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J Thorac Cardiovasc Surg 2002;123:810-815
© 2002 The American Association for Thoracic Surgery
Cardiothoracic Transplantation (TX) |
From the Division of Cardiothoracic Surgery, Cedars-Sinai Medical Center, Los Angeles, Calif.
Received for publication May 4, 2001. Revisions requested June 29, 2001; revisions received Aug 1, 2001. Accepted for publication Aug 31, 2001. Address for reprints: Carlos Blanche, MD, Division of Cardiothoracic Surgery, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Suite 6215, Los Angeles, CA 90048 (E-mail: Carlos.Blanche{at}cshs.org).
| Abstract |
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.50). Two patients in the older donor group died of nonspecific allograft failure, whereas 3 patients in the younger donor group experienced similar posttransplant complication (P
.50). | Introduction |
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| Patients and methods |
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Immunosuppressive therapy
Immunosuppressive therapy consisted of OKT3 induction therapy (5 mg intravenously daily) for 7 days. However, patients with impaired renal function (serum creatinine > 2.5 mg/dL) or patients undergoing combined heart-kidney transplantation received antithymocyte globulin (ATG) (15 mg/kg daily, adjusted for white blood cell count and platelet count) for 7 days. Maintenance immunosuppressive therapy consisted of cyclosporine (INN: ciclosporin) (5 mg/kg per day, for a level of 200 to 400 ng/mL, as measured by a monoclonal fluorescence polarization immunoassay, within the first 12 weeks after transplantation, and a level of 120 to 200 ng/mL thereafter, started postoperatively once the serum creatinine was less than 2.0 mg/dL); azathioprine (4 mg/kg preoperatively, and 2 mg/kg per day postoperatively, adjusted to the patient's white blood cell count and platelet count), but switched to mycophenolate mofetil (1000 mg twice daily) for all patients as of January 1997 (includes 7 patients in the older donor group and 73 patients in the younger donor group); and steroids (methylprednisolone sodium succinate, 1 mg at removal of the aortic crossclamp intraoperatively, and then 125 mg intravenously every 8 hours for 3 doses postoperatively, followed by prednisone, 0.25 mg/kg per day during OKT3 or ATG therapy, increased to 0.5 mg/kg per day, and then tapered off in the subsequent 3 to 8 months). Endomyocardial biopsies were performed according to our surveillance protocol or when acute cardiac rejection was clinically suspected. Cardiac rejection episodes were treated if greater than 1 B (International Society for Heart and Lung Transplantation classification). Routine 2-dimensional echocardiograms and coronary angiograms were performed at yearly intervals or more frequently when clinically indicated.
Cytomegalovirus prophylaxis
Most patients were given 6 doses of intravenous immunoglobulin (500 mg/kg) within 1 week after transplantation, with 5 doses of intravenous cytomegalovirus (CMV) specific immune globulin (125 mg/kg) after the first intravenous immunoglobulin dose. Intravenous ganciclovir was also administered (5 mg/kg every 12 hours but adjusted for renal function) for 14 weeks followed by oral ganciclovir (1000 mg twice daily but adjusted for renal function) for an additional 38 weeks for those patients who were donor CMV positive/recipient CMV negative (high risk). For those patients donor CMV positive/recipient CMV positive and for those donor CMV negative/recipient CMV positive (low risk), prophylaxis consisted of 6 doses of intravenous immunoglobulin and intravenous ganciclovir for 2 weeks followed by oral acyclovir (3200 mg daily but adjusted for renal function) for 24 weeks. Prophylaxis for high-risk patients spanned the first posttransplantation year, whereas CMV prophylaxis for low-risk patients lasted the first 6 months after transplantation.
| Results |
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.50). The mean posttransplant left ventricular ejection fraction in the older donor group was 56.5% ± 13.4% (range 45%-72%), but a statistically significant comparison with the younger donor group could not be made because of insufficient data in the latter group. Two patients in the older donor group died of nonspecific allograft failure in the late follow-up period (at 18 and 27 months, respectively), whereas 3 patients in the younger donor group had similar posttransplant complication (at 13, 21, and 42 months, respectively) (P
.50). Their postmortem diagnosis was confirmed in all patients by autopsy. The causes of death are shown in Table 4.
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| Discussion |
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However, some of these unfavorable results may be due to the fact that older donor hearts traditionally have been allocated to older recipients or high-risk patients and even used as a "biologic bridge" to transplantation until a younger allograft could be available.
2,6,12 Data from the Registry of the ISHLT
1 show that advanced recipient age is another strong factor that adversely affects survival, which may further compound the increased mortality associated with older donors. With the ever-expanding heart transplant recipient population, new strategies for increasing the donor pool have been pursued and the lack of the "ideal" donor heart has expanded the criteria for acceptance of potential donors. Older donor hearts with negative cardiac history and serologies, normal electrocardiogram and echocardiogram, low inotropic support, normal coronary angiogram, and an expected short ischemic time may fill this void. In a study by Ibrahim and colleagues,
5 extended ischemic time (>240 minutes, mean 255.8 ± 6.9 minutes) and increased donor age (>40 years, mean 46.4 ± 0.8 years) did not adversely affect early survival after heart transplantation although no long-term survival was reported. Although some series have reported satisfactory intermediate and long-term results after heart transplantation with the use of older donors,
2,3,6,8,12-14 there are studies that suggest that the extension of the donor age predisposes the recipient to allograft vasculopathy.
2,8
The role of CMV infection has been postulated to accelerate the development of allograft vasculopathy in older cardiac allografts although the exact mechanism is not clearly known.
15 As older individuals, and thus potential donors, tend to have a higher percentage of CMV seropositivity, this may adversely affect the development of CMV disease in recipients with older allografts.
16 Our experience as well as others
2 indicates no significant difference in the incidence of postoperative CMV infection or allograft rejection.
Some investigators advocate the use of selective, rather than routine, coronary angiography to evaluate the presence of CAD in the older donor heart.
2,4 As invasive preoperative studies are not always available at the donor hospital, these potential cardiac allografts should be carefully examined by visual inspection and palpation of the coronary arteries, although the sensitivity and specificity of such techniques are limited. In our experience, coronary arteriography was available in 65% of our older donor population. In the remaining 7 patients, this study was performed before discharge and failed to show any significantly obstructive coronary artery lesion in all of them. Although it appears that there is an increased incidence of CAD requiring posttransplant CABG and retransplantation in the younger-age donor group, along with a longer mean follow-up time, it did not achieve statistical significance. Only long-term follow-up of these 2 groups of heart transplant recipients involving large numbers of patients will accurately determine the true incidence of significant CAD in each cohort of patients. Thus, it may influence the use of older donors for heart transplantation. However, Chau and colleagues
6 reported a much greater incidence of chronotropic incompetence requiring placement of a permanent pacemaker in patients with older donor hearts that was independent of allograft ischemic time and pretransplantation amiodarone therapy. This seems to be a technical rather than a physiologic or an age-related event. We have completely abolished the need for a permanent pacemaker because of sinus node dysfunction in the early posttransplant period in our last 236 consecutive patients undergoing heart transplantation. This was accomplished by adopting an alternative technique for implantation of the cardiac allograft consisting of bicaval and pulmonary venous anastomoses as our standard technique, including all the patients reported in this study.
17 Further, even though there was a slight modification in the immunosuppressive protocol for all patients in the last 3 years of this study, it had no direct impact on the survivals in either group.
Although there are some limitations and methodologic restrictions of this studysuch as the small number of patients involved in the older donor group and the insufficient data regarding posttransplant angioplasty/stent interventions (usually performed at the referring hospital)some valid conclusions can be drawn. On the basis of our experience with older donor hearts, we believe that donor age per se should not be a contraindication for consideration for heart transplantation. These older donor hearts should be accepted regardless of age, provided they demonstrate satisfactory physiologic and hemodynamic performance. In fact, our allocation criteria for cardiac allografts 50 years of age and older have evolved since the completion of this study; those donor organs are now matched with the proper recipient on the basis of the clinical characteristics of the donor and recipient, regardless of the recipient's age. Exception is made in those rare circumstances of donor organs with documented limited CAD that require concomitant CABG at the time of allograft implantation; those cardiac allografts are usually matched with recipients 60 years of age and older who are in urgent need of transplantation. The selective use of older allografts for heart transplantation maximizes organ use and would expand the donor pool without an adverse effect on long-term results. This approach implies a careful selection and close surveillance for the development of allograft vasculopathy. Further, even the use of the "less than ideal" older donor heart should be considered and assessed on a case-by-case basis. Such is the case when mild to moderate CAD is present or a more prolonged period of allograft ischemic time would be expected, provided it is selectively allocated to the proper recipient. An exception to these expanded criteria is the use of hepatitis C-positive donors, even in hepatitis C-positive recipients since there is more than one strain of the virus and the presence of antiviral antibody does not guarantee immediate immunity.
18 Experience with kidney transplantation
19 indicates that nearly all recipients from hepatitis C-positive donors become infected with the virus. There is no reason to believe that hepatitis C-positive or hepatitis B-positive cardiac allografts would behave any differently.
Finally, with the exponential expansion of heart transplant recipient lists and the limited donor organ availability, the use of the less than ideal cardiac allograft has become a necessity and is no longer an isolated event. There is an accepted attitude to "bend the rules" and expand these criteria for the urgent transplant recipient with otherwise no possibility for survival. An older donor heart has traditionally represented a high-risk donor, but the clinical and ethical dilemma has been partially answered by the satisfactory long-term results achieved with the use of other "unacceptable" heart donors in younger and not so critically ill patients.
12 The objective of applying selection criteria to organ donors is to provide recipients with the optimum chance for a successful transplantation, and our study may help clarify this issue. When faced with a critically ill patient awaiting transplantation, we believe an available donor heart represents a viable alternative to mechanical assist devices (with their attendant inherent morbidity and mortality). Does an older cardiac allograft (defined as 50 years of age and older), with normal anatomic and physiologic function, represent a higher risk alternative then a mechanical ventricular assist device? Although the comparison of survivals of such alternatives is not clearly known, the reluctance of many transplant centers to use older donor organs for heart transplantation must be balanced against the disparity that exists between supply and demand of donor organs. Unfortunately, this gap continues to grow and such devices will not alleviate the exponentially growing demand for donor organs.
Is the use of older donor hearts for transplantation only acceptable to older recipients, in whom the feasibility of a mechanical assist device may be limited or perhaps contraindicated, or is it equally applicable to younger recipients awaiting heart transplantation in a more elective fashion? Many facets of this study warrant further investigation to answer the many questions raised, but the satisfactory results with this group of older donor hearts may expand the acceptance criteria even further in the future. In addition, it is fundamentally important to recognize patients' preferences regarding the different alternatives available, particularly for the younger and the not so urgent patients waiting for transplantation, to reconcile the practical, clinical, and moral issues involved.
A careful follow-up and continued analysis of these data from larger series and/or multicenter studies may define the true risks and benefits of this approach and may guide the limits of expanding the donor criteria.
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