Oriented to Thoracic Transplant Recipients -- January 1997

CHARACTERISTICS OF PATIENTS SURVIVING MORE THAN TEN YEARS AFTER CARDIAC TRANSPLANTATION

William M. DeCampli, MD, PhD, Helen Luikart, MS, RN, Sharon Hunt, MD, FACC, and Edward B. Stinson, MD, Stanford Calif

Cardiac transplantation has proved to be a reasonable therapeutic option for selected patients with end-stage heart failure. This conclusion is supported by the favorable survival rate and postoperative quality of life of patients who have undergone cardiac transplantation, compared with these findings in those cases managed medically. Most studies that support this conclusion, however, have had mean or median follow-up periods of only a few years and thus do not provide evidence of the clinical status and perceived quality of life in the longer run, that is, beyond a decade after operation.

This limitation is imposed by (1) the relatively low 10-year survival of patients operated on before 1982 (approximately 30'% at Stanford) and (2) the existence of only a very few institutions that performed a significant number of transplantation operations before 1983. With more than 2000 heart transplant operations currently done per year in the United States, and an actuarial 10-year survival rate of approximately 50%, an understanding of the clinical status and perceived quality of life more than a decade after operation is of obvious pertinence.

In this paper we present results of a study of 40 patients who are alive or who lived longer than 10 years after cardiac transplantation at a single institution, specifically, we tested the following hypotheses about these long-term survivors: (1) the prevalence of graft coronary artery disease (CAD) continues to increase with time and graft CAD is a significant source of mortality for this group of patients, (2) graft function is well-preserved beyond 10 years after transplantation, and (3) the exercise capacity of these patients and sense of well-being are reasonably close to those of the age-matched population at large.

Finally, we present a derivation of clinical factors that correlate with longer term survival in our institution' s total transplantation experience.

Patients and methods

The preoperative clinical status and postoperative clinical course (including regular follow-up history, physical examination, laboratory values. cardiac biopsy results, and cardiac catheterization data) of all patients undergoing heart transplantation at Stanford since 1970 were examined with the assistance of a database updated to January 1, 1992. The subset of patients who survived more than 10 years after their first heart transplant operation was examined in detail. Of the 661 patients in the database, 40 patients fell into this subset: 26 of these patients were alive and 14 had died. Seven of the 40 patients underwent cardiac retransplantation. All but two of these received retransplantation more than 10 years after the original operation. One patient had undergone retransplantation twice.

The current clinical status of the living patients was further determined either at Stanford or by review of records of the patient's primary cardiologist. The evaluation included a review of active and past medical problems. current medications, family and social history (including smoking, drinking, and job or marital status change since transplantation), physical examination (including current weight), laboratory values (including hematocrit, blood urea nitrogen, creatinine, fasting glucose, total cholesterol, triglycerides), and data from all available cardiac catheterization reports. Graft CAD was assessed either angiographically or at autopsy. The incidence was determined only for CAD occurring in first-time allografts (that is, CAD in a second allograft was not considered). Actuarial freedom from CAD was calculated and compared with that in the set of all other patients who underwent transplantation at this institution. Infection and acute rejection data were obtained from the database. Presence of acute rejection was noted when a cardiac biopsy specimen showed International Society of Heart and Lung Transplantation grade II or higher.

So that functional status could be assessed, exercise tests were done on available patients. The actual exercise protocol varied for each patient; however, a "maximal" test was completed and maximum heart rate, blood pressure, duration, and exercise capacity (expressed in metabolic equivalents [METS] standardized for each exercise or protocol) were determined. Results were compared with those of an age-matched sample of the normal population and with those of an age-matched cohort of patients who underwent transplantation an average of 7 months before evaluation.

So that we could evaluate patient-perceived health status or "sense of well-being," each patient in the subset completed both part I of the Nottingham Health Profile NHP) and the General Well Being (GWB) examinations. The NHP examination is purported to evaluate "perceived distress." The higher the score (0 to 100 for each of six sections), the more the distress. Weightings derived from the application by McKenna, Hunt, and McEwen of Thurstone's method of paired comparisons to the British population were applied to each question in the NHP survey. The GWB examination is best described as reflecting "expressions of psychiatric states of depression and anxiety or the absence thereof," according to Fazio. Scores from both tests were compared with those of published age and gender-matched norms. Correlations were calculated among the NHP and GWB scores, treadmill performance, employment and marital status, and number of current medical problems.

Because we were interested in factors that might contribute to (or at least be correlated with) the longevity of this subset of patients, two comparison groups were formed from the set of all patients who underwent transplantation at Stanford: (1) patients who survived 0.5 to 5.0 years after transplantation and (2) patients who survived 5 to 10 years after transplantation. The age at the time of transplantation; actuarial rates of freedom from acute rejection and from vital, bacterial, protozoal, and fungal infection; and cause of death were determined for each group and compared.

Finally, a formal multivariate analysis was done to further clarify the possible factors. Twenty-one variables were cited as possibly predictive of longevity. Variables evaluated at the time of transplantation included duration of preoperative illness, age at the time of transplantation, race, gender, hospital length of stay, number of human leukocyte antigen mismatches, serum creatinine level at the time of discharge, diastolic blood pressure at the time of discharge, donor age, donor race, donor gender, donor cytomegalovirus (CMV) status, and recipient CMV status. Variables evaluated at I year after operation included blood urea nitrogen. serum creatinine, diastolic blood pressure, left ventricular ejection fraction, degree of CAD (quantitated by the number of vessels with significant stenoses), number of acute rejection episodes, number of episodes of infection, and incidences of CMV infection (as determined by the presence of inclusion bodies in tissue, positive culture, or greater than fourfold rise in anti-CMV immunoglobulin G serologic titer). The nine most significant variables were determined. The set of all patients who underwent transplantation at this institution was then chosen and a subset determined that consisted of patients each meeting all of the following three criteria: ( 1 ) survival at least 1 year after operation, (2) not having retransplantation, and (3) having no missing data among the nine vanables. By including only patients who survived at least 1 year, we eliminated operative and early postoperative complications and early refractory rejection and infection as causes of mortality. The final subset, consisted of 122 cases.

Results

The majority (32/40) underwent transplantation before the introduction of cyclosporine into our program in December 1980. In comparison with patients in the short survival (0.5 to 5 years) group, the patients in the group with more than 10-year survival received transplantation at a younger mean age. In the former group, only 15 of 119 patients were younger than 30 years old at operation versus 18 of 40 for the long-term survivors.

By 0.5 years after operation only 15% of patients are free from at least one rejection episode. The mean number of infectious episodes was 2.24. In each of the four pathogen categories, the long-term survivors had significantly greater freedom from infection compared with patients in the 0.5- to 5-year and 5- to 10-year comparison groups. Similarly, when analyzed according to location of infection, the most significant difference favoring long-term survivors was found in the incidence of pneumonia. This fact is consistent with the fact that, when infection was the ultimate cause of death, the lungs were the most common primary site of infection.

The patients take an average of 6.6 medications per day (range 3 to 14). All patients take prednisone at a mean dose of 12.7 +/- 3mg/day, and nearly all are taking azathioprine. Patients who underwent transplantation or retransplantation after December 1, 1980, are taking cyclosporine.

Other common medications include a variety of antihypertensive drugs, diuretics, prophylactic antibiotics, and antiplatelet agents. Disorders possibly attributable to corticosteroid usage include hypertension (55%'), osteoporosis (35%), cataracts (27%), cushingold appearance (26%), diabetes melitus (24%), and weight gain (19.8 +/- 17.8 kg). Other chronic medical problems include seven cases of chronic renal insufficiency, 20 cases of graft CAD, and 27 noted miscellaneous problems (many attributable to adverse effects of medications).

Most recent laboratory values for the patients are shown in the following Table.

Item Value Range Hematocrit 42.0 34-48 Glucose (mg/dl) 109.7 59-257 Urea nitrogen (mg/dl) 23.8 6-51 Creatinine (mg/dl) 1.4 .6-2.8 Total cholesterol (mg/dl) 24.2 109-445 Total triglycerides (mg/dl) 173.4 58-468

Of the eight patients with serum creatinine values higher than 1.8 mg/dl, seven were taking cyclosporine and four of these seven had undergone retransplantation. The mean total cholesterol and triglyceride values are influenced by one patient with isolated hypertriglyceridemia (most recent measurement 468 mg/dl) and by two patients with combined disorders (cholesterol 445 and 293 mg/ dl, triglycerides 273 and 298 mg/dl, respectively).

A remarkable feature of the most recent cardiac catheterization data is the relatively normal hemodynamic data, indicating, on average, well-preserved graft function at this long follow-up interval. Aortic diastolic pressure and left ventricular end-diastolic pressure were mildly elevated. The prevalence of CAD was 51.0%. For each patient, we determined the earliest postoperative time in which anglographic evidence of graft CAD was detected: this mean value was 9.3 years. Values for number of acute rejection episodes, aortic diastolic pressure, serum cholesterol, current age, current weight, left ventricular end-diastolic pressure, and NHP score were not significantly different between the subgroups of patients with and without evidence of CAD.

Fourteen of 26 living patients underwent maximal exercise testing within 1 year of the current evaluation. The mean age of this subset was 4l .8 years. The results are shown in the following table:

Item Mean Range Duration (min.) 8.7 2.0-16.3 Max. HR (beats/min.) 136.0 86-155 Percent max. HR* 77.3 50-92 Max. systolic BP (ram Hg) 171.4 140-208 METS 9.2 5.5-12.9 * Maximum heart rate = 220 - age in years.

Patients with heart failure or poor overall medical condition tended to refuse the test and thus the results are biased on the high side. One test was stopped because of electrocardiographic evidence of ischemia and the remainder were patient-terminated because of fatigue. There was a significant correlation between METS performed and cardiac index on most recent cardiac catheterization.

Twenty-seven patients completed the GWB and NHP examinations. The average GWB score was 75.3_+ 21.6, which is nearly identical to the male normal population mean of 75. I + 14.8. The trends did seem to point to higher scores for the patients undergoing transplantation, especially in the oldest age group (50 to 64 years) and subdivisions of mobility, pain, sleep quality, and energy level. NHP scores correlated well with GWB scores. We could not find significant correlations between the GWB or NHP subdivision scores and variables such as number of current medical problems, complications of corticosteroids, or performance on the exercise test. Twenty percent of patients currently smoke, 52% are currently employed, 73% have changed jobs since transplantation, 37% have had a change in marital status since transplantation, and 38% report some sexual dysfunction.

The predominant cause of death was CAD in the long-term survivors, with no deaths attributable to complications of acute graft rejection. In the short-term survivors, rejection and infection play a dominant role in mortality.

The four variables found to be independently correlated with death after transplantation were age at transplantation, preoperative duration of illness, evidence of postoperative CMV infection, and ejection fraction at 12 months after operation. The relative risk of death associated with an increase of 5 years in the duration of illness was 1.53. An increase of 5 years in the age at transplantation carried a relative risk of 1.28. A decrease in the ejection fraction at 12 months of 0. 1 resulted in a relative risk of death of 1.51.

History of postoperative CMV infection approximately doubled the risk of death. The probability of death within 6 years after operation was 26.7% without CMV infection and 46.0% with CMV infection, a relative risk of 1.72.

Discussion

Although justification of cardiac transplantation as an effective treatment for end-stage heart failure is provided by prolonged (>2 year) survival and improved functional status, the argument in its favor is greatly strengthened by demonstration of the possibility of longer-term survival with sustained acceptable functional status. This demonstration was precisely how the current importance of renal transplantation was established 15 years ago. It is appropriate, therefore, to discuss our results in the context of this paradigm.

General medical condition. Aside from rejection and graft CAD, most of the aforementioned medical problems seen in our transplant recipients are probably complications of immunosuppressive therapy. Divakar and colleagues found a similar variety and incidence of problems in a group of 36 patients surviving greater than 10 years after renal transplantation. The specific role that corticosteroid usage plays in these problems has led many programs to use corticosteroid-free maintenance immunosuppression. Initial results of this regimen are encouraging, although the regimen is not feasible in many patients. We found that the incidence of chronic renal insufficiency was highly correlated to the use of cyclosporine in our group. This problem still remains, although trials using "low dose" cyclosporine and cyclosporine analogs such as FK 506 may hold some promise. The incidence of infection in our long-term group was remarkably low relative to that in the two comparison groups, an observation consistent with the fact that infection is a major cause of early death with immunosuppressive therapy. The fact that the curves of actuarial freedom from acute rejection in this group and both comparison groups were all nearly identical means, however, that other factors influenced the group's susceptibility to early fatal infection, such as differences in severity or frequency of rejection or exposure to pathogens, degree of augmentation of immunosuppressive drugs, or individual differences in the degree to which given doses of immunosuppressive drugs influence the host response to pathogens.

Graft function. The present work demonstrates, for the first time, preserved graft function well in to the second decade after transplantation. Von Scheidt and associates found no evidence of systolicdysfunction or dilated or restrictive cardiomyopathy in 71 patients followed up to 7 years after operation. Tischler and associate' s demonstrated mild increases in left ventricular endsystolic and end-diastolic volumes, but no significant change in left ventricular mass or ejection fraction in 22 patients doing well and followed up a mean of 4 years after operation. Frist and colleagues, in a study of 174 patients with a mean age of 36 years and follow-up period of 5 years, found no deterioration in graft hemodynamics. Mean cardiac index and left ventricular end-diastolic pressure were almost identical to those in the present group.

Exercise tolerance. Although the exercise tests described in this paper were not standardized to a particular protocol, certain points can be made. First. maximum heart rate and systolic blood pressure were lower than those of a closely age-matched sample of the normal population, but were similar to those of an age-matched group of transplant recipients evaluated a mean of 7 months after operation in a study by Kavanagh and associates. These results may be explained by the failure of the graft to regain sympathetic innervation a mean of 12 years after implantation. Second, when each patient's estimated maximal oxygen consumption (expressed in METS) is compared with the mean value from an age matched group of normal subjects not having transplantation, the group performed an average of 1. l 9 METS less than normal subjects as determined by Bruce, Kusumi, and Hosmer and 2.55 METS less than normal subjects as published more recently by Morris and colleagues. These results correspond to an exercise capacity of 88% + 6% and 79% + 6% of normal, respectively. Yet the group' s mean performance was substantially better than the average of 6.2 + 1.3 METS performed in the group of transplant recipients at 7 months after operation in the report of Kavanagh and associates. A possible interpretation of these data is that exercise capacity improves with duration after operation, which is a hypothesis that could be better tested by a longitudinal study. Alternatively, the data may indicate a time-related bias in patient selection. The cause of the remaining decrement in exercise capacity at 12 years after operation is uncertain, but it may be compensated for, as Kavanagh and associates' demonstrated, by an exercise training program.

Graft CAD. The most remarkable finding from the angiographic data is that this group of long-term survivors does not escape graft CAD. In fact, the actuarial incidence during the first 10 years after operation is similar to that of the transplant population as a whole. Furthermore, the data indicate that by 20 years after operation essentially all patients can be expected to have graft CAD identifiable by conventional angiographic techniques. The comparison between our group and the overall transplant population is made with some reservation; that is, because the overall transplant population is right-censored by death in the first 10 years, its actuarial prevalence of CAD will be underestimated relative to the estimate for our group. Studies that have attempted to determine risk factors for development of graft CAD give inconsistent results, and the reported prevalence of CAD varies widely. Indeed, we were unable to associate any variables with the presence of CAD in our small group of patients.

Psychosocial evaluation and perceived quality of life. In previous, shorter-term studies in this category, the principal findings were ( I ) overall sense of well-being improves after 'transplantation relative to the preoperative state, (2) on the average, there is no deterioration of quality of life with time, perceived quality does not correlate significantly with medical or demographic data, (4) a substantial minority of patients have problems that decrease quality of life, especially weakness, sleep disturbances, and sexual dysfunction (impotence), (5) the preoperative perceived quality of life affects the postoperative quality of life and perhaps survival, and (6) about 50% regain employment after operation.

Several of these findings seem to hold for the present group of patients evaluated more than 10 years after transplantation. The trends in the NHP scores are in accord with those of a large study by Rosenblum and associates, who found that a group of transplant recipients with a median age of 53 years had Sickness Impact Profile scores "similar to loose of cardiac arrest survivors and postmyocardial infarct patients." On the other hand, Aravot and colleagues found much lower NHP scores at a mean of 22 months of follow-up in a group of patients undergoing transplantation after age 60 years. It could be that a combination of older age and longer postoperative duration correlate with an increasing perception of distress. The percentage of patients employed is similar to that in other reports, indicating that there does not appear to be a decline of employment with duration after operation. As in prior reports, we could find no correlation between medical data and perceived quality of h re. In the future, longitudinal studies will permit a better assessment of the long-term, time-dependent trends in these psychosocial and quality-of-life parameters.

Multivariate analysis of survival. Age at the time of transplantation has been cited previously as a correlate with survival duration. This result should be interpreted with caution, however, because patients who received transplant earlier in our experience were younger at the time of transplantation than were patients who received transplant later in our experience. This bias means that relatively more right-censoring exists in the survival function of the older patients. A second problem with the interpretation of the age factor is that the instantaneous death rate of patients undergoing transplantation at older ages (>50 years old) is significantly influenced by that of the age-matched non transplanted population. This means that death beyond this age may well not be related to the sequelae of heart transplantation.

The duration of illness before transplantation was an intriguing correlate of survival. Evans and associates found that higher levels of pre transplantation functional impairment, correlated strongly with poorer post transplantation survival. O'Brien, Buxton, and Ferguson found that patients indicating fewer quality-of-life restrictions before transplantation had a better likelihood of long-term survival. The degree to which preoperative duration of illness correlates with these two factors is unclear. However, a relationship is suggested by the fact that congestive heart failure is usually progressively debilitating. It could be that subtle aspects of debilitation resulting from cardiac failure are not reversed with cardiac transplantation or are perhaps worsened by the adverse effects of immunosuppressive therapy.

In a recent study by Elkins and associates, primary or recurrent CMV infection occurred in 64% of heart transplant recipients a mean of 164 and median of 84 days after operation. Some of the decrease in survival as a result of CMV infection can be accounted for by various manifestations of the disease or syndrome. The correlation of a history of CMV infection with survival and with CAD incidence was first noted by Grattan and colleagues in 1989. CMV can regulate major histocompatibility complex class I expression on smooth muscle cells, and CMV infection is associated with progressive intimal thickening of intramyocardial arterioles in cardiac grafts. It is thus likely that the late effects of CMV infection on survival are due to its contribution to graft CAD. This notion is supported by our multivariate analysis, that is, partly because graft CAD is not usually detectable in the first 12 to 24 months by conventional angiographic analysis, CMV infection, and not graft CAD per se, was an independent risk factor for mortality.

The ejection fraction at 12 months was the fourth significant correlate with survival in our analysis. This result is not surprising. Myocardial dysfunction can result from a variety of causes, such as severe recurrent rejection, early graft CAD, myocarditis (often viral or drug-induced), cardiomyopathy, or "nonspecific" graft failure. In our analysis, ejection fraction at 12 months correlated somewhat with detection of CAD at 12 months, but not with diastolic blood pressure at 12 months, the total number of episodes of acute rejection, or the incidence of all viral infections.

The vast majority of this group of patients underwent operation in an era when many of the improved methods of patient management now in use were unavailable, such as cyclosporine, '!steroidfree" maintenance immunosuppression, specific ami-T cell induction immunosuppression, routine early antibiotic prophylaxis against CMV (ganciclovir) and Pneumocystis carinii (trimethoprim/sulfamethoxazole), third-generation antibiotics, early use of prophylactic calcium channel blockade (diltiazem) for reduction of graft CAD progression, improved donor selection, and other empiric features gained from acceleration of experience in cardiac transplantation worldwide after about 1983. Thus the conclusions we have drawn from our study are likely to be unique to this group.

Conclusions. Results of this study of longterm survivors of heart transplantation support the following conclusions: (1) graft function is well-preserved into the second decade after transplantation, (2) exercise capacity is 80% to 90% of that of the age-matched general population, (3) patient-perceived health and well-being is close to that of the age-and sex-matched general population, (4) the cumulative incidence of graft CAD is similar to that of the cardiac transplant population as a whole, continues to develop after 10 years, and is a significant source of mortality, and (5) long-term survival is correlated with four factors that can be evaluated by 1 year after transplantation; younger age at time of transplantation, shorter preoperative duration of illness, absence of postoperative CMV infection, and larger left ventricular ejection fraction at 1 year after operation.

Cardiac transplantation can provide patients with end-stage cardiac failure an acceptable general medical condition, functional status, and perceived quality of life well into the second decade after operation.

Discussion

Dr. Alfredo Trento (Malibu, Calif ). The importance of this review is not in the comparison between different groups of patients undergoing transplantation. These were groups of patients who received transplantation in different periods of time when there were different immunosuppressive regimens and in which there were very different understandings about the side effects of immunosuppression therapy and about how to prevent the side effects. The conclusions are extremely important and are those that we transplant surgeons have been expecting.

The conclusions are that the quality of the life for the surviving patients is similar to that of an age-matched population and that the main cause of late death beyond 10 years after transplantation is CAD. CAD is progressive to the point that if we wait long enough every transplant recipient would be affected. The other conclusion is that rejection and CAD together are the main cause of death in the patients who died within 10 years of transplantation. This brings me to my first question. In the manuscript the authors reported that only 15% of the patients are free of rejection 6 months after transplantation. I reviewed our experience and found that at I year after transplantation 60% of the patients are free of rejection and 60% of them have also been weaned from steroids. Can you clarity this high prevalence of rejection, and do you think that played a role in the long-term survival and in the incidence of CAD?

Dr. DeCampli. I think the important factor here is that these patients received transplantation in a unique interval of time in which we were on a very steep learning curve to understanding how to best manage transplant cases preoperatively, immediately postoperatively, and in the long term. The patients underwent transplantation between 1970 and 1982. Only a few of them ever received cyclosporine. It was probably the absence of cyclosporine, and not so much the absence of anti-CD4 induction therapy, that accounted for the high incidence of rejection in the first couple of months after operation. I qualify that by saying that even with the addition of cyclosporine in the modern era and with the addition of OKT3 routinely, Stanford's incidence of rejection in the first 6 months is still 75 % to 80%. That number does differ from yours and I cannot, offhand, explain that difference.

Dr. Trento. The manuscript points out the effect of CMV infection on survival: history of postoperative CMV infection doubles the risk of death at 6 years after transplantation. It is clear now that CMV infection seems to trigger some sort of generalized immunologic reactivation that may trigger a form of acute or chronic rejection that we do not know how to diagnose or to treat. This may play a role in the occurrence of CAD. For this reason, we have started at our institution an aggressive and also costly type of prophylaxis against CMV infection, which involves the administration of hyperimmune gamma globulin weekly for the first 4 weeks and then intravenous administration of ganciclovir for 2 weeks followed by oral agyclovir for 3 months. With this regimen we have decreased the incidence of postoperative CMV infection from a range of about 35 % to 70% as reported in the literature and from a range of about 50% reported in this paper to 4% in patients who were CMV positive before transplantation arid to about 26% in the difficult group of patients who were CMV negative before transplantation and received a CMV-positive organ. Would you comment on this aspect and also basically on the approach that Stanford is taking at the present for CMV prophylaxis?

Dr. DeCampli. Stanford's approach currently is as follows. Ill designate D as donor and R as recipient and D-negative R-negative means that neither was CMV positive, then we have no prophylaxis for D-negative R-negative situations. In the D-negative R-positive and D-positive R-positive situations, we give ganciclovir for 2 weeks intravenously and for 2 weeks orally for a total of 4 weeks of therapy. With this regimen we have achieved a significant reduction, as compared with the results of these long-term survivors, in CMV infection in the first 6 months. Thus the incidence is now approximately 15% rather than 50%. In the so-called CMV mismatch group, that is, D-positive R-negative, which is the most difficult group, we have found no benefit with 4 weeks of ganciclovir therapy. Stanford has empirically extended its coverage from 4 to 6 weeks. Stanford has found no particular benefit to the use of CMV antiglobulin, in particular in the D-positive R-negative group. We have had no early deaths from CMV infection in the past 5 years. However, we cannot yet make a statement on the effect of any of these prophylaxis regimens on the later incidence of graft CAD. I am not sure any institution can do that yet.

Dr. Trento. It is my feeling that any immunosuppression based on cyclosporine or cyclosporine analogs has reached a plateau and basically we have gotten out of cyclosporine everything that cyclosporine can give. Further improvement in results will probably be only minor unless a qualitative change in the immunosuppressive therapy is made. Would you like to comment on this last point?

Dr. DeCampli. If you ask how we can best improve the survival of patients undergoing transplantation and if you make the assumption that graft CAD is caused by a chronic rejection phenomenon, then the answer is more selective immunosuppression leading ultimately to what is now popularly known as "organ-specific clonal anergy." One possible way of achieving this is the use of total lymphoid irradiation for tolerance induction. The manner in which stem cells regenerate after total lymphoid irradiation is in a peculiar order that, in fact, favors acceptance of a transplanted organ; that is to say, suppressor cells seem to recover first after total lymphoid irradiation, blunting the effect of the particular lymphold subset that acts against the implanted organ. Total lymphold irradiation, in conjunction with the use of a new anti-CD4 antibody that actually depletes CD4 cells (rather than just altering their surface membrane structure), is currently being investigated as a combination that could give us more tolerance induction and organ-specific clonal anergy. Dr. Bruce Reitz is working on this problem in the laboratory at Stanford currently with primates.
(J. THORACIC & CARDIOVASCULAR SURGERY June 1995;109:1103-15)
(Abridged by D. Marshall)

DEATHS AT A CHICAGO HOSPITAL LEAD TO RESIGNATION AND REVIEW

By Thomas M. Burton - Staff Reporter of The Wall Street Journal

CHICAGO (12/12/96) -- Before getting a heart transplant, Edward A. Keller had reason to feel confident. He was a patient at a well-known hospital, Rush-Presbyterian-St. Luke's Medical Center. Its heart-transplant center was the eighth largest in the U.S. Its medical director was a renowned cardiologist who edited the nation's leading heart-transplant journal.

But unknown to him, some of Rush's own top surgeons had qualms about patient care in the transplant center, which had expanded its volume of surgery rapidly under the prominent medical director, Mafia Rosa Costanzo. Mr. Keller was about to become their latest case in point.

When healthy, the 59-year-old labor negotiator weighed between 180 and 190 pounds. But the heart Dr. Costanzo secured for him last April came from a 132-pound woman. That big a difference is generally a concern, but in this case it was especially so because Mr. Keller had pulmonary hypertension, a condition in which arteries supplying the lungs resist blood flow.

The unit's top surgeon, Alvaro Montoya, refused to do the surgery. "1 informed [Dr. Costanzo] that there was a donor-recipient mismatch which would result in right ventricular failure," he later wrote to the dean of Rush Medical College.

But Dr. Costanzo pressed less-senior surgeons to proceed, hospital correspondence and documents show. Five days after the operation, Mr. Keller died of what the documents describe as heart and liver failure. Dr. Costanzo declines to comment on the case, citing patient confidentiality- a principle that Rush's general counsel describes as a legal impediment to discussing cases.

Difficult Decisions
For every patient with a failing heart, transplant physicians must decide whether a transplanted one would be likely to prolong life and, if so, whether to use the first heart available or wait for one that is better-suited. While some centers are quicker to transplant than others, hospital records suggest the Rush Heart Failure and Cardiac Transplant Program has been particularly aggressive in this regard. It rapidly increased its volume of transplants. After opening in mid-1994, it vaulted to the No. 8 spot in the nation in 1995, doing 45 transplants that year.

Boosting the numbers has advantages, because hospitals need to achieve volume milestones before government and private insurers will reimburse the cost of the surgery. And some managed-care companies approve payment for transplants only at the busiest institutions, insurance executives say, on the premise that high volume makes for high success rates.

It hasn't at Rush. Of its 81 transplant patients, 20 have died, giving it a 75 % survival rate, well below that of many other major centers. New York's Columbia-Presbyterian Medical Center has a 91% survival rate over the same period, and the University of Arizona Health Sciences Center in Tucson has a 97% rate.

A critical test is survival for one month after surgery. Eighty-six percent of Rush's transplant patients have survived at least a month, a lower rate than at most of the other large transplant centers. Eleven of Rush' s 81 patients failed to last a month. By contrast, Cedars-Sinai in Los Angeles has done 160 consecutive transplants without a first-month fatality.

Request for a Review
Rush surgeons are alarmed. In documents obtained by The Wall Street Journal, three of Rush' s six transplant surgeons raise fundamental questions about quality of care both before and after transplant surgery. Questions also have been raised about some of the hearts used and about the transplant unit's methods of obtaining the scarce organs.

The hospital's chief of cardio-thoracic surgery, Hassan Najafi, recently persuaded administrators to review at least 11 of Rush's 20 transplant deaths. One member of the review committee, Rush transplant surgeon Michael J. DaValle, already has written an analysis saying: "Reviewing these deaths has reinforced to me my feeling that unless immediate major changes are made, 1 would prefer not to expose myself and apply my surgical skills to decisions that are being made by others, whose judgment is obviously in question."

As for Dr. Montoya, who is widely regarded as perhaps the top transplant surgeon in Illinois, he recently resigned, after imploring Rush officials to overhaul the program. In a letter to the dean of Rush Medical College, Dr. Montoya wrote: "The problems I have identified raise issues not only of poor judgment, but of potential malpractice."

Hospital officials say the fast attainment of high transplant volumes never compromised patient care. They note that the federal government recently approved Rush for reimbursement of transplant costs for Medicare patients, based partly on its survival rates, which Rush says "compare favorably with national and international standards." As far as is known, Rush hasn't been sued over any transplants.

Rush says it views transplant as a "last resort" to be used when "the only alternative is certain death." It says decisions to transplant are made by a team that includes surgeons, cardiologists, nurses, psychologists and social workers, and there is "no hard and fast formula" on when to proceed.

As for accepting donor hearts of questionable quality or size, Dr. Costanzo notes not only that heart-failure patients may die soon if they don't get a new heart, but also that she and other transplant physicians are working hard to increase the size of the donor pool. She cites medical articles suggesting that small hearts in large recipients may be acceptable. "I would take a heart that might appear initially to be questionable," she says. Much of the criticism, she explains, involves matters of medical judgment.

Why not give patients a voice in such matters? Mr. Keller never knew he was receiving the heart of a much smaller person, nor that the unit's top surgeon disapproved of the match, according to his wife; she says they requested but never received any information about the donor. Had they known about the questionable match, Mr. Keller "would have lived out his life and taken his chances at home," says Linda Keller. Dr. Montoya, the top surgeon who refused to do the operation, told administrators that Mr. Keller "was stable enough to wait for a more optimal donor heart."

Letters From Lawyers
Rush has tried to keep hidden all conflict over its transplant program. When physicians at two other hospitals accused Rush of taking questionable measures to get expedited access to donor hearts, the physicians got letters from a lawyer representing Rush, Thomas E. Johnson, calling their allegations "false and defamatory." And when Rush set up its own committee to look into the transplant unit, Rush General Counsel Max Douglas Brown warned committee members that "the medical center is prepared to take the strongest possible legal and disciplinary action against anyone making an "improper disclosure" of the panel's work.

A lot of money is at stake. A hospital may make as much as $25,000 in profit on the 100,000 cost of transplant surgery, and often gets lots of revenue afterward from long patient stays. Also, the prestige of a heart-transplant center can attract patients to other services.

Rush, a leading teaching hospital, rises imposingly above the Eisenhower Expressway just west of the skyscrapers in Chicago' s Loop. It is a health-care behemoth, employing 1,450 doctors and scientists. It is also the hub of a nine hospital medical system. But until 1994 the hospital didn't have a heart-transplant team, and early that year it set out to remedy this.

Rush spent nearly $12 million on staff, equipment and renovation, hiring five cardiologists and a team of nurses and assistants, and assigning several surgeons to the unit. Its prize hire was the Italian-born Dr. Costanzo, now 42 years old, a graduate of the University of Bologna medical school who had become editor of the Journal of Heart and Lung Transplantation. Dr. Costanzo, who is a cardiologist, not a surgeon, has delivered lectures at symposiums around the world. Under her stewardship, the heart-transplant program at Loyola University Medical Center became the busiest in the Chicago area.

Trying to Woo Patients
But just as would later happen at Rush, her aggressiveness at Loyola worried some cob leagues. "Maria is willing to take chances that I was uncomfortable with," says cardiac surgeon James Houck of the State University of New York at Buffalo, who worked with her at Loyola. "She exhorted me one time to take a heart that I knew was no good. She pretty much demanded that we take it, but we wouldn't." Dr. Costanzo declines to comment.

At Rush, Dr. Costanzo quickly stirred controversy. She sent letters to transplant patients at Loyola, trying to lure them away to Rush. One inducement: She said Rush was part of a clinical trial of two drugs that she termed "more effective" in preliminary research studies" than standard drugs at preventing the body from eventually rejecting a new heart.

Food and Drug Administration rules say a clinical investigator "shall not represent in a promotional context that an investigational new drug is safe or effective...." Dr. Costanzo defends her letter, saying: "What I said was that there were preliminary data, not a conclusive study, and that's the truth." Otherwise, the Rush program got off to a commendable start. Thirteen of the first 15 patients survived for more than a year, and remain alive. That one-year survival rate of 87% was in the same range as those at some established transplant centers.

Going to Top of the List
In 1995, Rush's transplant rate quickened, to nearly one a week. But Rush drew criticism, from both inside and outside, for a method it used that tended to enhance its access to donor hearts. It was putting an unusually high percentage of patients on a mechanical device called the Heart- Mate, which helps a failing heart to pump until a donor organ becomes available. Installing it requires making a 1 1/4-inch hole in the left ventricle, and poses stroke and infection risks. Intended for use in only the most serious cases, the HeartMate also had the effect in Illinois in 1995 of automatically pushing patients to the top of the donor-heart waiting list. Such was the policy, in 1995, of the Regional Organ Bank of Illinois.

From October 1994, when the FDA approved the HeartMate, through July 1995, Rush placed 52% of heart-transplant candidates on the machine. This compares with 20% at the University of Minnesota Hospital, 14% at Columbia Presbyterian and 5% at the University of Alabama at Birmingham.

Several Chicago-area physicians complained about heavy use of the machine at Rush. In a letter to federal transplant officials, two doctors from Evanston Hospital's transplant program and one from St. Francis Medical Center in Peoria wrote that Rush had snared many donor hearts by using the assist device" in very large numbers of patients, some of whom apparently were not ill enough to warrant this type of intervention." Robert B. Karp, chief of cardiac surgery at the University of Chicago Medical Center, in a 1995 letter to the regional organ bank, described relatives of transplant patients as saying that Rush had made them a "promise of early donor procurement."

Moreover, Karen Cheatum, a former nurse at the Rush transplant unit who left voluntarily last year, wrote a report accusing Rush of overstating the seriousness of patients' conditions in order to put them on the HeartMate and gain donor hearts. (Others later sent her report to a federal agency, from which The Wall Street Journal obtained it through the Freedom of Information Act; Ms. Cheatum declines to talk about it.)

Dr. Costanzo disputes these contentions and says the HeartMates were necessary to prevent patients' deterioration. She pointedly rejects the suggestion that any were installed to help Rush patients qualify faster for donor hearts. On July 31, 1995, the organ bank ended waiting-list preference for patients on the HeartMate.

The Size Issue
Another controversy involves what some Rush doctors have described as mismatched donor hearts. The American Heart Association in 1992 issued suggested criteria for cardiac donors including "donor body weight usually between 80% and 120% of recipient' s body weight." True, some surgeons have had success using hearts from donors only 70% or even 60% of the recipient's weight in dire cases. But prominent heart surgeons Norman Shumway and Sara Shumway have written that "this fact should not be construed as proof that smaller hearts will function as well as larger ones under all conditions."

In early 1995, Rush gave a new heart to Alice Romano of Mount Prospect, Ill. She was 49 years old and weighed 160 pounds; the heart came from a nine-year-old who weighed just 70 pounds -- 44% of the recipient's weight. Ms. Romano died about two days after transplant. This is one case Dr. Costanzo is willing to discuss. She defends the transplant, saying "we had a patient that was [facing] sudden death on a daily basis" because of a too-rapid heartbeat. But Ms. Cheatum, the former Rush nurse, said in the analysis she gave when she quit that Ms. Romano "was not in dire straits -- she was ambulatory."

Dr. DaValle, the Rush surgeon who is a member of the review committee, identified at least five other cases where he said patients got too-small or inappropriate hearts. And Dr. Montoya, the surgeon who resigned, wrote to the medical-school dean on Aug. 2: "I have identified a number of instances related to donor recipient mismatching and unacceptably high morbidity and mortality rates .... "

A Drug User's Heart
Size isn't the only issue. Angelos Voudouris of Greece was given the heart of a young gunshot victim in Santa Fe, N.M., and died three months later. The surgeon Rush sent to New Mexico to retrieve the heart, known as the harvesting surgeon, wasn't informed about a key fact: The donor was an intravenous drug abuser. A toxicity test showed he had been taking illegal drugs such as amphetamines, according to Rush documents. These conditions, Dr. DaValle wrote, "should have immediately made this heart not acceptable."

Dr. Costanzo says in a letter to The Wall Street Journal that in general, evidence of recent intravenous drug use (needle marks) engenders greater reluctance toward accepting organs for transplantation, but it does not exclude a donor from consideration."

Dr. DaValle criticized the Rush organ-harvesting system for leaving surgeons in the dark. In most transplant programs, there is extensive consultation before surgery between cardiologists and surgeons about the health of recipients and appropriateness of donor hearts. But at Rush, "the harvesting surgeon is often misinformed, or pertinent facts are left out, when told about the donor," he wrote. "It often seems that full disclosure on these patients is only given to cardiology. It especially becomes suspicious when organs that we accept had previously been turned down by several institutions on a regular basis."

A Heart or a Diet?
Dr. DaValle also said that in five of the heart-transplant deaths he studied, "poor judgment in recipient selection was used." For 308 pound, "morbidly obese" Manuel Tallungan, Dr. DaValle wrote, a "strict diet would have been more appropriate than to list him for heart transplant." But Rush gave him a transplant, after which he died of blood clots.

Giving a heart to an unpromising candidate deprives another patient somewhere of an organ that might save his or her lite. "There's always somebody in another bed who could use that organ," notes Lee Newcomer, chief medical officer at United Healthcare Corp., a managed-care insurer in Minneapolis.
Recipient selection was a different kind of issue in the case of Queen Stephens, a 52-year old beautician with a history of aberrant behavior. Someone given a new heart must be willing and able to take medication afterward. Records show Rush staffers had "concerns about non-compliance." Dr. Costanzo says Ms. Stephens could be trusted to take medication despite a "histrionic personality."

The matter was never really tested because Ms. Stephens's body immediately rejected the new heart she got. That raised still another issue of recipient selection. When given an antibody test to measure the likelihood of rejection, Ms. Stephens had scored a zero, meaning that rejection was unlikely. After she nonetheless quickly began rejecting the heart, a new test was done and produced a score of 96 of 100, meaning rejection was almost certain. Why the change? It turns out that between the first test and the transplant, Ms. Stephens had a blood transfusion at another hospital, a step that can radically alter a test result. Costanzo says Rush didn't know about this transfusion when it gave her the new heart. Ms. Cheatum' s 1995 report, however, said Rush staffers did know. Rush records refer to a transfusion without giving a date for it. Ms. Stephens died after her body rejected the new heart.

Long Transit Time
In one case, Rush implanted a heart that had been rejected by at least one other hospital because the donor had a blood condition called idiopathic thrombocytopenic purpura. The man Rush gave it to, 63-year-old Spiro G. Giatras, died soon afterward.

The heart's quality wasn't the only issue. This heart had to be brought all the way from Florida. It had a long "ischemic time," or period when it was preserved with ice and chemicals.

When it finally arrived in Chicago, the surgeon wasn't ready to implant it, documents show. He didn't get to the operating room until the patient had been "anesthetized and waiting for 45 minutes," Dr. Najafi wrote in a letter to the medical-school dean. He said this delay unnecessarily stretched out the ischemic time. Mortality increases if that exceeds four to five hours, medical literature says. In this case it reached six.

"The incision was made at 2:20 a.m., nearly two hours after the patient had arrived," Dr. Najafi wrote. "I believe the presence of the surgeon in the OR when the patient arrived would have expedited the procedure at least by 1 1/2 hours which would have had an unquestionable favorable impact." Mr. Giatras died soon after the surgery.

Dr. Najafi described the case as showing not "faulty judgment but rather negligence on the part of the responsible surgeon." Mr. Giatras's son, Robert, and a Rush doctor identify the surgeon as William Piccione, who is the Rush transplant program's surgical director. Dr. Piccione, in a brief interview, declined comment, saying, "Physicians just can't discuss patients' cases. This is outrageous." Rush General Counsel Brown says the "characterization of Dr. Piccione as being late for surgery is untrue."

In his study of deaths at Rush, Dr. DaValle also criticized postoperative care. He cited the death of James D. Payne, a 39-year-old Hammond, Ind., carpenter and father of two small children. Following Mr. Payne's transplant late last year, Dr. DaValle writes, his cardiac output deteriorated beginning at 2 o'clock the morning after transplant. But Dr. DaValle says it wasn't until 5:45 a.m. that an attending surgeon was notified when the patient went into cardiac arrest and needed resuscitation. Mr. Payne's "initial post-op low cardiac index was never addressed for several hours until it may have been too late," Dr. DaValle wrote. No Antibiotics

Similarly, patient Frank Radzienda, 61, of Oak Lawn, Ill., complained of abdominal pain for several days after his heart transplant, records show. It turned out he had no bowel activity, and his intestines ruptured. Mr. Radzienda "had abdominal pain for several days before a general surgery consult was even called, and this resulted in an eventual [intestinal] perforation, sepsis and death," Dr. DaValle wrote.

Mr. Radzienda and another patient weren't even placed on antibiotics after transplant surgery, Dr. DaValle wrote. Dr. DaValle's analysis blames the leadership of the transplant program, specifically including Dr. Piccione, for not ensuring proper post-operative care in the program; it says surgeons aren't allowed to be sufficiently involved afterward to make sure care is adequate.

Four patient deaths in quick succession rocked the program last December. Then four deaths among 21 patients this year occurred within one month of surgery. It was these deaths that moved Dr. Najafi to action. Although he won't comment, internal Rush correspondence makes clear that Dr. Naj aft for months lobbied the senior hospital administration to get an outside reviewer to evaluate the program.

By August, Dr. Najafi was urging that the transplant program in its current form be halted." Dr. Costanzo says no such halt has occurred, while others on staff say it has. The number of transplants has fallen from last year' s 45 to 21 in 1996.

Mr. Brown, Rush's general counsel, says the administration and physician leadership "stands behind the Heart Failure and Cardiac Transplant Program," adding: "We believe unequivocally that our patient care is of the highest caliber."

PVCS

Why is it that so often in social conversations a heart transplant is assumed to be heart bypass surgery? Most recently, while waiting to pay at the local general store, the owner turned to the other customer, a lady, at the counter and said, "This fellow has had a heart transplant." Her response was, "Oh, I've seen lots of those working as a nurse in Intensive care." 1 asked her what transplant center she might be connected with. "Oh, you mean transplant! No, I thought you meant by-pass. You really had a transplant? Boy, that just shows that it works!" And all that from a nurse.

Tx Barbara Barfield of Atlanta wrote that after careful study of my editorial on fear in the November issue, she was pretty sure I don't have any serious TCAD. On the other hand, she proffered that the onset of Alzheimer's disease would probably be a very real possibility. Gosh, you make the greatest friends in the world of transplantation!

Through 9 years of living as a transplant recipient I have collected all sorts of gimmicks to remind me when to take the required medications. Almost universally they have been rather unsuccessful. Unfortunately they all either buzz, ding, or beep, and much to the annoyance of my often questionably supportive family, all I get most often is, "Don, you're 'dinging' again." or, "Dad, your bells are going off and people are staring" or the 'treasure hunt', "OK guys, somewhere in this house one of dad's pill boxes is beeping, please try and find it, it's driving me nuts!" The problem lies in the fact that after 9 years of varying levels of prednisone et al, the old man can't really hear worth a hoot either. Therefore at Christmas everyone gathered 'round our tree was very pleased to observe me receive a vibrating alarm watch from Brookstone. Yes, it really does work. At this time I have neither the price, nor the catalog number, but it's called the Brookstone Vibrating Alarm Watch and their customer service number is 800-846-3000.

For those few interested, the combined U.N.O.S. and Department of Transplantation annual meeting usually scheduled for late February in D.C. has reverted to a bi-annual schedule with a meeting due again in 1998. Apparently both lack of funds and lack of good quality meeting content are the problem.

TRANSPLANT ETHICS

By Jay Reeves - Associated Press Writer
BIRMINGHAM, Ala. (AP 12/6/96)- A last-minute stay blocked an execution Friday so the condemned man could donate a kidney to his brother:-- which raised an ethical question for doctors who would oversee the donor' s recovery.

"Why 'do you allow someone to recover and be completely healthy before killing them?" said Dr. J. Harold Helderman, medical director of the Vanderbilt Transplant Center in Nashville, Tenn.

The idea of removing an organ from Alabama death row inmate David Larry Nelson and then helping him get well enough to be put to death in the state's electric chair was unsettling to physicians, who also wondered if Nelson was truly a voluntary donor.

"This sounds to me to be distasteful and I'm not sure what we will do here," said Helderman.

While various prisoners have given organs to relatives over the years, just last year for the first time did a man on death row do it. An inmate on Delaware' s death-row donated a kidney to his mother; he remains on death row.

Helderman said any surgery would be done by Vanderbilt doctors at a veterans hospital in Nashville because Nelson's 57-year-old brother, Louis, is a patient at the Alvin C. York VA Medical Center in nearby Murfreesboro, Tenn. Louis Nelson, who has diabetes, has lost a leg to the disease and his kidneys no longer function. He undergoes dialysis three times a week.

However, the six doctors on Vanderbilt's kidney transplant team must resolve ethical issues surrounding the odd situation before work proceeds toward an operation, Helderman said.

He said a medical ethicist at Vanderbilt, Dr. Richard Zaner, would be brought in to assist them.

"We try to reach a consensus. It's not as simple as raising a hand," said Helderman.

David Nelson, 51, was scheduled to die at 12:01 a.m. for the New Year's 1977 slaying of Wilson Thompson, shot in the back of the head as he had sex with Nelson's girlfriend. Nelson also was convicted in two other murders.

But the Alabama Supreme Court, in a 7-1 decision late Thursday, granted a three-week delay, allowing time for tests to determine whether Louis Nelson is a viable transplant candidate and if the inmate would be a suitable donor.

David Nelson jumped for joy with his two sisters after learning the stay had been granted, according to a Holman Prison spokesman. He had said he wanted to die but changed his mind, giving the transplant as his reason.

Relatives of the victims complained David Nelson had once again thwarted justice with the stay. Nelson came within a week of execution in 1989 but won a stay after initially saying he would not appeal. Assistant Attorney General Sandra Stewart said prosecutors would not appeal the latest delay. The state will seek a new execution date from the Supreme Court when the temporary stay ends.

Helderman rejected the idea of putting David Nelson to sleep, removing the kidney and then executing him by lethal injection on the operation table.

"Doctors do not commit murder. I would never be part of an execution," he said.

ITALIAN LOSES ONLY KIDNEY AS SURGEON SLIPS UP

PESCARA, Italy (Reuter 12/29/96) - A surgeon cut out his patient's only kidney by accident during a routine stomach ulcer operation earlier this month, health authorities said Sunday.

An official at the main hospital in this eastern Italian city said the surgeon thought the kidney was a malignant growth and cut it out.

Tests later showed it was a perfectly healthy kidney.

It also transpired that the 46-year old patient only had One kidney. He now has to undergo twice-daily dialysis treatment and is waiting for a transplant.

Magistrates have opened an inquiry into the operation.

Disclaimer: The material in this document has been collected by Don Marshall and friends. If any of the views and opinions expressed here are taken the wrong way, we can be nothing m ore than sorry. New ideas and materials are welcome all the time. As a policy, UpBeat is sent upon request to heart and heart/lung transplant recipients and other interested parties. Donations of $15 per year, or more, from Tx recipients, if not a burden, are vital. From all others t he donation is specifically requested. The date shown after the name on the address label indicates the last time a donation was received. Please make checks payable to Don Marshall, as we cannot afford to become nonprofit. Send materials, letters, or checks to:

Don Marshall
P.O. Box 482
Mathews, VA 23109-0482
804-725-3686
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