Trends and Outcomes in Transplantation for Complex Congenital Heart Disease: 1984 to 2004

Transcription

1 Trends and Outcomes in Transplantation for Complex Congenital Heart Disease: 1984 to 2004 Jonathan M. Chen, MD, Ryan R. Davies, MD, Seema R. Mital, MD, Michelle L. Mercando, BA, Linda J. Addonizio, MD, Sean P. Pinney, MD, Daphne T. Hsu, MD, Jacqueline M. Lamour, MD, Jan M. Quaegebeur, MD, and Ralph S. Mosca, MD Divisions of Pediatric Cardiac Surgery, Pediatric Cardiology, and Cardiology, Columbia University College of Physicians and Surgeons, New York, New York Background. Cardiac transplantation for patients with complex congenital heart disease poses several anatomic and physiologic challenges for the transplant surgeon. We undertook the current single center study to evaluate surgical outcomes and lessons learned through a nearly twenty year experience with cardiac transplantation for complex congenital heart disease. Methods. A retrospective review was performed to evaluate all patients undergoing cardiac transplantation from January 1, 1984 through January 1, Donor and recipient demographic and intraoperative and postoperative variables were acquired and correlated with perioperative (30-day) and late mortality in both univariate and multivariate analyses, and with Kaplan-Meier survival estimates. Results. One hundred and six patients underwent transplantation for complex congenital heart disease and were followed for a median of 56 months. Thirty-seven (34.9%) patients died. Male gender and later year of Despite substantial advances in the operative techniques and perioperative management of patients undergoing reparative surgery for congenital heart disease, orthotopic heart transplantation frequently remains the only option available to those patients who later develop end-stage myocardial failure. Indeed, while the success of transplantation for pediatric recipients with isolated cardiomyopathy has become largely incontrovertible, its widespread application in the setting of patients with complex congenital heart disease most of whom have undergone several attempts at surgical palliation has not been met with comparable enthusiasm. This particular cohort poses several anatomic and physiologic challenges for the transplant surgeon as outlined in previous reports from several large centers [1 8]. While early results for transplantation in these patients were less encouraging, our recent outcomes seem to compare favorably with those of our other noncongenital Accepted for publication April 1, Presented at the Fortieth Annual Meeting of The Society of Thoracic Surgeons, San Antonio, TX, Jan 26 28, Address reprint requests to Dr Chen, Pediatric Cardiac Surgery, Children s Hospital of New York, 3959 Broadway, Suite 2-273, New York, NY 10032; jmc23@columbia.edu. transplantation were protective, and neonatal age and pulmonary artery reconstruction detrimental in multivariable modeling of overall mortality. Transplantation to a physiologic or anatomic single lung did not impact on survival. Patients in the study cohort had comparable survival estimates when compared with all those in the entire cohort without complex congenital heart disease. When comparing patients by era of transplantation, both cohorts demonstrated improved survival with later transplantation. Conclusions. Outcomes with transplantation for complex congenital heart disease have improved annually over the past twenty years. Transplantation to an anatomic or physiologic single lung did not impair overall survival. Pulmonary artery reconstruction imparted an increase in mortality both short and long term, a finding which merits further investigation. (Ann Thorac Surg 2004;78: ) 2004 by The Society of Thoracic Surgeons recipients. We therefore undertook the current study to evaluate surgical outcomes and lessons learned at the Children s Hospital of New York throughout a nearly twenty year experience with cardiac transplantation for complex congenital heart disease. Material and Methods Patient Population A retrospective review was performed to evaluate all patients undergoing cardiac transplantation at the Columbia University Medical Center between January 1, 1984 and January 1, A total of 1,525 (1,151 male, 374 female) patients comprised this cohort, of whom 106 were patients transplanted with complex congenital heart disease; these patients form the basis of the current analysis of outcomes. Hospital chart review was conducted on each identified patient and their donor, and the data entered into a computerized database. Donor and recipient demographic and intraoperative and postoperative variables were acquired (Appendix). For the purposes of analysis, date of transplant was considered separately, both as a continuous variable as well as in three subgroups ( eras ); 1980 to 1989, 1990 to 1999, 2000 to This 2004 by The Society of Thoracic Surgeons /04/$30.00 Published by Elsevier Inc doi: /j.athoracsur

2 Ann Thorac Surg CHEN ET AL 2004;78: COMPLEX CONGENITAL TRANSPLANT 1353 Abbreviations and Acronyms ARDS adult respiratory distress syndrome ASO arterial switch operation AVC atrioventricular canal BiVAD biventricular assist device DILV double inlet left ventricle DOL day of life ECMO extracorporeal membrane oxygenation HLHS hypoplastic left heart syndrome LPA left pulmonary artery LVAD left ventricular assist device MR mitral regurgitation OHS open heart surgery POD postoperative day PS pulmonary stenosis RV right ventricular RVAD right ventricular assist device SPVR systemic or pulmonary venous reconstruction TGA transposition of the great arteries TR tricuspid regurgitation TxCAD transplant coronary artery disease VAD ventricular assist device VSD ventricular septal defect study received approval for exemption from the Institutional Review Board of Columbia University. Table 1. Baseline Demographic Parameters For 106 Patients Undergoing Cardiac Transplantation for Complex Congenital Heart Disease Mean Median (Range) Age at Transplant (0 to 56.6) Previous OHS (0 to 6) Statistical Methods Univariate and multivariate statistical methods were used to identify and estimate risk factors for all-cause mortality, as well as 30-day perioperative mortality in this population. In addition the study population was compared, using similar methods, to the cohort of all other patients undergoing cardiac transplantation at our institution. The methods of statistical analysis included: 2 test for comparisons of dichotomous risk factors with negative outcomes, Mantel-Haenszel 2 test for comparisons taking into consideration disease severity, and the Wilcoxon test for comparisons of continuous variables with negative outcomes (p 0.05). Logistic regression analysis of the cumulative incidence was used to evaluate the influence of risk factors for mortality. Life-table estimates (Kaplan-Meier) were calculated using the LIFETEST procedure of SAS 6.12 for PowerPC (SAS Institute, Cary, NC) with the log-rank test for difference between strata. Following univariate analysis, variables were entered into multivariate models (using the LOGISTIC procedure) in a forward stepwise manner in the following order: gender, pulmonary artery reconstruction, prior shunt, tetralogy of Fallot, single ventricle physiology, pulmonary atresia, year of transplant, and age. Age and year of transplantation were entered as both continuous and categorized variables; no significant differences between these analyses were noted. Cox proportional hazards regression models (using the PHREG procedure [SAS Institute]) were constructed in the same manner in order to identify those variables most predictive of improved survival functions. Threshold for entry into the model for both logistic regression and Cox regression was p less than Results N (%) Sex (male) 64 (60.4) Age Neonate ( 30 days) 7 (6.6) Infant (30 days to 1 yr) 5 (4.7) Child (1 to 17 yrs) 55 (51.9) Adult ( 18 yrs) 39 (36.8) Race Caucasian 52 (49.1) Hispanic 11 (10.4) Black 9 (8.5) Asian 2 (1.8) Other 1 (1.0) Not listed 31 (29.2) Diagnoses Single ventricle 62 (58.5) Palliation or no intervention 25 (23.6) Glenn 8 (7.5) Fontan 29 (27.4) Tetralogy of Fallot 10 (9.4) Transposition 36 (34.0) Pulmonary atresia 19 (17.9) Pulmonary stenosis 21 (19.8) Era of transplantation (15.1) (62.3) (22.6) SPVR 17 (16.0) OHS open heart surgery; reconstruction. SPVR systemic or pulmonary venous Patient characteristics are shown in Table 1. Available follow-up in these patients ranged from 0 to months (including patients who died immediately postoperatively) with a median of 56 months. Mantel-Haenszel 2 analysis of patients grouped by age, and analyzed by era, demonstrated increased mortality with younger age (p 0.044), particularly in the early era (p 0.021). Cardiopulmonary bypass time, aortic cross-clamp time, and donor heart ischemic times were mean (range), respectively: 228 (83 to 557) minutes; 135 (53 to 301) minutes; and 237 (68 to 443) minutes. These times notably were not significantly correlated with mortality, or with any pulmonary artery reconstruction. Four patients required deep hypothermic circulatory arrest to complete their transplant for an average time of 44.8 minutes (range, 18 to 80 minutes). Primary anatomic diagnoses are represented in Table 2. Donor-recipient height and weight mismatch did not predict early or late mortality.

3 1354 CHEN ET AL Ann Thorac Surg COMPLEX CONGENITAL TRANSPLANT 2004;78: Table 2. Primary Anatomic Diagnoses in the Cohort Primary Diagnosis n Single ventricle not otherwise specified 22 Tricuspid atresia 13 Hypoplastic left heart syndrome/shone s complex 12 Double inlet left ventricle 10 d-transposition of the great arteries 10 Tetralogy of Fallot pulmonary atresia 9 Pulmonary atresia/intact septum 8 1-transposition of the great arteries 6 Ebstein s anomaly 3 Other Patients undergoing pulmonary artery reconstruction were divided into groups based upon degree of reconstruction required: none, minor (oversewing of pulmonary arteriotomy, onlay patch angioplasty with donor pulmonary artery), moderate (requiring separate pulmonary artery patch angioplasty at prior shunt site, or extensive patch angioplasty with donor pulmonary artery), transplant to a single lung (from either anatomic or hemodynamic abnormalities), and extensive (requiring use of circumferential, synthetic material to establish pulmonary artery continuity). With regard to pulmonary artery reconstruction at the time of transplantation, 41 (38.7%) patients underwent no reconstruction, 33 (31.1%) minor reconstruction, 13 (12.2%) moderate reconstruction, 12 (11.3%) transplant to a single lung, and 7 (6.6%) extensive reconstruction. Their respective perioperative mortalities were: minor (15.2%), moderate (23.1%), transplant to a single lung (16.7%), and extensive (42.9%). Kaplan-Meier survival estimates did not demonstrate statistical significance between these subgroups; however, comparison of patients undergoing any pulmonary artery reconstruction with those who did not demonstrated a trend toward significance (p 0.051) as shown in Figure 1. Pretransplant pulmonary artery pressures and calculated indices were inconsistent owing partially to difficulties in calculating these data in the setting of shunts and other additional sources of pulmonary blood flow. However, of note, among those undergoing pulmonary artery reconstruction on whom full hemodynamic data were available, patients who died had a higher pretransplant transpulmonary gradient (12.5 mm Hg average; range, 7.4 to 17.7) than those who survived (6.8 mm Hg; range, 2.6 to 10.9) (p ). These differences were not demonstrable at cardiac catheterization one month posttransplant; survivors 7.2 mm Hg, nonsurvivors 7.8 mm Hg. Neither serum albumin nor serum total protein was directly associated with anatomic diagnosis, or perioperative mortality. Serum albumin levels preoperatively, 6 months postoperatively, and late postoperatively were, respectively, mean, median (range): 3.8, 3.9 (2 to 5.8); 4.5, 4.5 (2.1 to 5.9); 4.2, 4.3 (2.0 to 5.3). Only late postoperative serum albumin was significantly associated with all cause mortality (p 0.03), suggesting the poor physiologic condition of those patients who died. Thirty-seven (34.9%) patients died; their causes of death are represented in Table 3. Results of the univariate analysis of overall mortality are represented in Figure 2. A similar analysis of predictors of perioperative (30- day) mortality was performed. Only neonates were at higher risk of perioperative death (odds ratio 7.467, 95% confidence interval (CI) to ), p 0.005). Univariate analysis of continuous variables predictive of overall mortality demonstrated only earlier year of transplant to be predictive of overall mortality (p ). The results of Cox proportional hazards regression analysis are represented in Table 4. As shown, male gender and later year of transplantation were protective, while any pulmonary artery reconstruction, and neonatal age group, were associated with a higher overall mortality. Survival estimates for patients in the study cohort (n 106) were equivalent to those in the entire cohort without complex congenital heart disease (n 1,420) (Fig 3, p Fig 1. Kaplan-Meier survival analysis of patients undergoing cardiac transplantation for complex congenital heart disease. Ten-year survival estimates are illustrated as a function of the need for pulmonary artery (PA) reconstruction. p

4 Ann Thorac Surg CHEN ET AL 2004;78: COMPLEX CONGENITAL TRANSPLANT 1355 Table 3. Causes of Death in the Cohort (n 37) Age (Years) Gender Diagnosis PA Reconstruction Survival Cause of Death 12.7 F Tetralogy of Fallot, pulmonary atresia Severe Intraoperative Hemorrhage 7.7 F Tricuspid atresia, pulmonary atresia Mild Intraoperative Multiorgan failure 20.7 F Tricuspid atresia, pulmonary atresia Severe Intraoperative Primary nonfunction 43.1 F Tricuspid atresia, pulmonary atresia Single lung Intraoperative Primary nonfunction 1 day M HLHS (norwood) Mild POD 1 Pulmonary hemorrhage 3.8 M Single ventricle, L-TGA, PS Moderate POD 1 Hemorrhage 11.8 M Tricuspid atresia, VSD Mild POD 1 Multiorgan failure 15.0 F Single ventricle, d-tga Mild POD 1 Primary nonfunction 16.8 M Ventricular inversion, L-TGA, VSD, None POD 1 Primary nonfunction PS, TR 23.5 M d-tgv, hypoplastic RV, severe PS Severe POD 1 Hemorrhage 1.3 F AVC, d-tga, PS, LPA off PDA Mild POD 4 Cerebrovascular accident 20.3 M Tetralogy of Fallot, pulmonary atresia Single lung POD 6 Pulmonary hypertensive crisis 0.1 F Ebstein s anomaly None POD 8 Pulmonary hemorrhage 31.4 M DILV, PS Mild POD 8 Infection 56.6 M L-TGA None POD 11 Intracerebral hemorrhage 0.0 F d-tga, PS, sub PS, VSD (preop None POD 13 Pulmonary hemorrhage ECMO) 6 days F Hypoplastic Left heart syndrome None POD 15 Rejection/Multiorgan failure 1.2 F DORV, AVC, PS, AS, mitral atresia Moderate POD 26 Infection 15.1 M DILV, L-TGA, PS, ventricular Moderate POD 27 Infection (ARDS) inversion 21.4 M Pulmonary atresia/ivs (waterston, Single lung 1 month ARDS BDG) 13.0 M Pulmonary atresia/ivs Moderate 1.3 months Infection/-right-ventricular-failure 4.5 F Multiple VSD None 1.6 months Rejection 2.1 M AVC, PS Mild 4.7 months TxCAD 1.2 F Hypoplastic left heart syndrome Mild 10 months Infection (ECMO) 28.2 F DILV, d-tga None 1.1 years Rejection 21.1 F Tetralogy of Fallot Single Lung 3.2 years Rejection/infection 13.8 M Tetralogy of Fallot None 3.2 years TxCAD 13.8 M L-TGA, VSD, PS, Ventricular Inversion, Dextrocardia None 3.3 years Tx CAD/rejection (noncompliance) 17.0 M DORV, PS, VSD, L-TGA Mild 4.1 years TxCAD/rejection 8.2 F Tricuspid atresia, VSD, d-tga Moderate 5.7 years TxCAD 1.0 F HLHS (norwood) Mild 6.1 years TxCAD 4 days M Pulmonary atresia/ivs Mild 6.3 years Rejection 0.9 F HLHS Mild 7.7 years Infection 17.7 M Tricuspid atresia, Pulmonary atresia, Moderate 8.8 years PTLD VSD, MR 3.7 M L-TGA, VSD, Ventricular inversion, Mild 9 years Infection (ECMO) Pulmonary Atresia 15.8 F Hypertrophic Cardiomyopathy, Coarct None 9.6 years TxCAD 8.0 M DORV, d-tga, VSD, small mitral, pulmonary atresia Moderate 10 years TxCAD/rejection AVC atrioventricular canal; BDG bidirectional Glenn procedure; DILV double inlet left ventricle; DORV double outlet right ventricle; ECMO extracorporeal membrane oxygenation; HLHS hypoplastic left heart syndrome; IVS intact ventricular septum; LPA left pulmonary artery; MR mitral regurgitation; POD postoperative day; PS pulmonary stenosis; PTLD posttransplantation lymphoproliferative disorder; RV right ventricle; RVAD right ventricular assist device; TGA transposition of the great arteries; TR tricuspid regurgitation; TxCAD transplant coronary artery disease; VSD ventricular septal defect. 0.05). This was also true when the analysis was stratified by era of transplantation, as shown in Figure 4. However, when comparing patients by era of transplantation, evaluation of all patients (both complex congenital heart disease and the control cohort) revealed improved survival with later transplantation (p ). Proportional hazards regression analysis of the entire population (n 1,525) undergoing transplant during the time interval studied revealed similar predictors of poor outcomes as the analysis of the cohort with complex congenital heart disease (Table 5). As demonstrated, male gender was again protective, as was later year of transplantation. While neonatal age group portended an impaired survival, interestingly children had a significantly improved mortality when compared with all those older than 18. In contrast, univariate analysis of 30-day mortality between the two cohorts demonstrated increased mortality in those patients with a history of complex congenital heart disease (odds ratio 2.6, 95% CI to 4.571, p 0.001). Multivariate analysis confirmed the higher inci-

5 1356 CHEN ET AL Ann Thorac Surg COMPLEX CONGENITAL TRANSPLANT 2004;78: Fig 2. Univariate predictors of overall mortality. *p (CI confidence interval; PA pulmonary artery; Pulm pulmonary; Reconst SVR reconstruction systemic vascular resistance; TOF tetralogy of Fallot; TGV transposition of the great vessels.) dence of perioperative mortality in those patients (odds ratio 2.194, 95% CI to 3.946, p ). Seven patients required mechanical assistance preoperatively, four patients needed mechanical assistance perioperatively, and two patients required assistance late postoperatively; Table 6 summarizes these cohorts. As demonstrated, patients were bridged on average 5.3 days (median 6 days; range, 1 day to 10 days) before transplantation with a variety of devices. All three mortalities were in the immediate postoperative period, and all three involved a component of intractable hemorrhage. There was a trend toward increased perioperative (risk ratio 2.891, 95% CI to , p 0.075) and overall (risk ratio 1.434, 95% CI to 6.778, p 0.648) mortality in these patients. One of the patients required extracorporeal membrane oxygenation (ECMO) support after trans- Table 4. Cox Parametric Regression of Survival (Dependent Variables) Regression Analysis Variable Parameter Estimate Standard Error p Value Odds Ratio a Gender (male) (0.232 to 0.897) PA reconstruction (any) (1.446 to 7.459) Year of transplantation b (0.825 to 0.966) Neonatal patient ( 30 days old) (1.646 to ) a 95% confidence intervals on odds ratios are given in parentheses. b Reduction in risk is calculated for each additional year of experience in transplantation for congenital heart disease. Stepwise selection with entry intro model at p Criteria for assessing model fit: 2 Log L: without covariates: ; with covariates: ; 2 for covariates: with 3 DF (p ). PA pulmonary artery.

6 Ann Thorac Surg CHEN ET AL 2004;78: COMPLEX CONGENITAL TRANSPLANT 1357 Fig 3. Kaplan-Meier survival analysis of all patients undergoing heart transplantation. Ten-year survival estimates are illustrated as a function of the presence of complex congenital heart disease (CHD). p plantation for primary graft failure and was retransplanted 8 days later, and one required ECMO after transplantation for primary nonfunction and was decannulated two days later. Two adult patients who were placed on intraoperative right ventricular assist device (RVAD) support (for primary nonfunction and right ventricular failure) died intraoperatively. Both patients had undergone significant pulmonary artery reconstruction: the first patient had undergone transplantation after two failed Fontan operations; her pulmonary artery confluence had been reconstructed with a 12 mm Dacron graft to which the donor pulmonary artery was anastomosed. The second patient had undergone bilateral modified and classic Blalock-Taussig shunts, and had also had a classic Glenn procedure and required a transplant to her right lung only. The first patient was unable to wean from cardiopulmonary bypass despite right RVAD support; the second died ultimately of a combination of hemorrhage and pulmonary edema. Two patients required ECMO late posttransplant for progressive respiratory decompensation in the setting of adult respiratory distress syndrome (ARDS) and sepsis. Nine (8.4%) patients were retransplanted; one for primary graft nonfunction, one for post-transplantation lymphoproliferative disorders in the donor graft, and 7 for transplant coronary artery disease and chronic rejection. One patient was retransplanted twice for transplant coronary disease. The average time between primary and secondary transplant was 4.9 years (median 5 years; range, 8 days to 10 years). Patients transplanted before October 1986 received double drug immunosuppression regimens with cyclosporine and steroids. All patients thereafter received triple drug immunosuppression regimens, consisting of steroids, cyclosporine or tacrolimus, Fig 4. Kaplan-Meier survival analysis of patients undergoing heart transplantation. Five-year survival estimates are illustrated as a function of decade of transplantation and presence of complex congenital heart disease (CHD). p not significant for comparison of CHD to non-chd. p for comparison of transplants across decades.

7 1358 CHEN ET AL Ann Thorac Surg COMPLEX CONGENITAL TRANSPLANT 2004;78: Table 5. Cox Parametric Regression of Survival in All Patients Undergoing Transplantation (Dependent Variables) Regression Analysis Variable Parameter Estimate Standard Error p Value Odds Ratio a Gender (male) (0.669to0.954) Age at transplantation 30 days (neonate) (2.456to8.251) Between 1 and 18 yrs (child) (0.456to0.811) Year of Transplantation (0.910to0.939) a 95% confidence intervals on odds ratios are given in parentheses. Stepwise selection with entry intro model at p Variables tested were: gender, age at transplantation, year of transplantation, and history of complex congenital heart disease. Criteria for assessing model fit: 2 log L: without covariates: ; with covariates: ; 2 for covariates: with4df(p ). and azathioprine or mycophenolate mofetil. Rejection protocols have evolved over the past 20 years, but essentially involve a steroid boost as primary therapy, with a combination of ATGAM, methotrexate, total lymphoid irradiation, or OKT3 for refractory rejection. Donor hearts received University of Wisconsin solution (15 ml/kg) for preservation until July 2003, after which time Celsior (SangStat Medical Corp, Freemont, CA) (15 ml/ kg) was used. We do not routinely readminister cardioplegia before transplantation. Comment Orthotopic heart transplantation has evolved over the past four decades to become a standard treatment for neonates, children, and adults with end-stage heart disease. While significant advances have been made in the surgical repair and postoperative management of patients with complex congenital heart disease, transplantation still remains the final therapeutic alternative for those patients who ultimately develop irreversible myocardial failure. Such patients with complex congenital heart disease, either previously palliated or even unrepaired, present anatomic and physiologic challenges to the transplant surgeon. Although numerous reports have demonstrated the technical feasibility of transplantation in this setting, most are small series owing to the relative infrequency of these lesions [1 8]. We therefore undertook the current study to evaluate our single center experience with transplantation for complex congenital heart disease, and thereby sought to highlight trends and lessons learned in our nearly twenty year experience. The success of cardiac transplantation as a therapy for patients with single ventricle physiology has prompted some investigators to endorse its application as a primary therapy for these diagnoses, most notably for hypoplastic left heart syndrome [9]. Indeed, while the results of this approach at certain centers have been remarkably good, the application of this strategy nationwide would be epidemiologically impractical, given the limited number of neonatal and infant donors. In contrast, others have proposed staged palliation and other means to defer Table 6. Patients Requiring Mechanical Support Age Type of Support Duration of Support Outcome Bridge-to-Transplant Death (pulmonary hemorrhage) DOL 1 ECMO post ASO 8 days POD years ECMO post Fontan 5 days Alive and well 2.0 years ECMO post Glenn 10 days Alive and well 3.8 years ECMO post Fontan 7 days Death (hemorrhage) POD1 7.7 years ECMO post Fontan 1 day Death (hemorrhage/primary nonfunction) intraoperative 18.4 years ECMO/LVAD for dilated cardiomyopathy 1 day Alive and well 19.8 years Abiomed BiVAD for cardiomyopathy many 2 days Alive and well years after Mustard Perioperative 2 weeks ECMO post OHT (graft nonfunction) 3 days Alive and well 3 months ECMO post OHT (graft failure) 8 days Retransplanted 20.7 years Abiomed RVAD Intraoperative Death (primary nonfunction/rv Failure) intraoperative 43.1 years Abiomed RVAD 1 day Death (primary nonfunction/ RV-Failure) intraoperative Late Posttransplant 1.2 years ECMO 10 months posttransplant 5 days Death (infection) 3.7 years ECMO 9 years posttransplant 2 days Death (infection) ASO arterial switch operation; BiVAD biventricular assist device; DOL day of life; ECMO extracorporeal membrane oxygenation; LVAD left ventricular assist device; OHT orthotopic heart transplantation; POD postoperative day; RV right ventricular; RVAD right ventricular assist device.

8 Ann Thorac Surg CHEN ET AL 2004;78: COMPLEX CONGENITAL TRANSPLANT 1359 transplantation until the patient reaches adolescence, citing better donor organ availability and results in this setting [10]. Our results demonstrated several findings in the complex congenital cohort with regard to age: (1) neonates tended to have poorer outcomes, most notably in the earliest era of transplantation, and (2) patients in older age groups demonstrated a trend toward survival advantage in the univariate analysis of overall mortality. However, among all patients transplanted, infants and children regardless of their type of congenital heart disease demonstrated a survival advantage in the multivariable domain. It is likely that some of the inconsistencies of these findings may be due to small sample size, variance of follow-up with respect to age, and nature and limits of the given statistical test. We hope such discrepancies will be elucidated better with a larger cohort. More recently, improved long-term outcomes with staged procedures toward ultimate Fontan completion have approached those of transplantation, achieving in many cases comparable survival without the burden of lifelong immunosuppression regimen. Nonetheless, as higher risk patients are considered for staged repair, and as these patients age, a growing subset of patients fail these protocols, thereby comprising a group who present for transplantation after a variety of prior palliative procedures. In this setting, some have advocated early consideration for heart transplantation before high-risk Fontan, so as to help eliminate the reported increased mortality for rescue transplantation [11, 12]. We did not find the stage of the procedure per se to confer a statistically significant change in outcome; however, this may be due to the relatively low numbers considered. We also did not find, as has been previously described, an increase in mortality attributable to reconstruction of systemic or pulmonary venous return when coupled with transplantation [1, 13]. Our data are notable for several key observations. First, although stage of the procedure (for those single ventricle patients) was not specifically associated with a difference in mortality, both a prior shunt procedure and pulmonary artery reconstruction demonstrated impairment in perioperative and long-term survival. These two characteristics demonstrated substantial overlap. However, pulmonary artery reconstruction demonstrated the strongest association with mortality (odds ratio 3.3) in regression models that best fit the data set. In an effort to better understand this association, the cohort was further segregated on the basis of degree of reconstruction, and this demonstrated an incremental risk of perioperative mortality from mild to moderate to extensive reconstruction (15.2%, 23.1%, 42.9% 30-day mortality, respectively); this was not true of overall mortality (36.4%, 53.9%, 42.9%). When considered as a group, patients with any pulmonary artery reconstruction demonstrated a strong trend toward impaired survival (p 0.051) throughout the follow-up period when compared by Kaplan-Meier actuarial analysis. Our explanations for this phenomenon are only speculative. While it is conceivable that this cohort may have occult pulmonary parenchymal lung disease from longstanding arterial shunts, it remains difficult to associate fully this with all-cause mortality. This concept is supported by the finding of an increase in transpulmonary gradient on preoperative catheterization in those patients undergoing pulmonary artery reconstruction who died. In many congenital heart transplant candidates, and in particular in this cohort of patients with prior pulmonary artery anatomic abnormalities (eg, prior shunt, discontinuous pulmonary arteries, pulmonic stenosis, and atresia), preoperative pulmonary artery pressures and calculated indices of pulmonary vascular resistance can be both difficult to assess and misleading. Investigation of posttransplant pulmonary indices did not demonstrate findings to account for this difference. As investigators from our institution have previously asserted, in this setting the essential problem is achieving an acceptable pulmonary vascular resistance after transplantation [8]. Second, and relatedly, we found that in those twelve patients who underwent transplantation to a single lung, perioperative mortality was comparable to those who underwent no pulmonary artery reconstruction. We are increasingly referred such patients in whom one pulmonary artery was iatrogenically (eg, prior shunt) or naturally atretic or discontinuous. In those with true anatomic variance, we have chosen to baffle the donor pulmonary artery toward the functional side. In others, in whom the difference is more physiologic (eg, longstanding pulmonary venous obstruction), the reconstruction is routine, although the flow is unquestionably preferential [14]. Four of these patients died. One patient died intraoperatively, despite RVAD support, one patient died on postoperative day 6 during a pulmonary hypertensive crisis, one patient died one month postoperatively of ARDS and multiorgan failure, and one patient died 3 years later of chronic rejection. We have been pleasantly surprised by the relatively good outcome of this group, and have learned that aggressive pulmonary toilet and avoidance of events that may precipitate pulmonary hypertensive crises are essential. Third, the survival benefit afforded male patients in the overall cohort was magnified in the group with complex congenital heart disease. We have previously demonstrated this finding in our overall cohort, and additional investigators have speculated that, in adult patients, multiparity, immunologic reactivity, and gender and size mismatch may account for poorer long-term outcomes (and organ availability) for women [15 17]. However, this does not seem a likely explanation in children. While the overall cohort itself demonstrates a slight male predominance, it is not enough to account for this difference, which remains unexplained. Fourth, neonatal patients tended to have a higher mortality than all others, especially in the early era (before 1990). Certainly, over the past twenty years, the overall perioperative management of neonates has improved, and this is reflected in our data as well. While this cohort is limited in number, it is notable that three of the four deaths involved pulmonary hemorrhage, likely due in part to lung prematurity. Fifth, our outcomes with the use of mechanical assistance as a bridge-to-transplantation and for posttransplant support have been variable. Certainly with the likely advent of newer, smaller devices for mechanical ventricular assis-

9 1360 CHEN ET AL Ann Thorac Surg COMPLEX CONGENITAL TRANSPLANT 2004;78: tance, VAD support in this cohort may become more prevalent. All of the deaths in the cohort bridged with ECMO relate to bleeding complications, undoubtedly due partially to the requirement of systemic anticoagulation for the duration of pretransplant support. We have used ECMO occasionally posttransplant for early graft insufficiency in other congenital heart disease patients, and its low prevalence in this cohort is likely due to sample bias. One patient who did require ECMO for primary graft failure was successfully retransplanted 8 days later; the other was weaned from ECMO and decannulated after 48 hours of support. Although anecdotal, it would appear from our experience that unilateral RVAD support is not recommended for this group of patients, many of whom have pulmonary resistances that, when coupled with supraphysiologic right sided (ie, device) output, may produce pulmonary edema and early mortality. In these patients, complete right sided decompression with ECMO may be better tolerated. Sixth, year of transplantation remains a strong predictor of mortality in both univariate and multivariable modeling. Indeed, when considered as a continuous variable in the Cox regression analysis, the effect on overall mortality was such that for each more recent year of transplantation, mortality decreased by approximately 11%. Advances in surgical techniques, preservation protocols, perioperative adjuncts, immunosuppression regimen, and long-term management all contribute to this improvement. Although the association between year of experience and improved survival was evident in both study and control cohorts (Fig 4), this relationship was stronger in those with complex congenital heart disease (Tables 4 and 5). Finally, the survival estimates of our patients transplanted with and without complex congenital heart disease were comparable (Fig 3). While there was a significant difference in mortality demonstrated in the perioperative period by univariate and multivariable analysis, the longterm survival of this cohort was comparable to all others without complex congenital heart disease. Several investigators have described a similar phenomenon when considering all patients with congenital heart disease (including those with isolated cardiomyopathy); however, we demonstrate this to be true in cases that otherwise might be considered high-risk. In addition, adults in our cohort (who comprise an increasingly larger subgroup at our program) demonstrated excellent overall survival, a finding in keeping with our previous reports, as well as the reports of others with regard to heart, heart-lung, and lung transplantation in this setting [18, 19]. We report encouraging results regarding transplantation for complex congenital heart disease in children and adults. Future advances in the selection and management of patients who may require substantial pulmonary artery reconstruction may help to better define the association with short-term and long-term mortality. However, transplantation to an anatomic or physiologic single lung should not in itself be a contraindication to transplantation. We hope that the future availability of ventricular assist devices of appropriate sizes for children may help bridge more patients in this cohort to transplantation, and that their appropriate implementation might reduce wait list mortality, and that advances in the treatment of transplant coronary artery disease may meaningfully impact on long-term survival. Limitations Several limitations must be highlighted in the current study. First, by its nature, this evaluation is subject to the restrictions of a retrospective study. Second, pretransplant information on patients transplanted in the early era was inconsistently available. Third, the value of preoperative calculated pulmonary hemodynamic indices remains complicated, in particular for those in whom a significant discrepancy was present between branch pulmonary arteries. Future studies will hopefully better elucidate nuances in patient selection to better define mortality risk stratification among patients in this cohort. References 1. Mayer JE, Perry S, O Brien P, et al. Orthotopic heart transplantation for complex congenital heart disease. J Thorac Cardiovasc Surg 1990;99: Kanter KR, Tam VKH, Vincent RN, Cuadrado AR, Raviele AA, Berg AM. Current results with pediatric heart transplantation. Ann Thorac Surg 1999;68: Bando K, Konishi H, Komatsu K, et al. Improved survival following pediatric cardiac transplantation in high-risk patients. Circulation 1993;88(Part 2): Vouhé PR, Tamisier D, LeBidois J, et al. Pediatric cardiac transplantation for congenital heart defects: surgical considerations and results. Ann Thorac Surg 1993;56: Hsu DT, Quaegebeur JM, Michler RE, et al. Heart transplantation in children with congenital heart disease. J Am Coll Cardiol 1995;26: Webber SA, Fricker FJ, Michaels M, et al. Orthotopic heart transplantation in children with congenital heart disease. Ann Thorac Surg 1994;58: Dellgren G, Koiorala B, Sakopoulus A, et al. Pediatric heart transplantation: improving results in high-risk patients. J Thorac Cardiovasc Surg 2001;121: Cooper MM, Fuzesi L, Addonizio LJ, Hsu DT, Smith CR, Rose EA. Pediatric heart transplantation after operations involving the pulmonary arteries. J Thorac Cardiovasc Surg 1991;102: Bailey LL, Assaad AN, Trimm F, et al. Orthotopic transplantation during early infancy as therapy for incurable congenital heart disease. Ann Surg 1991;208: Carrel T, Neth J, Pasic M, et al. Should cardiac transplantation for congenital heart disease be delayed until adult age? Eur J Cardiothorac Surg 1994;8: Michielon G, Parisi F, DiCArlo D, et al. Orthotopic heart transplantation for failing single ventricle physiology. Eur J Cardiothoracic Surg 2003;24: 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 II):II140 II Larsen RL, Eguchi JH, Mulla NF, et al. Usefulness of cardiac transplantation in children with visceral heterotaxy (asplenic and polysplenic syndromes and singe right-sided spleen with levocardia) and comparison of results with cardiac transplantation in children with dilated cardiomyopathy. Am J Cardiol 2002;89: O Sullivan J, Hasan A, Mitchell L, Hamilton L, Dark JH. Differential pulmonary flow after heart transplantation in

10 Ann Thorac Surg CHEN ET AL 2004;78: COMPLEX CONGENITAL TRANSPLANT 1361 patients with malposition of the great arteries. J Heart Lung Transplant 1997;16: John R, Rajasinghe HA, Chen JM, et al. Long-term outcomes after cardiac transplantation: an experience based on different eras of immunosuppressive therapy. Ann Thorac Surg 2001;72: Fabbri A, Bryan AJ, Sharples LD, et al. Influence of recipient and donor gender on outcome after heart transplantation. J Heart Lung Transplant 1992;11(Part 1): Prendergast TW, Furukawa S, Beyer JA, Browne BJ, Eisen JH, Jeevanandam V. The role of gender in heart transplantation. Ann Thorac Surg 1998;65: Lamour JM, Addonizio LJ, Galantowicz ME, et al. Outcome after orthotopic cardiac transplantation in adults with congenital heart disease. Circulation 1990;100(Suppl II):II200 II Pigula FA, Gandhi SK, Ristich J, et al. Cardiopulmonary transplantation for congenital heart disease in the adult. J Heart Lung Transplant 2001;20: Appendix Variables Analyzed Year of transplant (continuous) Early Era : 1984 to 1989 Middle Era : 1990 to 1999 Late Era : 2000 to 2003 Last follow-up Donor Height Weight Body surface area Donor heart ischemic time Recipient Age Neonate ( 30 days) Infant (31 days to 1 year) Child (1 year to 18 years) Adult ( 18 years) Appendix. Continued Height Weight Body surface area Gender Race Number of prior open heart surgeries Preoperative, 6 month postoperative, and latest serum albumin and total protein Preoperative, 1 month postoperative, 1 year postoperative, and latest hemodynamic variables: pulmonary artery pressure, pulmonary capillary wedge pressure, cardiac output, pulmonary vascular resistance Waiting time Preoperative/postoperative length of stay Anatomic diagnosis Hypoplastic left heart syndrome Single ventricle (and stage of repair) Tetralogy of Fallot Transposition of the great vessels Pulmonary atresia Pulmonary stenosis Prior shunt Intraoperative Duration of cardiopulmonary bypass Aortic cross-clamp time Pulmonary artery reconstruction Minor Moderate Transplant to a single lung Extensive Systemic venous or pulmonary venous reconstruction Length of stay (days) Preoperative Postoperative Days spent awaiting transplant Time from last open heart surgery to transplant DISCUSSION DR THOMAS SPRAY (Philadelphia, PA): I think this is an excellent series and certainly the outcomes are to be commended. It is interesting that almost all of the difference in mortality between the various eras is early postoperative mortality. This would suggest that we re getting better at reconstructing these patients. If that s the case, then, the other thing that strikes me is that the cross-clamp times, or overall operative times, seem to be similar in the congenital group and the adult group. Now, is that reflecting the fact that your adult population is skewed largely now towards patients who have had multiple reoperations and ventricular assist device implants and, therefore, the total time of operation is similar? One would assume that in the congenital as well? DR CHEN: Thank you, Dr Spray, for your comments. We did in fact analyze ischemic times, cross-clamp times and overall OR times throughout the study period, and I was also surprised to find that the congenital group was comparable to all others. Some of this, as you point out, is due to the fact that our noncongenital adult population is similarly comprised of complex patients who have had many prior operations and LVADs, etc., and part of it is likely due to the fact that we have improved the coordination of our transplants. Not infrequently, we may delay cross-clamp at the donor hospital until we are sure that we are out of the woods in the recipient case, so as not to prolong the ischemic time unnecessarily. This, I suspect, may be the reason that there was not a correlation between complexity of the PA reconstruction and overall ischemic time. All of which, however, is not to detract from your conclusion that we are getting better at reconstructing these patients I d like to think that this is true as well.