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J Thorac Cardiovasc Surg 2007;133:632-639
© 2007 The American Association for Thoracic Surgery
Surgery for Congenital Heart Disease |
a Michael E. DeBakey Department of Surgery, Division of Congenital Heart Surgery, Baylor College of Medicine, Houston, Tex
b Division of Congenital Heart Surgery, Texas Children’s Hospital, Houston, Tex
c Division of Pediatric Cardiology, Department of Pediatrics, Baylor College of Medicine, Houston, Tex
d Texas Heart Institute at St Luke’s Episcopal Hospital, Department of Thoracic and Cardiovascular Surgery, Houston, Tex.
Read at the Eighty-sixth Annual Meeting of The American Association for Thoracic Surgery, Philadelphia, Pa, April 29-May 3, 2006.
Received for publication April 29, 2006; revisions received August 25, 2006; accepted for publication September 25, 2006. * Address for reprints: David L.S. Morales, MD, Division of Congenital Heart Surgery, Texas Children’s Hospital, 6621 Fannin St, MC-WT 19345H, Houston, TX 77030. (Email: dlmorale{at}texaschildrenshospital.org).
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Abstract |
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 Top Abstract IntroductionPatients and MethodsResultsDiscussionThirty-two variables analyzed to...References |
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Methods: Between November 1, 1984, and October 3, 2005, 164 consecutive orthotopic heart transplants were performed on 154 patients. Characteristics: mean age 7.1 ± 6.0 years, mean body surface area 0.8 ± 0.5 m2. Diagnosis at transplant: cardiomyopathy 53.0% (n = 87), congenital heart defect 39.0% (n = 64), retransplant 7.9% (n = 13). Multivariate risk factor analysis of 32 variables was completed by Cox proportional hazards regression models.
Results: Mean follow-up was 5.9 ± 4.8 years. Overall Kaplan–Meier survival was 82% at 1 year, 65% at 5 years, and 54% at 10 years. After 1995, Kaplan–Meier survival (91% at 1 year and 71% at 5 years) was significantly improved over pre-1995 survival (71% at 1 year, 57% at 5 years, and 48% at 10 years; P =.026). Hospital survival improved in the post-1995 era (96%) compared with the pre-1995 era (77%; P < .001). Life-table analysis by yearly increments demonstrates only an improved survival (pre-1995, 71% 
post-1995, 91%) in the first posttransplant year (P = .001); every subsequent year the mortality rates are the same (P = .92). Risk factors for overall mortality are prolonged postoperative intubation (>5 days) and longer cardiopulmonary bypass time.
Conclusions: Primarily attributable to an increase in early survival, overall pediatric heart transplant survival is improved. However, after the first posttransplant year, the rate of mortality has not changed in 21 years. This highlights the need for new therapies to treat children both with or in need of a heart transplant.
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Introduction |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionThirty-two variables analyzed to...References |
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On December 6, 1967, Dr Adrian Kantrowitz and his associates1 in Brooklyn, New York, performed the first pediatric heart transplant on a 17-day-old infant with Ebstein anomaly. This occurred just 3 days after Dr Christian Barnard’s2 first human-to-human transplant on December 3, 1967, in South Africa.3 In 1984, nearly 20 years later, the first successful infant heart transplant was performed by Dr Denton Cooley and his colleagues4 on an 8-month-old girl at Texas Children’s Hospital (TCH).
Pediatric heart transplantation has become an accepted management strategy for pediatric patients with end-stage heart failure resulting from cardiomyopathy or inoperable congenital heart disease (CHD). Since 1982, more than 6000 pediatric heart transplants have been performed, with consistent improvement in survival.5 Increasing early survival, most likely a manifestation of the advancements in perioperative management, has been the driving force improving outcomes.5,6 Although not statistically proven, the rate of late attrition of pediatric patients undergoing heart transplantation has seemingly not changed since the advent of cyclosporine in the early 1980s.4,5,7,8 No therapies in the past 20 years have significantly changed the rate of chronic rejection; thus, the uncertainty of long-term survival remains. The objective of this study is to review the 21-year experience with pediatric heart transplantation at a single institution, assessing how survival has changed over time and the variables that affect survival.
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Patients and Methods |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionThirty-two variables analyzed to...References |
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Mean age at transplant was 7.1 ± 6.0 years (median 5.2 years [20 days-21 years]), with a mean body surface area of 0.8 ± 0.5 m2. Age distribution at time of transplantation was as follows: 17.7 % (n = 29) infants (age < 1 year old), 48.8% (n = 80) children (1 year old < age < 11 years old), and 33.5% (n = 55) adolescents (11 years old 
age 20.3 years old). Four patients were older than 18 years, all of whom had CHD. Diagnoses at transplant were cardiomyopathy in 53.0% (n = 87 [dilated 70% (61), restrictive 16% (14), hypertrophic 8% (7), other 6% (5)]), congenital heart defect in 39.0% (n = 64 [ie, hypoplastic left heart syndrome 16, D-transposition of the great arteries 11, failing Fontan circulation 7]), and cardiac graft failure 7.9% (n = 13). Ethnic diversity in this series consisted of 46.3% white (n = 76), 29.9% Hispanic (n = 49), 18.9% African American (n = 31), and 4.9% other (n = 8). Patients had a mean of 0.9 ± 1.1 (0-5) prior cardiac operations. Pulmonary vascular resistance index (PVRI) was calculated on 67% (104) of the transplant candidates with an average PVRI of 3.1 ± 2.1 Wood units · m2 (0.2-10.5 Wood units · m2). Preoperative patient characteristics are listed in Table 1.
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The donor graft is presently perfused with Celsior solution, and for patients less than 1 year old, a noncommercial buffered hyperkalemic extracellular solution (Melbourne solution) is used. Biatrial anastomoses were performed exclusively until 1995 (n = 78). After 1995, transplants were routinely performed by a standard bicaval anastomotic technique with caval and pulmonary artery anastomoses completed with the heart beating. Inhaled nitric oxide was first used for transplant patients at TCH in June of 1994.
Presensitized patients (panel reactive antibodies by flow cytometry to class I and class II HLA antigens greater than 10%) were (1) listed with unacceptable antigens based on specific HLA antibody titrations, (2) preoperatively treated with intravenous immunoglobulin and rituximab, and/or (3) transplanted with an exchange transfusion on cardiopulmonary bypass and, if there was a retrospective positive cross-match, treated with plasmapheresis, intravenous immunoglobulin, and rituximab. The immunosuppressive protocol has not included induction therapy. Patients routinely receive mycophenolate mofetil (MMF) (20 mg/kg) (previously azathrioprine 1mg/kg) preoperatively and methylprednisone (10 mg/kg) intraoperatively. Postoperatively, the patients receive and are discharged on triple immunosuppressive therapy: a calcineurin inhibitor, an antimetabolite, and steroids. Tacrolimus was first used in October of 1998 but was not regularly prescribed until 2002; since then, it has been used in 47% (17/36) of patients. Patients are followed up frequently in clinic and with endocardial biopsies for the first year, after which a clinic visit or biopsy is every 6 months. Patients were considered lost to follow-up if contact by TCH had not been made within 18 months of the study’s completion.
Rejection was considered to be a biopsy score of the International Society for Heart and Lung Transplantation (ISHLT) grade 3A or higher or the clinical suspicion of rejection regardless of biopsy score. Acute cellular rejection on the basis of histologic examination only without evidence of hemodynamic changes was treated with pulsed steroids. However, if there was hemodynamic compromise, then first-line therapy was either antithymocyte globulin or OKT3 (monoclonal antibody to CD3 positive T cells). The TCH immunosuppressive regimen was recorded and the incidence of rejection was analyzed for the cohort of patients receiving a primary cardiac transplant after 1998 (n = 70), when MMF became the primary antimetabolite and tacrolimus use began (Table 2).
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2 test was used to compare hospital and 1-year survivals between the early and late eras. All risk factor and Kaplan–Meier analyses were based on the patient’s first transplant at TCH (n = 154). Survival analyses were performed with the Kaplan–Meier method and then compared with the log-rank test. All survivals are Kaplan–Meier unless the ratio of survivors to patients in the cohort of interest is specified. Early era (November 1984 to July 1995; n = 66) and late era (July 1995 to October 2005; n = 88) survival was also analyzed in yearly increments with the Cutler–Ederer method (life-table analysis) to determine the probability of survival within each 1-year time period of follow-up, independent of survival before or after that 1-year interval. Comparison of early and late era life tables was performed with the Wilcoxon–Gehan statistic. Thirty-two covariates were organized according to clinical categories as follows: (1) patient variables, (2) donor variables, and (3) intraoperative and postoperative variables (Appendix 1). Donor graft data were supplied by the United Network for Organ Sharing research division and were only available after 1987, capturing 81% to 90% of the TCH cohort depending on the variable. Multivariate risk factor analyses were completed for discrete and continuous variables by the Cox proportional hazards model. Significant risk factors found from these analyses, excluding continuous variables, were further analyzed by odds ratios with 95% confidence intervals to determine whether they were independent risk factors. Overall mortality, 1-year mortality, 5-year mortality, and 5-year mortality conditional on 1-year survival were tested for risk factors. For the 104 patients who had PVRI data, a separate Cox proportional hazards model including all patient variables was used to determine whether PVRI as a continuous variable was a risk factor for overall and conditional 5-year mortality. All analyses were conducted with SPSS 13.0 (SPSS, Inc, Chicago, Ill).
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Results |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionThirty-two variables analyzed to...References |
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The median wait time (n = 146, 89% capture) for a recipient on the United Network for Organ Sharing list was 61 days (0-498 days). The median donor age (n = 147, 90% capture) was 4 years (0-28 years) and the median weight ratio (n = 134, 82% capture) was 1.2 (0.7-3). In regard to donor-recipient gender pairing (n = 137, 89% capture), the number of male donor to female recipients was 35 (54% of all female recipients) and of female donors to male recipients was 37 (37% of all male recipients). Comparing each of the gender-mismatched recipient cohorts with their respective gender-matched recipient cohorts revealed gender-mismatched male recipients to have a lower survival, with 49% survival at 10 years versus 78% for gender-matched male recipients (P = .053). Median donor ischemic time reported by TCH records was 232 minutes (68-452 minutes).
From January of 1999 to October of 2005, 61% (43/70) of patients had rejection during the first year of transplant, with 40% of this group (17/43) having only one episode of rejection. The Kaplan–Meier survival curves of those patients with and those without rejection in the first year were not significantly different (P = .35).
The overall length of follow-up was 5.9 ± 4.8 years (0.4-19.5 years). There are 95 (62%) living patients (79% are followed up at TCH and 21% by adult specialists), and 91% are in New York Heart Association class I. One patient (0.6%) was lost to follow-up. Overall Kaplan–Meier survival (1 year, 82.3%; 5 years, 65.3%; and 10 years, 54.4%) is demonstrated in Figure 1, A. There were 59 deaths overall, with 34% (n = 20) from transplant coronary artery disease (diagnosed premortem and postmortem), 25% (n = 15) from postoperative multisystem organ failure, 14% (n = 8) from rejection, and all other causes having a frequency of 3% or less. Survival is statistically greater in the late era (30 days, 100%; 1 year, 91%; and 5 years, 71%) compared with the early era (30 days, 89%; 1 year, 71%; and 5 years, 57%) (P = .026) (Figure 1, A). Life-table analysis of the early and late eras demonstrates that the probability of survival in the first year was significantly different (early 71% vs late 91%; P = .001) between the eras, but after the first year, the probability of survival for each 1-year interval of follow-up is statistically the same (P = .92) between the eras (Figure 1, B). Pre-1995 and post-1995 survivals censored for mortality in the first year are not statistically different (Figure 2). Survival analysis for patients with the preoperative diagnoses of cardiomyopathy versus CHD demonstrated no difference (P = .68). Early (1-year) survival for patients with CHD was significantly higher in the late era (92%, 36/39) than in the early era (68%, 17/25) (P = .011). Comparison of the survival curves for the different age groups demonstrated that infants’ survival was worse than that of children (P = .03) and adolescents (P = .013). Analysis of the age cohorts by era demonstrates that the infants in the late era (30 days, 100%; 1 year, 88%; and 5 years, 60%) have a significantly higher survival than in the earlier era (30 days, 58%; 1 year, 33%; and 5 years, 33%) (P = .012). In the late era, infant survival was not different from that of the 1- to 10-year-old (P = .538) and the 11- to 20-year-old (P = .717) cohorts. Comparison of conditional 5-year survival between the age groups demonstrates that the 11- to 20-year-old cohort did have a significantly lower survival (67%) than those younger than 11 years old (infants 80% and children 86%) (P = .025). Independent risk factors for overall, 1-year, 5-year, and conditional 5-year mortality are listed in Table 3. PVRI, analyzed as a continuous variable, was not a risk factor at any level for overall or 5-year conditional mortality.
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Discussion |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionThirty-two variables analyzed to...References |
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This difference is clearly driven by an improvement in early survival as highlighted in the current series by the significant increase in the post-1995 hospital (96% vs 77%) and 1-year (91% vs 71%) survivals when compared with the pre-1995 era. This improvement in early survival is likely due to the progress in critical care and operative management of transplant patients and, in particular, patients with CHD and infants. In the present series, the early (1-year) survival of infants between the eras (post-1995 88% vs pre-1995 33%) clearly improved, to the extent that in the modern era, infant survival was the same as for children and adolescents. Previous series have found that patients with cardiomyopathy fared better than those with CHD.5 However, the current series, like other large single-center series, have found their survivals to be similar.9,10 This is probably secondary to the significant advancements in the perioperative care of patients with CHD undergoing cardiac surgery in general. These improvements are evidenced in this series by the significant increase in early survival for patients with CHD between the early (68%) and the late (92%) eras. Also, CHD patients presenting for transplant in the modern era are better palliated, perhaps making them superior transplant candidates.
As reported by other authors and supported by the TCH results, when comparing the early and modern experiences with pediatric heart transplantation, the rate of mortality (ie, the slope of the Kaplan–Meier survival curve) after the first year is the same.5 In an attempt to quantify this observation, we used the Culter-Ederer method to analyze the pre-1995 and post-1995 survivals in yearly increments to determine the probability of survival over each 1-year period of follow-up. This analysis revealed that during the first year after transplant, the pre-1995 cohort had a 71% chance of survival, significantly lower than the 90% chance for the post-1995 era. However, the probability of survival in every subsequent 1-year interval was not statistically different between the eras and averaged 95% for the early era and 96% for the post-1995 era. This was further verified by creating survival curves for the pre-1995 and post-1995 eras that censored early mortality so that a direct comparison of midterm and late survival was possible without early mortality contamination. These curves are not significantly different and, in fact, are virtually identical (Figure 2). Therefore, after the first post-transplant year of follow-up, the mortality rate for pediatric heart transplantation has not changed in more than 20 years, despite shifting trends in immunosuppression (ie, increased use of MMF and tacrolimus).
In addition to survival analyses between eras, the longevity of the TCH series allowed survival analysis of multiple factors that could affect survival. Male recipients who received female donor hearts had a decreased survival compared with male recipients who were donor gender matched. Patient status permitting, gender-matched donor selection for male recipients could result in improved survival.11,12
Prolonged intubation was the most consistent and dominant risk factor, in that it increased the risk of death overall as well as at 1 and 5 years, more than any other risk factor. The transplant team’s aggressive policy toward extubation has resulted in a median length of cumulative intubation of 1 day. Therefore, the inability to extubate a patient within 5 days after transplantation clearly indicated a poor clinical course, as evidenced by the 56% mortality (15/27) seen in this cohort. Prolonged intubation is more likely a reliable predictor for death than a cause.
Risk factors for 5-year mortality conditional on 1-year survival allow the effect of early mortality to be eliminated so that risk factors reflect the true risks for late mortality. Being white increased the probability of survival at 5 years once early mortality was censored. Differences in pediatric post–heart transplant survival among ethnic groups have been documented before. Series have found Hispanic and African American patients (91% of TCH’s non-white cohort) to be at increased risk for recurrent rejection and thus death.10,13 Increasing donor age was an independent risk factor for conditional 5-year survival. This has been demonstrated in another pediatric series that had a proportion of older (>40 years) donors, but in the current series, only 4 of the donors were more than 20 years old with the oldest being 28 years old.14 Another possible explanation is that the adolescent cohort, who has a significantly lower 5-year conditional survival, contains the patients most likely to receive older donor hearts. Therefore, perhaps increasing donor age is serving as a surrogate to identify the adolescent group, which has been recognized by multiple centers to have an increased rate of late attrition, primarily related to compliance issues.5,15
Since the 1980s, pediatric heart transplantation has become a safe and effective management strategy for pediatric patients with end-stage heart failure. Improving survival in pediatric cardiac transplantation is predominately related to increased early survival. For patients surviving the first posttransplant year, the subsequent mortality rate has not changed in more than 21 years. This highlights the ongoing need for novel therapies to treat children with or in need of a heart transplant.
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Thirty-two variables analyzed to determine risk factors for mortality and definitions |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionThirty-two variables analyzed to...References |
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Acknowledgments |
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