Apr 29, 1985 - prine and steroids with frequent addition of rabbit anti- thymocyte ..... at Penn State, under the leadership of my colleague, Dr. John Pennock,.
Cardiac Transplantation Changing Patterns in Evaluation and Treatment KEITH REEMTSMA, M.D., MARK A. HARDY, M.D., RONALD E. DRUSIN, M.D., CRAIG R. SMITH, M.D., ERIC A. ROSE, M.D.
This study reports the authors' experience with 66 heart transplants in 64 patients done over an 8-year period (1977-1985). In the early series, a high frequency of complications involving serious infections was noted. In April 1983, the immunosuppressive regimen was changed to cyclosporine and low-dose steroids. Patients were monitored wAith frequent myocardial biopsies and determinations of serum cyclosporine levels. Although this is not a controlled study, the authors believe that the improved results, including reduced frequency and severity of infections, are related to altered immune suppression. They speculate that patients with successful cardiac grafts develop a form of specific unresponsiveness and now are studying the mechanisms of this adaptation. E REPORT HERE OUR EXPERIENCE over the last 8
years (1977-1985) in patients with heart transplants. On the basis of this experience, we are evolving different approaches and methods in evaluation and management of these patients. We believe that some of these changing patterns may have relevance to the field of organ transplantation in general. The early years of transplantation were marked by extensive emphasis on immunologic evaluation and monitoring, and reliance on high-dose immunosuppression with various cytotoxic and cytostatic drugs. Conventional wisdom at that time held that immunologic reactions of the host to transplants were uniformly destructive, and, therefore, efforts were directed toward "abrogation of the immune response." We now hold a different view. We believe that patients with successful transplants show specific immunologic suppression, and that this is an active, continuing process. Therefore, we search for immunosuppressive approaches Presented at the 105th Annual Meeting of the American Surgical As-
sociation, April 25-27, 1985, New Orleans, Louisiana. Supported in part by NIH Grant, HL14799, and GCRC Grant of the Division of Research Resources, RR00645. Reprint requests: Keith Reemtsma, M.D., Department of Surgery, Columbia University College of Physicians and Surgeons, 622 West 168th Street, New York, NY 10032. Submitted for publication: April 29, 1985.
From the Departments of Surgery and Medicine, Columbia University College of Physicians and Surgeons and Presbyterian Hospital, New York, New York
that will permit the development of such active immunologic unresponsiveness, shifting the host's immunologic balance away from the processes of rejection. Our premise is that successful organ transplantation requires some form of adaptation. Our goal is to understand these processes from the physiologic and immunologic views. We believe that adaptation is additive. This report focuses on our experience in clinical heart transplantation, which serves as a framework for our evolving understanding of processes of adaptation. Historical Review
Almost 2 decades have passed since clinical cardiac transplantation was introduced, and interest in the procedure has fluctuated widely. There is now a resurgence of effort as results have shown striking improvement. Although clinical efforts in this field are relatively recent, experimental cardiac transplantation was reported in the first decade of this century.' In 1933, Mann2 and associates evaluated electrocardiographic patterns in transplanted hearts, and Demikhov3 introduced intrathoracic transplantation of the heart, with and without portions ofthe lungs. Heart transplants were used to study the physiology ofassisted circulation4 and to evaluate immunosuppression.5 However, the modern era of cardiac transplantation began with the studies of Lower and Shumway.6 Their demonstration of survival of an animal after transplantation of the heart in the orthotopic position set the stage for clinical work. Although clinical applications by Hardy7 and Barnard8 preceded the effort of Shumway and his colleagues, it has been the Stanford group that has provided leadership and continuity in cardiac transplantation.
Vol. 202 * No. 4
Methods and Results Recipients Our clinical heart transplantation program at Columbia-Presbyterian Medical Center in New York began in 1977. Our first experiences were in individuals requiring mechanical circulatory support, a group of patients not then accepted by other transplantation groups. This included seven patients, all of whom survived the operation, and four of whom survived longer than 1 year.9 We now consider all patients with end-stage heart disease, using the criteria that are commonly accepted in this field. We have extended the acceptance of potential recipients to include those patients up to age 55. We initially adhered to the Stanford criterion on pulmonary vascular resistance (PVR), accepting patients with resistance measured as high as 8 Woods Units (W.U.). Five perioperative deaths due to acute right heart failure in patients who satisfied this criterion led to a revised approach to pulmonary resistance. Any patient with elevated PVR is presently considered suitable for transplantation if PVR falls with a nitroprusside infusion to less than 4.0 W.U. Twenty-two patients who have shown this pharmacologic reversibility of pulmonary hypertension have survived the perioperative period. Donors In our initial efforts with the first 14 recipients, we confined organ donation to cadaver donors who were in our hospital. In this group (I1977-198 1), we restricted the age of donors to under-30 and otherwise followed the guidelines of organ donation outlined by others.'0 In 1981, we began the transporting of donor hearts, using cardioplegic perfusion and topical cooling. Since that time, we have transplanted 38 hearts obtained outside of the New York metropolitan area, from as far as 1200 miles from our center and including preservation for up to 4.5 hours. It is possible, but unproved, that two of our transplant deaths were caused by poor donor organ preservation resulting in extensive myocardial infarction in the immediate postoperative period. Because of the increasing shortage of donor hearts, we have liberalized our donor age requirements to 40 years in men and 45 in women." We have performed eight transplants using donors in this age group, and all the recipients of these hearts are alive and well with excellent cardiac function. Cardiac donor evaluation includes an EKG, chest x-ray, and absence of previous hypertension, diabetes mellitus, or malignancy, other than brain or skin. We have transplanted hearts from patients who have had chest tubes, pulmonary infiltrates, fractured ribs, and cardiac arrests. In occasional donors, coronary angiograms or echocardiograms are done. Most of the donors were
identified through renal organ procurement organizations, and usually the heart was only one organ among many obtained as part of a multiple organ procurement effort. 12 Immunologic Evaluation Before January 1983, all cardiac recipients were tissuetyped for HLA-A and B, and DR antigens, and crossmatched prospectively against donor B and T cells of lymph nodes or spleen, or both, whenever viable antigen preparation was available. Prospective panel screening (panel of 50) of monthly recipient sera was performed in the first 14 patients in this series. Cross-matches were done on all available recipient sera by the method of SuciuFoca et al.'3 Since 1983, only the most recent recipient serum was used when a cross-match was performed. A presensitization rate of greater than 20% panel-reactive antibodies (PRA) against a panel of 50 was present in only five of 64 patients and included one of only three women recipients in this series. In 66 transplants performed in 64 patients, 26 pretransplant cross-matches were negative for both T and B cells at 37 C, while two were positive against T cells at 37 C. Heart transplants were performed in both these patients because of the severity and urgency of their disease, and neither had a hyperacute rejection. One patient died of hepatitis 7 months after the transplant, while the second survived for 14 months and died of complications of peptic ulcer disease. No evidence of severe coronary artery disease or endothelial changes was apparent at postmortem examination. Cross-matches were not performed prospectively in 30 cardiac transplants either because insufficient viable donor cells were available or because the urgency of the recipient's condition was so great that a donor heart was accepted only on the basis of compatible ABO blood grouping. No hyperacute rejections occurred and cross-matches performed retrospectively, whenever possible, were negative against T and B cells at 37 C. No effort was made to select the donor-recipient pairs on the basis of HL-A, B, or DR match, although one perfect match was found retrospectively with HLA-A, B, and DR identity of donor and recipient. Postoperative immunological evaluation of the cardiac recipients was performed extensively before 1983 and was evaluable in 22 cardiac allograft recipients. The tests included T-cell enumeration initially by E-rosette counts, subsequently by OKT3 monoclonal antibody staining and immunofluorescence, lymphoblast counts, screening of recipients' sera for the appearance of donor specific and nonspecific anti-T-cell and anti-B-cell antibodies, and the appearance of inhibition of MLC by sera of the recipients. These tests were described previously by us in publications on renal transplantation.'4'15 The results are summarized in Table 1. Lymphoblast counts were intermittently increased over baseline and
REEMTSMA AND OTHERS
TABLE 1. Postoperative Immunologic Monitoring
Weeks After Transplant
counts 2/22 14/22 10/22 3/22 10/22 10/18 Anti-T cell antibodies 0/22 0/22 2/22 2/22 6/22 Anti-B cell antibodies 0/22 1/22 2/22 6/22 7/22 MLC inhibition 0/22 0/22 1/22 2/22 5/22 -
Rejection by biopsy Lymphoblast
2/22 14/22 6/22
this was frequently associated with rejection episodes proven by endomyocardial biopsies. The incidence of false positive results was high and usually associated with infection. The appearance of anti-T cell antibodies in the recipients' sera frequently was associated with significant rejection episodes and usually resulted in the appearance of anti-T and anti-B cell antibodies of broad specificities. On the other hand, the appearance of nonspecific anti-B cell antibodies alone was frequently associated with measurable inhibitory activity of an MLC reaction and in three of five patients was followed by no evidence of rejection and successful cardiac graft outcome for longer than 1 year. The characterization of T cells was done usually in patients receiving antithymocyte globulin and served primarily to measure the effectiveness ofthat treatment. The enumeration of T-cell subsets using monoclonal antibodies, OKT3, OKT4, and OKT8 (Ortho, Inc., Raritan, NJ), in the peripheral blood was not found to be predictive of either rejection or infection. When such staining was performed on the weekly endomyocardial biopsies, no diagnostic redistribution of cells was seen in 55 specimens in 10 patients. No correlation was seen between OKT3, OKT4, and OKT8 stained cells in the biopsies and rejection as diagnosed by myonecrosis; on the other hand, there was a suggestion that the presence of NK cells stained with OKM may be associated with cardiac allograft rejection. 16,17 Diagnosis ofRejection The diagnosis of rejection episodes was made primarily by histologic evaluation of endomyocardial biopsies done weekly for 8 weeks after transplantation, then on alternate weeks for 8 additional weeks, and monthly thereafter. The criterion for rejection in cyclosporine-treated patients was myocyte necrosis confirmed by two observers. We have reported previously the use of two-dimensional echocardiography as a noninvasive method of studying rejection.'8"'9 Since 1983, 17 patients treated with cyclosporine have had two-dimensional echos two to three times a week for the first 30 days after cardiac transplan-
Ann. Surg. * October 1985
tation. In this group, there was a significant increase in left ventricular mass during biopsy-proven rejection episodes, from baseline values of 142 ± 4 gms to 152 ± 4 gm (p < 0.05). We have made the preliminary observation that left ventricular mass increases in patients receiving cyclosporine over time, independent of rejection. This test may prove to be important in evaluating rejection and also long-term changes in the transplanted heart. We have described also the use of indium- 11 1 labeled platelets and lymphocytes as an indicator of rejection in experimental models of cardiac transplantation20 but have found these approaches to be laborious and not fully dependable. We are presently exploring the use of indium111 labeled F(ab')2 fragments of antimyosin antibody to detect early signs of myocyte necrosis and rejection. This approach appears promising in the nonhuman primate cardiac allograft model (unpublished). Immunosuppression
We have done 66 transplants in 64 patients. In April 1983, we began to use cyclosporine and low-dose steroids in all our recipients. Before April 1983, we used azathioprine and steroids with frequent addition of rabbit antithymocyte globulin (ATG) for treatment of rejection. In this report, we compare our experience before and after this change, which we believe has had a major impact on our results. Although this is not a controlled study, we believe that this series suggests that a change in immune alteration of the host has led to improved results, including reduction in the incidence and severity of infection. Before April 1983, our immunosuppressive regimen consisted of conventional drugs in the high doses commonly used in cardiac transplantation centers at that time. Of the 24 patients transplanted, only seven are still alive after 28 to 52 months. The high incidence of infections, especially Aspergillosis in nine patients, forced us to reevaluate our use of high-dose immunosuppression. In April 1983, we changed our immunosuppression to cyclosporine and low-dose steroids. Before surgery, immunosuppression was begun with 10-12 mg/kg. Cyclosporine was given orally. During surgery, methyl-prednisolone 500 mgm was given, followed by 125 mg intravenously every 8 hours for the first 24 hours. Thereafter, cyclosporine was continued at 10-12 mg/kg per day, orally or by nasogastric tube, in two divided doses. Doses of cyclosporine were adjusted to maintain a serum creatinine level of less than 2.0 mg/dl and serum trough levels of