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Ann Thorac Surg 1995;59:813-820
© 1995 The Society of Thoracic Surgeons

Lung Transplantation in Children and Young Adults With Cardiovascular Disease

Divisions of Cardiothoracic Surgery, Pediatric Pulmonology, and Pediatric Cardiology, Washington University School of Medicine and St. Louis Children's Hospital, St. Louis, Missouri

	Abstract

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Single or bilateral lung transplantation was performed in 20 patients with pulmonary hypertension or an inadequate pulmonary vascular bed; all but 1 had congenital heart disease. The average age was 6.3 years (range, 3 months to 23.9 years). All were in New York Heart Association class IV, and 6 were hospitalized and receiving intensive support before transplantation. Hospital survival was 70% (14/20), with three additional deaths at 7, 11, and 27 months. A prior thoracic operation contributed to three of six hospital deaths from hemorrhage. All late deaths were due directly or indirectly to obliterative bronchiolitis. At a mean follow-up of 19 months (range, 2 to 48 months), 10 of 11 survivors are in New York Heart Association class I. Survival after hospital discharge and incidence of obliterative bronchiolitis are similar in a contemporary group of 41 patients of comparable age who underwent lung transplantation for pulmonary disease (p = not significant). Single or bilateral lung transplantation is an acceptable therapy for children with pulmonary hypertension, congenital heart disease, or both. Further investigation in the areas of pretransplantation survival, operative risk factors, and long-term outcome of single-lung recipients and recipients with hemodynamically insignificant intracardiac lesions are needed to develop optimal decision-making strategies for these patients.

	Introduction

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
See also page 820

Single or bilateral lung transplantation has evolved as an alternative therapy for patients with pulmonary hypertension, congenital heart disease, or both who in the past have been considered for combined heart and lung transplantation, particularly in the pediatric population. This is reflected in the registry data of the International Society for Heart and Lung Transplantation; since 1989, the number of heart and lung transplantations performed has decreased, concurrent with a dramatic increase in the number of single and bilateral lung transplants. Although primary pulmonary hypertension and congenital heart disease currently account for only 10% of lung transplant procedures in adults, these conditions account for 30% of lung transplant procedures in children [1]. Since July 1990, 26 children and young adults referred to St. Louis Children's Hospital with pulmonary hypertension, congenital heart disease, or both were considered candidates for lung transplantation. Of these, 6 died while waiting for a donor. The remaining 20 patients, who underwent single or bilateral lung transplantation with cardiac repair as necessary, are the subject of this report.

	Material and Methods

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Patients
Between July 1990 and July 1994, 20 patients having a primary cardiovascular diagnosis underwent single or bilateral lung transplantation at St. Louis Children's Hospital. These patients ranged in age from 3 months to 23.9 years (average, 6.3 +/- 1.5 years); 8 were female. Waiting time ranged from 4 to 298 days, with an average of 81 +/- 19 days. All transplant procedures were carried out using cardiopulmonary bypass. In 3 patients (patients 1, 11, and 20), extracorporeal membrane oxygenation (ECMO) was used for preoperative stabilization and support for 13, 8, and 26 days, respectively; in these 3 patients, the ECMO circuit was used for cardiopulmonary bypass at the time of transplantation. Among the 17 patients who were not on ECMO at the time of transplantation, 3 (patients 3, 12, and 16) were being supported with pressors and mechanical ventilation before transplantation.

The clinical characteristics of and the operations performed on the 20 patients are detailed in Table 1. Only 1 (patient 10) had primary pulmonary hypertension; all of the others had either irreversible pulmonary hypertension or an inadequate pulmonary vascular bed in association with a congenital heart lesion. In 3 patients (patients 2, 4, and 14), irreversible pulmonary hypertension was present in association with a ventricular level shunt that was either unrepaired or repaired after the age of 2 years; these patients fit the clinical picture of Eisenmenger syndrome. In 5 patients (patients 1, 3, 7, 18, and 19), irreversible pulmonary hypertension in association with congenital heart disease developed unexpectedly at a very young age, the oldest child in this subgroup being 21 months old at the time of lung transplantation (Fig 1). An additional 4 patients (patients 11, 12, 13, and 20) also had irreversible pulmonary hypertension in association with congenital heart disease at a very young age, but with lesions in which this is not unexpected (congenital pulmonary vein stenosis in 3 and scimitar syndrome in 1). The association of pulmonary hypertension and congenital heart disease may have been coincidental in 2 patients (patients 5 and 15), as they had lesions that would not be expected to produce pulmonary hypertension. Finally, 5 patients (patients 6, 8, 9, 16, and 17) had congenital heart disease in association with an inadequate pulmonary vascular bed (tetralogy of Fallot with pulmonary atresia and absent central pulmonary arteries in 4 patients, and atrial septal defect with multiple sites of peripheral pulmonic stenosis in 1). A prior thoracic operation had been performed in 12 of the 20 patients.

View larger version (116K): [in this window] [in a new window]   Fig 1. . (A) An unrestrictive patent ductus arteriosus (PDA) in an 18-month-old child (patient 19). A balloon catheter has been positioned over a wire that passes through the PDA into the descending aorta. Inflation of the balloon to 12 mm results in subtotal occlusion of the PDA. (B) Aortogram and (C) right ventriculogram in the same patient 6 months after bilateral sequential lung transplantation and suture obliteration of the PDA.

An additional 6 patients (4 with primary pulmonary hypertension, 1 with pulmonary vein stenosis, and 1 with repaired congenital heart disease) were listed for lung transplantation but died before organs became available. The time between listing and death ranged from 2 to 526 days, with a median of 12 days. All had severe pulmonary hypertension without an intracardiac or extracardiac shunt, and were listed late in the course of their disease.

The technique of operation and immunosuppressive regimen used were as described previously [2, 3].

Statistical Methods
All values are expressed as the mean +/- standard error of the mean. Age, sex, diagnostic category, prior thoracic operation, type of procedure performed, and level of preoperative support were analyzed as possible predictors of hospital survival using the ² test or linear regression. Actuarial survival was analyzed by the Kaplan-Meier method. Survival among these patients was compared with survival in a contemporary group of children undergoing single or bilateral lung transplantation for primary pulmonary diagnoses (cystic fibrosis, pulmonary fibrosis) using the Mantel-Haenszel statistic.

	Results

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Survival
There were six hospital deaths, for a surgical mortality of 30%. There were, in addition, three late deaths, for an overall survival of 55%. Among 3 patients supported with ECMO preoperatively, 1 survived, and among 3 patients who were not supported with ECMO but who were supported preoperatively with pressors and mechanical ventilation, 2 survived. Postoperative ECMO support was used in 4 patients, 1 of whom also had been on ECMO preoperatively; 1 of these patients survived. Analysis of age, sex, use of preoperative or postoperative ECMO, use of preoperative mechanical ventilation and pressor support, type of transplant (one lung versus two lungs), and prior operation as possible predictors of outcome revealed no statistically significant associations, possibly because of sample size. Nevertheless, 5 of 12 patients having a prior thoracic operation died in the hospital, accounting for all but one of the early deaths. A prior thoracic operation increased the technical difficulty of operation in all 5, and was a contributing factor in the deaths of 3 patients (patients 8, 9, and 16), who died of uncontrollable hemorrhage.

The three late deaths occurred 7 to 27 months after transplantation. Obliterative bronchiolitis was the direct or indirect cause of death in all of these patients. In 1, death was due to pulmonary insufficiency as a consequence of bronchiolitis obliterans; 1 died shortly after repeat lung transplantation for this diagnosis; and in the third patient, the cause of death was invasive aspergillosis, which developed on a substrate of obliterative bronchiolitis.

Survival among these 20 patients was compared with survival in a contemporary group of 41 patients of comparable age undergoing single or bilateral lung transplantation for pulmonary disease. Actuarial survival for all patients in both groups is shown in Figure 2. The mortality is higher among patients with a cardiovascular diagnosis (p = 0.02); the difference in survival is accounted for almost entirely by the greater hospital mortality. In Figure 3, survival among hospital survivors in the two groups is compared and is seen to be similar (p = 0.6).

View larger version (20K): [in this window] [in a new window]   Fig 2. . Actuarial survival after lung transplantation among 20 patients with a cardiovascular diagnosis, compared with that of 41 patients with pulmonary disease. The difference in mortality (p = 0.02) is largely due to higher hospital mortality among patients with a cardiovascular diagnosis.

View larger version (19K): [in this window] [in a new window]   Fig 3. . Actuarial survival after lung transplantation among 14 hospital survivors having a cardiovascular diagnosis, compared with 39 hospital survivors having a pulmonary diagnosis (p = 0.6).

Among the 14 hospital survivors, 6 were mature enough for reliable testing of pulmonary function. Their studies are characterized by a restrictive pattern in the early postoperative period that improves over time, as shown in Figure 4A. An obstructive pattern developed in 3 patients at 3, 6, and 21 months (Fig 4B); all of these patients died of obliterative bronchiolitis. All but 1 of the current survivors is fully saturated on room air.

View larger version (25K): [in this window] [in a new window]   Fig 4. . (A) Sequential pulmonary function studies after lung transplantation (patient 17). The restrictive pattern that is seen early and resolves over time is characteristic after either single or bilateral lung transplantation. (B) Sequential pulmonary function studies after lung transplantation in a patient in whom obliterative bronchiolitis developed (patient 5). (fev1 = forced expiratory volume in 1 second; fvc = forced vital capacity.)

Postoperative echocardiography revealed no significant residual cardiac lesions, normal to mildly diminished biventricular function, and low right ventricular pressure in all hospital survivors.

All 20 patients in this report were compromised severely by their disease before transplantation; 6 of the 20 were hospitalized and required critical levels of support. Among the 11 current survivors (among whom are 3 who required critical levels of support before transplantation), 10 are in New York Heart Association class I. In 1 patient (patient 18) who had undergone an arterial switch operation before transplantation, aortic valve endocarditis developed 6 months after lung transplantation. A cardiac catheterization performed after antibiotic treatment of the endocarditis revealed moderate aortic insufficiency, mild aortic stenosis, increased left ventricular filling pressures, mild pulmonary venous desaturation, proximal right coronary artery obstruction, right ventricular ischemia, and moderate pulmonary hypertension responsive to oxygen and vasodilators. This patient is currently at home, with improving functional status on a regimen of oxygen and nifedipine.

	Comment

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Although a statistically significant association cannot be demonstrated, prior thoracic operations probably contributed to four of the six early deaths in this group. The majority of children with congenital heart disease who are referred to us for lung transplant evaluation have had one or more prior thoracic operations. We do not consider this a contraindication to lung transplantation. However, the favorable outcomes that we and others [4–6] have seen after single lung transplantation for pulmonary hypertension indicate that this option should be considered seriously, especially if it allows avoidance of operation in a previously entered hemithorax.

Other investigators have expressed concerns about both long-term function and the incidence of bronchiolitis obliterans in patients with pulmonary hypertension undergoing single-lung transplantation [7, 8]. The 2 long-term survivors of single-lung transplantation in this series are in New York Heart Association class I at a follow-up of 25 and 48 months. We found no discernable difference in the incidence of obliterative bronchiolitis according to pretransplantation diagnosis or the type of transplant procedure performed. However, the number of patients having single-lung transplantation is small, and it is conceivable that with a larger experience, a difference might emerge.

Although no child with a significant right to left shunt died while waiting for an organ, the pretransplantation mortality among those with pulmonary hypertension and no intracardiac or extracardiac site for shunting was quite high (6/16, 38%). This is consistent with previously reported observations in similar patients: the average survival from the time of diagnosis of primary pulmonary hypertension is only 2.8 years [9], whereas almost 75% of children diagnosed with Eisenmenger syndrome can be expected to survive into adulthood [10]. The interval between listing and death in 4 of these 6 children was short (2 to 16 days), indicating that they were listed quite late in their disease process. The ``correct'' time to list a patient is determined by the patient's expected survival and the expected waiting time for an organ, neither of which is known with certainty. The data generated by a study of survival in 194 adults with primary pulmonary hypertension [9] may be used to estimate survival in children with this disease, and should in theory be useful in determining when to list a patient [11]; however, as it is known that children with primary pulmonary hypertension differ from their adult counterparts in several respects (eg, mode of presentation, response to vasodilators [12–14]), it cannot be assumed that their survival is similar. There are few data currently available that allow one to predict survival in children who have irreversible pulmonary hypertension in association with congenital heart disease, particularly when this occurs at a very young age. At our center, we tend to rely on those measurements that are most predictive in primary pulmonary hypertension, ie, right atrial pressure, pulmonary artery pressure, and cardiac index, as well as degree of cyanosis and functional status. This is an area that requires further investigation.

Among 6 patients requiring critical levels of preoperative support, 3 are alive and in New York Heart Association class I at 3, 18, and 46 months after lung transplantation. This outcome is not demonstrably different from the outcome of patients not requiring intensive preoperative support (3/6 survivors versus 11/14 survivors), although it is possible that a statistically significant difference might be found in a larger group of patients. We do not consider preoperative support with ECMO, pressors, or mechanical ventilation to be contraindications to lung transplantation.

The complication of aortic valve endocarditis in a patient who was known to have an abnormal aortic valve before transplantation may indicate that heart and lung transplantation would have been a better choice for this patient. Even the best possible repair does not produce a normal heart in a patient born with a congenital heart defect, although it probably comes close with some lesions (atrial septal defect, paramembranous ventricular septal defect). Whether hemodynamically insignificant abnormalities of the cardiac valves constitute important risk factors for children undergoing lung transplantation will only be determined by a larger experience and careful follow-up. At present, the decision to offer bilateral lung transplantation with cardiac repair rather than heart and lung transplantation is made on a case-by-case basis. In general, if the cardiac lesion is one that in and of itself would allow a biventricular repair, and if the performance of the systemic ventricle is adequate, we favor cardiac repair over cardiac transplantation. As of this writing, we have not attempted lung transplantation in the setting of a Fontan palliation.

Long-term survival and quality of life in this group as in other reported groups is determined largely by rejection, infection, and the development of obliterative bronchiolitis. Except for the probable increased risk of intracardiac infection, there is no indication in this relatively small group that these risks are different among those with congenital heart disease or pulmonary hypertension than they are among patients with a primary pulmonary diagnosis.

In conclusion, single or bilateral lung transplantation for children and young adults with severe pulmonary hypertension, congenital heart disease, or both is associated with a medium-term survival of 55%. Hospital mortality is relatively high in these patients compared with those having a primary pulmonary diagnosis, at least in part due to prior thoracic operations. Prudent patient selection and increased use of single-lung transplantation to avoid entering a previously entered hemithorax may decrease this early mortality. Survival after discharge from the hospital among patients with a cardiovascular diagnosis is similar to that of patients with a pulmonary diagnosis, and functional status among medium-term survivors is excellent. Pretransplantation mortality is high among those with pulmonary hypertension and no intracardiac or extracardiac site for shunting. Increased experience and investigation focusing on the issues of predicted survival before transplantation, the long-term course of single-lung recipients, and the long-term course of recipients with hemodynamically insignificant cardiac abnormalities are needed to develop optimal decision-making strategies for these patients.

	Acknowledgments

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
We gratefully acknowledge the assistance of Lynne Sekarski, RN, and Bobby Mackey, RN, MSW, in the preparation of the manuscript.

	Footnotes

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Presented at the Forty-first Annual Meeting of the Southern Thoracic Surgical Association, Marco Island, FL, Nov 10--12, 1994.

Doctor Bridges' current address is Cardiology Division, Children's Hospital of Philadelphia, 34th St and Civic Center Blvd, Philadelphia, PA 19104.

Address reprint requests to Dr Spray, Division of Pediatric Cardiothoracic Surgery, Children's Hospital of Philadelphia, 34th Street and Civic Center Blvd, Philadelphia, PA 19103.

	References

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 

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3. Spray TL, Mallory GB, Canter CE, Huddleston CB. Pediatric lung transplantation. Indications, techniques, and early results. J Thorac Cardiovasc Surg 1994;107:990–1000.[Abstract/Free Full Text]
4. Fremes SE, Patterson GA, Williams WG, et al. Single lung transplantation and closure of patent ductus arteriosus for Eisenmenger's syndrome. J Thorac Cardiovasc Surg 1990;100:1–5.[Abstract]
5. Calhoon JH, Grover FL, Gibbons WJ, et al. Single lung transplantation. Alternative indications and technique. J Thorac Cardiovasc Surg 1991;101:816–25.[Abstract]
6. Pasque MK, Kaiser LR, Dresler CM, et al. Single lung transplantation for pulmonary hypertension. Technical aspects and immediate hemodynamic results. J Thorac Cardiovasc Surg 1992;103:475–82.[Abstract]
7. Trinkle JK. Discussion of: Pasque MK, Kaiser LR, Dresler CM, et al. Single lung transplantation for pulmonary hypertension. J Thorac Cardiovasc Surg 1992;103:481.
8. Lupinetti FM, Bolling SF, Bove EL, et al. Selective lung or heart-lung transplantation for pulmonary hypertension associated with congenital cardiac anomalies. Ann Thorac Surg 1994;57:1545–9.[Abstract]
9. D'Alonzo GE, Barst RJ, Ayres SM, et al. Survival in patients with primary pulmonary hypertension. Results from a national prospective registry. Ann Intern Med 1991;115:343–9.[Medline]
10. Young D, Mark H. Fate of the patient with Eisenmenger syndrome. Am J Cardiol 1971;28:658–69.[Medline]
11. Nootens M, Freels S, Kaufmann E, Levy PS, Rich S. Timing of single lung transplantation for primary pulmonary hypertension. J Heart Lung Transplant 1994;13:276–81.[Medline]
12. Barst RJ. Pharmacologically induced pulmonary vasodilation in children and young adults with primary pulmonary hypertension. Chest 1986;89:497–503.[Abstract/Free Full Text]
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This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Charles B. Huddleston Thomas L. Spray Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Bridges, N. D. Articles by Spray, T. L. Search for Related Content PubMed PubMed Citation Articles by Bridges, N. D. Articles by Spray, T. L. Related Collections Related Article