Determinants of Hospital Survival After Cardiac Transplantation

Transcription

1 Determinants of Hospital Survival After Cardiac Transplantation Moheb Ibrahim, MBBCh, Roy G. Masters, MD, Paul J. Hendry, MD, Ross A. Davies, MD, Stuart Smith, MD, Christine Struthers, RN, Virginia M. Walley, MD, and Wilbert J. Keon, MD University of Ottawa Heart Institute, Divisions of Cardiac Surgery, Cardiology, Anatomical Pathology, and Nursing, Ottawa Civic Hospital Ottawa, Canada To identify the preoperative factors that influence hospital survival after transplantation we analyzed our consecutive experience of 183 transplantations in 179 patients over a 10-year period. There were 151 male and 29 female transplant recipients ranging in age from 10 days to 70 years (mean, 48 ± I years). Diagnoses included coronary disease in 110 patients, cardiomyopathy in 55 patients, valvular disease in 6 patients, and congenital heart disease in 9 patients. Seventy-seven had undergone a previous cardiac operation, and 30 patients required preoperative mechanical support. Forty patients received hearts from donors who were 40 years old or older (range, 40 to 62 years). Ischemic time was greater than 240 minutes in 32 cases, and pulmonary vascular resistance was greater than 3 Wood units in 40 patients (range, 3.1 to 10.0 Wood units). Cyclosporlne induction was used in 52 patients, whereas 128 recipients received polyclonal antibody prophylaxis. There were 25 hospital deaths. Recipient diagnosis, use of mechanical support, donor age, and the immune suppression protocol were related to hospital survival according to univariate analysis. Using multiple logistic regression, only the method of immune suppression induction and the use of mechanical assists were significant independent determinants of survival. In conclusion, we believe that extended ischemic times and donor age do not adversely affect the early success of transplantation, whereas induction with immune globulin may reduce early mortality. Patients requiring mechanical support before transplantation continue to be a challenge. (Ann Thorac Surg 1995;59"604-8) ardiac transplantation is currently an accepted ther- C apy for patients with end-stage heart disease. With the improving results there has been a broadening of selection criteria for both recipients and donors. It is, we believe, important to review constantly the results of this procedure. This study therefore was conducted to evaluate the factors influencing early survival after heart transplantation in our 10-year experience at the University of Ottawa Heart Institute. Patients and Methods Data from consecutive patients undergoing cardiac transplantation at the University of Ottawa Heart Institute from May 29, 1984, to January 11, 1994, inclusive, were compiled in a database. The group consisted of 183 cardiac transplantations in 179 patients. Four patients underwent retransplantation: 3 acutely within 30 days of the initial procedure and before discharge from the hospital and 1 late, at 9 years after the first procedure. The latter patient therefore is included twice in statistical analyses. The recipients consisted of 151 male and 29 female patients with an average age of years (range, 10 days to 70 years). The group included 9 Accepted for publication Nov 3, Address reprint requests to Dr Masters, Ottawa Heart Institute, 1053 Carling Ave, Ottawa, Canada KIY-4E9. pediatric recipients: 3 infants aged 10, 34, and 43 days; 3 children aged 4, 6, and 10 years; and 3 teens aged 16, 17, and 18 years. All donor hearts were preserved with St. Thomas" Hospital (Abbott Laboratories, North Chicago, IL) crystalloid cardioplegia and topical cold saline solution. Until 1986 donor hearts were transported in a cooler at 4 C; after 1986 the temperature was maintained between 8 and 10 C during transportation [1]. All transplantations were orthotopic, using a standard technique as described previously [2]. Induction of immune suppression was with either intravenous cyclosporine or immune globulin in conjunction with steroids. The immune globulin used for induction was either antilymphocyte globulin (15 mg.kg -1. day 1) or antithymocyte globulin (10 mg kg -1. day -l) administered for 5 days. Maintenance of immunosuppression in all patients consisted of triple therapy based on steroids (1 mg. kg -~. day -1 in tapering doses), azathioprine (2 mg. kg 1. day-l), and cyclosporine (2.5 to 5.0 mg/kg twice daily to achieve a trough plasma level of 200 to 400 ng/ml). Our initial experience was with cyclosporine induction; however, use of immune globulin has become routine in recent years. For the province of Ontario, the urgency of transplantation is expressed as the Multi-Organ Retrieval and Exchange (MORE) priority status. Patients awaiting heart transplantation at home are assigned the lowest rank, status "1". Status "'2" refers to patients waiting in the 1995 by The Society of Thoracic Surgeons /95/$ (94)

2 Ann Thorac Surg IBRAHIM ET AL ;59:604-8 HOSPITAL SURVIVAL ALTER TRANSPLANTATION hospital whereas status "3" recipients require intravenous inotropic agents or vasodilators in the hospital. Status "4", the highest priority, is for patients who require mechanical circulatory or ventilatory support. For this study we considered status "1" and "2" as elective and status "3'" and "'4" urgent. We defined hospital survival as survival to discharge from the hospital and analyzed the following risk factors: recipient age, sex, diagnosis, priority (MORE status), pulmonary vascular resistance, previous cardiac operation, donor age and sex, and ischemic time. Univariate analyses were performed to test the hypothesis that each risk factor was associated with hospital survival. Discriminant variables were analyzed by the )(2 test or Fisher's exact test. Logistic regression analysis then was used to define a subset of variables that were independent determinants of hospital mortality. Comparisons of continuous variables between survivors and nonsurvivors were performed with the Student's t test. A p value of less than 0.05 was considered statistically significant. R e s u l t s There were 25 hospital deaths in this study (Table 1). Of these, sepsis accounted for 9 (36%), hemorrhage 4 (16%), rejection 4 (16%), myocardial infarction 3 (12%), graft failure of undetermined cause 3 (12%), and cytomegalovirus disease 2 (8%). Of the 9 patients who died of sepsis, 2 had sternal wound infections, 4 had pneumonia, and 1 each had pancreatitis, perforated colon, and line sepsis. In all 4 cases of death due to hemorrhage, death occurred intraoperatively because of uncontrollable bleeding. Of the 4 deaths caused by rejection, 1 was hyperacute and occurred in the operating room and 1 presented as the sudden onset of lethal arrhythmias. Among the deaths due to myocardial infarction, 2 were right ventricular and 1 was left ventricular, with autopsy demonstration of normal coronary arteries in all 3 cases. In the 3 cases of death due to graft failure, autopsy failed to demonstrate any structural abnormality. Of 2 patients dying of cytomegalovirus disease, 1 presented with massive gastrointestinal bleeding due to ulcerations and 1 had pneumonitis. Of the 3 patients who required retransplantation acutely, 2 had rejection and I had idiopathic graft failure. All died in the hospital with sepsis, pneumonia, or rejection. The 1 patient who required late retransplantation is alive and well. The recipient diagnoses included cardiomyopathy in 55 patients, coronary disease in 110, valvular disease in 6, and congenital heart disease in 9. Survival to discharge by diagnosis was 94.5% for cardiomyopathy, 86.3% for coronary disease, 33.3% for valvular disease, and 66.6% for congenital heart disease. By MORE status 102 patients were elective and 78 were urgent. Hospital survival was 90.1% for the elective group and 80.7% for the urgent group (p = 0.083). There were 79 patients in MORE status 1, 23 in status 2, 48 in status 3, and 30 in status 4. The hospital survival was 89.8%, 91.3%, 89.5%, and 66.6%, respectively (p = 0.009). Of the 30 patients in MORE Table 1. Effect of Risk Factors on Hospital Survival Hospital Survival p Value No. of Univariate Variable Patients No. Percent Analysis Recipient age < 50 years %... > 50 years %... Recipient sex Female %... Male %... Donor age < 40 years %... -> 40 years %... Donor sex Female %... Male %... Diagnosis Cardiomyopathy %... Other %... Priority a MORE %... MORE %... MORE %... MORE %... Priority Elective %... Urgent %... Ischemic time < 240 minutes %... > 240 minutes %... PVR < 3 Wood units %... 3 Wood units %... Immune a suppression Cyclosporine %... induction Immune %... globulin induction Previous operation No %... Yes %... a Significant independent factor by logistic regression analysis. MORE = Multi-organ Retrieval and Exchange priority status; pulmonary vascular resistance. PVR= status 4 the type of mechanical assist consisted of the intraaortic balloon pump in 10 patients, a ventilator in 1 patient, biventricular support with the Thoratec ventricular assist device (Thoratec Laboratories, Berkeley, CA) in 3 patients, and the total artificial heart in 16 patients. Survival was 90.0% (9/10), 0% (0/1), 66.6% (2/3), and 56.3% (9/16), respectively. Of the 9 pediatric patients, congenital heart disease was present in 6 and cardiomyopathy in 3. Survival to discharge was 88.9% in this group of patients, with death occurring in 1 infant due to graft failure after an anoxia time of 5 hours.

3 606 IBRAHIM ET AL Ann Thorac Surg HOSPITAL SURVIVAL AFTER TRANSPLANTATION 1995;59:604-8 By univariate survival analysis, recipient age was not a determinant of hospital survival. There were 99 recipients more than 50 years of age (mean, 56.1 _+ 0.5 years) with a survival of 83.8% and 81 recipients 50 years old or younger (mean, years) with a survival of 88.8% (p = 0.225). Our experience also included 19 recipients more than 60 years of age (mean, 62.9 _+ 0.6 years) with a hospital survival of 73.6% compared with 87.6% survival for those 161 recipients 60 years of age or younger (p = 0.163). There was no difference in survival according to recipient sex. Male patients had an 86.7% survival whereas female patients had an 82.7% survival (p = 0.374). Donor age, however, was a determinant of survival according to univariate analysis. Among the 140 patients receiving transplants from donors less than 40 years of age (mean, years), survival to discharge was 89.2% whereas survival with donors 40 years old or older (mean, years) fell to 75.0% (p = 0.035). Donor sex, however, was not a determinant of survival according to univariate analysis, with 88.0% and 82.5% survival with male and female donors, respectively (p = 0.212). Ischemic time also did not appear to be an important determinant of early outcome. Survival to discharge was 86.4% for the 148 patients with ischemic times of less than 240 minutes (mean, minutes) and 84.3% for the 32 patients with ischemic times of 240 minutes or longer (mean, _+ 6.9 minutes; p = 0.779). By univariate analysis, recipient diagnosis was a determinant of hospital survival after transplantation. Of the patients with cardiomyopathy there was a 94.5% (52/55) survival compared with 86.3% for coronary disease, 33.3% (2/6) for valvular disease, and 66.6% (6/9) for congenital disease. Compared with all other diagnoses, patients with cardiomyopathy had a statistically higher survival to discharge (p = 0.021). Previous cardiac operation was not associated with a significantly increased mortality in this study. There were 77 patients in our study who had a previous cardiac operation more than 30 days before transplantation with a survival of 84.4% compared with 87.3% for the 103 patients who had not had a previous operation (p = 0.664). The method of induction of immune suppression was a determinant of outcome in the univariate analysis. Immune suppression with cyclosporine induction was used in 52 patients, with a 75.0% survival to discharge, whereas immune globulin was used for induction in 128 patients, with a survival of 90.6% (p = 0.01). There was, however, no difference in the occurrence of rejection before discharge from the hospital between the two groups. With cyclosporine induction 13.5% of patients and with immune globulin induction 13.2% of patients experienced rejection requiring treatment (p = 0.99). Similiarly, the frequency of renal failure necessitating either hemodialysis or hemofiltration was similiar between the two groups (3.8% versus 2.3%, respectively; p = 0.63). Pretransplantation pulmonary vascular resistance was considered normal (3.0 Wood units or less) in 140 patients and elevated (more than 3.0 Wood units) in 40 recipients. Survival to discharge was 84.2% in the former and 92.5% in the latter (p = 0.28). By multivariate analysis we identified only two independent determinants of hospital survival in this study, namely MORE status (odds ratio = 3.85 with 95% confidence range = 1.45 to 10.0) and the method of induction of immune suppression (odds ratio = 3.13 with 95% confidence range = 1.23 to 7.98). Comment The Registry of the International Society for Heart and Lung Transplantation, which has data on approximately 18,000 heart transplants, has shown a 30-day mortality of approximately 9% to 10% for those patients undergoing heart transplantation in recent years [3]. In its most recent report of 1993, the 30-day mortality for adult recipients was 8.5% whereas for pediatric patients it was 14.1% [3]. Our overall hospital mortality in this study, which includes both adults and children and patients of both low and high priority, was 13.7%. By 1992, however, our overall hospital mortality had decreased to 6.0%. This prompted us to define what, in our experience, are the determinants of hospital survival after heart transplantation. In our experience, recipient age greater than 50 years was not a risk factor for early mortality. There was, however, an increased risk for those patients more than 60 years of age, though the numbers were small, making statistical inference difficult. Other investigators have also shown that patients more than 60 years of age can undergo cardiac transplantation with early results similiar to those of younger recipients [4]. We agree with these authors that advanced age, in isolation, should not preclude consideration for cardiac transplantation. In the Stanford University experience [5], although advanced age was not associated with increased early mortality, none of the recipients was more than 60 years of age. Bourge and associates [6], however, in reporting the experience of 25 heart transplant centers in the United States, found that patients older than 50 years have a slight but progressive increase in expected mortality rate. Most importantly, they suggested that older patients are more likely to survive heart transplantation when they are actively screened and selected for the absence of other associated risk factors. In its most recent report, the Registry only identified the very young (age, 0 to 5 years) as being at increased risk of death within 30 days [1]. In our experience, recipient sex also was not identified as a risk factor for early mortality, although some authors have suggested that female patients are at increased risk [1, 4, 6]. Our patients with congenital heart disease, ischemic heart disease, or valvular disease did not fare as well after transplantation compared with those with cardiomyopathy. Although diagnosis was not an independent determinant of hospital survival there appears to be increased risk in patients with valvular heart disease, who, in our small experience, do poorly. Congenital heart disease was the only preoperative diagnosis found to be a signif-

4 Ann Thorac Surg IBRAHIM ET AL ;59:604-8 HOSPITAL SURVIVAL AFTER TRANSPLANTATION icant risk factor for death within 30 days of heart transplantation in the 1993 Registry report [1]. Although donor age greater than 40 years was a significant risk factor with univariate analysis, it failed to achieve significance in our multiple logistic regression model. Similar experience with older donors has been reported by others [1, 7-13]. Bourge and colleagues [6] found that the risk of death did increase gradually but significantly when donor age increased from 25 to 50 years in the adult recipient. Wahlers and co-workers [14] also observed a trend toward more early deaths in recipients with older donors. In that study, however, the donors were screened only by examination at the time of cardiectomy because neither echocardiography nor cardiac catheterization were available. We believe that donor age should not be an absolute contraindication for heart transplantation. Older donors, however, should be carefully screened, particularly if they are requiring high doses of inotropic agent support. This should include echocardiography and often coronary angiography if available. Donor sex was not a significant predictor of early death in our series. Although this also was not identified as a risk factor in the 1993 Registry Report [3], Fabbri and associates [15] reported a significantly higher early mortality rate among recipients of female donor grafts. Donor ischemic time of more than 4 hours was not a significant risk factor for mortality in this series. Pflugfelder and associates [16] found that cardiac allograft ischemic times of 4 to 6 hours were not associated with an increase in short-term graft loss or adverse effects on graft function measured at 3 months after transplantation. Sweeney and co-workers [10] suggested that it is even acceptable to use less than ideal donor hearts with ischemic times longer than 5 hours. Only when the ischemia time was greater than 360 minutes was there an increased risk noted in the Registry [1]. These findings were contradictory to those of Bourge and colleagues [6], who reported that donor ischemic times more than 300 minutes were associated with a higher risk of death [6]. Based on our previous experimental work we believe that monitoring of temperature is important in donor heart preservation [1]. With short ischemic times, the myocardial temperature may never attain a level that is protective, whereas with longer ischemic times the temperature may reach a level that is potentially damaging. We did not find preoperative pulmonary hypertension to be a risk factor for hospital death. In the multiinstitutional study by Bourge and associates [6], high pulmonary vascular resistence in children was reported to increase the risk for early-term death. Kirklin and co-workers [17] found that elevated pulmonary vascular resistance contributed to early death, but these authors did not report whether there was a difference in the outcome if the pulmonary hypertension was reversible. Costard-Jackle and colleagues [5] reported that when pulmonary hypertension was not responsive to nitroprusside, there was an increased risk of premature death after cardiac transplantation. We believe, as do others, that in most cases of chronic cardiac failure, pulmonary vascular resistance and transpulmonary gradient may be reduced by pharmacologic intervention, which should be attempted before cardiac transplantation is denied [18]. O'Connell and associates [19] suggested that if the use of nitroprusside and prostaglandin E 1 fail to reduce the pulmonary vascular resistance, prolonged intensive medical treatment, including chronic parenteral administration of inotropic or vasodilator drugs, may gradually reduce pulmonary vascular resistance to an acceptable range. We have found this to be effective in a number of our patients. Previous cardiac operation before admission for transplantation, was not a risk factor for early mortality in our study. A similar experience also has been reported by Lammermeier and colleagues [20]. In our experience, only the recipient priority status and the method of induction of immune suppression were independent determinants of hospital survival according to multivariate analysis. Successful use of mechanical assist devices as a bridge to transplantation continues to be a challenge. The 1993 Registry identified "'Life Support" as a risk factor for early death and the use of a ventricular assist device or total artificial heart as a factor contributing to a significantly lower 1- and 5-year survival [1]. In the 1992 report of the total artificial heart registry of the Minneapolis Heart Institute [21] there were 171 patients who received the total artificial heart as a bridge to transplantation. Of these, 69% (118/171) underwent transplantation and 57% (67/118) were alive 1 year later [21]. The clinical experience with the Thoratec ventricular assist device as a bridge to transplantation was reviewed by Farrar and co-workers [22] in Of 186 patients who received implants, 63% (118/186) underwent transplantation and 81% (96/118) were discharged from the hospital. In our experience the survival to discharge was 66.6% in patients requiring mechanical support. The survival rate was 90% (9/10) for those who could be sustained with the intraaortic balloon pump but fell to 57.8% in those who required either a ventricular assist device or a total artificial heart (11/19). That death was imminent in all these patients who were in profound cardiogenic shock must be emphasized when these resuits are considered. We found that induction of immune suppression with immune globulin has a favorable effect on hospital survival compared with cyclosporine induction. Immune suppression avoiding cyclosporine in the perioperative period was introduced by Cabrol and associates [23] in The efficacy of using polyclonal antibodies for prophylaxis of acute rejection has been demonstrated in many studies [24-26]. In a retrospective comparison of induction with rabbit anti-thymocyte globulin or cyclosporine, Carrier and colleagues [27] did not find any survival difference between the two groups. In that study, however, perioperative renal function was better preserved and the actuarial freedom from rejection was higher in the former. The survival advantage seen in our study simply may reflect our growing experience with transplantation, as we used cyclosporine induction predominantly in the initial years of the study. The data do suggest that it is not due to a difference in the frequency

5 608 1BRAHIM ET AL Ann Thorac Surg HOSPITAL SURVIVAL AFTER TRANSPLANTATION 1995;59:604-8 of rejection or in the occurrence of severe renal failure. Induction with immune globulin, however, may result in improved renal function and fluid balance with a resultant enhanced early survival. In summary, these data suggest that older recipients can expect similiar early results after cardiac transplantation to younger recipients. Further, carefully expanding the donor pool to meet the increasing demands on transplant resources by accepting longer ischemic times and older donors may not adversely affect survival. Although the use of immune globulin for induction of immune suppression appears to have a salutary influence on outcome, the reason for this was not clear from this study. Finally, patient selection, choice of device, and timing of implantation all remain a challenge in the management of patients in cardiogenic shock who require mechanical support. We thank the Heart Transplant Association of the Ottawa Heart Institute for their continued support and Mr Daniel Duguay for assistance with statistical analyses. References 1. Hendry PJ, Walley VM, Koshal A, Masters RG, Keon WJ. Are temperatures attained by donor hearts during transport too cold? J Thorac Cardiovasc Surg 1989;98: Lower RR, Shumway NE. Studies on orthotopic homotransplantation of the canine heart. Surg Forum 1960;11: Kaye MP. The Registry of the International Society for Heart and Lung Transplantation: tenth official report J Heart Lung Transplant 1993;12: Frazier OH, Marcis MP, Duncan MJ, Van Buren CT, Cooley DA. Cardiac transplantation in patients over 60 years of age. Ann Thorac Surg 1988;45: Costard-Jackle A, Hill I, Schroeder JS, Fowler MB. The influence of preoperative patient characteristics on early and late survival following cardiac transplantation. Circulation 1991;84(Suppl 3): Bourge RC, Naftel DC, Costanzo-Nordin MR, et al. 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