(Circulation. 1995;92:206-209.)
© 1995 American Heart Association, Inc.
Articles |
Pretransplant Risk Factors and Causes of Death or Graft Loss After Heart Transplantation During Early Infancy
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).
From the Departments of Pediatrics (R.E.C., R.L.L., J.R.E.) and Surgery (L.L.B.), Loma Linda University Children's Hospital and Medical Center and Loma Linda University School of Medicine, Loma Linda, Calif.
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Abstract |
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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.
Key Words: transplantation • rejection • pediatrics • mortality
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Introduction |
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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.
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Methods |
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Patient Population
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.
Pretransplant Factors
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.
Statistical Analysis
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).
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Results |
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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.
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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).
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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 
2). 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
2).
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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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
).
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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.
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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.
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Acknowledgments |
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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.
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Footnotes |
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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.
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References |
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TopAbstractIntroductionMethods Results Discussion References |
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1. 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.
2. 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. [Medline] [Order article via Infotrieve]
3. Johnston JK, Mathis CM. Determination of rejection using non-invasive parameters following cardiac transplantation in very early infancy—the Loma Linda experience. Prog Cardiovasc Nurs. 1988;3:13-18. [Medline] [Order article via Infotrieve]
4. 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.
5. Hosenpud JD, Novick RJ, Breen TJ, Daily OP. The registry of the International Society for Heart and Lung Transplantation: eleventh official report—1994. J Heart Lung Transplant. 1994;13:561-570. [Medline] [Order article via Infotrieve]
6. Bourge RC, Naftel DC, Costanzo-Nordin MR, Kirklin JK, Young JB, Kubo SH, Olivari MT, Kasper EK. Pretransplantation risk factors for death after heart transplantation: a multiinstitutional study. J Heart Lung Transplant. 1993;12:549-562. [Medline] [Order article via Infotrieve]
7.
Fukushima N, Gundry SR, Razzouk AJ, Bailey LL.
Risk factors for graft failure associated with pulmonary
hypertension after pediatric heart transplantation.
J Thorac Cardiovasc Surg. 1994;107:985-989.
8.
Hosenpud JD, Breen TJ, Edwards EB, Daily OP, Hunsicker
LG. The effect of transplant center volume on cardiac transplant
outcome: a report of the United Network for Organ Sharing Scientific
Registry. JAMA. 1994;271:1844-1849.
9. 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.
10. O'Connel JB, Gunnar RM, Evans RW, Fricker FJ, Hunt SA, Kirklin JK. Task force 1: organization of heart transplantation in the U.S. J Am Coll Cardiol. 1993;22:1-14.[Medline] [Order article via Infotrieve]
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