H tients with end-stage pulmonary hypertension was

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1 Pediatric Lung Transplantation for Pulmonary Hypertension and Congenital Heart Disease Thomas L. Spray, MD, George B. Mallory, MD, Charles E. Canter, MD, Charles B. Huddleston, MD, and Larry R. Kaiser, MD St. Louis Children s Hospital, Washington University School of Medicine, St. Louis, Missouri Five children underwent lung transplantation for endstage pulmonary hypertension and respiratory insufficiency associated with congenital heart disease. One (17 mo) had pulmonary hypertension with a patent ductus arteriosus and required two periods of preoperative extracorporeal membrane oxygenation before successful bilateral sequential lung transplantation. One (21 mo) required bilateral lung transplantation for pulmonary hypertension and bronchopulmonary dysplasia associated with iatrogenic injury to the left pulmonary artery. This child also had patent ductus arteriosus ligation and preoperative catheter closure of an atrial septal defect. Extracorporeal membrane oxygenation was required for early postoperative pulmonary support. One child underwent right single-lung transplantation and closure of an atrial septal defect for pulmonary hypertension. Two patients had single-lung transplantation for Eisenmenger s syndrome: 1 with muscular inlet ventricular septal defect closure, atrial septal defect closure, and right single-lung transplantation; 1 with ventricular septal defect closure, patent ductus arteriosus ligation, right ventricular outflow tract patch repair, and single-lung transplantation. All patients survived operation, with one late death (lymphoproliferative disease). The 4 survivors are all ambulatory without oxygen and have evidence of normal pulmonary artery pressure 9 to 12 months after transplantation. (Ann Thorac Surg 1992;54:216-25) eart and lung transplantation as treatment for pa- H tients with end-stage pulmonary hypertension was pioneered by Reitz and associates [l] and has led to early and midterm success. More recently combined heart and lung transplantation has been extended to pediatric patients with congenital heart disease associated with Eisenmenger s syndrome or end-stage secondary pulmonary hypertension [24]. After successful single-lung transplantation in patients with pulmonary fibrosis and emphysema, Cooper and others have applied single- and double-lung transplantation techniques to patients with end-stage pulmonary vascular disease of either primary or secondary etiologies [%lo]. Encouraging early results of isolated lung transplantation for pulmonary hypertension have prompted application of the procedure to children and young adults with pulmonary hypertension associated with congenital heart disease amenable to direct repair. From August 1990 to February children have undergone 15 single or bilateral sequential lung transplantations at St. Louis Children s Hospital. Five of these children, who were treated with lung transplantation for pulmonary hypertension associated with correctable congenital heart disease, are the subject of this report. Presented at the Twenty-eighth Annual Meeting of The Society of Thoracic Surgeons, Orlando, FL, Feb S5, Address reprint requests to Dr Spray, St. Louis Children s Hospital, 400 South Kingshighway, Suite 5W24, St. Louis, MO Patients and Methods Patient characteristics are summarized in Table 1. The 5 patients ranged in age from 1.5 to 23 years, with a mean age of 10.8 years. Preoperative cardiac diagnoses included pulmonary hypertension and a patent ductus arteriosus in a 17-month-old girl (patient 1). This patient had pulmonary artery pressures at systemic levels with a pulmonary to systemic vascular resistance ratio of 0.9 (Table 2). Progressive peripheral arterial desaturation and pulmonary deterioration prompted intubation and paralysis, and ultimately this child required placement on extracorporeal membrane oxygenation on two separate occasions. Five days after reinitiation of extracorporeal membrane oxygenation support, bilateral sequential lung transplantation was performed with suture obliteration of a large patent ductus arteriosus. A 21-month-old girl (patient 2) sustained an iatrogenic injury of the left pulmonary artery at the time of ductus ligation shortly after birth. Despite an attempted repair of the left pulmonary artery the perfusion of the left lung was sacrificed. Bronchopulmonary dysplasia of both lungs with pulmonary hypertension developed and the patient was transferred to St. Louis Children s Hospital on full ventilatory support for consideration for lung transplantation. Before transfer, the patient had undergone ligation of the patent ductus arteriosus at 6 months of age and catheter occluder device closure of an atrial septal defect at 8 months of age at the referring institution. She was listed for bilateral lung transplantation and showed progressive disability over the following 17 days while awaiting donor lungs. She required paralysis and 100% oxygen ventilatory therapy, by The Society of Thoracic Surgeons /92/$5.00

2 Ann Thorac Surg 1992;54:21&25 SPRAYETAL 217 Table 1. Pediatric Lung Transplantation and Cardiac Repair, August 1990 Through Februa y 1991 Patient Age No. (Y) Diagnosis Type ECMO PHTNIPDA Bilateral x2 preop PHTN/PDA, ASD Bilateral Postop closure 3 12 Eisenloutlet VSD, PDA Single R PHTN/ASD Single R Eisenlinlet VSD, ASD Single R... ASD = atrial septal defect; ECMO = extracorporeal membrane oxygenation; Eisen = Eisenmenger s syndrome; PDA = patent ductus arteriosus; PHTN = pulmonary hypertension; R = right; VSD = ventricular septal defect. but despite these measures, by the day of transplantation had serious deterioration with decreasing urine output and oxygen saturation of 50% to 70% despite maximum ventilatory support. Extracorporeal membrane oxygenation was required in this child for early postoperative pulmonary support. One 15-year-old boy (patient 4) required right singlelung transplantation and closure of an atrial septal defect for pulmonary hypertension and right ventricular failure, with a right ventricular radionuclide ejection fraction of Two patients underwent right single-lung transplantation and cardiac repair for Eisenmenger s syndrome. One 12-year-old boy (patient 3) underwent patch closure of an outlet ventricular septal defect (VSD), pericardial patch enlargement of the right ventricular outflow tract, patent ductus arteriosus suture ligation, and right single-lung transplantation; one 23-year-old woman (patient 5) underwent closure of a muscular inlet VSD, suture closure of an atrial septal defect, and right single-lung transplantation. The mean preoperative pulmonary artery pressure for the 5 patients was 67 mm Hg, and the mean pulmonary to systemic vascular resistance ratio was 1.0 (see Table 2). Operative Technique Operation was performed through a right anterolateral thoracotomy extended across the sternum into the left chest or bilateral anterolateral thoracotomies with transection of the sternum. All 5 patients required use of cardiopulmonary bypass for pulmonary transplantation. The 1 child on extracorporeal membrane oxygenation at the time of transplantation underwent ductus ligation in situ and bilateral sequential lung transplantation with use of the extracorporeal membrane oxygenation circuit as the bypass device. The remaining 4 patients were placed on cardiopulmonary bypass through the aorta and right atrium, and cardioplegic arrest was used in the 2 children who required intracardiac repair. In the initial patient (patient l), omentum was mobilized and brought through defects in the diaphragm to wrap the bronchial anastomoses. In the remaining 4 patients, pericardial pedicles were mobilized from the pericardiotomy incision to wrap the bronchial anastomoses. The patient with atrial septal defect and pulmonary hypertension (patient 4) underwent primary atrial septal defect closure in two layers with fibrillatory arrest at normothermia before right single-lung transplantation. The child who had undergone preoperative closure of a patent ductus arteriosus and catheter closure of an atrial septal defect (patient 2) underwent bilateral sequential lung transplantation on bypass without intracardiac repair; however, reconstruction of the origin of the left pulmonary artery by use of a cuff of donor pulmonary artery with anastomosis to the patient s main pulmonary artery was performed. The patient with an outlet ventricular septal defect (patient 3) and patent ductus arteriosus underwent suture obliteration of the patent ductus arteriosus on bypass and patch closure of the VSD under cardioplegic arrest through a right ventriculotomy incision. A patch of pericardium was used to enlarge the right ventricular outflow tract in this patient, who had evidence of dynamic right ventricular outflow tract obstruction on preoperative catheterization. The inlet ventricular septal defect in patient 5 was closed with a large Dacron patch through a transatrial approach. An associated ostium secundum atrial septal defect was closed primarily in this patient. Right singlelung transplantation was performed while the patient was rewarmed on cardiopulmonary bypass after completion of the cardiac repair in both of these patients. The technique of implantation of the single right lung or the bilateral sequential lungs has been previously described [5, 71. The bronchial anastomoses were performed with continuous absorbable suture for the membranous and interrupted suture for the cartilaginous portions of the bronchus. An end-to-end bronchial anastomosis was performed in all cases, with care taken not to telescope the donor bronchus into the recipient bronchus. Wrapping of the bronchial anastomosis was performed to aid in bronchial healing and prevent contact of the bronchial anastomosis to the adjacent pulmonary arterial anastomosis. The pulmonary arterial and venous anastomoses were created with continuous absorbable suture to allow for maximum anastomotic growth. After completion of the pulmonary transplantation the patients were weaned off cardiopulmonary bypass in the operating room, and the Table 2. Pulmonary Artery Pressure Pre-Tx Post-Tx Patient S/D/M S/D/M No. (mm Hg) PVlUSVR (mm Hg) PVlUSVR l l /70/ /17/ /60/ /18/ Mean 92/54/ /17/ SEM 4.9l4.Ol l1.2l1.3 D = diastolic; M = mean; PVR = pulmonary vascular resistance; S = systolic; SEM = standard error of mean; SVR = systemic vascular resistance; Tx = transplantation.

3 218 SPRAY ET AL Ann Thorac Surg 1992;54:21&25 sternum was closed with a single stainless steel wire. In 1 patient (patient 5) the donor right lung was too large to allow for chest closure without compressing the myocardium and, therefore, some peripheral parenchyma of the middle and lower lobes was excised with a stapling device. Immunosuppression Our immunosuppression protocol for pediatric lung transplantation is similar to that used for infant and pediatric cardiac transplantation. Azathioprine is begun at 2 to 3 mg kg-' day-' and a dose is given before transplantation. Cyclosporine is given at a dose of 0.25 to 0.5 mglkg over 3 hours intravenously as an initial dose and then 1.5 to 2.5 mg/h intravenously in the early postoperative period to maintain a whole blood immunofluorescence cyclosporine level of 300 to 350 ng/ml. As gastrointestinal function returns, the patient is begun on oral cyclosporine therapy and the intravenous dose decreased until adequate gastrointestinal absorption is confirmed. The patient is maintained on a cyclosporine dosage to produce initial blood levels of 300 to 350 ng/ml, and the dosage is then adjusted in the first 1 to 6 months to maintain blood levels at approximately 300 ng/ml. After 6 months, the cyclosporine level is allowed to decrease to 200 to 300 ng1ml. Prednisone administration is begun immediately after transplantation at 1 mg - kg-' * day-' for the first 2 weeks after transplantation, either as an oral or intravenous dose. The dosage is then decreased to 0.5 mg - kg-' - day-' in the first 6 months and subsequently to 0.2 mg * kg-' * day-' from 6 months to 1 year after transplantation. No cytotoxic induction therapy is used. Antiviral agents are administered for documented cytomegalovirus infection based on culture of blood buffy-coat or tracheobronchial washings. Rejection episodes, as diagnosed by evidence of increasing infiltrates on chest roentgenograms, fever, leukocytosis, or a decrease in peripheral arterial oxygen saturation and ventilatory function, or development of new pleural effusions, are treated with bolus steroids followed by transbronchial lung biopsy if rapid resolution does not occur. Refractory rejection not responding to increased steroid therapy is treated with antilymphocyte globulin or OKT3. Rejection Surveillance The technical difficulty in obtaining transbronchial biopsy specimens from infants and small children mandates an infrequent surveillance biopsy schedule. Bronchoscopy is performed frequently in the early postoperative period after transplantation to assess bronchial healing. In the 2 young children in this series (patients 1 and 2) biopsy was performed through a rigid bronchoscope using a modified cardiac bioptome. In the older children, biopsies are performed through a fiberoptic bronchoscope, with sampling of at least two areas of the transplanted lungs. Three to six biopsy specimens are obtained at each biopsy session, and if inadequate material is obtained to confirm the diagnosis of rejection or to exclude rejection or infection, open biopsy is then undertaken. Evidence for progressively decreasing respiratory function by spirometry without evidence of rejection on biopsy has been a relative indication in our patients for open biopsy to determine the presence of bronchiolitis obliterans. One to three biopsies are generally performed in the first 3 months after transplantation and then every 6 months. The patients undergo pulmonary function tests at 2 weeks and then weekly. Infant pulmonary function tests are required in the younger and smaller recipients. Exercise stress tests are performed at 6 weeks, 3 months, and 6 months and the patient is followed up with home spirometry and oximetry. All children participate in supervised daily rehabilitation exercises for the first 3 months after transplantation to provide maximum cardiopulmonary recovery. Results All 5 patients who underwent single or bilateral sequential lung transplantation for pulmonary hypertension associated with congenital heart disease survived the operation. Patient 1, a 1.5-year-old girl who underwent bilateral sequential lung transplantation while on extracorporeal membrane oxygenation support, was weaned from extracorporeal membrane oxygenation in the operating room and was extubated on the fifth postoperative day. She had several episodes of rejection treated with increased steroids and lymphocytotoxic agents. Cytomegalovirus infection was noted on biopsy approximately 2 weeks after transplantation and the patient was placed on antiviral therapy. She was briefly discharged from the hospital, but was readmitted with evidence of increasing infiltrates on chest roentgenograms (Fig 1). Open lung biopsy revealed a monoclonal lymphoproliferative disorder. Despite a decrease in immunosuppression, pulmonary function rapidly deteriorated and the child died 2 months after lung transplantation. Autopsy examination revealed severe monoclonal lymphoproliferative disorder of the transplanted lungs and bone marrow with cytomegalovirus inclusions. The remaining 4 patients have been discharged from the hospital and have been followed up for 2 to 15 months after transplantation (mean, 10 months). Actuarial survival of the patients is shown in Figure 2. All patients have had at least one episode of suspected rejection, treated with bolus steroids, and 2 children required cytolytic therapy with antilymphocyte globulin or OKT3 for rejection episodes unresponsive to increased steroids. Two patients had documented bacterial pulmonary infection which responded to antibiotic therapy. Pulmonary artery pressures and pulmonary vascular resistance decreased dramatically after successful transplantation and cardiac repair (see Table 2). Mean pulmonary artery pressures decreased from 67 to 24 mm Hg, as measured in the 3 patients who had pulmonary artery catheters at operation or follow-up right heart catheterization after transplantation. Mean pulmonary artery systolic pressures decreased from 92 to 37 mm Hg, with a mean diastolic pressure decrease from 54 to 17 mm Hg. Pulmonary vascular resistance to systemic resistance ratio decreased from 1.0 to 0.1 in the 3 patients who underwent

4 Ann Thorac Surg 1992;5421&25 SPRAY ET AL 219 A B Fig 1. (Patient 1.) (A) Chest radiograph before bilateral lung transplantation showing diffuse interstitid infiltrates and the extracorporeal membrane oxygenation cannulas in place in the carotid artery and jugular vein. (B) Posttransplantation radiograph showing clear lung fields and removal of extracorporeal membrane oxygenation cannulas. (C) Chest radiograph 2 months after transplantation with progressive pulmonary infiltrates that were confirmed to be due to lymphoproliferative disorder on biopsy examination. C right heart catheterization 6 to 12 months after transplantation. Measurement of pulmonary perfusion showed a marked increase in perfusion to the transplanted lung in the 3 patients who had single right lung transplants (Table 3). Patient 2, in whom the left pulmonary artery had been ligated early after birth, had complete blood flow to the right lung before transplantation and maintained primary perfusion to the right transplanted lung postoperatively. This patient had the left pulmonary artery of the transplanted lung anastomosed to the proximal main pulmonary artery. Evidence for stenosis of the pulmonary arterial anastomosis was present by Doppler examination after operation. In addition, the left chest in this child was significantly smaller than the right chest and allowed for less pulmonary expansion, possibly accounting for a decrease in ventilation matching the perfusion deficit on the left side. In the 1 patient (patient 1) who underwent bilateral sequential lung transplantation without a previous left chest operation, the perfusion was fairly evenly PERCENT SURVIVAL (1) 1 I I I I MONTHS POST-OP Fig 2. Actuarial survival of the 5 patients at a mean follow-up of 10 months.

5 220 SPRAY ETAL PEDIATRIC LUNG TRANSPLANTATlON Ann Thorac Surg 1992;54:21&25 matched, with 64% of perfusion to the right transplanted lung and 36% to the left transplanted lung. Due to the presence of ventricular septal defects and coupling of the ventricular function, the preoperative and postoperative ventricular function studies in the older patients who underwent single-lung transplantation showed maintenance of ventricular function after transplantation. Patient 3 (Table 4), the 12-year-old boy who underwent outlet VSD closure and right ventricular outflow tract patching in addition to right single lung transplantation, had preservation of the right ventricular ejection fraction of 0.60 after transplantation. The 23-year-old woman with a right single-lung transplant and inlet VSD closure had improvement in right ventricular ejection fraction from 0.47 to 0.60 after transplantation. One patient (patient 4) who had severe right ventricular dysfunction preoperatively with an ejection fraction of 0.13 has evidence of normal echocardiographic right ventricular function after transplantation. Radionuclide ejection fraction 1 year after transplantation was 0.45 on the right side and 0.65 on the left side. Two patients have undergone follow-up cardiac catheterization for assessment of repair of their congenital heart defects. Catheterization revealed closure of the outlet ventricular septal defect in patient 3 and a trivial residual shunt at the ductus level, which was now left to right (Fig 3). Good ventricular function was present, and the anastomosis of the donor and recipient main pulmonary artery showed no evidence of stenosis. The 23-year-old patient who underwent inlet VSD closure and atrial septal defect closure and right single-lung transplantation showed an intact ventricular septal patch with good biventricular function and no evidence of stenosis at the pulmonary arterial anastomosis (Fig 4). Bronchoscopic examination of all surviving patients revealed good healing of the bronchial anastomosis with no evidence of serious airway narrowing. At a mean of 10 months after transplantation, no patient has evidence of bronchiolitis obliterans by transbronchial lung biopsy. Comment The initial approach to patients with pulmonary hypertension and congenital heart disease has been cardiopulmonary transplantation rather than repair of the cardiac Table 3. Pulmonaru Perfusion Pre-Tx (%) Post-Tx (%) Patient No. Type R L R L 1 B B S S S B = bilateral sequential; L = left; R = right; S = single; Tx = transplantation. Table 4. Ventricular Function Pre-Tx Post-Tx Patient No. RVEF LVEF RVEF LVEF LVEF = left ventricular ejection fraction; ejection fraction; Tx = transplantation. RVEF = right ventricular defects [24]. The application of single-lung transplantation to patients with primary pulmonary hypertension has shown that adequate relief of pulmonary hypertension and improvement in right heart function can be obtained with this approach [2, 4, 6, 8, lo]. This success has led to the use of single-lung transplantation in patients with Eisenmenger s physiology or pulmonary hypertension with correction of associated cardiac or extracardiac defects [9, 111. Despite the success of cardiopulmonary transplantation there has been a shortage of suitable combined heart and lung donors. The long waiting times for heart-lung donors and the cardiopulmonary instability of many recipients has resulted in the deaths of a substantial number of patients while awaiting donor organs. Increased experience with transplantation of either single or bilateral lungs will hopefully optimize the utilization of heart and lung donors [12]. Despite the success of pediatric lung transplantation, modification of the technique used in adults has been necessary in the majority of our patients. The tenuous nature of the omentum in small children and in malnourished patients has made it less suitable for use in protective revascularization of the bronchial anastomosis [ 131. Pedicles of pericardium and pericardial fat were used to protect the bronchial anastomosis in the majority of our patients with no evidence of airway disruption. Cardiopulmonary bypass has been necessary in all patients with pulmonary hypertension and congenital heart disease to provide cardiac support during the transplant procedure and facilitate cardiac repair. The use of a bilateral transverse thoracotomy incision or a right anterolateral thoracotomy with transection of the sternum permits cannulation of the heart in the chest in small children, who often have small femoral vessels. Extracorporeal membrane oxygenation has been helpful in the pediatric patient as a bridge to transplantation or for early posttransplantation support of pulmonary and cardiac function. Extracorporeal membrane oxygenation has also occasionally been used successfully in adult patients for early respiratory support after lung transplantation [Cooper JD, personal communication, May Although heart-lung transplantation may remain the best option for children with left heart dysfunction or noncorrectable congenital heart disease with pulmonary hypertension, bilateral sequential lung transplantation

6 Ann Thorac Surg 1992;54: SPRAY ET AL 221 A C B Fig 3. (Patient 3.) (A) Preoperative angiogram shows an outlet ventricular septal defect (closed arrow) with infundibular obstruction and a patent ductus arteriosus (open arrow) with right to left shunting. (B) Left ventricular angiogram 6 months after transplantation shows closure of the ventricular septal defect and trivial ductal flow. (C) Right ventricular angiogram shows the pericardial patch enlargement of the right ventricular outflow tract (arrow). (D) Pulmonary angiogram after transplantation showing the patent right pulmona ry artery anastomosis (arrow) and minimal flow to the left (native) lung. D and repair of congenital heart defects may be preferable in those children in whom satisfactory ventricular function may be expected after repair. However, the effects of correction of long-standing congenital heart disease on ventricular myocardial compliance and function are still unknown. The satisfactory maintenance or improvement of ventricular function seen in patients with Eisenmenger s physiology and intracardiac defects in our series is encouraging in this regard. If good long-term ventricular function is maintained, then expansion of the use of lung transplantation and cardiac repair may be considered for children and young adults with more complex forms of congenital heart disease. Potential candidates for lung transplantation and cardiac repair include patients with severe pulmonary hypertension and atrial septal defect, VSD, or patent ductus arteriosus, and those with atrioventricular canal amenable to repair without serious atrioventricular valve regurgitation. In addition, patients with transposition of the great vessels associated with VSD or Eisenmenger s physiology are potentially correctable by

7 222 SPRAY ET AL Ann Thorac Surg 1992;54: A B Fig 4. (Patient 5.) (A) Postoperative chest radiograph showing clear lung fields after right single-lung transplantation. (B) Left ventricular angiograni after transplantation showing intact inlet ventricular septa1 defect patch (arrow). (C) Pulrnonury arteriogram after transplantation showing open anastomosis of donor and recipient pulmonary artery (arrow) and preferential perfusion to the right (transplanted) lung. C either atrial or arterial switch procedures and single-lung transplantation. Most patients who have undergone correction of congenital cardiac lesions who have a biventricular repair as a result could potentially undergo lung transplantation if progressive pulmonary hypertension is the major physiologic problem. A potentially new area for use of lung transplantation techniques is the patient with pulmonary atresia, VSD, and nonconfluent pulmonary arteries with either hypertensive pulmonary vascularity from aortopulmonary bronchial collaterals or progressive cyanosis from restricted pulmonary blood flow. Singlelung transplantation and repair of the cardiac defects with anastomosis of the right ventricle to a single-lung transplant could possibly correct these patients condition. One potential advantage of the use of lung transplantation with correction of congenital heart defects is the possible avoidance of progressive coronary artery disease of the transplanted heart in combined heart-lung transplantation. The accelerated graft atherosclerosis seen in heartlung transplantation suggests that maintenance of the recipient s own heart by reipair may well be preferable to use of heart-lung transplantation or domino transplantation [14, 151. Reports of the use of living related-donor pulmonary lobes for transplantation into infants and children has generated substantial interest in these techniques [2, 161. In our patients, bilateral sequential lung transplantation has been used for very small children in hopes of providing the maximum possible pulmonary vascular bed and alveolar volume for continued lung growth and development. Nevertheless, the early reports by Starnes and associates [2, 161 suggest that single-lung transplantation may be applicable to the very young patient with satisfactory relief of pulmonary hypertension and maintenance of good cardiac function. The late ventilation/perfusion abnormality, with the majority of flow going to the transplanted lung in our 1 patient who underwent bilateral sequential lung transplanttation at 21 months of age with anastomosis of the left pulmonary artery to the main pulmonary artery, would support Starnes and associates

8 Ann Thorac Surg 1992;54:21&25 SPRAYETAL 223 data. This child has good cardiac function and evidence for low pulmonary artery pressures, despite a marked preference of perfusion to the right-sided lung transplant. Thus, this child may well have had a similar good result from a right single-lung transplant. In spite of these early observations, size considerations of lobar donation and potential limitation of growth of adult pulmonary lobes remain concerns for additional study. It is clear from experimental models that a pulmonary lobe from an immature animal will grow with the recipient; however, it is unclear whether adequate growth and alveolar capacity occurs if an adult lobe is transplanted into a growing infant [17, 181. A single lobe from an adult may offer suitable volume of lung tissue for only the smallest of potential lung recipients. If bilateral transplantation is necessary to provide adequate alveolar volume for long-term growth, this would potentially limit the utilization of living related donors. Obliterative bronchiolitis remains a serious potential complication of single and bilateral sequential lung transplantation. Recent studies have confirmed that the incidence of obliterative bronchiolitis has not been decreased by the use of pulmonary transplantation over cardiopulmonary transplantation [ Obliterative bronchiolitis may be of particular importance in pediatric patients, in whom episodes of rejection and viral challenges seem more frequent than in adult patients. The rapid development of bronchiolitis obliterans has been encountered in pediatric heart-lung transplantation, although reports of a decrease or abatement of the progression of the disease with augmented immunosuppressive agents has been noted [19, 241. Although none of our patients have evidence of bronchiolitis obliterans at a mean of 10 months of follow-up, continued surveillance for the development of this complication is required. Our preliminary experience with lung transplantation and repair of cardiac defects for treatment of pulmonary hypertension and congenital heart disease suggests that such an approach is feasible. It is apparent that pulmonary transplantation can be performed in the pediatric age range with acceptable early results. Associated repair of cardiac lesions can also be performed in combination with lung transplantation to deal with both the primary and secondary effects of congenital heart disease. In spite of our encouraging early results, serious technical problems occur in dealing with pediatric patients, and careful patient selection and attention to multiple conditions related to the underlying cardiac disease are required for optimal results. The use of these techniques may improve the distribution of donor organs by permitting effective use of donor lungs and maintenance of the recipient s heart in patients who would otherwise be candidates for combined heart-lung transplantation. References 1. Reitz BA, Wallwork JL, Hunt SA, et al. Heart-lung transplantation: successful therapy for patients with pulmonary vascular disease. N Engl J Med 1982;306: Starnes VA, Oyer PE, Bernstein D, et al. Heart, heart-lung, and lung transplantation in the first year of life. Ann Thorac Surg 1992;53: Smyth RL, Scott JP, Whitehead 8, et al. Heart-lung transplantation in children. Transplant Proc 1990;22:147&1. 4. Bolman RM, Shumway SJ, Estrin JA, Hertz MI. Lung and heart-lung transplantation: evolution and new applications. Ann Surg 1991;214: Toronto Lung Transplant Group. Unilateral lung transplantation for pulmonary fibrosis. N Engl J Med 1986;314: Cooper JD. The evolution of techniques and indications for lung transplantation. Ann Surg 1990;212: Pasque MK, Cooper JD, Kaiser LR, Haydock DA, Triantafil- IOU A, Trulock EP. Improved technique for bilateral lung transplantation: rationale and initial clinical experience. Ann Thorac Surg 1990;49: Levine SM, Gibbons WJ, Bryan CL, et al. Single lung transplantation for primary pulmonary hypertension. Chest 1990; 98~ 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; 1OO:l Starnes VA, Stinson EB, Oyer PE, et al. Single lung transplantation: a new therapeutic option for patients with pulmonary hypertension. Transplant Proc 1991;23: McCarthy PM, Rosenkranz ER, White RD, et al. Single-lung transplantation with atrial septa1 defect repair for Eisenmenger s syndrome. Ann Thorac Surg 1991;52:30& Todd TR, Goldberg M, Koshal A, et al. Separate extraction of cardiac and pulmonary grafts from a single organ donor. Ann Thorac Surg 1988;46: Morgan E, Lima 0, Goldberg M, Ayabe H, Ferdman A, Cooper JD. Improved bronchial healing in canine left lung reimplantation using omental pedicle wrap. J Thorac Cardiovasc Surg 1983;85: Pucci A, Forbes RDC, Barry GJ, Rowan RA, Billingham ME. Accelerated post-transplant coronary atherosclerosis in combined heartkng transplantation. Transplant Proc 1991;23: i22a9. 15 Yacoub MH, Banner NR, Khaghani A, et al. Heart-lung transplantation for cystic fibrosis and subsequent domino heart transplantation. J Heart Transplant 1990;9: Starnes V, Stoehr C, Theodore J, Lewiston N. Deciding to perform a living-donor lung transplantation: the paradigm. Poster Presented at American Thoracic Society, Anaheim, CA. _..,. Mav..., Hislop AA, Odom NJ, McGregor CGA, Haworth SG. Growth potential of the immature transplanted lung: an experimental study. J Thorac Cardiovasc Surg 1990;lOO: Haverich A, Dammenharn L, Demertzis S, Reimers P. Lung growth after experimental pulmonary transplantation. J Heart Lung Transplant 1991;10: Scott JP, Sharples L, Mullins P, et al. Further studies on the natural history of obliterative bronchiolitis following heartlung transplantation. Transplant Proc 1991;23: Maurer JR, Morrison D, Winton TL, Patterson GA. Late pulmonary complications of isolated lung transplantation. Transplant Proc 1991;23: Scott JP, Higenbottam TW, Clelland CA, Smyth RL, Stewart S, Wallwork J. The natural history of chronic rejection in heart-lung transplant recipients: a clinical, pathological and physiologic review of 29 long-term survivors. Transplant Proc 1990;22:147& Theodore J, Marshall S, Kramer M, Duncan S, Lewiston N, Starnes V. The natural history of the transplanted lung: rates of pulmonary functional change in longterm survivors of heartllung transplantation. Transplant Proc 1991;23: LoCicero J, Robinson P, Fisher M. Chronic rejection in single lung transplantation manifested by obliterative bronchiolitis. J Thorac Cardiovasc Surg 1990;99: Glanville AR, Baldwin JC, Burke CM, Theodore J, Roben ED. Obliterative bronchiolitis after heart/lung transplantation: apparent arrest by augmented immunosuppression. Ann Intern Med 1987;10730M.

9 224 SPRAY ET AL Ann Thorac Surg 1992;54: DISCUSSION DR VAUGHN A. STARNES (Stanford, CA): I would like to thank The Society for the privilege of discussing this fine manuscript presented by Dr Spray. This is a very nice report of 4 children and 1 adult undergoing single-lung or double-lung transplantation for pulmonary hypertension. I think Dr Spray is to be commended on a very fine technical outcome in terms of the early success rate in these patients. At Stanford we have performed 21 transplantations in 18 children. We had 6 patients undergoing heart-lung or single-lung transplantation for Eisenmenger s syndrome and 3 patients with primary pulmonary hypertension. We have also performed transplantation in 2 infants, 1 17 days of age for diaphragmatic hernia and 1 at 28 days for pulmonary hypertension. I think the real question revolves around the issue of outcomes, and certainly, in this report, the early outcomes are excellent, with 4 of the 5 patients surviving. After single-lung transplantation for pulmonary hypertension, the pulmonary arterial pressures return to normal. As noted by Dr Spray and associates and documented by our group with catheterization at 1 year, the pulmonary artery pressures have remained in the normal range. My concern is long-term outcome. We have investigated a group of 20 consecutive patients who underwent transplantation for pulmonary hypertension. Eight patients received single lungs and 12 received heart-lungs. Although the p value is not significant, there is a separation of the actuarial survival rate of 71% in the heart-lung group versus 49% in the single-lung group at 1 year. Taking this into consideration, I wonder if we are not proposing an operation that is driven by donor issues rather than recipient outcomes, and in light of that I would like to ask Dr Spray if he thinks single-lung transplantation will continue to be the preferred operation in patients with congenital heart disease. DR SPRAY I would like to thank Dr Starnes for his comments. Clearly I think it is too early to know what the preferred approach will be for patients with pulmonary hypertension and congenital heart disease. The obvious advantage of a combined heart and lung transplant is the presence of an essentially normal heart and the advantage of having, potentially, two normal lungs instead of one normal lung with preferential flow to that one, normal transplanted lung. The difficulty I see is that there is clearly a donor-driven issue here. Heart and lung donation is difficult to come by, the waiting times are long, and these patients with pulmonary hypertension, some of whom as witnessed in our series may require preoperative, even extracorporeal membrane oxygenation, support, simply cannot wait for such a long period of time. The optimal utilization of donor organs, 1-think, is a critical issue, and the ability to use one lung for one patient, a heart for another patient, and the other lung for an additional patient is a very important issue for the long term. Obviously these results have to be evaluated in the long term to see whether the single donor lung maintains a low pulmonary pressure for the patient s lifetime. Obviously extension of these techniques to patients with even more complex forms of congenital heart disease is important, and I think that it is possible that many types of cardiac disease that have now been considered only for heart and lung transplantation may be amenable to direct repair and use of a single lung if these early data are consistent in follow-up. DR HANI SHENNIB (Montreal, Que, Canada): Dr Spray, I enjoyed your presentation very much. I have one comment and a couple of questions. I think that most of the statisticians would tell us that the success of any procedure or medical therapy starts from the intent of therapy and not the actual transplantation. Recognizing that donors, particularly for children with smaller sizes, are not easy to come by, my first question to you is, how many of your patients have you actually listed and how many have actually survived until transplantation was performed? Certainly in our series we have seen about a 40% death rate on our children s wait list until a transplantation is done. The second question has to do with the issue of bronchial anastomosis. In the joint Marseille-Montreal lung transplant program, we have done about 22 sequential lung transplantations, which puts about 44 bronchial anastomoses at risk, and we have certainly seen and continue to see a substantial risk of about 20% to 25% of bronchial complications. So, what is your experience as far as long-term results with those bronchial anastomoses? And the final question has to do with development of bronchiolitis obliterans in these patients. We do not believe that the issue is going to be maintaining adequate long-term pulmonary artery pressure and pulmonary vascular resistance as much as it is going to be bronchiolitis obliterans. What is your method of follow-up in those patients? DR SPRAY I agree that bronchiolitis obliterans is the Achilles heel of lung transplantation as graft atherosclerosis is the Achilles heel of heart transplantation. I do not think we know yet in how many of these patients it will develop, how rapidly it will occur, and how to prevent it. So I do not know how to answer the question other than to agree that it is a serious problem. Certainly your own experience in pediatric patients and our limited experience in patients with cystic fibrosis suggests that obliterative bronchiolitis will be a problem in lung transplant patients as it has been in heart-lung transplant patients. The smaller the recipient the greater we worry about problems with bronchial anastomoses. So far we have not seen serious bronchial complications in the few small patients that we have done. However, we do believe that use of absorbable sutures and a telescoping anastomosis is not a good idea in older patients. We have had bronchial complications in that subset of patients, primarily because of malacia at the anastomosis rather than actual disruption. Although waiting times for donor lungs seem to be increasing, we have not yet had a patient die while awaiting transplantation. DR BARTLEY P. GRIFFITH (Pittsburgh, PA): Dr Spray, that was a wonderful presentation and we are all very much interested in the follow-up of those children. I wonder if you have considered not only extracorporeal membrane oxygenation as a bridge to transplantation but single-lung transplantation as an extended bridge to life. Some pediatric diseases of the lung may in fact resolve and the transplanted organ ultimately may not be necessary. It is kind of a unique way of looking at things, but I wonder if you have thought about the residual lung in those patients who receive single lungs and whether you have any idea as to whether there is any resolution of the primary abnormality. DR SPRAY: We have actually been following up the patients who had single-lung transplantations for pulmonary hypertension and tried to evaluate whether or not there was an increase in flow to the nontransplanted lung with time. So far we have not seen that. The preferential flow is still to the transplanted lung, but admittedly the follow-up is short.

10 Ann Thorac Surg 1992;54: SPRAY ET AL 225 I do believe that extracorporeal membrane oxygenation can be a bridge to life in patients who may have adult respiratory distress syndrome, for example, or fibrosis of the parenchyma. Certainly it is difficult to know how many of these patients will ultimately require transplantation, and our very limited experience in trying to do transplantation for acute lung disease has not been very good. Single-lung transplantation in that setting results in a very bad ventilation-perfusion abnormality, and we think bilateral transplantation will be required. It is very difficult to discriminate which patients will require transplantation for the acute types of lung disease like adult respiratory distress syndrome, for example. DR GRIFFITH It might be interesting to perform follow-up biopsies in the host lung as well as in the contralateral lung, especially for vascular changes. DR SPRAY We actually have done that in the patients with Eisenmenger s syndrome, and 1 of the patients did show evidence of thrombosis of some of the vessels in the nontransplanted lung, which was an interesting finding.