H of treatment for children with end-stage heart disease.

Transcription

1 Pediatric Cardiac Transplantation for Congenital Heart Defects: Surgical Considerations and Results Pascal R. Vouhe, MD, Daniel Tamisier, MD, Jerome Le Bidois, MD, Daniel Sidi, MD, Philippe Mauriat, MD, Philippe Pouard, MD, Didier Lefebvre, MD, Sonia B. Albanese, MD, Wassim Khoury, MD, Jean Kachaner, MD, and Francine Leca, MD Laennec Hospital and Enfants-Malades Hospital, Paris V University, Paris, France Among 54 children who underwent 55 heart transplantatiuns, 24 (44%) (mean age, 4.9 & 4.8 years; range, 9 days to 18 years) had congenital defects with the following diagnoses: single-ventricle variants (6), hypoplastic left heart syndrome variants (51, transposition complex (6), and miscellaneous defects (7). Twenty patients (83%) had undergone 43 prior operations. Additional surgical procedures included repositioning of transposed great arteries (11), reconstruction of the aortic pathway (41, reconstruction of the pulmonary pathway (8), correction of situs inversus (l), and correction of anomalous pulmonary (1) or systemic (1) venous drainage. Reconstructive procedures were performed using donor or recipient tissue or both. There were six early deaths (hyperacute rejection, 1 patient; pulmonary hypertension, 1; graft failure, 2 patients; infection, 2) and six late deaths (sudden death, 2; chronic rejection, 2; nonspecific graft dysfunction, 1; lymphoproliferative disease, 1). The sur- viva1 rate was 43% f 12% at 3 years. No deaths were related to surgical technique. Survival was not significantly different in pediatric recipients with cardiomyopathy (67% 9%; p = 0.22). Accelerated coronary artery disease was noted in 4 operative survivors (22%; 70% confidence limits, 12% to 36%). All late survivors were free from cardiac symptoms after a mean follow-up of 34 f 24 months (range, 6 to 71 months). Based on this study, we reached three conclusions. (1) Careful planning of both harvesting and transplantation procedures allows heart transplantation in recipients with congenital heart diseases. (2) The surgical technique may be demanding, but the early risk is not increased. (3) Late results are ambiguous: complete functional rehabilitation is achieved in all survivors, but the high incidence of accelerated coronary artery disease may be a major limiting factor in the long term. (Ann Thorac Surg 1993;56:123947) eart transplantation is becoming an established form H of treatment for children with end-stage heart disease. Congenital heart defects account for an increasing percentage of the pediatric indications [l]. It has been anticipated that as many as 10% to 20% of patients alive with anatomical congenital heart lesions may undergo transplantation [2]. Most of these potential candidates have undergone previous palliative or reparative operations. The underlying complex anatomy and the potentially distorting anatomical effects of previous operations may increase the surgical risk of transplantation or influence the long-term results. Our experience at Laennec Hospital with such patients has prompted this report. Material and Methods Patient Population From January 1987 to December 1992, 54 children underwent 55 orthotopic heart transplantations. The indications were cardiomyopathy (28 patients), congenital heart de- Presented at the Twenty-ninth Annual Meeting of The Society of Thoracic Surgeons, San Antonio, TX, Jan 25-27, Address reprint requests to Dr Vouh6, Department of Cardiovascular Surgery, Laennec Hospital, 42, rue de Sevres, Paris Cedex 07, France. fects (24), valvular disease (1 patient), Kawasaki disease (l), and retransplantation (1). In the patients with congenital heart defects, transplantation was done at a mean age of years (2 the standard deviation), with a range of 9 days to 18 years. Diagnoses included singleventricle variants (6 patients), hypoplastic left heart syndrome variants (5 patients), transposition complex (6 patients), and miscellaneous anomalies (7 patients). The specific anatomical abnormalities and the previous operations are shown in Tables 1 to 4. Forty-three operations (21 without cardiopulmonary bypass and 22 under cardiopulmonary bypass) had been performed in 20 patients. All recipients had severe limitation in physical activity (New York Heart Association class I11 or IV); 5 (21%) of them were on artificial ventilation and intravenous inotropic support at the time of transplantation. Immunosuppression was induced using a three-drug protocol: rabbit antithymocyte globulin, cyclosporine, and steroids. Maintenance immunosuppression was achieved with cyclosporine and azathioprine alone; steroids were not given routinely. However, oral steroids were added for patients in whom acute rejection was not shown to have resolved on endomyocardial biopsy. Cyclosporine dose was adjusted to achieve whole-blood residual levels by The Society of Thoracic Surgeons /93/$6.00

2 1240 VOUHB ET AL Ann Thorac Surg 1993;56:1239%47 Table 1. Summa y of Data on Patients With Single Ventricle Variants Patient Age No. (Y) Anatomy Previous Operations Outcome 1 10 Single ventricle, TGA 2 18 Single ventricle, TGA, pulmonary stenosis, dextrocardia 3 13 Single ventricle, TGA, CoA 4 7 Tricuspid atresia 5 2 Single ventricle, TGA, pulmonary stenosis, CAVC, TAPVC 6 10 Single ventricle, TGA, pulmonary stenosis, CAVC, LSVC Blalock-Hanlon procedure; pulmonary banding; Fontan operation; pacemaker insertion Modified Blalock-Taussig shunt; Fontan operation; pacemaker insertion CoA repair, pulmonary banding; Fontan operation; apicoaortic valved conduit; pacemaker insertion Pulmonary banding; Fontan operation Modified Blalock-Taussig shunt; bidirectional Glenn shunt, TAPVC repair CAVV replacement, central shunt; pacemaker insertion Died of lymphoproliferative disease, 30 mo Died of infection, day 4 Alive, 39 mo Died suddenly, 2.5 mo Alive, 17 mo Alive, 11 mo CAVC = common atrioventricular canal; CAVV = common atrioventricular valve; CoA = aortic coarctation; LSVC = left superior vena cava; TAPVC = total anomalous pulmonary venous connection; TGA = transposition of great arteries. of 200 to 400 ng/ml during the first year and 100 to 200 ng/ml thereafter. Rejection episodes were treated with pulsed steroids with additional rabbit antithymocyte globulin or OKT3 monoclonal antibody if the patient did not respond to treatment. Rejection episodes were suspected on noninvasive criteria (clinical status, electrocardiographic and echocardiographic changes) and confirmed by endomyocardial biopsies. Endomyocardial biopsies were performed as a routine follow-up procedure four times during the first year; as often as necessary in the case of clinical suspicion of rejection; and as a control test to assess the result of treatment of a rejection episode. Surgical Management DONOR OPERATION. According to the planned reconstructive procedures needed in the recipient, donor heart harvesting included the entire aortic arch and the de- scending aorta, the pulmonary artery bifurcation and the main pulmonary arteries, the superior vena cava and its branches, and the pulmonary veins. The method of graft preservation evolved over time; the current technique includes cold crystalloid cardioplegia at the time of procurement, multidose cold blood cardioplegia during the transplantation procedure, and warm blood cardioplegic reperfusion prior to aortic unclamping. The average ischemic time of the graft was 182 & 40 minutes (range, 120 to 275 minutes). RECIPIENT OPERATION. The transplantation procedure was performed under hypothermic cardiopulmonary bypass; short periods of hypothermic circulatory arrest were occasionally necessary [3]. In 6 patients, conventional orthotopic heart transplantation using the technique described by Lower and Shumway [4] was performed. In all 18 other patients (75%), additional procedures were required. Table 2. Summary of Data on Patients With Hypoplastic Left Heart Syndrome Variants Patient No. Age (days) Anatomy Previous Operations Outcome 1 34 AS, MS, endocardial None Alive, 71 mo fibroelastosis 2 40 HLV, CoA CoA repair Died of primary graft failure, day HLV, CoA CoA repair Alive with coronary artery disease, 65 mo 4 13 AS, MS, endocardial None Died of nonspecific graft dysfunction, 2 mo fibroelastosis 5 9 AS, CoA, endocardial None Died of primary graft failure, day 0 fibroelastosis AS = aortic stenosis; CoA = aortic coarctation; HLV = hypoplastic left ventricle; MS = mitral stenosis.

3 Ann Thorac Surg 1993: VOUHB ET AL 1241 Table 3. Summary of Data on Patients With Transposition Complex Patient No. Age Anatomy Previous Operations Outcome 1 58 mo TGA, VSD, Lecompte procedure Died of hyperacute rejection, day 0 pulmonary stenosis 2 33 mo TGA, VSD, CoA Arterial switch, VSD closure, CoA repair Died suddenly, 4 mo 3 6 mo TGA Arterial switch Alive, 13 mo 4 10 Y CTGA, VSDs Pulmonary banding; closure of VSDs; pacemaker insertion Died of pulmonary hypertension, day mo CTGA, VSD, Modified Blalock-Taussig shunt; Died of chronic rejection, 22 mo pulmonary atresia, VSD closure, LV-PA conduit, mitral valve MVR; repeat MVR anomaly 6 24 mo CTGA, VSD, Modified Blalock-Taussig shunt Alive, 36 mo pulmonary atresia CoA = aortic coarctation; CTGA = corrected transposition of great arteries; LV-PA = left ventriclepulmonary artery; MVR = mitral valve replacement; TGA = transposition of great arteries; VSD = ventricular septal defect. Mediastinal adhesions. Extensive mediastinal adhesions were present in 17 recipients. Careful liberation of the heart from the pericardium was carried out using electrocautery, great care being taken to avoid damaging the phrenic nerves. In 2 patients, severe cardiac injury occurred at the time of sternal splitting and required urgent institution of femoral-femoral cardiopulmonary bypass. When severe adhesions between the cardiac structures and the chest wall are anticipated, partial bypass should be instituted before the sternum is reopened; this was done recently in 2 patients. Transposition of the great arteries. Eight patients had transposed great arteries. Extensive mobilization of the aortic arch and the main pulmonary arteries (including division of the ligamentum arteriosum, a previous Blalock-Taussig shunt, or both) allowed end-to-end anastomosis of the donor and recipient aorta and pulmonary trunk without tension or kinking (Fig 1). Three other children with transposition of the great arteries had previously undergone complete repair with the Lecompte maneuver. After division of the ascending aorta and the pulmonary trunk, the great vessels were extensively mobilized. The pulmonary bifurcation was placed behind the ascending aorta, thus allowing conventional anastomoses with the donor great arteries (Fig 2). Abnormalities of the aortic pathway. Three infants with hypoplastic aortic arch and aortic coarctation underwent transplantation using the modifications of Bailey and Table 4. Summa y of Data on Patients With Miscellaneous Diagnoses Patient No. Aae Anatomy Previous Operations Outcome 1 32 mo Partial AV canal Complete repair; mitral Alive, 16 mo valvuloplasty; mitral valve replacement; pacemaker insertion 2 6Y CAVC, LV hypoplasia Pulmonary banding; Ao-PA fistula Alive, 50 mo y TOF, VSDs Modified Blalock-Taussig shunt; complete repair Died of chronic rejection, 13 mo 4 8Y TOF CAVC, situs Complete repair Alive, 6 mo inversus, azygos extension of LIVC y Ebstein s anomaly ASD closure Died of infection, day y Interrupted aortic arch, VSD, subaortic stenosis Neonatal complete repair; recoarctation repair; resection Alive, 18 mo; retransplantation at of subaortic stenosis; pacemaker insertion 15 mo 7 11 mo Multiple VSDs, None Alive, 70 mo pulmonary stenosis, cardiomyopathy Ao-PA = aofia-pulmonary artery; ASD = atrial septal defect; AV = atrioventricular; CAVC = complete atrioventricular canal; LIVC = left inferior vena cava; LV = left ventricular; TOF = tetralogy of Fallot; VSD = ventricular septal defect.

4 1242 VOUHfi ET AL Ann Thorac Surg 1993; Abnormalities of systemic venous or pulmonary venous drainage. One patient had a common atrium and a left superior vena cava. The operation was carried out under hypothermic circulatory arrest to avoid multiple venous cannulations. An intraatrial baffle was constructed using a prosthetic patch to partition the atrium into a right-sided chamber receiving the systemic veins and a left-sided chamber receiving the pulmonary veins. Standard heart transplantation was then carried out. One patient had previously undergone repair of a supracardiac total anomalous pulmonary venous drainage by direct anastomosis of the common pulmonary venous sinus to the left atrium. This anastomosis was taken down, and the ostium of the anastomosis was used to connect the pulmonary veins to the graft left atrium. Fig 1. Orthotopic heart transplantation in transposition of the great arteries: (A) division of the great arteries; (B) mobilization of the great arteries; and (C) end-to-end anastomoses. associates [5]; under hypothermic circulatory arrest, the donor aortic arch was used to enlarge the aortic arch of the recipient. In 1 patient with single ventricle, an apicoaortic valved conduit had to be removed. Abnormalities of the pulmonary pathway. Abnormalities involving the pulmonary trunk (aortopulrnonary fistula, Fontan operation with direct right atrium-pulmonary trunk anastomosis) (5 patients) were managed by direct end-to-end anastomosis between the distal donor pulmonary trunk and the recipient pulmonary bifurcation. Abnormalities involving the main pulmonary branches (cavopulmonary anastomosis, Fontan operation with bidirectional cavopulmonary anastomosis, pulmonary branch stenosis) (3 patients) required takedown of the previous anastomoses and separate end-to-end anastomoses of both pulmonary arteries and both venae cavae (Fig 3). Abnormalities of position or situs. One patient had situs solitus and dextrocardia. Standard heart transplantation was performed, but the implantation of a prosthetic mesh was necessary to avoid right-sided position of the graft, which might have caused obstruction to venous inflow. Situs inversus with azygos extension of the left inferior vena cava to the left superior vena cava was present in 1 patient, who had previously undergone complete repair for tetralogy of Fallot with complete atrioventricular canal (Fig 4A). The transplantation procedure was performed under hypothermic cardiopulmonary bypass with one venous cannula inserted into the left superior vena cava; the blood returning from the hepatic veins was picked up by a cardiotomy sump sucker; short periods of circulatory arrest were used as needed for exposure during complicated parts of the operation. The heart was removed from the thorax in the usual fashion. The left superior vena cava was divided at its cardiac entry. The right atrium was separated from the left atrium at the atrial septum, which left the right atrium attached to the hepatic veins as a flap for later reconstruction (see Fig 4A). Two separate sizable cuffs of left atrial wall were excised around both the right and left pulmonary venous ostia, and the pulmonary veins were dissected free as far as possible. As described by Doty and colleagues [6], the right atrial wall was used as a flap to construct a composite conduit from the common orifice of the hepatic veins across the midline to the right side. The Fig 2. Orthotopic heart transplantation after Lecompte maneuver for transposition of the great arteries: (A) division of the great arteries; (B) mobilization of the great arteries; and (C) end-to-end anastomoses.

5 Ann Thorac Surg 1993; VOUHE ET AL 1243 Fig 3. Orthotopic heart transplantation after total cavopulmonary anastomosis (Fontan operation). (A) The venae cavae are divided. The main pulmonary arteries are divided. The right atrium and the proximal right pulmonary artery are resected. (B) Heart transplantation is performed by anastomosing the recipient and donor venae cavae, the donor right pulmonary artery to the recipient distal right pulmonary artery, and the recipient left pulmonary artery to the donor pulmonary trunk. I W I right atrial wall was cut back to the orifice of the hepatic veins. The medial edge of this orifice was sewn to the pericardium on the surface of the diaphragm. The right atrial flap was sewn to the pericardium to create a tunnel that crossed the midline to reach a point on the right side of the diaphragm that would approximate the normal entry point of the inferior vena cava (Fig 4B). The donor graft was placed in the operative field. Two orifices were managed in the posterior left atrial wall of the graft and were anastomosed to the two recipient pulmonary venous cuffs; this was made easy by the previous mobilization of the pulmonary veins, which brought them to the left side of the midline (Fig 5A). The inferior vena cava orifice of the graft was connected to the orifice of the composite conduit on the pericardium of the diaphragm. Reconstruction of the superior vena cava by direct anastomosis between the recipient left superior vena cava and the donor innominate vein was not possible because of a major size discrepancy between the two vessels. A segment of donor descending aorta was used to establish continuity between the recipient left superior vena cava and the graft right atrial appendage (Fig 5B). The transplantation procedure was completed in the usual fashion. Results The results are summarized in Tables 1 to 4. Mortality Six patients (25%; 70% confidence limits, 16% to 37%) died before discharge from the hospital. No deaths were related to the surgical procedure or the complexity of the cardiac anatomy. The early mortality rate was similar in the 28 children who underwent transplantation for cardiomyopathy during the same period (7128, 25%; 70% confidence limits, 16% to 36%). Early deaths were related to hyperacute rejection (1 patient), irreversible pulmonary hypertension (1 patient), infection (2 patients), and primary graft failure (2 patients). Graft failure was due in 1 Fig 4. Orthotopic heart transplantation in situs inversus with azygos extension of the inferior vena cava. (A) The left superior vena cava is divided. The right atrium is separated from the left atrium at the septum. (B) Two separate left atrial cuffs are managed around the ostia of the pulmonary veins, and the pulmonary veins are mobilized. The right atrium is used as a flap to construct a composite tunnel from the ostium of the hepatic veins across the midline to the right side. \-

6 1244 VOUHI? ET AL Ann Thorac Surg 1993; Fig 5. Orthotopic heart transplantation in situs inversus with azygos extension of the inferior vena cava. (A) The recipient pulmonay venous cufs are anastomosed separately to the donor left atrium. (B) The ostium of the donor inferior vena cava is anastomosed to the orifice of the composite tunnel. A segment of donor thoracic aorta is interposed between the recipient left superior vena cava and the donor right atrial appendage. infant to a major donorhecipient size discrepancy (donor/ recipient weight ratio was 0.45); in the other infant, the cause of graft failure was unclear (myocardial preservation of the graft was less than optimal; the postmortem examination showed lesions suggestive of hyperacute rejection). Six patients died after discharge from the hospital. Two patients died suddenly 2.5 and 4 months postoperatively. One of them had an uneventful postoperative course, although echocardiographic evaluation showed immediate left ventricular hypertrophy with preservation of systolic function. Acute rejection was diagnosed and successfully treated on day 15. The echocardiographic abnormalities remained unchanged until sudden death 2.5 months after transplantation. The other patient required prolonged circulatory assistance after transplantation because of preoperative pulmonary hypertension, but the postoperative course was uneventful thereafter; there was no rejection, and the echocardiogram was normal. He died suddenly at home 4 months postoperatively. In both cases, postmortem examination was not performed. The other causes of late mortality were nonspecific graft dysfunction (1 patient), lymphoproliferative disease (1 patient), and chronic rejection with accelerated coronary artery disease (2 patients). None of the late deaths were related to the underlying congenital heart disease or to the surgical procedure. Age at the time of transplantation did not influence the overall mortality rate: 43% (70% confidence limits, 21% to 68%) for infants less than 1 year old; 40% (70% confidence limits, 8% to 78%) for patients 1 to 3 years of age; and 58% (70% confidence limits, 40% to 75%) for children more than 3 years old. Actuarial survival rate (? the standard error) was 58% * 10% at 1 year and 43% * 12% at 3 years. Survival was not significantly different for recipients with cardiomyopathy (71% * 9% at 1 year, 67% f 9% at 3 years; p = 0.22) (Fig 6). Complications REJECTION. There were 42 rejection episodes documented in the 18 operative survivors, a linearized rejection rate of 0.29 episode per 100 patient-days. Most of the rejection episodes (34/42, 81%) occurred during the first postoperative year, but acute rejection was documented up to 5 Fig 6. Actuarial survival for children undergoing heart transplantation for cardiomyopathy (CMy) (28 patients) and congenital heart defects K.H.D.) (24 patients). p = " C.H.D.(24) I* "

7 Ann Thorac Surg 1993;56: VOUHfi ET AL 1245 years after transplantation. All patients had at least one rejection episode. Infants had fewer rejection episodes than older children. At the end of l year, the linearized rejection rate for infants less than 1 year old was 0.13 event per 100 patient-days compared with 0.56 episode per 100 patientdays for older children (p = not significant). The lack of significance was possibly due to the small number of patients in the infant group. At last follow-up, 6 patients were maintained on a double-drug regimen (cyclosporine, azathioprine). One was on a regimen of cyclosporine alone because of persistent leukopenia; the other 5 were on a triple-drug regimen with steroids added because of mild but resistant rejection on serial endomyocardial biopsies. INFECTION. There were 18 serious infections in 11 patients with two early deaths and no late deaths. One patient died 4 days after transplantation of fulminant bacterial infection. Lung infection was present preoperatively, but transplantation was undertaken because cardiac status was critical. The other early death occurred on postoperative day 22 and was due to systemic fungal infection in a patient with multiorgan failure. The infections were bacterial in 28% of the instances, viral in 50%, protozoal in 17%, and fungal in 5%. CORONARY ARTERY DISEASE. Accelerated coronary artery disease was diagnosed in 4 operative survivors (22%; 70% confidence limits, 12% to 36%). Two of them died 13 and 22 months postoperatively, 1 underwent successful retransplantation at 15 months, and 1 was alive and well 65 months postoperatively with a 50% stenosis of the left anterior descending coronary artery. Three of the patients were on a triple-drug immunosuppression regimen because of persistent rejection when coronary artery disease was discovered. Only 1 patient had had primary cytomegalovirus infection. LYMPHOPROLIFERATIVE DISEASE. Epstein-Barr virusrelated lymphoproliferative disease occurred in 1 operative survivor (6%; 70% confidence limits, 0% to 17%) and was responsible for the death of the patient 30 months after transplantation. Functional Status All the late survivors were free from cardiac symptoms and were leading a fully active, normal life. Arterial pressure was normal and antihypertension therapy was not required, even for the patients maintained on a triple-drug immunosuppression regimen. Height and weight were normal in all the patients. Left ventricular morphology and function, as assessed by echocardiography, were normal in all the late survivors except 1, who had left ventricular hypertrophy with preservation of systolic function 17 months postoperatively. This patient had essentially normal coronary arteries at coronary angiography but was on a triple-drug regimen because of persistent mild rejection. Comment The number of children undergoing heart transplantation is increasing steadily. More than 1,000 cases have been reported to the International Registry [7], and this probably reflects only a part of the overall experience. Cardiomyopathy remains the most common indication, but a growing number of children undergo transplantation for complex congenital heart defects. Approximately 40% to 45% of pediatric heart transplantations are currently performed in such patients. A large part of this increase is attributable to the growing number of neonates with hypoplastic left heart syndrome, but the application of transplantation to other complex defects has also been promoted. This is clearly emphasized by many recent reports [ Most patients with complex congenital defects have previously undergone one or more palliative or corrective procedures. The complexity of the native cardiac anatomy or the distorting effects of previous operations or both may be regarded as contraindications to heart transplantation or may be an incremental risk factor for early mortality. It is now clearly established that there is no anatomical contraindication to heart transplantation, and the present report produces further evidence of this. All anatomical abnormalities can be managed using the donor or recipient tissue or both [5, 6, 9-12]. This requires careful planning of both harvesting and transplantation procedures. The additional reconstructive procedures increase the complexity of the transplantation operation but probably do not increase the early risk of the procedure. In our experience, no deaths among the recipients with congenital defects were related to the surgical procedure itself, and the early mortality rate was similar for recipients with congenital defects and those with cardiomyopathy who underwent a standard orthotopic heart transplantation. Despite continuing improvements, a lower survival is observed in pediatric recipients than in adult recipients. The actuarial survival rate for the adult population reported in the International Registry was 82% at 1 year and 75% at 5 years; in the pediatric population (1 to 18 years old), the survival rates were 76% and 67%, respectively, and lower survival rates were noted for neonatal recipients (67% at 1 year and 61% at 5 years) [7]. Similar results were reported from various centers for the overall pediatric population [l, 17, 181. In one large experience [15], actuarial survival at 4 years was 69% for children with cardiomyopathy and 48% for children with congenital heart defects, results very similar to our own. The reasons for the lower survival rates in pediatric recipients are not entirely clear. In the present series, the early mortality rate was unacceptably high (25%). This was particularly true early in our experience and may be due, at least in part, to a less than optimal overall management. Half of the early deaths were related to the fact that there was not strict adherence to criteria necessary for a successful outcome: 1 patient had irreversible pulmonary vascular changes that were underestimated; 1 recipient had severe preoperative

8 1246 VOUHB ET AL Ann Thorac Surg 1993: lung infection; and a very small (1,800 g) anencephalic donor was accepted. In our recent experience, the usual criteria for a suitable donor and a potential recipient have been strictly enforced, and the early mortality rate has been reduced to less than 10%. The justified desire to offer the last chance to every terminally ill child may prompt a team to undertake transplantation even if all optimal conditions are not fulfilled. This approach cannot be supported for medical and ethical reasons, especially considering the lack of suitable pediatric donors. As far as late mortality is concerned, most late deaths are due to rejection [l, 15, 171. In the present series, 2 patients died of chronic rejection with accelerated coronary artery disease, and two sudden deaths might have been due to acute rejection, although this was not definitely confirmed. This is again strikingly different from the adult experience in which rejection and coronary artery disease account for approximately 50% of late deaths. Optimal immunosuppression remains controversial. Most centers advocate a classic triple-drug regimen [13, 14, 16-19], whereas some centers try to avoid the routine use of steroids [15]. Contradictory data have been reported. Triple-drug immunosuppression has been shown to offer acceptable rejection and infection rates [14, 18, 201. In one experience [15], cyclosporine-based immunosuppression also provided low rejection rates, particularly in patients less than 10 years of age. The optimal immunosuppression protocol remains to be defined. Recent experience with FK 506 may provide a substantial improvement [16]. Accelerated coronary artery disease represents the main cause of late failure after pediatric heart transplantation, the incidence ranging from 20% to more than 40%. The present series confirms this serious drawback. The exact incidence of accelerated coronary artery disease may be underestimated because coronary angiography is difficult to perform in small children and is probably not sensitive enough to detect early subtle coronary abnormalities. Many questions remain unanswered regarding the pathophysiology of accelerated coronary artery disease. The respective role of multiple rejection episodes, primary cytomegalovirus infection, anti-donor human lymphocyte antigen (HLA) antibodies, and other factors have yet to be determined [21]. Accelerated coronary artery disease probably represents a form of immunological injury, but the mechanisms responsible for this injury are completely unknown. It is clear that a better understanding of these mechanisms is necessary before adequate preventive manipulations can be designed. Meanwhile, the high incidence of accelerated coronary artery disease will remain the major determinant of long-term survival in pediatric cardiac recipients. The most gratifying aspect of our experience has been the excellent functional results noted in the surviving patients. All the late survivors were leading a normal and active life, were able to attend school, and could participate in recreational activities that they had been unable to enjoy before because of chronic cardiac illness. In summary, orthotopic heart transplantation is possible in all potential candidates with complex congenital heart diseases. Careful planning of both harvesting and transplantation procedures is necessary. The surgical technique may be demanding, but the early risk is probably not increased. The early mortality should be minimized by strict donor and recipient selection. Excellent functional rehabilitation can be obtained, but enthusiasm for the procedure must be tempered by the high prevalence of accelerated coronary artery disease. We believe that cardiac transplantation in children with congenital heart defects should be reserved for patients in whom all other medical and surgical options have been exhausted. We express our appreciation to Corinne Pasquet for secretarial assistance. References 1. Pennington DG, Noedel N, McBride LR, Naunheim KS, Ring WS. Heart transplantation in children: an international survey. Ann Thorac Surg 1991;52:71&5. 2. Penkoske PA, Rowe RD, Freedom RM, Trusler GA. The future of heart and heart-lung transplantation in children. J Heart Transplant 1984;3:22% Menkis AH, McKenzie FN, Novick RJ, et al. Extending applicability of transplantation after multiple prior palliative procedures. Ann Thorac Surg 1991;52: Lower RR, Shumway NE. Studies on orthotopic homotransplantation of the canine heart. Surg Forum 1960;11: Bailey LL, Conception W, Shattuck H, Huang L. Method of heart transplantation for treatment of hypoplastic left heart syndrome. J Thorac Cardiovasc Surg 1986;92: Doty DB, Renlund DG, Caputo GR, Burton NA, Jones KW. Cardiac transplantation in situs inversus. J Thorac Cardiovasc Surg 1990;99:49>9. 7. The Registry of the International Society for Heart and Lung Transplantation: ninth official report J Heart Lung Transplant 1992; 11 : Mayer JE Jr, Perry S, OBrien P, et al. Orthotopic heart transplantation for complex congenital heart disease. J Thorac Cardiovasc Surg 1990;99: Menkis AH, McKenzie FN, Novick RJ, et al. Special considerations for heart transplantation in congenital heart disease. J Heart Transplant 1990;9: Chartrand C, Guerin R, Kangah M, Stanley P. Pediatric heart transplantation: surgical considerations for congenital heart diseases. J Heart Transplant 1990;9: Cooper MM, Fuzesi L, Addonizio LJ, Hsu DT, Smith CR, Rose EA. Pediatric heart transplantation after operations involving the pulmonary arteries. J Thorac Cardiovasc Surg 1991;102: Chartrand C. Pediatric cardiac transplantation despite atrial and venous return anomalies. Ann Thorac Surg 1991;52: 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: Backer CL, Zales VR, Idriss FS, et al. Heart transplantation in neonates and children. J Heart Lung Transplant 1992;ll: Radley-Smith RC, Yacoub MH. Long-term results of pediatric heart transplantation. J Heart Lung Transplant 1992;ll: S Armitage JM, Fricker FJ, del Nido P, Starzl TE, Hardesty RL, Griffith BP. A decade (1982 to 1992) of pediatric cardiac transplantation and the impact of FK 506 immunosuppression. J Thorac Cardiovasc Surg 1993;105: Trento A, Griffith BP, Fricker FJ, Kormos RL, Armitage J, Hardesty RL. Lessons learned in pediatric heart transplantation. Ann Thorac Surg 1989;48: Addonizio LJ, Hsu DT, Smith CR, Gersony WM, Rose EA.

9 Ann Thorac Surg 1993; VOIJHI? ET AL 1247 Late complications in pediatric cardiac transplant recipients. Circulation 1990;82(Suppl 4): Braunlin EA, Hunter DW, Canter CE, et al. Coronary artery disease in pediatric cardiac transplant recipients receiving triple-drug immunosuppression. Circulation 1991;84(Suppl 3): Braunlin EA, Canter CE, Olivari MT, Ring WS, Spray TL, Bolman RM 111. Rejection and infection after pediatric cardiac transplantation. Ann Thorac Surg 1990;49: Hosenpud JD, Shipley GD, Wagner CR. Cardiac allograft vasculopathy: current concepts, recent developments, and future directions. J Heart Lung Transplant 1992;11:9-23. DISCUSSION DR JOHN E. MAYER, JR (Boston, MA): I will echo several of the points that Dr Vouhe made, in particular those about technical considerations. I think harvesting sufficient amounts of donor tissue allows one to overcome almost all the potential anatomical problems. That has certainly been our experience in the 16 or so patients who have had transplantation by us for a variety of congenital heart defects. 1 think one important technical consideration outlined by Dr Vouhe is the use of cavo-caval anastomoses, particularly when there have been complex intraatrial repairs, such as after atrial level repairs for transposition. Also the use of separate right and left pulmonary artery anastomoses allows one to overcome the problems with central pulmonary artery distortion from prior shunts, Glenn operations, or any of the other iatrogenic problems we create in the pulmonary vasculature. Therefore I support most of the conclusions of Dr Vouhe. For reasons that are unclear to me, my colleagues and I have not seen nearly the incidence of coronary disease in our pediatric patients, who have all been managed routinely with a three-drug regimen. Dr Vouhe, do you have any thoughts about why the coronary disease problem is so high in your series? Do you think modified immunosuppression might have a role in reducing the incidence? DR VOUHE: Thank you for your comments. It is clear that our current main concern is represented by the high incidence of coronary artery disease that we have observed. Although the immunosuppression regimen probably plays a major role, contradictory data have been reported. In some experiences, as in yours, it seems that a triple-drug regimen reduces the incidence of coronary artery disease. In other experiences, particularly that of Dr Yacoub, the risk of coronary artery disease is decreased in patients receiving a double-drug regimen. I believe that further long-term evaluation is necessary before clear conclusions can be drawn regarding this very important issue. DR ADNAN COBANOGLU (Portland, OR): I believe the operative mortality rate for your patients who underwent cardiac transplantation for cardiomyopathy was in the range of 25%. Our cardiac transplant experience in Portland with the infant and pediatric population is not very extensive; it comprises 12 patients in the pediatric group. Patients with complex congenital heart disease and patients with cardiomyopathy respond differently after transplantation. In our experience, those with cardiomyopathy and those older than 1% to 2 years seem to do much better, and the survival curves are really not too different from those of adult heart transplant patients, at least for the first 5 years. I am interested in the early operative mortality for your cardiomyopathy patients. I also am interested to know the follow-up for the patient who underwent operation using the innovative technique described by Dr Doty. I believe that in the pediatric group, the primary limiting factor is coronary artery disease or graft vasculopathy. The incidence of this disease in the first or second year after operation has varied among different groups, and we still have a lot to learn about coronary vasculopathy. I think transplantation, like some of the other operations these patients undergo, should be considered only as palliation. DR VOUHE: In our early experience, the early mortality rate was high among recipients with congenital defects as well as those with cardiomyopathy. This was due mainly to a less than optimal overall management, particularly nonobservance of the usual conditions required for a successful outcome. Our current early mortality rate is much reduced (around 10%) and remains the same for recipients with congenital defects and those with cardiomyopathy. The child with situs inversus who underwent transplantation using the innovative techniques of Dr Doty had an excellent hemodynamic result 6 months after transplantation.