Heart-Lung
Transplantation
in Infants,
Children,
and Adolescents
By Vaughn A. Starnes, Sara E. Marshall, Norman J. Lewiston, James Theodore, Edward B. Stinson, and Norman E. Shumway
Stanford, California l We have performed heart-lung transplantation in IO children for the preoperative diagnoses of primary pulmonary hypertension (4). complex congenital heart disease with pulmonary hypertension (4), pulmonary atresia (1). and cystic fibrosis (1). Ages ranged from 4 months to 18 years. There were 15 episodes of pulmonary rejection, with an occurrence rate of 1.67 episodes per patient. Pulmonary infections occurred frequently, with an occurrence rate of 3.3 episodes per patient. The actuarial survival rate at 1 and 2 years was 78% and 47%, respectively. Patient attrition between 1 and 2 years was attributable to the complications of obliterative bronchiolitis, which has effected 71% (5/7) of the long-term survivors. Four of the 5 surviving children have minimal physical limitation and are in functional class I. These data support continued investigation into heart-lung transplantation in children and set the stage for further program development into single-lung transplantation in children. Copyright o 7997 by W.B. Saunders Company INDEX WORDS:
Heart-lung transplantation.
H
EART-LUNG transplantation has evolved from an experimental procedure to an accepted therapeutic option for adults with end-stage cardiopulmonary disease. This evolution is the result of better patient selection, improved graft procurement and protection, and improved methods of detecting pulmonary rejection. Although progress has been evidenced by improving survival, many unresolved problems remain.’ The insidious development of obstructive airway disease following heart-lung transplantation is the most frequent serious complication in the long-term survivors.2,3 Although obliterative bronchiolitis (OB) was recognized early in the heartlung experience, it is a poorly understood process.42s Chronic graft rejection and/or infection have been frequently implicated as etiologic factors.2X6Although heart-lung transplantation has many problems, the survival and quality of life of the transplant recipient has improved with increased experience with the
From the Departments of Cardiovascular Surgery and Pediattics, and the Division of Pulmonary Medicine, Stanford University Medical Center, Stanford, CA. Supported in part by the National Institutes of Health Grant No. HL13108. Presented at the 21st Annual Meeting of the American Pediatric Surgical Association, Vancouver, British Columbia, May 19-22, 1990. Address reprint requests to Vaughn A. Stames, MD, Department of Cardiovascular Surgery, Stanford University Medical Cenier, Stanford, CA 94305. Copyright o 1991 by W B. Saunders Company 0022-3468/91/2604-OOI3$03.00/0
434
procedure. Based on the success in adults, heart-lung transplantation in children was begun in 1988. Lessons from the adult heart-lung transplants have been valuable in managing the younger population. Specific issues of transplantation in the pediatric population form the basis of this report. MATERIALS AND METHODS
Patient Selection In 1981, the first successful heart-lung transplant was performed at Stanford University Medical Center. Since 1981, 80 heart-lung transplants have been performed in 77 patients. The preoperative diagnoses have included primary pulmonary hypertension (30) Eisenmenger’s physiology (34), cystic fibrosis (lo), emphysema (2) bronchiectasis (1) and failed single-lung transplant (1). In 1988, we began heart-lung transplantation in the pediatric age group. Clinical indications for transplantation included a limited life expectancy (< 12 months), absence of other systemic illness, preservation of hepatic and renal function, absence of active infection, and a social situation that would insure care of the child in the posttransplant period. Clinical diagnoses considered for transplantation were categorized by age (Table 1). Ten children have undergone heart-lung transplantation (Table 2). The preoperative diagnoses in this group included primary pulmonary hypertension (4) complex congenital heart disease with pulmonary hypertension or absent pulmonary arteries (5), and cystic fibrosis (1). There were 6 boys and 4 girls with an age range of 4 months to 18 years. Four additional children were listed, but died before a donor became available (Table 2). The length of time waiting either to transplant or death ranged from 14 to 765 days (mean, 176 days). Children with pulmonary hypertension were noted to be at a higher risk for sudden death than those with other diagnoses.
Heart-Lung Graft Procurement The heart-lung donor was assessed according to A90 compatible blood grouping, size, and gas exchange. As noted in Table 3, donor and recipient size match were similar in height and weight. A PaO, of greater than 100 mm Hg on an inspired oxygen concentration of ~40% was considered evidence of adequate gas exchange in the donor. Chest roentgenograms were required to be free of infiltrates. Gram and fungal stains of endotracheal aspirate were performed to exclude infection. Graft preservation was insured with crystalloid cardiopulmonoplegia solution, as described previously.’
Immunosuppression Immunosuppression was based on a three-drug protocol consisting of cyclosporine, azathioprine, and prednisone (Table 4). Preoperatively, cyclosporine, 2 to 4 mgkg, orally, and azathioprine, 4 mgikg, intravenously (IV), were given. On discontinuance of cardiopulmonary bypass following transplantation, methylprednisolone, 10 mg/kg, was given. Postoperatively, cyclosporine was given to maintain a serum level of 150 to 250 ng/mL by radioimmunoassay. The average cyclosporine dose given to maintain the Journal of Pediatric Surgery, Vol26, No 4 (April), 1991: pp 434-438
HEART-LUNG TRANSPLANTATION
435
IN CHILDREN
Table 3. Donor-Recipient
Table 1. Clinical Diagnoses Considered for Heart-Lung Transplantation
by Age
Height(cm)
Infants (O-1 yr)
TransplantNo.
Complex CHD with pulmonary hypertension Pulmonary atresia Bronchopulmonary
dysplasia
Children (I-10 yr) CHD with pulmonary hypertension (Eisenmenger’s syndrome) Primary pulmonary hypertension Postviral end-stage parenchymal lung disease Cystic fibrosis Adolescents (IO-18 yr) Cystic fibrosis
appropriate level was 10 to 12 mg/kg/d, orally, given in divided doses. Azathioprine, 2 m&g, orally, was given to white blood cell tolerance in order to maintain a white blood count of greater than 4,000 cells/ml. During the first 14 days, the monoclonal antibody, OKT3, 0.1 to 0.2 mg, IV, was given to maintain a T cell count (CD3) below 1% to 5%. Beginning on day 14, prednisone was started at 1.0 m&g/d and tapered to 0.2 mgikg/d by 6 weeks.
Pulmonary Rejection Pulmonary rejection has occurred in the majority of patients following heart-lung transplantation. Cardiac pathology does not mirror pulmonary changes following heart-lung transplantation; therefore, cardiac biopsy was not useful for detecting pulmonary rejection. Asynchronous pulmonary rejection occurred more frequently than asynchronous cardiac rejection8 In the children and adolescents. the presence of rejection was determined by serial transbronchial biopsies and pulmonary function studies. PulmoTable 2. Preoperative Characteristics
of Pediatric Candidates
for Heart-Lung Transplantation Pulmonary Artery Pressures lmm Hg) Mean
Age
Recipient
Diagnosis
-
Transplanted
1
165.0
170.2
62.0
62.0
176.7
172.7
74.3
61.6
3
155.0
157.5
41.0
50.0
4
90.0
84.0
14.4
12.0
5
153.0
152.0
45.0
53.2
6
165.0
155.0
49.5
69.6
7
107.5
124.5
15.5
24.0
8
61.0
48.5
4.2
2.8
9
75.0
80.0
8.4
9.2
67.5
30.4
121.4 + 14.5
6.3
117.5 + 16.7
34.6 2 8.6
RESULTS
There were two perioperative deaths (20%) secondary to pulmonary infection at 3 and 4 months. The first child required retransplantation because of parainfluenza B pneumonia and died following the second transplant due to recurrent viral pneumonia. The second death occurred in a child with cystic fibrosis secondary to pneumonia with a resistant strain of Pseudomonas aeruginosu. One child (transplant no. 10) was recently transplanted and is in the immediate postoperative period. Postoperatively, the heart-lung grafts performed well in all children.
1
15yr
PPH
92
16yr
PPH
68
3
IOyr
PPH
43
4
2 vr 18yr
PPH
70
Cyclosporine
4 mg/kg (PO)
5
AVSD with PH
62
Azathioprine
4 mg/kg (IV)
6
15yr
AVSD with PH
90 -
7 vr
Cystic fibrosis Single ventricle/pul.
8
4mo
monary atresia
11 mo
ventricle/PH
64 60
Pulmonary vein 10
13 mo
stenosis/PH
Table 4. Immunosuppressive
lntraoperative Methylprednisolone
65
4mo
PPH
79
2
6 vr
PPH
Methylprednisolone
5 mg/kg (IV) every 8 h x 3
OKT3
0.1 mg/kg/d x 14d
Azathioprine
1 to 2 mg/kg/d (PO)
Cyclosporine
Given orally in divided doses,
75
tain serum trough level at 150 to 250 ng/mL (range, 8
Eisenmenger’s
Abbreviations:
10 mg/kg (IV)
dosage adjusted to main-
1
3
(at ter-
Postoperative
Died waiting
4
Protocol
Preoperative
mination of bypass)
Hypoplastic left 9
4.6 32.3 + 7.9
nary rejection in infants was suspected by a clinical syndrome of hypoxemia, pulmonary hilar infiltrates with effusion, fever, and irritability in the absence of pulmonary infection. Currently available bronchoscopic forceps are too large to fit pediatric flexible bronchoscopes. Characteristics of pulmonary rejection on biopsy included perivenular, periarteriolar, and peribronchiolar lymphocytic infiltrates. Increasing severity of rejection was associated with endovasculitis, mononuclear bronchiolitis, and alveolar wall infiltrates.‘” Rejection was treated with daily IV methylprednisolone in high dosage (15 mg/kg/d up to 1 g) for a total of 3 days.
2
7
Donor
disease
Abbreviation: CHD, congenital heart disease.
No.
Weight (kg)
Donor
2
Mean + SE
Primary pulmonary hypertension
Transplant
Recipient
10
Eisenmenger’s syndrome End-stage cardiopulmonary
Size Match
4 vr 16 yr
disease Cystic fibrosis
to 15 mg/kg/dj 67 -
PPH, primary pulmonary hypertension; AVSD, atrio-
ventricular septal defect; PH. pulmonary hypertension.
Prednisone
Beginning on day 14, 1.0 mg/ kg/d and taper to 0.2 mg/ kg/d by 6 wk
Abbreviations: PO, orally; IV, intravenously.
436
Donor ischemia time ranged from 50 to 240 minutes (mean, 158 2 19.0 minutes). There were no tracheal anastomotic complications in early or late follow-up. The two infants with follow-up of 1 year have not demonstrated any evidence of tracheal stenosis. Omental wrap was not performed in any patient. Of the 7 discharged patients, all were initially in functional class I. Two patients (transplant nos. 5 and 6) died at 12 and 14 months, respectively, due to complications from OB. Of the remaining 5 discharged patients, 4 are without limitations. One patient (transplant no. 3) has chronic rejection and is awaiting a second transplant. Pulmonary Rejection
Pulmonary rejection was common, and was observed in 8 of the 9 (89%) patients with follow-up greater than 3 months. There were 15 rejection episodes, with a mean of 1.67 rejection episodes per patient. Thirteen of the 15 rejections were biopsyproven. Two episodes of pulmonary rejection in the infants were suspected on clinical grounds. Moderate rejection was present on 12 biopsies and severe in one. Of the 15 episodes of rejection, 13 (87%) episodes responded to pulse methylprednisolone. The mean time to first rejection was 12 days (range, 6 to 21 days). Pulmonary Infection
There were 30 episodes of respiratory tract infection. The mean number of infections per patient was 3.3. Infections were diverse in etiologies, including viral infections (cytomegalovirus [CMV], respiratory syncytial virus [RSV], and parainfluenza) in 5 patients and fungal infection with Candida orAspergillus in 5 patients. The most common bacterial infections were Pseudomonas, Enterococcus, and Staphylococcus. Pneumocystis carinii pneumonia occurred in one patient and responded well to therapy. Pulmonary Function
Pulmonary function studies were performed in all discharged patients except for the infants. Serial determinations of pulmonary function were performed in an attempt to detect obstructive airway changes early. The adult heart-lung experience has demonstrated a 30% to 35% incidence of chronic obstructive airway disease (OB). The hypothesis of chronic rejection causing OB prompted early intervention with antirejection therapy, with reversibility of the airway disease being demonstrated in adults. In children, serial pulmonary function, as reflected by the FEV, (forced expiratory volume in first second) showed a slow deterioration in the first year followed
STARNES ET AL
by stabilization (Fig 1). The mean FEV, (% predicted, 80% to 120% normal) at 3 months was 72.6% + 14.3% and fell to 44.8% k 18.0% at 12 months. Continued follow-up showed an FEV, of 34.4% rt 12.5% at 2 years. The PaO, remained stable at 3, 12, and 24 months, with a PaO, of 98.0 + 6.2,75.8 f 19.2, and 73.4 -+ 9.6 mm Hg, respectively. Of the long-term survivors, 5 of 7 (71%) have demonstrated clinical evidence of OB. Two patients (transplant nos. 5 and 6) died at 12 and 14 months secondary to OB. The two infants have demonstrated no evidence of obstructive airway disease. Although 5 children demonstrated evidence of OB with pulmonary function tests, 80% (4/5) had minimal physical restriction. One child (transplant no. 3) was relisted for transplantation because of restrictive lung disease of unknown etiology. Cardiac Function
Cardiac rejection occurred infrequently (20%). There were no noted arrhythmias. Cardiac function, as determined by echocardiogram and annual cardiac catheterization, was normal. One patient (transplant no. 5) developed difbrse coronary artery disease along with OB and died of myocardial infarction. Survival
Actuarial survival for heart-lung transplantation has lagged behind heart transplantation. However, actuarial survival has steadily improved over the past 8 years. In adults, the current l-, 2-, and 3-year survival rates are 64%, 55%, and 48%, respectively. In children, the follow-up has extended to 2 years, with a l- and 2-year actuarial survival of 78% and 47% (Fig 2). The decline in survival at 2 years has been attributed to the complications of OB. DISCUSSION
Heart-lung transplantation in children evolved from our initial experience with over 65 heart-lung transplants in adults. The technical aspects of heart-lung
Fig 1.
Pulmonary function over time as assessedby FEV, and PaO,.
HEART-LUNG TRANSPLANTATION
437
IN CHILDREN
March 1991 . May I,1999
49 \ 20 -
.L.-.
Fig 2. Actuarial survival comparing heart-lung transplantation children versus adults (P = NS).
in
transplantation, graft preservation, and postoperative care used in children are a result of this clinical experience. At present, the major limitation to heart-lung transplantation in children, like adults, is the insidious development of chronic obstructive airway disease (OB).2,3 In this preliminary report, 5 of 7 (71%) of the discharged pediatric heart-lung patients developed OB. Although the incidence of 71% seems excessive, over 50% of the initial adult heart-lung patients developed OB.‘* The current incidence of OB in adults is 30%.13 The reduction in the occurrence of OB correlates with a new protocol involving increased immunosuppression and frequent surveillance for rejection. The reduced incidence of OB also correlates well with our current hypothesis of chronic rejection and/or infection as causative factors. Augmented immunosuppression stabilized patients with OB from further deterioration and reduced the number of documented rejection episodes. In 1988, serial transbronchial biopsies with pulmonary function tests became part of the routine follow-up care of the heart-lung patient. The information on biopsy demonstrated that histopathology of pulmonary rejection correlated with a deterioration in expiratory flow volumes (FEV,, FEF 25-27.’ The correlation of histopathology with function permits detection of rejection at a stage prior to irreversible injury to the airways. If OB is the end stage of a rejection-
mediated injury-repair mechanism, then early detection is essential to the prevention of this chronic airway disease. At present, the higher incidence of OB noted in children may be a reflection of inadequate immunosuppression or the late detection of rejection at a more advanced stage. As in adults, we anticipate the reduction in OB in children as more clinical experience is accrued and further revisions in immunosuppressive protocols occur. This preliminary experience sets the stage for further program development. Single-lung transplantation in infants and children is on the horizon. The transplantation of infants with diaphragmatic hernias is currently being debated. We recently performed a single-lung transplant in an 11-month-old infant with bronchopulmonary dysplasia. The infant healed the bronchial anastomosis, but died of a resistant Pseudomonas infection. As is true in the adult population, the technical aspect of the operation is not the limiting factor. Outcome will again depend on the postoperative care of these children and the prevention of chronic airway injury related to pulmonary rejection and infection. As noted in this report, the infection rate is 3.3 episodes per patient and the rejection rate is 1.67 episodes per patient in children undergoing heart-lung transplantation. Are these rates of infection and rejection to be expected in the single-lung transplant group? Our initial experience with 14 single-lung transplants in adults suggests that the rate of infection and rejection is similar to the adult heart-lung counterparts. Therefore, we do expect the experience in single-lung transplantation in children to be reflected by the current experience in heart-lung transplantation. The reported l-year actuarial survival of 78% supports continued investigation of heart-lung and lung transplantation in children. However, the sharp decline in survival from 78% to 47% by the end of the second year suggests that many problems remain. Further advancement in lung transplantation will depend on the understanding of pulmonary rejection and how it relates to chronic airway disease.
REFERENCES 1. McCarthy PM, Starnes VA, Theodore J, et al: Improved survival after heart-lung transplantation. J Thorac Cardiovasc Surg 99:54-60,199O 2. Burke CM, Theodore J, Dawkins KD, et al: Post-transplant obliterative bronchiolitis and other late lung sequelae in human heart-lung transplantation. Chest 86:824-829,1984 3. Theodore J, Jamieson SW, Burke CM, et al: Physiologic aspects of human heart-lung transplantation: Pulmonary function status of the post-transplanted lung. Chest 86:349-357,1984 4. Burke CM, Morris AJR, Dawkins KD, et al: Late airflow obstruction in heart-lung transplantation recipients. Heart Transplant 4:437-440,1985
5. Starnes VA: Heart-lung transplantation: diol Clin 8159-168, 1990
An overview. Car-
6. Burke CM, Glanville AR, Theodore J, et al: Lung immunogenicity, rejection, and obliterative bronchiolitis. Chest 92:547-549, 19x7 _,_I 7. Baldwin JC, Frist WH, Starkey TD, et al: Distant graft procurement for combined heart and lung transplantation using pulmonary artery flush and simple topical hypothermia for graft preservation. Ann Thorac Surg 43:670-673,1987 8. Starnes VA, Theodore J, Oyer PE, et al: Evaluation of heart-lung transplant recipients with prospective, serial transbron-
438
STARNES ETAL
chial biopsies and pulmonary function studies. J Thorac Cardiovasc Surg 98:683-690,1989 9. Higenbottam T, Stewart S, Penketh A, et al: Transbronchial lung biopsy for the diagnosis of rejection in heart-lung transplant patients. Transplantation 46:532-539,1988 10. Stewart S, Higenbottam TW, Hutter JA, et al: Histopathology of transbronchial biopsies in heart-lung transplantation. Transplant Proc 20:764-766,1988 (suppl 1) 11. Higenbottam T, Stewart S, Wallwork J: Transbronchial lung
biopsy to diagnose lung rejection and infection of heart-lung transplants. Transplant Proc 20:767-769,1988 (suppl 1) 12. Glanville AR, Baldwin JC, Burke CM, et al: Obliterative bronchiolitis after heart-lung transplantation: Apparent arrest by augmented immunosuppression. Ann Intern Med 107:300-304, 1987 13. Starnes VA, Baldwin JC, Harjula A: Combined heart and lung transplantation: The Stanford experience. J Appl Cardiol 2:71-89,1987
Discussion D.G. Hall (Seattle, WA): This fine paper is the result of 30 years of disciplined surgical investigation of transplantation by the Stanford group. Dr Starnes, you are to be congratulated. You have opened the possibility of heart-lung transplantation to a huge pool of patients-diaphragmatic hernia, complex congenital heart disease, cystic fibrosis, etc. My questions are, will the new immunosuppresant from the Mount Fuji area in Japan improve your outcome? Is there a window of opportunity for transplantation in the neonate? What is the cost for heart-lung transplantation? Are xenographs any hope for the future? I applaud your efforts in this difficult area with its philosophical issues, economic consequences, and medical dilemmas. D. Tapper: Dr Starnes, on your last slide, it showed that you had treated some adult patients with Eisenminger’s complex as was mentioned by a previous discussant, and I wondered if you might expand on that and answer the following question. Do you foresee that in some of these children you might repair the congenital defect and then just use the same lung and not essentially have to carry the lung with the heart transplant? KA. Stames (response): This is the first patient that I performed a single-lung transplant on for Eisenminger’s physiology. She had a previous atria1 septal defect closure, so this made her at high risk for heart-lung transplant. I elected to do a right singlelung transplant on cardiopulmonary bypass and closed the defect. This is her immediate postoperative film and her film 6 months following transplant. Her pulmonary artery pressure systolic was 160 mm Hg preoperation and fell to 35 mm Hg at follow-up evaluation 6 months postoperatively. We have gone on to do 5 patients with single-lung transplants for either primary pulmonary hypertension or Eisenminger’s physiology. All except one patient had a very
nice response. We do think this technique holds some promise, particularly in small children in whom we could do an intracardiac repair followed by single lung transplantation. Dr Hall, I wouldn’t convert my ranch just yet. I think xenografts present a real problem for us physicians in terms of rejection. As you can tell from my clinical data, rejection is still a major problem. In our initial adult experience, 60% of our patients developed OB. We have decreased this number in our most recent transplant group to 30% and we believe this is a result of improved immunosuppression and earlier detection of rejection. There is an optimal transplant window because we believe this is an investigational procedure and we certainly don’t offer this therapy to children too early in their course of disease. However, we have noted that the patients with primary pulmonary hypertension and the Eisenminger’s physiology in particular have a high mortality once they become symptomatic and frequently will die within 2 months. We believe that once you make the diagnosis in those children, particularly if they have a pulmonary artery systolic measure that is supersystemic, they probably ought to be placed on the transplant list. Does the Fuji drug offer anything over our current immunosuppressive protocols, I think time will tell. Certainly it is a cyclosporin-like drug. I think it has some of the similar complications that cyclosporin has. We hope, as you have heard this morning concerning immunomodulation for tumor, that we can apply the same technology to transplantation. Cost is a very major factor. A heart-lung transplant at Stanford right now costs approximately $120,000, and I think this is related not only to a longer hospital stay but also the cost of retrieving organs, transplantation, and all the costly immunosuppressive agents, So right now this is a limiting factor if we are totally dependent on our third-party payers, Medicare, or Medicaid.
Transplantation
in Infants,
Children,
and Adolescents
By Vaughn A. Starnes, Sara E. Marshall, Norman J. Lewiston, James Theodore, Edward B. Stinson, and Norman E. Shumway
Stanford, California l We have performed heart-lung transplantation in IO children for the preoperative diagnoses of primary pulmonary hypertension (4). complex congenital heart disease with pulmonary hypertension (4), pulmonary atresia (1). and cystic fibrosis (1). Ages ranged from 4 months to 18 years. There were 15 episodes of pulmonary rejection, with an occurrence rate of 1.67 episodes per patient. Pulmonary infections occurred frequently, with an occurrence rate of 3.3 episodes per patient. The actuarial survival rate at 1 and 2 years was 78% and 47%, respectively. Patient attrition between 1 and 2 years was attributable to the complications of obliterative bronchiolitis, which has effected 71% (5/7) of the long-term survivors. Four of the 5 surviving children have minimal physical limitation and are in functional class I. These data support continued investigation into heart-lung transplantation in children and set the stage for further program development into single-lung transplantation in children. Copyright o 7997 by W.B. Saunders Company INDEX WORDS:
Heart-lung transplantation.
H
EART-LUNG transplantation has evolved from an experimental procedure to an accepted therapeutic option for adults with end-stage cardiopulmonary disease. This evolution is the result of better patient selection, improved graft procurement and protection, and improved methods of detecting pulmonary rejection. Although progress has been evidenced by improving survival, many unresolved problems remain.’ The insidious development of obstructive airway disease following heart-lung transplantation is the most frequent serious complication in the long-term survivors.2,3 Although obliterative bronchiolitis (OB) was recognized early in the heartlung experience, it is a poorly understood process.42s Chronic graft rejection and/or infection have been frequently implicated as etiologic factors.2X6Although heart-lung transplantation has many problems, the survival and quality of life of the transplant recipient has improved with increased experience with the
From the Departments of Cardiovascular Surgery and Pediattics, and the Division of Pulmonary Medicine, Stanford University Medical Center, Stanford, CA. Supported in part by the National Institutes of Health Grant No. HL13108. Presented at the 21st Annual Meeting of the American Pediatric Surgical Association, Vancouver, British Columbia, May 19-22, 1990. Address reprint requests to Vaughn A. Stames, MD, Department of Cardiovascular Surgery, Stanford University Medical Cenier, Stanford, CA 94305. Copyright o 1991 by W B. Saunders Company 0022-3468/91/2604-OOI3$03.00/0
434
procedure. Based on the success in adults, heart-lung transplantation in children was begun in 1988. Lessons from the adult heart-lung transplants have been valuable in managing the younger population. Specific issues of transplantation in the pediatric population form the basis of this report. MATERIALS AND METHODS
Patient Selection In 1981, the first successful heart-lung transplant was performed at Stanford University Medical Center. Since 1981, 80 heart-lung transplants have been performed in 77 patients. The preoperative diagnoses have included primary pulmonary hypertension (30) Eisenmenger’s physiology (34), cystic fibrosis (lo), emphysema (2) bronchiectasis (1) and failed single-lung transplant (1). In 1988, we began heart-lung transplantation in the pediatric age group. Clinical indications for transplantation included a limited life expectancy (< 12 months), absence of other systemic illness, preservation of hepatic and renal function, absence of active infection, and a social situation that would insure care of the child in the posttransplant period. Clinical diagnoses considered for transplantation were categorized by age (Table 1). Ten children have undergone heart-lung transplantation (Table 2). The preoperative diagnoses in this group included primary pulmonary hypertension (4) complex congenital heart disease with pulmonary hypertension or absent pulmonary arteries (5), and cystic fibrosis (1). There were 6 boys and 4 girls with an age range of 4 months to 18 years. Four additional children were listed, but died before a donor became available (Table 2). The length of time waiting either to transplant or death ranged from 14 to 765 days (mean, 176 days). Children with pulmonary hypertension were noted to be at a higher risk for sudden death than those with other diagnoses.
Heart-Lung Graft Procurement The heart-lung donor was assessed according to A90 compatible blood grouping, size, and gas exchange. As noted in Table 3, donor and recipient size match were similar in height and weight. A PaO, of greater than 100 mm Hg on an inspired oxygen concentration of ~40% was considered evidence of adequate gas exchange in the donor. Chest roentgenograms were required to be free of infiltrates. Gram and fungal stains of endotracheal aspirate were performed to exclude infection. Graft preservation was insured with crystalloid cardiopulmonoplegia solution, as described previously.’
Immunosuppression Immunosuppression was based on a three-drug protocol consisting of cyclosporine, azathioprine, and prednisone (Table 4). Preoperatively, cyclosporine, 2 to 4 mgkg, orally, and azathioprine, 4 mgikg, intravenously (IV), were given. On discontinuance of cardiopulmonary bypass following transplantation, methylprednisolone, 10 mg/kg, was given. Postoperatively, cyclosporine was given to maintain a serum level of 150 to 250 ng/mL by radioimmunoassay. The average cyclosporine dose given to maintain the Journal of Pediatric Surgery, Vol26, No 4 (April), 1991: pp 434-438
HEART-LUNG TRANSPLANTATION
435
IN CHILDREN
Table 3. Donor-Recipient
Table 1. Clinical Diagnoses Considered for Heart-Lung Transplantation
by Age
Height(cm)
Infants (O-1 yr)
TransplantNo.
Complex CHD with pulmonary hypertension Pulmonary atresia Bronchopulmonary
dysplasia
Children (I-10 yr) CHD with pulmonary hypertension (Eisenmenger’s syndrome) Primary pulmonary hypertension Postviral end-stage parenchymal lung disease Cystic fibrosis Adolescents (IO-18 yr) Cystic fibrosis
appropriate level was 10 to 12 mg/kg/d, orally, given in divided doses. Azathioprine, 2 m&g, orally, was given to white blood cell tolerance in order to maintain a white blood count of greater than 4,000 cells/ml. During the first 14 days, the monoclonal antibody, OKT3, 0.1 to 0.2 mg, IV, was given to maintain a T cell count (CD3) below 1% to 5%. Beginning on day 14, prednisone was started at 1.0 m&g/d and tapered to 0.2 mgikg/d by 6 weeks.
Pulmonary Rejection Pulmonary rejection has occurred in the majority of patients following heart-lung transplantation. Cardiac pathology does not mirror pulmonary changes following heart-lung transplantation; therefore, cardiac biopsy was not useful for detecting pulmonary rejection. Asynchronous pulmonary rejection occurred more frequently than asynchronous cardiac rejection8 In the children and adolescents. the presence of rejection was determined by serial transbronchial biopsies and pulmonary function studies. PulmoTable 2. Preoperative Characteristics
of Pediatric Candidates
for Heart-Lung Transplantation Pulmonary Artery Pressures lmm Hg) Mean
Age
Recipient
Diagnosis
-
Transplanted
1
165.0
170.2
62.0
62.0
176.7
172.7
74.3
61.6
3
155.0
157.5
41.0
50.0
4
90.0
84.0
14.4
12.0
5
153.0
152.0
45.0
53.2
6
165.0
155.0
49.5
69.6
7
107.5
124.5
15.5
24.0
8
61.0
48.5
4.2
2.8
9
75.0
80.0
8.4
9.2
67.5
30.4
121.4 + 14.5
6.3
117.5 + 16.7
34.6 2 8.6
RESULTS
There were two perioperative deaths (20%) secondary to pulmonary infection at 3 and 4 months. The first child required retransplantation because of parainfluenza B pneumonia and died following the second transplant due to recurrent viral pneumonia. The second death occurred in a child with cystic fibrosis secondary to pneumonia with a resistant strain of Pseudomonas aeruginosu. One child (transplant no. 10) was recently transplanted and is in the immediate postoperative period. Postoperatively, the heart-lung grafts performed well in all children.
1
15yr
PPH
92
16yr
PPH
68
3
IOyr
PPH
43
4
2 vr 18yr
PPH
70
Cyclosporine
4 mg/kg (PO)
5
AVSD with PH
62
Azathioprine
4 mg/kg (IV)
6
15yr
AVSD with PH
90 -
7 vr
Cystic fibrosis Single ventricle/pul.
8
4mo
monary atresia
11 mo
ventricle/PH
64 60
Pulmonary vein 10
13 mo
stenosis/PH
Table 4. Immunosuppressive
lntraoperative Methylprednisolone
65
4mo
PPH
79
2
6 vr
PPH
Methylprednisolone
5 mg/kg (IV) every 8 h x 3
OKT3
0.1 mg/kg/d x 14d
Azathioprine
1 to 2 mg/kg/d (PO)
Cyclosporine
Given orally in divided doses,
75
tain serum trough level at 150 to 250 ng/mL (range, 8
Eisenmenger’s
Abbreviations:
10 mg/kg (IV)
dosage adjusted to main-
1
3
(at ter-
Postoperative
Died waiting
4
Protocol
Preoperative
mination of bypass)
Hypoplastic left 9
4.6 32.3 + 7.9
nary rejection in infants was suspected by a clinical syndrome of hypoxemia, pulmonary hilar infiltrates with effusion, fever, and irritability in the absence of pulmonary infection. Currently available bronchoscopic forceps are too large to fit pediatric flexible bronchoscopes. Characteristics of pulmonary rejection on biopsy included perivenular, periarteriolar, and peribronchiolar lymphocytic infiltrates. Increasing severity of rejection was associated with endovasculitis, mononuclear bronchiolitis, and alveolar wall infiltrates.‘” Rejection was treated with daily IV methylprednisolone in high dosage (15 mg/kg/d up to 1 g) for a total of 3 days.
2
7
Donor
disease
Abbreviation: CHD, congenital heart disease.
No.
Weight (kg)
Donor
2
Mean + SE
Primary pulmonary hypertension
Transplant
Recipient
10
Eisenmenger’s syndrome End-stage cardiopulmonary
Size Match
4 vr 16 yr
disease Cystic fibrosis
to 15 mg/kg/dj 67 -
PPH, primary pulmonary hypertension; AVSD, atrio-
ventricular septal defect; PH. pulmonary hypertension.
Prednisone
Beginning on day 14, 1.0 mg/ kg/d and taper to 0.2 mg/ kg/d by 6 wk
Abbreviations: PO, orally; IV, intravenously.
436
Donor ischemia time ranged from 50 to 240 minutes (mean, 158 2 19.0 minutes). There were no tracheal anastomotic complications in early or late follow-up. The two infants with follow-up of 1 year have not demonstrated any evidence of tracheal stenosis. Omental wrap was not performed in any patient. Of the 7 discharged patients, all were initially in functional class I. Two patients (transplant nos. 5 and 6) died at 12 and 14 months, respectively, due to complications from OB. Of the remaining 5 discharged patients, 4 are without limitations. One patient (transplant no. 3) has chronic rejection and is awaiting a second transplant. Pulmonary Rejection
Pulmonary rejection was common, and was observed in 8 of the 9 (89%) patients with follow-up greater than 3 months. There were 15 rejection episodes, with a mean of 1.67 rejection episodes per patient. Thirteen of the 15 rejections were biopsyproven. Two episodes of pulmonary rejection in the infants were suspected on clinical grounds. Moderate rejection was present on 12 biopsies and severe in one. Of the 15 episodes of rejection, 13 (87%) episodes responded to pulse methylprednisolone. The mean time to first rejection was 12 days (range, 6 to 21 days). Pulmonary Infection
There were 30 episodes of respiratory tract infection. The mean number of infections per patient was 3.3. Infections were diverse in etiologies, including viral infections (cytomegalovirus [CMV], respiratory syncytial virus [RSV], and parainfluenza) in 5 patients and fungal infection with Candida orAspergillus in 5 patients. The most common bacterial infections were Pseudomonas, Enterococcus, and Staphylococcus. Pneumocystis carinii pneumonia occurred in one patient and responded well to therapy. Pulmonary Function
Pulmonary function studies were performed in all discharged patients except for the infants. Serial determinations of pulmonary function were performed in an attempt to detect obstructive airway changes early. The adult heart-lung experience has demonstrated a 30% to 35% incidence of chronic obstructive airway disease (OB). The hypothesis of chronic rejection causing OB prompted early intervention with antirejection therapy, with reversibility of the airway disease being demonstrated in adults. In children, serial pulmonary function, as reflected by the FEV, (forced expiratory volume in first second) showed a slow deterioration in the first year followed
STARNES ET AL
by stabilization (Fig 1). The mean FEV, (% predicted, 80% to 120% normal) at 3 months was 72.6% + 14.3% and fell to 44.8% k 18.0% at 12 months. Continued follow-up showed an FEV, of 34.4% rt 12.5% at 2 years. The PaO, remained stable at 3, 12, and 24 months, with a PaO, of 98.0 + 6.2,75.8 f 19.2, and 73.4 -+ 9.6 mm Hg, respectively. Of the long-term survivors, 5 of 7 (71%) have demonstrated clinical evidence of OB. Two patients (transplant nos. 5 and 6) died at 12 and 14 months secondary to OB. The two infants have demonstrated no evidence of obstructive airway disease. Although 5 children demonstrated evidence of OB with pulmonary function tests, 80% (4/5) had minimal physical restriction. One child (transplant no. 3) was relisted for transplantation because of restrictive lung disease of unknown etiology. Cardiac Function
Cardiac rejection occurred infrequently (20%). There were no noted arrhythmias. Cardiac function, as determined by echocardiogram and annual cardiac catheterization, was normal. One patient (transplant no. 5) developed difbrse coronary artery disease along with OB and died of myocardial infarction. Survival
Actuarial survival for heart-lung transplantation has lagged behind heart transplantation. However, actuarial survival has steadily improved over the past 8 years. In adults, the current l-, 2-, and 3-year survival rates are 64%, 55%, and 48%, respectively. In children, the follow-up has extended to 2 years, with a l- and 2-year actuarial survival of 78% and 47% (Fig 2). The decline in survival at 2 years has been attributed to the complications of OB. DISCUSSION
Heart-lung transplantation in children evolved from our initial experience with over 65 heart-lung transplants in adults. The technical aspects of heart-lung
Fig 1.
Pulmonary function over time as assessedby FEV, and PaO,.
HEART-LUNG TRANSPLANTATION
437
IN CHILDREN
March 1991 . May I,1999
49 \ 20 -
.L.-.
Fig 2. Actuarial survival comparing heart-lung transplantation children versus adults (P = NS).
in
transplantation, graft preservation, and postoperative care used in children are a result of this clinical experience. At present, the major limitation to heart-lung transplantation in children, like adults, is the insidious development of chronic obstructive airway disease (OB).2,3 In this preliminary report, 5 of 7 (71%) of the discharged pediatric heart-lung patients developed OB. Although the incidence of 71% seems excessive, over 50% of the initial adult heart-lung patients developed OB.‘* The current incidence of OB in adults is 30%.13 The reduction in the occurrence of OB correlates with a new protocol involving increased immunosuppression and frequent surveillance for rejection. The reduced incidence of OB also correlates well with our current hypothesis of chronic rejection and/or infection as causative factors. Augmented immunosuppression stabilized patients with OB from further deterioration and reduced the number of documented rejection episodes. In 1988, serial transbronchial biopsies with pulmonary function tests became part of the routine follow-up care of the heart-lung patient. The information on biopsy demonstrated that histopathology of pulmonary rejection correlated with a deterioration in expiratory flow volumes (FEV,, FEF 25-27.’ The correlation of histopathology with function permits detection of rejection at a stage prior to irreversible injury to the airways. If OB is the end stage of a rejection-
mediated injury-repair mechanism, then early detection is essential to the prevention of this chronic airway disease. At present, the higher incidence of OB noted in children may be a reflection of inadequate immunosuppression or the late detection of rejection at a more advanced stage. As in adults, we anticipate the reduction in OB in children as more clinical experience is accrued and further revisions in immunosuppressive protocols occur. This preliminary experience sets the stage for further program development. Single-lung transplantation in infants and children is on the horizon. The transplantation of infants with diaphragmatic hernias is currently being debated. We recently performed a single-lung transplant in an 11-month-old infant with bronchopulmonary dysplasia. The infant healed the bronchial anastomosis, but died of a resistant Pseudomonas infection. As is true in the adult population, the technical aspect of the operation is not the limiting factor. Outcome will again depend on the postoperative care of these children and the prevention of chronic airway injury related to pulmonary rejection and infection. As noted in this report, the infection rate is 3.3 episodes per patient and the rejection rate is 1.67 episodes per patient in children undergoing heart-lung transplantation. Are these rates of infection and rejection to be expected in the single-lung transplant group? Our initial experience with 14 single-lung transplants in adults suggests that the rate of infection and rejection is similar to the adult heart-lung counterparts. Therefore, we do expect the experience in single-lung transplantation in children to be reflected by the current experience in heart-lung transplantation. The reported l-year actuarial survival of 78% supports continued investigation of heart-lung and lung transplantation in children. However, the sharp decline in survival from 78% to 47% by the end of the second year suggests that many problems remain. Further advancement in lung transplantation will depend on the understanding of pulmonary rejection and how it relates to chronic airway disease.
REFERENCES 1. McCarthy PM, Starnes VA, Theodore J, et al: Improved survival after heart-lung transplantation. J Thorac Cardiovasc Surg 99:54-60,199O 2. Burke CM, Theodore J, Dawkins KD, et al: Post-transplant obliterative bronchiolitis and other late lung sequelae in human heart-lung transplantation. Chest 86:824-829,1984 3. Theodore J, Jamieson SW, Burke CM, et al: Physiologic aspects of human heart-lung transplantation: Pulmonary function status of the post-transplanted lung. Chest 86:349-357,1984 4. Burke CM, Morris AJR, Dawkins KD, et al: Late airflow obstruction in heart-lung transplantation recipients. Heart Transplant 4:437-440,1985
5. Starnes VA: Heart-lung transplantation: diol Clin 8159-168, 1990
An overview. Car-
6. Burke CM, Glanville AR, Theodore J, et al: Lung immunogenicity, rejection, and obliterative bronchiolitis. Chest 92:547-549, 19x7 _,_I 7. Baldwin JC, Frist WH, Starkey TD, et al: Distant graft procurement for combined heart and lung transplantation using pulmonary artery flush and simple topical hypothermia for graft preservation. Ann Thorac Surg 43:670-673,1987 8. Starnes VA, Theodore J, Oyer PE, et al: Evaluation of heart-lung transplant recipients with prospective, serial transbron-
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chial biopsies and pulmonary function studies. J Thorac Cardiovasc Surg 98:683-690,1989 9. Higenbottam T, Stewart S, Penketh A, et al: Transbronchial lung biopsy for the diagnosis of rejection in heart-lung transplant patients. Transplantation 46:532-539,1988 10. Stewart S, Higenbottam TW, Hutter JA, et al: Histopathology of transbronchial biopsies in heart-lung transplantation. Transplant Proc 20:764-766,1988 (suppl 1) 11. Higenbottam T, Stewart S, Wallwork J: Transbronchial lung
biopsy to diagnose lung rejection and infection of heart-lung transplants. Transplant Proc 20:767-769,1988 (suppl 1) 12. Glanville AR, Baldwin JC, Burke CM, et al: Obliterative bronchiolitis after heart-lung transplantation: Apparent arrest by augmented immunosuppression. Ann Intern Med 107:300-304, 1987 13. Starnes VA, Baldwin JC, Harjula A: Combined heart and lung transplantation: The Stanford experience. J Appl Cardiol 2:71-89,1987
Discussion D.G. Hall (Seattle, WA): This fine paper is the result of 30 years of disciplined surgical investigation of transplantation by the Stanford group. Dr Starnes, you are to be congratulated. You have opened the possibility of heart-lung transplantation to a huge pool of patients-diaphragmatic hernia, complex congenital heart disease, cystic fibrosis, etc. My questions are, will the new immunosuppresant from the Mount Fuji area in Japan improve your outcome? Is there a window of opportunity for transplantation in the neonate? What is the cost for heart-lung transplantation? Are xenographs any hope for the future? I applaud your efforts in this difficult area with its philosophical issues, economic consequences, and medical dilemmas. D. Tapper: Dr Starnes, on your last slide, it showed that you had treated some adult patients with Eisenminger’s complex as was mentioned by a previous discussant, and I wondered if you might expand on that and answer the following question. Do you foresee that in some of these children you might repair the congenital defect and then just use the same lung and not essentially have to carry the lung with the heart transplant? KA. Stames (response): This is the first patient that I performed a single-lung transplant on for Eisenminger’s physiology. She had a previous atria1 septal defect closure, so this made her at high risk for heart-lung transplant. I elected to do a right singlelung transplant on cardiopulmonary bypass and closed the defect. This is her immediate postoperative film and her film 6 months following transplant. Her pulmonary artery pressure systolic was 160 mm Hg preoperation and fell to 35 mm Hg at follow-up evaluation 6 months postoperatively. We have gone on to do 5 patients with single-lung transplants for either primary pulmonary hypertension or Eisenminger’s physiology. All except one patient had a very
nice response. We do think this technique holds some promise, particularly in small children in whom we could do an intracardiac repair followed by single lung transplantation. Dr Hall, I wouldn’t convert my ranch just yet. I think xenografts present a real problem for us physicians in terms of rejection. As you can tell from my clinical data, rejection is still a major problem. In our initial adult experience, 60% of our patients developed OB. We have decreased this number in our most recent transplant group to 30% and we believe this is a result of improved immunosuppression and earlier detection of rejection. There is an optimal transplant window because we believe this is an investigational procedure and we certainly don’t offer this therapy to children too early in their course of disease. However, we have noted that the patients with primary pulmonary hypertension and the Eisenminger’s physiology in particular have a high mortality once they become symptomatic and frequently will die within 2 months. We believe that once you make the diagnosis in those children, particularly if they have a pulmonary artery systolic measure that is supersystemic, they probably ought to be placed on the transplant list. Does the Fuji drug offer anything over our current immunosuppressive protocols, I think time will tell. Certainly it is a cyclosporin-like drug. I think it has some of the similar complications that cyclosporin has. We hope, as you have heard this morning concerning immunomodulation for tumor, that we can apply the same technology to transplantation. Cost is a very major factor. A heart-lung transplant at Stanford right now costs approximately $120,000, and I think this is related not only to a longer hospital stay but also the cost of retrieving organs, transplantation, and all the costly immunosuppressive agents, So right now this is a limiting factor if we are totally dependent on our third-party payers, Medicare, or Medicaid.
