Volume 107, Number 4 April 1994 The Journal of THORACIC AND CARDIOVASCULAR SURGERY Cardiac and Pulmonary Transplantation Risk factors for graft failure associated with pulmonary hypertension after pediatric heart transplan ta tion Postoperative pulmonary hypertension can be a major cause of early death after heart transplantation in children. To identify predictive risk factors of pulmonary hypertension after heart transplantation, we performed a retrospective analysis of our 194 infant and pediatric recipients who underlvent heart transplantation between 1987 and 1992. Because the response of pulmonary vasculature may change during growth, the patients were divided into two groups: age less than 1 year in group I (n = 152) and 1 year or older in group C (n = 43). The fouowing risk factors were evaluated: cardiomyopathy, congenital heart disease and hypoplastic left heart syndrome, pretransplant pulmonary hypertension, history of operation, oversized donor (donor/recipient weight ratio greater than 2), donor's history of cardiopulmonary resuscitation, and prolonged graft ischemic time (graft ischemic time 360 minutes or longer). Though there was no significant difference between group I and group C in overall early mortality including early graft loss (19 of 152 versus 5 of 42), the mortality rate from pulmonary hypertension in group I was significantly lower than that in group C (2 of 152 versus 4 of 42; p < 0.05). The mortality rate from pulmonary hypertension in patients with congenital heart disease in group I was significantly lower than that in group C (0 of 44 versus 4 of 24; p < 0.05). In group I, there was no significant difference in the early mortality rate or the mortality rate from pulmonary hypertension from any factors studied. The mortality rate from pulmonary hypertension in association with prolonged graft ischemic time in group C was significantly bigher than when no prolonged graft ischemic time was present in group C and with either prolonged graft ischemic time or no prolonged graft ischemic time in group I (4 of 16 versus 0 of 26, 0 of 37, and 2 of 115). In conclusion, older patients had a higher mortality rate from pulmonary hypertension after heart transplantation, especiauy in patients with congenital heart disease who received a graft preserved more than 6 hours. This study demonstrates another benefit of early heart transplantation in infancy, that is, prevention of death from pulmonary hypertension. (J THORAC CARDIOVASC SURG 1994;107:985-9) Noribide Fukushima, MD, Steven R. Gundry, MD, Anees J. Razzouk, MD, and Leonard L. Bailey, MD, Lorna Linda, Calif. From Lorna Linda University Medical Center, Department of Surgery, Division of Cardiothoracic Surgery, Lorna Linda, Calif. Read at the Nineteenth Annual Meeting of The Western Thoracic Surgical Association, Carlsbad, Calif., June 23-26, 1993. Address for reprints: Steven R. Gundry, MD, Professor of Surgery, Chief, Division of Cardiothoracic Surgery, Lorna Linda University Medical Center, 11234 Anderson St., Lorna Linda, CA 92354. Copyright @ 1994 by Mosby-Year Book, Inc. 0022-5223/94 $3.00 + 0 12/6/52977 985
9 8 6 Fukushima et al. The Journal of Thoracic and April 1994 Orthotopic cardiac transplantation has become an important therapeutic option in the treatment of certain congenital and acquired heart diseases in infants and children. I, 2 Because of increases in pulmonary vascular resistance (PVR) in children with congenital heart disease (CHD) or chronic heart failure, or both, before heart transplantation, pulmonary hypertension can be fatal early after transplantation. To identify risk factors predictive for pulmonary hypertension after heart transplantation, we performed a retrospective analysis of our 194 infant and pediatric recipients who underwent this operation between 1987 and 1992 at Lorna Linda University Medical Center. Materials and methods Between January 1987 and December 1992, 194 infant and pediatric patients underwent 196 heart transplantation procedures. Because the response of pulmonary vasculature may change during growth, the patients were divided into two groups on the basis of their age. Group I included 152 infants (mean age 23.1 days; range birth to 345 days). Group C included 42 children (mean 1961 days; range 388 to 6233 days). To assess the risk factors for pulmonary hypertension after heart transplantation, we evaluated the following factors: cardiomyopathy, CHD and hypoplastic left heart syndrome (HLHS), pulmonary hypertension before heart transplantation, history of operation before heart transplantation, oversized donor, donor's history of cardiopulmonary resuscitation, and prolonged graft ischemic time. Pulmonary hypertension was defined as a mean pulmonary artery pressure higher than 25 mm Hg. If cardiac catheterization was not done before heart transplantation, pulmonary hypertension was considered to be present if the ductus arteriosus maintained the systemic circulation, such as would occur with HLHS, or if the systemic ventricle directly connected to the pulmonary artery without stenosis, such as doubl(>{)utlet single ventricle. Death from pulmonary hypertension was defined as either a sudden deterioration in blood pressure, accompanied by a rising central venous pressure or pulmonary artery pressure, desaturation, and failure to respond to inotropic agents, or progressive rise in right-sided pressure and dilation ofthe right side of the heart by echocardiography in concert with increasing pulmonary artery pressures leading to death. In all such cases, no evidence of rejection or acute ischemic damage to the heart was subsequently found at autopsy. An oversized donor was defined as a donor/recipient weight ratio of more than 2. Prolonged graft ischemic time was defined as graft ischemic time longer than 360 minutes (6 hours). Cardiopulmonary resuscitation for donors meant the requirement of cardiac massage with or without epinephrine injection for hemodynamic distress before the determination of brain death. Statistical analysis was done with the x 2 test (using the ST AX computer program; Nakayama Shoten, Tokyo, Japan). A value of p less than 0.05 was considered significant. Results Eighteen (11%) patients in group I and five (11%) in group C died within 3 months after heart transplantation. One patient in group I required retransplantation because of primary graft failure without pulmonary hypertension and is still alive. Two (1 %) patients in group I and four (10%) in group C died of pulmonary hypertension. One patient in group C underwent repeat heart transplantation because of pulmonary hypertension, but died 22 days after the second heart transplantation. The patients who died of pulmonary hypertension are listed in Tables I and II. There was no significant difference in overall early mortality including early graft loss between group I and group C (19/152 versus 5/42), but the mortality rate from pulmonary hypertension in group I was significantly lower than that in group C (2/152 versus 4/42; p < 0.05); Table III). In group J, there was no significant difference among patients with HLHS, other CHD, or cardiomyopathy in early deaths (I 3/95, 6/44, and 0/11, respectively) and in deaths from pulmonary hypertension (2/95, 0/44, and 0/11, respectively). However, in group C, early mortality and mortality from pulmonary hypertension in patients with CHD was significantly higher than in those with cardiomyopathy (5/24 versus 0/18 and 4/24 versus 0/18, respectively;p < 0.05). Mortality from pulmonary hypertension in patients with CHD in group I was significantly lower than that in group C (0/44 versus 4/24; p < 0.05), whereas there was no significant difference in early mortality in patients with CHD between the two groups (6/44 versus 5/24). Pretransplant pulmonary hypertension was detected in 122 infants (80%) and 17 children (40%). Sixty-five infants and II children received donor hearts from patients who underwent cardiopulmonary resuscitation before brain death. Sixty-two infants and nine children received hearts from an oversized donor. As shown in Table II, in both groups, there was no significant difference in early deaths or deaths from pulmonary hypertension from these factors. Fifteen infants (I 0%) and 25 children (60%) had undergone palliative operations before heart transplantation. All children with CHD had at least one or more operations before the transplant operation. Both early mortality and deaths from pulmonary hypertension in children with previous operations was significantly higher than in those who had no previous operation (5/25 versus 0/17 and 4/25 versus 0/ 17, respectively; p < 0.05). Thirty-seven infants and 16 children received hearts with ischemic times greater than 360 minutes. Death from pulmonary hypertension with grafts with long ischemic times in group C (4/16) was significantly higher than that with grafts with short ischemic times in group C (0/26) and that with grafts with either long or short ischemic times in infants (0/37 and 2/115; p <0.05).
The Journal of Thoracic and Volume 107, Number 4 Fukushima et al. 9 8 7 Table I. Characteristics of patients who died of pulmonary hypertension after heart transplantation Patient D/Rwt No. Group Age (days) Sex Disease ratio (kg) GIT (min) PH CPR 3 M HLHS 3.5/3.9 95 + 2 I 22 M HLHS 9.3/3.4 181 + 3 C 769 M AS 14.0/9.9 476 + 4 C 1305 F PAA 12.0/10.8 379 5 C 2416 F SV 19.6/14.5 407 + + 6* C 4810 F SV 35.0/38.6 362 + DIR wt ratio, Donor-recipient weight ratio; CIT, graft ischemic time; PH, pulmonary hypertension before heart transplantation; CPR, donor's history of cardiopulmonary resuscitation; M, male; AS, supravalvular aortic stenosis; F, female; PAA, pulmonary atresia with intact ventricular septum; SV, single ventricle (right ventricular type). 'Patient who underwent retransplantation. Discussion Elevated PVR has previously been identified as a risk factor for death after heart transplantation in adults 3-6 and children. 7 Although exceptions may be made, a high PVR (more than 4 Wood units/m in adults 2, 3, 5 and 6 Wood units/m 2,7 in children) or high transpulmonary pulmonary gradients (more than 15 mm Hg 6 ) are considered to be contraindications for heart transplantation or at least make the transplant high-risk. However, no such guidelines exist for neonatal and infant heart transplantation, perhaps because the experience in neonatal and infant heart transplantation is relatively new. Nevertheless, most patients who require neonatal or infant heart transplantation have forms of CHD such as HLHS in which the systemic circulation is ductus dependent, the PVR by definition must be high to maintain the systemic circulation. Luckily, in infancy, PVR is rarely fixed before I year of age despite huge left-to-right shunts; furthermore, it seems to decrease more rapidly after heart transplantation than in children or adults. Therefore, a high PVR has not been considered a contraindication for neonatal or infant heart transplantation in our institution. As such, catheterization to measure absolute pulmonary artery pressures has not been done in all patients before heart transplantation, because anatomic indications for transplantation can be obtained via echocardiograms. In the present study, we performed a retrospective analysis of our 194 infant and pediatric recipients and divided these patients into two groups according to their age at heart transplantation. Between the two groups there was no significant difference in early mortality, including early graft loss. Although the rate of pretransplantation pulmonary hypertension in group I was significantly higher than that in group C (I22/144, 85% versus 17/34, 50%; p < 0.05), mortality from pulmonary hypertension after heart transplantation in group I was significantly lower than that in group C. These data suggest that high PVR is not a contraindication for heart transplantation in infancy. Moreover, there was no sig- Table II. Palliative operations before heart transplantation in patients who died of pulmonary hypertension Patient No. Age at initial operation 1 2 3 23mo 4 8 days 9mo 19mo 28mo 34mo 37mo 5 1 mo 6 3 days 6yr 12 yr Operation None None Removal of web in the ascending aorta Trans-right ventricular pulmonary valvotomy and central shunt Right ventricular outflow reconstruction, right Blalock-Taussig shunt Left Blalock-Taussig shunt Right Glenn shunt Fenestrated Fontan operation Balloon occlusion of atrial septal defect Banding of pulmonary artery Balloon a trial septostomy, right Waterson shunt Central shunt Atrioventricular valvuloplasty, right Glenn shunt nificant difference in early mortality or mortality from pulmonary hypertension between children with and without pretransplantation pulmonary hypertension in group C. These data do not correspond with the findings of other investigators, who have suggested that pretransplanta-
9 8 8 Fukushima et al. The Journal of Thoracic and April 1994 Table III. Early death including early graft loss and mortality from pulmonary hypertension Group I Groupe No. M-E % M-PH % No. M-E % M-PH % Total 19 12.5 2 1.3 42 5 11.9 4* 9.5 Disease HLHS 95 13 13.7 2 2.1 CHD 44 6 13.6 0 0.0 24 5t 20.8 4* 16.7 CM 11 0 0.0 0 0.0 18 0 0.0 0 0.0 Pulmonary hypertension before heart transplantation Yes 122 15 12.3 2 1.6 17 3 17.6 2 ll.8 No 12 2 16.7 0 0.0 17 3 ll.8 2 11.8 Donor history of cardiopulmonary resuscitation Yes 65 6 9.2 0 0.0 11 2 18.2 2 18.2 No 74 8 10.8 2 2.7 28 3 10.7 2 7.1 Oversized donor grafting Yes 62 5 8.1 1.6 9 0 0.0 0 0.0 No 92 14 15.2 l.l 35 5 14.3 4 11.4 History of operation before heart transplantation Yes 15 4 26.7 0 0.0 25 5t 20.0 4*t 16.0 No 137 15 10.9 2 1.5 17 0 0.0 0 0.0 Prolonged graft ischemic time (more than 360 minutes) Yes 37 4 10.0 0 0.0 16 4 25.0 4*t 25.0 No 115 14 12.2 2 1.7 26 3.8 0 0.0 M-E, Mortality from early graft loss; M-PH, mortality from pulmonary hypertension; em, cardiomyopathy. 'p < 0.05 versus group 1. tp < 0.05 versus no. tion pulmonary hypertension was a predictive risk factor for early death after heart transplantation in adults 3, 5 and children. 7 Addonizio and colleagues 7 have shown that six of thirteen children with a PVR index greater than 6 died perioperatively, and four of them died of pulmonary hypertension. Nevertheless, that group reported that seven patients with PVR indexes greater than 6 survived perioperatively. To us, these data indicate that successful transplantation can be achieved even in children with extremely elevated PVR. Conversely, in our present study, two children with mean pulmonary artery pressures lower than 20 mm Hg (14 and 18 mm Hg) before heart transplantation died of pulmonary hypertension. Therefore it is not just those patients with elevated PVR before heart transplantation who are at risk for death from pulmonary hypertension after operation. Of the patients with CHD other than HLHS, 27% (l2/44) in group I and 100% (24/24) in group C had a previous operation before heart transplantation. Four (17%) of these 24 patients in group C died of pulmonary hypertension, whereas none (0/44) in group I died of pulmonary hypertension. The types of operations done before heart transplantation in the children who died of pulmonary hypertension were all different (Table II). Two patients with HLHS in group I died of pulmonary hypertension but underwent no operation before heart transplantation. Therefore, a history of operations before heart transplantation itself is not considered to be a predictive risk factor for death from pulmonary hypertension in infancy, but a previous palliative operation before heart transplantation should be viewed with caution in children. Although there was no significant difference in early mortality and mortality from pulmonary hypertension with the use of oversized donor grafts or with donors with a history of cardiopulmonary resuscitation before brain death in group I, prolonged graft ischemic time was a risk factor for mortality from pulmonary hypertension in group C. These data suggest that a graft, especially a right ventricle, with prolonged ischemic time has little capacity to tolerate pulmonary hypertension after heart transplantation, which in turn leads to recipient death. In conclusion, older children have a higher mortality rate from pulmonary hypertension after heart transplantation, especially those children who have had previous palliative operations for CHD and/or who receive a graft preserved longer than 6 hours. Conversely, neonates and infants have a low mortality rate from postoperative pulmonary hypertension. Moreover, pulmonary hypertension before heart transplantation and prolonged graft ischemic times are not predictive risk factors for early death or death from pulmonary hypertension in neonatal and infant heart transplantation. This study demonstrates another benefit of transplantation early in infancy, rather than delaying transplantation to an older age by means of
The Journal of Thoracic and Volume 107, Number 4 Fukushima et al. 989 first-stage palliative operation, that is, early transplantation greatly lessens the risk of posttransplantation death from pulmonary hypertension. REFERENCES I. Bailey LL, Nehlsen-CannareUa SL, Doroshow RW, et a1. Cardiac allotransplantation in newborns as therapy for hypoplastic heart syndrome. N Engl J Med 1986;315:949-51. 2. Bailey LL, Assad AN, Trimm RF, et a1. Orthotopic transplantation during early infancy as therapy for incurable congenital heart disease. Ann Surg 1988;208:279-86. 3. Griepp RB, Stinson EB, Dong E Jr, Clark DA, Shumway NE. Determination of operative risk in human heart transplantation. Am J Surg 1971;122:192-7. 4. Kirklin JK, Naftel DC, Kirklin JW, Blackstone EH, White-Williams C, Bourge RC. Pulmonary vascular resistance and the risk of heart transplantation. J Heart Transplant 1988;7:331-6. 5. Bourge RC, Kirklin JK, Naftel DC, White-Williams C, Mason DA, Epstein AE. Analysis and predictors of pulmonary vascular resistance after cardiac transplantation. J THORAC CARDIOVASC SURG 1991;\01 :432-45. 6. Kormos RL, Thompson M, Hardesty RL. Utility ofpreoperative right heart catheterization data as a predictor of survival after heart transplantation [Abstract]. J Heart Transplant 1986;5:391.. 7. Addonizio LJ, Hsu DT, Fuzei L, Smith CR, Rose EA. Optimal timing of pediatric heart transplantation. Circulation 1989;80(Suppl III):84-9.