rates were not statistically different. Furthermore, comparing the six Fontan patients who had cardiac transplantation within six months of their Fontan procedure to the other Fontan patients, one-year survival rates were similar (83% vs 81%).
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Excessive pulmonary venous return was a common problem during the transplant operation due to systemic-topulmonary collateral arteries. It often was necessary to reduce cardiopulmonary bypass flow during the pulmonary artery anastomosis to aid visualization. A generous amount of donor pulmonary artery was procured to allow for extensive patching of the native pulmonary arteries including the site of the previous Glenn anastomosis, if present. To prevent right ventricular distention in the transplanted heart, a left atrial vent was always used and often an additional vent was placed in the pulmonary artery during rewarming. Commonly, the heart from a donor larger than the recipient was used and prolonged donor travel times were avoided as much as possible to reduce donor ischemic time.
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Fig 1. Kaplan-Meier actuarial freedom from death stratified by patients who had a previous Fontan procedure () and those who did not (X). The survival estimates are not statistically different (p ⫽ 0.4975).
Of the twelve patients with PLE, ten survived more than six months after transplantation; all ten had complete resolution of the PLE. The presence of PLE did not affect one-year survival after transplantation (83%) compared with those Fontan recipients who did not have PLE (one-year survival 80%). The incidence of acute rejection at 30 days was statistically significantly more frequent in the Fontan patients (Fig 2) even though the percentage of patients with elevated levels of preformed antibodies as measured by PRA greater than 10% was comparable between the two groups (Table 1). By one year, the incidence of acute rejection was similar between the two groups (Fig 2).
Fig 2. Incidence of rejection episodes per patient at thirty days and one year after transplantation. (Fontan [black]; non-Fontan [horizontal striped].)
On average follow-up of 6.7 ⫾ 5.2 years, cardiac retransplantation was performed in five (18.5%) of the Fontan patients an average of 4.9 ⫾ 3.6 years after initial transplantation. One 4.3-year-old Fontan patient required acute retransplantation for acute right heart failure due to uncontrolled systemic-to-pulmonary artery collateral arteries. The child required support with ECMO (extracorporeal membrane oxygenation) after transplantation. While on ECMO, she had coil occlusion of multiple large systemic-to-pulmonary collateral arteries in the Cardiac Catheterization Laboratory. She was listed for retransplantation. A suitable donor became available two days after her initial transplant and she underwent successful retransplantation and did well (after a prolonged hospitalization) for seven years more until she developed transplant vasculopathy. The other four retransplant operations in the Fontan group were more than one year after the initial transplant procedure and were for transplant coronary artery disease or for nonspecific graft dysfunction with poor diastolic compliance of the transplanted heart. On follow-up of 6.1 ⫾ 5.7 years, the incidence of retransplantation in the nonFontan patients was 18 of 163 (11.0%) , which was not significantly statistically different from the Fontan patients. Freedom from retransplantation and death for the two groups is shown in Figure 3. The two groups are statistically not different.
Comment Early reports showed poor survival after transplantation in patients who have had a previous Fontan procedure
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Fig 3. Kaplan-Meier actuarial freedom from death or retransplantation (graft survival) comparing Fontan () patients with non-Fontan patients (X) showing no statistical difference in graft survival (p ⫽ 0.4215).
[1– 8]. The group from Columbia University [3, 5] reported a 33% incidence of early death in nine patients who had a Fontan, all within the first week of transplantation. A later report from the Columbia group [2] identified a 37.9% overall mortality in Fontan patients who underwent transplantation (11 deaths in 29 patients). Other institutions reported similar discouraging results with transplantation after the Fontan procedure. The group from Newcastle in England [1] identified three operative deaths in nine patients with a Fontan procedure (both adults and children) with no late deaths on follow-up. Michielon and colleagues [6, 7] in Rome reported a 67% perioperative mortality rate with four deaths out of six patients with a Fontan procedure. A more recent paper by Jayakumar and colleagues from Columbia [4] identified nine deaths within two months of transplantation in 24 adults and children undergoing transplantation after a Fontan procedure, resulting in a 62.5% one-year survival with a 57% five-year survival. Similarly, Petko and colleagues [8] from the Children’s Hospital of Philadelphia reported four perioperative deaths in nine patients transplanted after a Fontan procedure with an additional two late deaths. The 2009 pediatric report of the International Society of Heart and Lung Transplantation [17] reaffirms that for pediatric heart transplantation, the basic diagnosis of congenital heart disease is a risk factor for poor survival at one and five years. A recent multiinstitutional study [18] combining results from the Pediatric Heart Transplant Study Group and the Cardiac Transplant Research Database identified 107 adults and children with a Fontan procedure who underwent transplantation at a mean age of 15 years. The relative risk for death was 8.6 for Fontan patients compared with non-Fontan patients who had a
congenital diagnosis. The one-year survival was 71%. These authors identified younger recipient (recipient age between 6 and 12 years) as a risk factor, with 28% more deaths in this group. This continued to be a risk factor for death even after the early posttransplant period. Analyzing only pediatric patients, Bernstein and colleagues and the Pediatric Heart Transplant Study Group [19] identified 97 patients younger than 18 years of age listed for heart transplantation after a Fontan procedure. The mean age was 10.7 ⫾ 5.4 years at transplant. Seventy of these 97 patients were transplanted with a one-year survival of 76% and a five-year survival of 68%. There are, however, isolated single-institution reports demonstrating reasonable survival after heart transplantation in patients with a Fontan procedure. Mitchell and colleagues from Denver [10, 20] described 14 patients undergoing heart transplantation after a Fontan procedure. The average age at transplant was 11.6 years. There was only one death at six months posttransplant giving an actuarial graft survival of 93% at three years and 82% at five years. The group from Bergamo, Italy [21] also showed reasonable survival after heart transplantation for adults and children after the Fontan procedure. They identified fourteen patients (half less than 18 years old) with an average age at transplantation of 17.2 ⫾ 6.3 years. The one-year and five-year actuarial survival was 86% and 77%, respectively. In the current series, the twenty-seven children with a Fontan procedure undergoing heart transplantation were younger (mean age 8.2 ⫾ 5.0 years) compared with most series in which the average age at transplantation is in the mid-to-late teens. These patients were clearly complex with an average number of previous operations of 4.9 ⫾ 1.9 operations per patient. Two-thirds of the pa-
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tients were UNOS status I and 22% on the ventilator at the time of transplantation. A total of 18.5% of the patients were presensitized with a class I PRA greater than 10% (Table 1). Despite the high complexity of the operative procedure, including pulmonary reconstruction in all patients (which previously has been identified as a risk factor for transplantation [2]), the early perioperative results were similar compared with the non-Fontan patients. The only early death in the Fontan group was in a patient who was essentially moribund at the time of transplantation with anuric renal failure, ventilator dependence, and severe heart failure. Using donor ischemic time and cardiopulmonary bypass time as surrogates for operative complexity, the Fontan patients had significantly more complex transplant operations. Accordingly, their time in the intensive care unit and time in the hospital after transplantation were significantly longer compared with the non-Fontan transplant patients (Table 2). Despite this, the actuarial survival out to five years (Fig 1) was not different from those patients who had not had a Fontan procedure. Although nine of the Fontan transplanted patients had their Fontan procedure within one year of transplant (six ⬍6 months), we did not find that these patients fared any worse than those Fontan patients undergoing transplantation more than one year after their transplant procedure. This is in contrast to the report by Bernstein and colleagues [19] which showed that patients who are transplanted as UNOS status I or who were less than 6 months from their Fontan procedure at the time of transplant had a poor outcome. Twelve of the 27 Fontan transplant patients (44%) had PLE. All ten of these 12 patients who survived more than six months after transplant had complete resolution of their PLE. This confirms the observations of other groups who have also noted resolution of PLE after transplantation [4, 10, 19, 21–24]. The degree of pretransplant sensitization in our patient population did not differ between the patients who had previously undergone a Fontan procedure compared with those who did not (Table 1). Intuitively, compared with the non-Fontan patients one would have expected the Fontan patients to have a higher incidence of preformed antibodies due to exposure to blood products during prior operations. A partial explanation for this inconsistency would be that the truly highly sensitized Fontan patients listed for transplantation died before transplantation while waiting for a suitable donor with a negative prospective crossmatch. Nonetheless, the multiinstitutional review from the Pediatric Heart Transplant Study Group [19] identified only 16.5% of their Fontan patients as having an elevated PRA (defined as ⬎20% in their study). Although the incidence of acute rejection was higher within 30 days of transplant in the Fontan patients, there was no statistically significant difference at one year of age (Fig 2). This is in contrast to the report by Gamba and colleagues from Bergamo, Italy [21] that suggested that rejection episodes were less common in Fontan patients compared with non-Fontan patients.
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In summary, our report suggests that, contrary to multiple previous reports, children undergoing cardiac transplantation after a Fontan procedure can be transplanted with results similar to patients who have not had a prior Fontan procedure. This is despite higher operative complexity and a more difficult postoperative course as suggested by prolonged posttransplant ventilation and longer hospital stays. There is an ongoing incidence of death and retransplantation in these patients (Fig 3). Medium-term follow-up in our series suggests that their outlook is similar to other pediatric heart transplant recipients. Although our series may suffer from small numbers of patients and its retrospective nature, we contend this single-institution report demonstrates that carefully selected children with a failing Fontan procedure can undergo successful cardiac transplantation.
References 1. Carey JA, Hamilton JR, Hilton CJ, et al. Orthotopic cardiac transplantation for the failing Fontan circulation. Eur J Cardiothorac Surg 1998;14:7–13. 2. Chen JM, Davies RR, Mital SR, et al. Trends and outcomes in transplantation for complex congenital heart disease: 1984 to 2004. Ann Thorac Surg 2004;78:1352– 61. 3. Hsu DT, Quaegebeur JM, Michler RE, et al. Heart transplantation in children with congenital heart disease. J Am Coll Cardiol 1995;26:743–9. 4. Jayakumar KA, Addonizio LJ, Kichuk-Chrisant MR, et al. Cardiac transplantation after the Fontan or Glenn procedure. J Am Coll Cardiol 2004;44:2065–72. 5. Lamour JM, Addonizio LJ, Galantowicz ME, et al. Outcome after orthotopic cardiac transplantation in adults with congenital heart disease. Circulation 1999;100(19 Suppl):II200 –5. 6. Michielon G, Parisi F, Di CD, et al. Orthotopic heart transplantation for failing single ventricle physiology. Eur J Cardiothorac Surg 2003;24:502–10. 7. Michielon G, Parisi F, Squitieri C, et al. Orthotopic heart transplantation for congenital heart disease: an alternative for high-risk Fontan candidates? Circulation 2003;108(Suppl 1):II140 –9. 8. Petko M, Myung RJ, Wernovsky G, et al. Surgical reinterventions following the Fontan procedure. Eur J Cardiothorac Surg 2003;24:255–9. 9. Hosseinpour AR, Cullen S, Tsang VT. Transplantation for adults with congenital heart disease. Eur J Cardiothorac Surg 2006;30:508 –14. 10. Mitchell MB, Campbell DN, Ivy D, et al. Evidence of pulmonary vascular disease after heart transplantation for Fontan circulation failure. J Thorac Cardiovasc Surg 2004;128:693– 702. 11. Simmonds J, Burch M, Dawkins H, Tsang V. Heart transplantation after congenital heart surgery: improving results and future goals. Eur J Cardiothorac Surg 2008;34: 313–7. 12. Kanter KR, Vincent RN, Raviele AA. Importance of acquired systemic-to-pulmonary collaterals in the Fontan operation. Ann Thorac Surg 1999;68:969 –74. 13. Doty DB, Renlund DG, Caputo GR, Burton NA, Jones KW. Cardiac transplantation in situs inversus. J Thorac Cardiovasc Surg 1990;99:493–9. 14. Chartrand C, Guerin R, Kangah M, Stanley P. Pediatric heart transplantation: surgical considerations for congenital heart diseases. J Heart Transplant 1990;9:608 –16.
15. Mayer JE Jr, Perry S, O’Brien P, et al. Orthotopic heart transplantation for complex congenital heart disease. J Thorac Cardiovasc Surg 1990;99:484 –91. 16. Griffiths ER, Kaza AK, Wyler von Ballmoos MC, et al. Evaluating failing Fontans for heart transplantation: predictors of death. Ann Thorac Surg 2009;88:558 – 63. 17. Kirk R, Edwards LB, Aurora P, et al. Registry of the International Society for Heart and Lung Transplantation: twelfth official pediatric heart transplantation report-2009. J Heart Lung Transplant 2009;28:993–1006. 18. Lamour JM, Kanter KR, Naftel DC, et al. The effect of age, diagnosis, and previous surgery in children and adults undergoing heart transplantation for congenital heart disease. J Am Coll Cardiol 2009;54:160 –5. 19. Bernstein D, Naftel D, Chin C, et al. Outcome of listing for cardiac transplantation for failed Fontan: a multiinstitutional study. Circulation 2006;114:273– 80.
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20. Mitchell MB, Campbell DN, Boucek MM. Heart transplantation for the failing Fontan circulation. Semin Thorac Cardiovasc Surg Pediatr Card Surg Annu 2004;7:56 – 64. 21. Gamba A, Merlo M, Fiocchi R, et al. Heart transplantation in patients with previous Fontan operations. J Thorac Cardiovasc Surg 2004;127:555– 62. 22. Brancaccio G, Carotti A, D’Argenio P, Michielon G, Parisi F. Protein-losing enteropathy after Fontan surgery: resolution after cardiac transplantation. J Heart Lung Transplant 2003; 22:484 – 6. 23. Holmgren D, Berggren H, Wåhlander H, Hallberg M, Myrdal U. Reversal of protein-losing enteropathy in a child with Fontan circulation is correlated with central venous pressure after heart transplantation. Pediatr Transplant 2001;5:135–7. 24. Mertens LL, Hagler DJ, Canter CE, et al. The outcome of heart transplantation for protein-losing enteropathy after the Fontan operation (abstract). Circulation 1999;100:I-602.
DISCUSSION DR ROBERT JAQUISS (Little Rock, AR): I would like to congratulate Kirk and his colleagues for truly outstanding results in what I think are the riskiest group of pediatric heart transplant patients. And I would say before this paper what I thought I knew about patients who need transplants after Fontan is that they don’t do as well as non-Fontan patients, and Kirk has clearly shown us that doesn’t have to be true. I knew it from a bunch of other reports, particularly a couple from the PHTS [Pediatric Heart Transplant Study], one of which Kirk is an author on, that have examined this fairly closely. One of them, the earlier one from 2006, showed that there is a significant waiting list mortality, and I will ask you about that in a second; as high as 22% depending on status, and then after transplant the survival was worse as well, all of which seems to be, as Kirk has shown, front– end loaded. So the early survival after transplant is where the big difference is. And this was really confirmed in a publication from the PHTS, the one that Kirk was a coauthor on, that showed that Fontan patients have an odds ratio of 8.6 for early death when compared to all other diagnoses. So this is really a tremendous accomplishment to make the survival curves match when they haven’t in other reports. I think this suggests that Kirk and his team have solved the early risk problem, and this is an example of the power of single-center studies to bring excellence to our attention and show us who we need to go to to learn from. So with that backdrop, I have got two questions for you, Kirk. One is that the only difference I could find between your patients and the PHTS patients is that yours are actually statistically significantly younger at the time of transplant after a Fontan. Do you think that you are better at identifying who is going to fail or who is failing, getting them listed, supporting them, and getting them transplanted? My second question has to do with what I talked about a moment ago, which is waiting list attrition. In the PHTS study, that was as high as 22% of kids dying before getting a transplant if they were listed as status 1. Do you have any tips about that or comments about your experience? What do you think about getting these kids into better shape before we transplant them, perhaps the PLE [protein-losing enteropathy] kids, maybe putting a device in them or something like that? Again, I congratulate you on outstanding results. DR KANTER: Our patients did tend to be younger than in other reports; however, if you read the PHTS report carefully, you will see that the age group between two and six had a 28% increased risk of mortality. This 28% increased risk was an ongoing risk
looking at both the acute phase and in the constant phase. There was still an ongoing mortality hazard for children transplanted at two to six years of age even just looking at those patients who survived six months. Since our average age at transplant was about eight years old that means that almost half of our patients were under six at the time of transplant. I can assure you that our cardiologists are not sending these patients to us when they are still healthy as evidenced by the fact that two-thirds of them were UNOS [United Network for Organ Sharing] status I. As you know, at that age they have to be on a ventilator or on inotropic support to be status I. So they were fairly sick at time of transplant, and certainly the 40% who had PLE were quite a challenging group. Regarding attrition on the waiting list, we, too, saw that. During the same time period we had seven Fontan patients who were listed who were not transplanted. One family decided to come take their son off the list. The other six died while waiting. Earlier, I mentioned that I was surprised that the percentage of patients with preformed antibodies was similar in the Fontan and non-Fontan groups. Perhaps the patients who died on the waiting list were highly sensitized so we just couldn’t get a donor in time. If we had transplanted all the patients we had listed for transplant in the Fontan group, I suspect our percentage of presensitized individuals would have been significantly different from the non-Fontan patients. Up until a year ago we would have done a prospective cross match if the PRA [panel reactive antibody] were above 20%. We have now started doing virtual cross matches. Hopefully in the future, those sensitized patients won’t die on the waiting list. DR KIMBERLY L. GANDY (Milwaukee, WI): Dr Kanter, I would like to echo those thoughts. Those are absolutely fantastic results for this patient population. My question for you that you partially answered does relate to the sensitization rate in these patients. Many of us are recently seeing rates as high as 30 to 60% in our transplant population, even the non-Fontan patient population. So my question for you is, are you seeing more of that now? Is this your baseline rate, which is just a very low rate of sensitization, or is part of the reason that some of these patients were excluded beforehand as you just mentioned? DR KANTER: I am surprised that our presensitization rate is under 20% for all of these children who have had an average of almost five operations per patient. Of course, this translates to exposure to many blood products. Because of the timing of the series, many of these patients had their early operations before
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we were even thinking about transplant. At our institution now, we wash the blood in all patients undergoing heart surgery with the thought that they may eventually need a transplant, but in those days you just gave regular blood. So I was really surprised. PEDIATRIC CARDIAC
DR GANDY: So you are not using HLA [human leukocyte antigen]–matched blood or any special tricks for these kids beforehand? DR KANTER: No we are not. DR GANDY: Thank you. DR CONSTANTINE MAVROUDIS (Cleveland, OH): Dr Kanter, your presentation was excellent. Did any of your patients require placement of a ventricular assist device as a bridge to cardiac transplantation? If not and if you were presented with a situation today, would you use a right ventricular assist device, a left ventricular assist device, a biventricular assist device, or a DeBakey rotary ventricular assist device? DR KANTER: None of our patients required a VAD [ventricular assist device] pretransplant. One that I mentioned who required early retransplantation had ECMO [extracorporeal membrane oxygenation] between the two transplants (I suppose you could consider ECMO a form of a VAD). Faced with the need for a VAD pretransplant, I would assume that the pulmonary vascular resistance is reasonably low as evidenced by surviving, albeit somewhat poorly, with a Fontan circulation. So if you can support the systemic ventricle, even if it is a morphologic right ventricle, then they are living on a Fontan circulation and therefore just isolated left heart support should be adequate to
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get them through as a bridge to transplant. Since we have not yet done it, that is just speculation, but, I think, educated speculation. DR MAVROUDIS: I am not sure that would help somebody with protein-losing enteropathy. DR KANTER: The patients with protein-losing enteropathy are quite challenging due to their severe malnutrition and immune compromise pretransplant. If you can get by without a devastating infection, you are lucky. I think we were quite lucky in this series. DR JOHN EDMUND MAYER, JR (Boston, MA): Just one quick comment, and I think all of us should think about this. What we are probably really interested in is impedance in the pulmonary vascular bed rather than resistance, and I think it is pretty clear that when we measure pulmonary vascular resistance we are not exactly measuring what a right ventricle that is actually pumping blood is going to face when it pumps into that Fontan circulation. So we either have to rethink how we assess pulmonary vascular impedance in the normal and then the rest of our congenital heart surgery experience, or at least we need to recognize that what we are measuring in a Fontan circulation is truly pulmonary vascular resistance, because it is pretty nonphasic flow for the most part as opposed to what we measure in all the other circumstances where there is pulsatile flow. DR KANTER: I think Marc De Leval also made the observation that you cannot accurately measure pulmonary vascular resistance in a patient with a Fontan circulation.