Pretransplant Risk Factors and Causes of Death or Graft Loss After Heart Transplantation During Early Infancy
Background This study was performed to report causes of death or graft loss and to identify possible pretransplant risk factors for death or graft loss in infants after heart transplantation.
Methods and Results Pretransplant risk factors were compared for 153 infants registered for heart transplantation within 90 days of life and transplanted from November 1985 to June 1994. Factors assessed were diagnosis, age at transplantation, race, weight, blood type, sex, donor/recipient blood type match, sex match, weight ratio, fetal registration, locale of pretransplant waiting period, mechanical ventilation, ischemic time, and the need for atrial septostomy or septectomy pretransplantation. No factor was associated with death or graft loss at 1 month or 1 year. Causes of death or graft loss were determined using clinical course and pathology data when available. Death or grafts lost at 1 month, 1 year, and >1 year were 14, 13, and 15, respectively. Causes of death or graft loss expressed as a percent (at 1 month, 1 year, and >1 year, respectively) were acute rejection (14, 23, 27), chronic rejection and posttransplant coronary disease (0, 8, 47), infectious causes (21, 15, 13), early graft failure (21, 0, 0), technical issues (21, 23, 0), chronic graft dysfunction (0, 15, 0), and miscellaneous (21, 15, 13). The graft loss rate at 1 year was significantly correlated (linear regression, r2=.66; P<.05) with the year of transplantation. Actuarial survival in this population was 91% at 1 month, 81% at 1 year, and 73% at 3 years.
Conclusions Heart transplantation in the young infant can be performed with acceptable short-term and midterm results. Causes of death or graft loss and survival are similar to adult data. No pretransplant risk factors were identified. The experience level of the transplant team members affects survival. The diagnosis and management of rejection remain a major challenge.
An understanding of the causes of and pretransplant risk factors leading to death or graft loss after heart transplantation in infants should lead to improved survival. This study was performed to report causes of death or graft loss and to identify possible pretransplant risk factors in infants after heart transplantation.
All recipients (n=153) registered for a donor organ within 90 days of birth and who underwent transplantation between November 1985 and June 1994 were included. Pretransplant diagnoses included hypoplastic left heart syndrome (HLHS) (n=82), other potentially lethal structural heart defects (n=69), and congenital cardiomyopathy (n=2). Diagnoses were made using echocardiographic criteria and were verified by examination of the explanted heart. Pretransplant pulmonary artery pressures were not measured in this population. No child required mechanical circulatory support before transplantation. Median age at transplantation was 33 days (range, 0 to 183 days). Actuarial survival in this population was 91% at 1 month, 81% at 1 year, and 73% at 3 years.
Management of Immunosuppression
Patient management after transplantation has been described elsewhere.1 Briefly, immunosuppression was accomplished with cyclosporine and azathioprine based double therapy. Antithymocyte induction therapy has evolved from no induction from 1985 to 1990, random assignment to induction from 1990 to 1992, and now induction therapy in all patients >30 days of life. Antithymocyte induction therapy consisted of a 5-day course of rabbit antithymocyte serum (N/R ATS, Applied Medical Research). Chronic oral steroid therapy was used only for resistant rejection.
In this infant population, acute rejection episodes were diagnosed primarily using noninvasive parameters. Echocardiographic findings consistent with rejection have been previously reported in detail2 and include functional as well as morphological changes. Findings consistent with rejection on ECG include a 25% or greater reduction in QRS voltage, a significant change in QRS axis, change in conduction pattern, or arrhythmias.3 Clinical findings with rejection include irritability, lethargy, poor feeding, tachycardia, tachypnea, and a gallop rhythm.4 Endomyocardial biopsy was used for clinically confusing cases and in cases of poor response to therapy for acute rejection. Chronic rejection and posttransplant coronary artery disease are considered synonymous for this report.
Therapy for acute rejection consisted of high-dose intravenous methylprednisolone. Recurrent rejection and rejection accompanied by hemodynamic compromise were treated with antithymocyte preparations (N/R ATS or antithymocyte gammaglobulin, ie, ATGAM, Upjohn) and methotrexate. Total lymphoid irradiation was used in two patients for particularly recalcitrant rejection.
Determination of Cause of Graft Loss
The causes of graft loss (n=42) were determined using clinical course and pathological correlations. Complete autopsies were available for 33 patients. Autopsy limited to the heart was available in 3 patients, with another 3 explanted hearts available from retransplantation procedures. Autopsy was declined by 3 families. Early graft failure is defined as functional deterioration of the graft occurring within 5 days of transplant that had no response to antirejection therapy and with no rejection found on autopsy. Chronic graft dysfunction refers to persistent poor function of the graft with no response to antirejection therapy and with no rejection or significant coronary artery disease at autopsy.
Data from patients undergoing transplantation before 1993 were retrospectively gathered by chart review and entered into a computerized database. Since 1993, data have been prospectively entered into the database on all patients. The pretransplant factors evaluated are the following: pretransplant diagnosis (HLHS versus other diagnoses), age at transplantation both as a continuous variable and newborn (age ≤30 days) versus non-newborn, Caucasian race versus non-Caucasian, recipient weight, recipient blood type=“O” versus not “O,” blood type match, recipient sex, donor/recipient sex match, weight ratio both as a continuous variable and a ratio ≥2 versus <2, whether the recipient was registered as a fetus, whether the patient waited before transplantation at the referral center versus at the transplant center, requirement for mechanical ventilation at the time of transplantation, ischemic time both as a continuous variable and ≥240 minutes versus <240 minutes, and the need for atrial septostomy or septectomy before transplantation.
The relation between risk factors and death or graft loss at 1 month and at 1 year was evaluated using multiple logistic regression. Correlation between year of transplant and percent graft loss was evaluated using linear regression. Survival curves were generated using the Kaplan-Meier technique. All values were considered statistically significant at P<.05. All statistical analyses were performed using spss for windows, Release 6.0 (SPSS, Inc).
Causes of Graft Loss
Causes of death or graft loss, grouped by time of graft loss, are summarized in Table 1⇓. Two patients underwent retransplantation for posttransplant coronary artery disease, and 1 patient was retransplanted for severe acute rejection. Early graft failure included 2 patients with primary graft failure in the absence of rejection and 1 patient with graft failure secondary to pulmonary hypertension. This was the only patient with death related to pulmonary hypertension, occurring at 3 months of life. Death due to “technical issues” included an oversized donor organ in 2 patients. One patient each died due to an anesthetic mishap, recurrent pulmonary venous obstruction, inability to anastomose the pulmonary veins, and a significant aortic thrombus unrecognized before transplant. Miscellaneous causes of death included 2 patients who died due to perforated ulcers and 1 patient each who succumbed to chronic enteropathy, hemorrhage after circumcision, smoke inhalation, reperfusion injury to the lung, and pulmonary hemorrhage. Infectious causes of death included pneumonia in 4 patients, sepsis in 2 patients, and meningitis in 1 patient.
Pretransplant Risk Factors
There were no significant differences for any of these risk factors in the groups with death or graft loss at 1 month or at 1 year after transplantation.
Transplant Team Experience
Historical experience was evaluated by comparing the percent death or graft loss by 1 year after transplantation for each year of transplant center experience (Fig 1⇓) and cumulative death or graft loss at 1 month and 1 year after transplantation versus total number of transplantation procedures performed (Fig 2⇓). Linear regression analysis (Fig 1⇓) revealed a trend of more death or graft loss at 1 year in the earliest years of our experience, 20% to 40%, versus the more recent years at 10% to 15% (r2=.66; P<.05).
An increase in 1-year death or graft loss was noted for 1989. Additional evaluation revealed that 60% of patients with 1-year graft loss due to acute rejection were transplanted in 1989 (P=.054 by χ2). Examinations of graft loss at any time due to acute rejection revealed that 4 of 9 patients (44%) were transplanted in 1989 (P=.03 by χ2).
This is the largest single center experience reported to date of heart transplantation in this age group. The actuarial survival in these young patients is nearly identical to that reported by UNOS (United Network for Organ Sharing) and the International Society for Heart and Lung Transplantation (ISHLT) data for all patients transplanted from 1988 to 19935 (Fig 3⇓).
Causes of graft loss in this young infant population are similar to recent results reported by Bourge et al6 from a large multiinstitutional study (Transplant Cardiologists Research Database; TCRD) involving mainly adult patients (Table 2⇓). Risk factors for 1-year heart transplantation mortality as reported by Hosenpud et al5 included ventilator requirement, young age, female recipient, and prolonged ischemic time. The TCRD report6 found that younger age, longer ischemic time, and donor and recipient who were not both blood type “O” were risk factors for death after transplantation. Unlike these reports, however, we were unable to detect a significant difference in any risk factor analyzed between the groups experiencing death or graft loss at 1 month or 1 year after transplantation when compared with those who had still-functioning grafts. Increased pulmonary vascular resistance has been associated with early graft failure in pediatric patients.7 But, this is an unlikely event in the present study because of the patients’ young age.
Even though this is a large series of patients, it is possible that a small effect may not be detected without larger numbers of patients. However, at this point we are unable to identify from the current study any pretransplant risk factors that are associated with early (1 month or 1 year) death or graft loss. Although this does not help us to select a recipient with a better chance for long-term graft survival, it is reassuring that scarce donor resources can be allocated without the need for concern of matching some potentially difficult factors (eg, sex and race). It is also important to note that some factors considered potentially risky in this population did not in fact affect graft survival.
The transplant team at Loma Linda has been headed by the same senior surgeon since its inception. The primary follow-up physicians have been members of the team for 6 and 8 years. The senior transplant coordinator has 9 years’ experience. Therefore, the data in this study are believed to represent cumulative experience rather than changes in transplant personnel. This study showed that there was a decline in percent graft loss at our center with increasing transplant team experience over time. This is consistent with UNOS data analyzing center volume and survival.8
There was an increase in percent graft loss noted for 1989. The most significant difference in clinical practice during this time period is believed to be unavailability of antithymocyte preparations for induction or rescue therapy. During this period, recalcitrant rejection was managed with repeated steroid bursts and long-term oral prednisone. Monoclonal anti-CD3 antibody was used as well but was less effective and associated with greater late mortality.9
The implications of center experience with regard to regionalization of heart transplant services and third-party payer issues have recently been addressed by a task force of the American College of Cardiology.10 The task force acknowledged an “overabundance of heart transplantation centers in the U.S.,” and they recommended that “the development of new programs and continuation of existing programs should be dependent on regional/societal medical needs.” An understanding of the “learning curve” phenomenon is helpful in this continuing debate.
Finally, since approximately 45% of graft failures in the present series resulted from either acute or chronic rejection (ie, posttransplant coronary artery disease), the appropriate diagnosis and management of acute rejection and the prevention of posttransplant coronary artery disease remain the most fruitful areas for research efforts to improve survival in this population.
Supported in part by a grant from the McDonnell-Douglas Employees Community Fund. The authors wish to express sincere appreciation to Sharon Robie, RN, Joyce Johnston, RN, Kay Ogata, RN, Sharon Fritzsche, RN, Laura Vander Dussen, RN, and Laurel Wood, RN, for data collection and expert assistance in the care of these patients.
Reprint requests to Richard E. Chinnock, MD, Pediatric Heart Transplant Program, Loma Linda University Children’s Hospital, 11234 Anderson St, Schuman Pavilion Room 1638, Loma Linda, CA 92350. E-mail Richard Chinnock at LLUMC@ccmail.llu.edu.
Presented during the 67th Scientific Sessions of the American Heart Association, Dallas, Tex, November 14-17, 1994, published in abstract form (Circulation. 1994;90[suppl I]:I-97).
- Copyright © 1995 by American Heart Association
Chinnock R, Baum M, Larsen R, Bailey L. Rejection management and long-term surveillance of the pediatric heart transplant recipient: the Loma Linda experience. J Heart Lung Transplant. 1993;12(suppl 2):S255-S264.
Boucek MM, Mathis CM, Boucek RJ, Hodgkin DD, Kanakriyeh MS, McCormack J, Gundry SR, Bailey LL. Prospective evaluation of echocardiography for primary rejection surveillance after infant heart transplantation: comparison with endomyocardial biopsy. J Heart Lung Transplant. 1994;13:66-73.
Chinnock RE, Johnston J, Baum M, Janner D, Robie S, Larsen R. Signs and symptoms of graft rejection in the infant heart transplant recipient. Cardiology in the Young. 1993;3(suppl 1):59. Abstract.
Boucek MM, Mathis CM, Chinnock RE, Kanakriyeh MS, Nehlsen-Cannarella S, Gundry SR, Bailey LL, Boucek RJ. Polyclonal versus monoclonal anti-T cell antibody therapy in infant heart transplantation. J Heart Lung Transplant. 1991;9:161A. Abstract.