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Immediate causes of death in short-term surviving heart transplant recipients
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Immediate Causes of Death in Short-term Surviving Heart Transplant Recipients Pietro Gallo, MD? Lucia Agozzino, MD,? Eloisa Arbustini, MD,* Giovanni Bartoloni, MD:* Giorgio Baroldi, MD,?? Edgardo Bonacina, MD,?? Cesare Bosman, MD,** Gualtiero Catani, MD,*** Cira di Gioia, MD,* Teresio Motta, MD,??? Angela Fucci, MD,*** Maurizio
Rocco, MD,**** and Gaetano Thiene, MD,????
Sections ofCardiovascular Pathology, Cardiac Tmnsplantation Units of *Rome (“La Sapienza” University), TNaples, $Pavia, **Catania, ttMilan, $*Rome (“Bambino Gesli” Hospital), ***Cagliari, tt+Bergamo, ***Turin, ****Udine, and *+++Padua,Italy.
From 1985 to 1992,1068 cardiac transplants have been performed in the Italian units. The immediate causes of death of 142 of the 148 orthotopic cardiac transplantation recipients who died within the first 6 postoperative months were surveyed. Deaths were grouped into three periods: perioperative (l (3 months, 23.2X), and advanced (>3 (6 months, 8.5%). Acute graft failure (arising from the ischemic damage to the donor heart, from surgical problems, from severe pulmonary hypertension, or from multiorgan failure) accounted for 49 % of perioperative deaths and, along with noncardiac emergencies (23 % of perioperative deaths), was significantly more frequent in this period than in the subsequent ones. The dissection of thoracic arteries was responsible for 4% of postoperative deaths, occurring exclusively among patients transplanted for ischemic or valvular heart disease. In the early and advanced periods, untreatable acute rejection (13 %) and fatal infections (38%), mostly saprophytic, were significantly more frequent. Ischemic heart damage secondary to graft vasculopathy already caused 26% of deaths between the fourth and sixth months after transplantation. Some diseases, such as acute rejection, had the same frequency as both underlying disease and immediate cause of death. On the contrary, graft failure is more common as primary disease, leading to death also through noncardiac complications and saprophytic infections. Bacterial infections have the same frequency as both prime and immediate cause of death, viral infections are more common as primary disease, and the opposite is true for saprophytic infections.
From 1985 to 1992, 1068 cardiac transplants have been performed in the Italian units. Long-term results are satisfactory (the 7-year actuarial survival rate being 74%) and are fully comparable with those of other outstanding transplant centers (l-6). However, short-term mortality is comparatively high, as demonstrated by the fact that nearly three fourths of the deceased recipients died within the first 6 postoperative months. The purpose of the present paper is to describe the pathology of these short-term survivors.
Supportedin part by a grant of the Italian Ministry of Health and of the Fkgione Lazio. Manuscript received October 19, 1993; accepted February 15, 1994. Address for reprints: Prof. Pietro Gallo, Cattedra di Anatomia Patologica Canii ovasa~la~, Diwto di Medicina Sperkentale, Ft&linic~~ Umberto I, Viale Regina Elena 324, I-00161 Roma, Italy; telephone and fax: 39-64461484. Q 1994 by Elsevier Science Inc
In a recent paper (7), the prime causes of death of our transplant recipients were reported When a survey on large autopsy series is performed, prime and immediate causes of death should be studied separately (8-11). In fact, death is usually the result of a chain of morbid events, originated by a primary underlying disease and eventually leading to a final disorder: the immediate cause of death. Obviously, the prime and immediate causes of death may also coincide, as in the case of most transplant recipients dying of acute rejection. The immediate causes of death of long-term survivors are usually a matter of little practical importance compared with serious primary diseases, such as graft arteriopathy or tumors. On the contrary, a survey of the immediate causes of death seemed to be more appropriate in short-term survivors. In this period, indeed, death is not so much caused by major intervening pathologies as by an ominous complex of emergencies that might be treated or prevented. For instance, know1054.8807/94/$7.00
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Table 1. Absolute Frequency and Percentage Distribution of Immediate Causes of Death among
Short-term Surviving Orthotopic Transplant Recipients Timine of Death Ultimate Cause of Death Graft failure Pump failure Myocz&ial ischemia Arrhythmia Massive graft thrombosis Total Dissection of thoracic arteries Noncardiac emergencies Stroke Pulmonary embolism DIC DAD Acute pancreatitis Renal failure GI hemorrhages Ischemic enteritis Total Acute rejection Infections Pneumonia Bacterial Fungal Viral Protozoal Myocarditis Fungal Protozoal Encephalitis Sepsis Total Others
Perioperative (1 Month (n = 97)
Early >1-<3 Month (n = 33)
Advanced >3-(6 Month (n = 12)
Total (n = 142)
42 (43) 5 (5) 1 (1) 48 (49)
7 (21) 2 (6) 1 (3) 10 (30)
1 (8) 3 (26) 10 5 (42)
50 (35) 10 (7) 2 (1) 1 (1) 63 (44)
4 (4)
-
-
4 (3)
9 (10) 4 (4) 3 (3) 2 (2) 2 (2) 1 (1) 1 (1) 22 (23)
2 (6) 1 (3) 3 (9)
1 (8) _ 1 (8) 2 (16)
12 (9) 4 (3) 3 (2) 2 (1) 2 (1) 1 (1) 2 (1) _J_.@_ 27 (19)
8 (9)
6 (18)
5 (5) 3 (3) 1 (1) -
1 (3) 7 (21) 3 (9) -
1 (8) 3 (26) 1 (8)
7 (5) 13 (9) 4 (3) 1 (1)
1 (1) 1 (1) 2 (2) 1 (1) 14 (14)
1 (3) 12 (36)
_ 5 (42)
1 (1) 2 (1) 2 (1) 1 (1) 31 (22)
1 (1)
2 (7)
-
3 (2)
14 (10)
Note: Numbers enclosed within parentheses refer to percentages. DIC, disseminated intravascularcoagulation; DAD, diffuse alveolar damage; GI, gastrointestinal
ing that in a particular center many recipients died of saprophytic infections (immediate cause of death) after having been treated for acute rejection (prime cause of death) is extremely valuable to refining the dosage of immunosuppressive treatment: if deaths had been erroneously attributed to rejection, immunosuppression dosage should have been further augmented, with ominous results. Data about the immediate causes of death in short-term survivors may also contriiute to a better treatment of recipients, singling out categories at risk for definite postoperative complications.
Materials and Methods We studied 1068 heart transplants pertbrmed in the 11 Italian transplant units from November 1985 to April 1992. Most patients underwent orthotopic transplantation (1029/
1068,96.4%), but 13 heterotopic (1.2%), 12 hear-lung (l.l%), and 14 orthotopic retransplants (1.3%) were also performed. In 4 orthotopic transplants the donor’s heart was obtained through a domino procedure. Because orthotopic transplants represent the large majority of our series, and heterotopic and heart-lung transplants raise peculiar problems, the study of the causes of death was limited to orthotopic transplantation only, so that we could obtain a more homogeneous group without losing considerable information. The analysis of mortality data was also limited to shortterm survivors: i.e., to the recipients who died within the first 6 months after transplantation. All the recipients have been treated with a similar immunosuppressive procedure (triple therapy with cyclosporine A, prednisone, and azathioprine) and monitored with a sched-
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ule of endomyocardial biopsies (12). The present multicenter study has the advantage of reporting a large series that was collected from a homogeneous population, undergoing the same monitoring procedures. Further details about the characteristics of the study population and of data collecting and analysis have been reported elsewhere (7,12). Actuarial survival rates were computed according to Kaplan and Meier’s estimate (13). The &i-square method was used for comparison of percentage ratios. A p < 0.05was considered statistically significant.
Results Survival in the whole group of orthotopic transplant recipients. During the first 6.5 years of the Italian Units experience, 1029 patients have undergone orthotopic transplantation (14 recipients were transplanted twice), and 195 of them died (crude death rate 18.9%). Half of the 195 deaths (49.7%) occurred by the first postoperative month, 136 (69.7%) by 3 months, and 148 (75.9%) by 6 months. The actuarial survival rate is 89 % at the end of the first postoperative month, 85 % and 84 % at 3 and 6 months, respectively, and 83 % at 1 year. After the first year, the survival percentage slightly but steadily falls at a mean rate lower than 2 % per year, reaching 74% at 6.5 years. Short-term surviving orthotopic transplant recipients. The present analysis has been limited to the 148 short-term survivors who had received an orthotopic transplantation. The data were mainly drawn from the postmortem examination, which was performed in 127/148 patients (85.8%). In the remaining cases, autopsy was impossible because the patient died suddenly at home or consent was denied. The immediate cause of death could be definitively determined on pathological or clinical grounds in 142/148 cases.
Figure 1. Histologicalpicture of the heart of a recipientwho died in the operatingmom of immediate graft failure. The only obvious feature is represented by myecardial interstitial edema. (Hematoxylin-eosin stain, x loo.)
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The distribution of pathologies observed at the postmortem examination substantially varies according to the survival interval. We consequently subdivided the 142 short-term survivors, whose immediate cause of death was determinable, into three groups (Table 1): perioperative deaths (within the first month after transplantation: 97 patients, 68.3 %), early deaths (after the first month but before the end of the third month: 33 patients, 23.2%), and advanced deaths (>3 <6 months; 12 patients, 8.5%). Distribution of the immediate causes of death by survival intervals. A different spectrum of pathologies occurred according to the time elapsed from transplantation to death (Table 1). Graft failure was the most frequent cause of death (49 %) in the perioperative period. In spite of its wide use in the literature, this term actually covers several different conditions. Immediate graft failure usually occurs in the operating room and may be caused by ischemic damage to the donor heart, to surgical problems, or to severe pulmonary hypertension. It manifests itself with acute right ventricular dilation and pump failure. The pathological picture is usually poor (Figure 1)and consists of myocardial interstitial edema and hemorrhage, sometimes with fibrin thrombi in the arterioles. Untreatable pump failure, eventually leading to congestive heart decompensation, may also ensue later in the postoperative course and is usually caused hy multiorgan failure or pulmonary hypertension (Figure 2). A frequent pathological feature in recipients who died of acute graft failure in the postoperative period is the presence of myocardial ischemic necrosis. This may be so extensive
as to be considered the immediate cause of death (even subendocardial infarctions were observed) or it may consist of focal areas of myocardial ischemic necrosis, named “early” or “A type” ischemic damage according to the working formu-
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GALL0 ET AL. CAUSES OF DEATH IN HEART TRANSPLANT RECIPIENTS
Figure 2. The trunk and main branches of the pulmonary artery
of a recipient who died of acute graft failure (dilation of the rightsided chambers and passive congestion of liver and spleen) on the fifth postoperative day. The recipient artery is dilated and disseminated of atherosclerotic plaques (the presence of hypertensive pulmonary vascular disease was histologically confirmed in the lungs). The suture with the donor pulmonary trunk is evident at the bottom of the figure.
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lation nomenclature (14,15). Patchy ischemic damage is usually attributable to the reperfusion injury (Figures 3 and 4), especially after a distant procurement of the donor heart, or to the infusion of high doses of catecholamines (Figure 5) either to the donor prior to heart removal or to the recipient during the early postoperative period. Finally, two transmural infarctions-which had been observed 1 day and 2 months, respectively, after transplantation-were attributable to the unexpected pre-existence of atherosclerotic stenoses in the coronary arteries of the donor heart. If ischemic damage (which appears also later as a consequence of graft vasculopathy) is left out, graft failure is significantly @ < 0.02) more frequent in the perioperative period than in the later ones. Except for gastrointestinal hemorrhages, which are probably a side effect of steroid therapy and develop later, all the other noncardiac emergencies (dissection of thoracic arteries, strokes, pulmonary embolism, disseminated intravascular coagulation, diffuse alveolar damage, acute pancreatitis, acute renal failure, and ischemic enteritis) were significantly more frequent @ < 0.02) in the perioperative period. Hyperacute rejection was never observed in our series. The frequency of both untreatable acute rejection (9%) and infections (14 X) in the perioperative stage was lower than in the later periods (13% and 38 % , respectively), but such difference is statistically significant (p < 0.01) for infections only. Conversely, the early and advanced periods were characterized by the appearance of gastrointestinal hemorrhages, by the sharp fall of the other noncardiac emergencies, and mostly by the gradual rise of fatal infections (36% and 42% in the early and advanced periods, respectively). In these stages, infections were not only more frequent but also showed a different pattern of pathogens, with a significant @ < 0.01) rise of saprophytic infections, increasing from 5 % of the immediate causes of death in the perioperative period to 27% in the subsequent stages.
Figure 3. Patchy reperfusion injury of the left ventricular myocardium in a recipient who died of acute graft failure a few days after transplantation. A focal, sharply circumscribed area of coagulative necrosis, with a hemorrhagic component, is present in the left half of the figure. (Hematoxylineosin stain, X40.)
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4. Reperfusion damage. Higher magnificationof the same lesion as in Figure 3. Coagulative necrosis of myocytes (left) and hemorrhagic infiltrationof the interstitium(right) are evident. (Hematoxylineosin stain, x250.)
Figure
In spite of the similarities in the distribution of many of the immediate causes of death, early and advanced periods differ as to prevalence of rejection. As a cause of death, acute rejection (Figures 6 and 7) had the highest frequency in the early period (18 %) and was not present in the advanced one. Chronic rejection was a prominent cause of death in the advanced period (26%), in the form of graft vasculopatby (Figures 8 and 9) and myocardial ischemic damage (“late” or “B type” ischemic necrosis). Immediate causes of death versus underlying primary dkeases. The prime causes of death in the present series have been analyzed elsewhere (7). In the perioperative period, graft failure was considered to be the underlying disease in 64 % and the immediate cause of death in 49 % of patients. As a primary disease, graft failure was attributed to a combination of causes: mainly to the poor state of the recipient (arriving at the grafting procedure
Fiie 5. A small, patchy area of ischemic necrosis, probably attributable to catecholamine effect (the patient died of HSV pneumoniaon the 5 1st postoperative day and had been treated for postoperative low cardiac output syndrome). Empty sarcolemmal sheaths are still visible, with a scant mononuclear infiltration. (Hematoxylin-eosin stain, x250.)
in condition of severe pulmonary hypertension or multiorgan failure syndrome), rarely to the poor preservation of the donor heart, and sometimes (especially in pediatric transplants) to the excessive volume mismatch between donor and recipient hearts. Graft failure was considered to represent the ultimate disorder in a smaller number of patients, because of the intervening onset of saprophytic infections or noncardiac emergencies that might be potentially treatable or preventable. Severe surgical complications, often attributable to the preexistence of diffise atherosclerotic changes in patients undergoing transplantation for ischemic heart disease, were the original disorder in a minority of patients (10X), whereas many immediate causes of death (pulmonary embolism, disseminated intravascular coagulation, diffuse alveolar damage, and acute pancreatitis) might have been the result of any major surgery. Fatal acute rejection was considered to be both the prime
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Figure 6. The right ventricular cavity of a recipient (note the suture line on the pulmonary trunk) who died of acute rejection on the 39th postoperative day. Mural myocardium has a marbled appearance because of heavy mononuclear infiltration.
and immediate cause of death in 13 of 15 cases. In one more patient, acute rejection was the underlying disease, causing pump failure and requiring assisted circulation: as a consequence, disseminated intravascular coagulation ensued, and
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that was the immediate cause of death, whereas the cardiac condition was improving. In another patient the underlying disorder was prolonged postoperative bleeding: it demanded manitbld transfusions and accordingly prevented adequate control of the cyclosporine hematic level, so that acute rejection arose and was the immediate cause of death. As far as infections are concerned, bacterial diseases were usually considered to be both the prime and immediate cause of death. Viral infections were more common as prime than as immediate cause of death (5 % vs. 3 % of patients, respectively), whereas the opposite was true for saprophytic infections (5% vs. 12%). Distribution of the immediate causes of death by reasons for transplant. The death risk of cardiac transplantation recipients varies according to the pathology that required the grafting procedure. In our series, patients transplanted for cardiomyopathies are significantly @ < 0.01)more numerous among alive than among deceased recipients (56.2 vs. 43.1%) and their percentage rate further falls to 40.3 % among short-term recipients (Table 2). The pathology requiring transplantation, though affecting the overall survival, does not significantly influence the percentage distribution of the immediate causes of death (Table 2). However, it is noteworthy that an ominous complication such as the dissection of the aortic arch (3 patients), the innominate artery (1 patient), or the common iliac artery (1 patient) was exclusively observed in atherosclerotic patients transplanted because of ischemic or valvular heart disease (Table 2).
Discussion In the first decades of the history of human heart transplantation, the main goal was to control acute rejection. This has been almost entirely achieved, thanks to the development
F&u12 7. The right ventricular myocardium of a recipient who died of acute rejection two months after transplantation. There is perivascular and diffuse interstitial mononuclear in8ltration with cytotoxic myocellular damage (diffise, borderline-severe, acute rejection: grade 3B, according to the working formulation). (Hematoxylin-eosin stain, X100.)
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F&ure 8. Short-axis view of the recipient heart of a patient who died of graft vascular disease. The myocardium is disseminated of gray areas of ischemic damage in different stages of organization.
Fcgure 9. Colliquative myocytolysis of the subendocamial right ventricular myocanhum of a recipient who died of graft vascular disease. (Hematoxylin-eosin stain, x250.)
of the endomyocardial biopsy technique and to the consequent assessment of monitoring strategies. The main obstacle to long-term survival is now represented by graft vasculopathy, and much research effort is devoted to this particular subject (16). However, in the world series (17)) as well as in ours, half of deaths still occur in the first postoper-
ative month. As a consequence, knowledge of the spectrum of immediate causes of death occurring in short-term survivors is mandatory in order to prevent them: reducing perioperative mortality could dramatically improve the overall survival of heart transplant recipients. In the present study, we collected mortality data about or-
Table 2. Distribution of Reasons for Transplant in Alive Patients and in Short-term Survivors (Subdivided by Immediate Cause of Death) Percentage
Pathology Cardiomyopathies Ischemic HD Valvular HD Others HD = heart disease.
Percentage
Distribution
Distribution
In Alive Patients
In Short-term Survivors
Graft Failure
Arterial Dissection
Acute Rejection
56.2 34.1 5.2 4.5
46.3 40.5 9.5 9.7
45.6 45.0 57.1 50.0
0.0 6.7 7.1 0.0
12.3 6.7 0.0 21.4
of Immediate
Causes of Death
Saprophytic Infections 10.5 16.7 7.1 7.1
Bacterial Infections
Other
5.3 6.7 7.1 7.1
26.3 18.2 21.6 14.4
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thotopic heart transplant recipients who died before the end of the sixth postoperative month, out of the 1054 patients who were transplanted in Italy from 1985 to 1992. Thanks to an autopsy rate that is high compared with that of other units (18), we could collect information from 142 of 148 such patients. In a recent paper (7) we surveyed the prime causes of death in our series. For the subset of short-term survivors, however, being aware of the immediate causes of death is almost as important as knowing the underlying diseases. Acute graft failure was the most frequent (44 %) immediate cause of death among our short-term survivors (Table 1). Postoperative pump failure may be associated with a poor preservation of the donor heart, especially with distant procurement of the organ (19), surgical problems, severe pulmonary hypertension, or the need for mechanical or inotropic support (17) of recipients, who are sometimes transplanted when already affected by multiorgan failure. When graft failure ensued during or immediately after surgery, the pathological findings were usually poor at the myocardial level; when pump failure was less immediate, Yarly” ischemic myocardial necrosis was often seen, even in the form of subendocardial infarction. After the first three months, graft failure was mostly attributable to “late” ischemic necrosis, as an effect of graft vasculopathy. Finally, we observed that two patients died of transmural myocardial infarctions caused by the unexpected pre-existence of severe atherosclerotic stenoses in the donor coronary arteries. Undetected pathologies in the donor heart have been observed in other series (2421) and are no longer surprising. In fact, after showing a sharp rise from 1981 to 1986, the world-wide number of heart transplants has gone up only slightly in the last few years (17), because of organ shortage. Consequently, the maximum age of acceptable donors is being raised (4); the presence of native atherosclerotic lesions in the grafts is accordingly going to become more and more frequent with the growing age of donors (4). Patients transplanted for cardiomyopathies have a significantly better outcome (7) than patients transplanted for ischemic, valvular, or congenital heart disease (22,23); this is usually ascribed to the fact that they suffer from a disease limited to the heart and are not expected to have undergone any previous surgery. However, acute graft failure had a similar frequency in our short-term survivors transplanted for cardiomyopathies as well as for ischemic or valvular heart disease (Table 2). The only noticeable difference applies to an infrequent but ominous postoperative complication: the dissection of an atherosclerotic artery (Table 2). Surgeons should be alerted when transplanting a new heart into a patient suffering diffise atherosclerotic changes. The relatively high frequency of strokes in short-term survivors (9%) may be related to a large number of causes, including the presence of pretransplant atherosclerosis of cerebral arteries and systemic hypertension, postoperative low-output syndrome, and the side effects of immunosuppressive treatment. Steroid therapy is usually held responsible for the occurrence of gastroenteric hemorrhages in the early and
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advanced periods (1% of our short-term survivors), Other noncardiac emergencies (Table l), such as pulmonary embolism, disseminated intravascular coagulation, diffuse alveolar damage, and acute pancreatitis, exclusively occurred in the perioperative period and are common to major surgery of any type. In three recipients who died in the advanced period (>3 <6 months), the immediate cause of death was myocardial ischemic necrosis attributable to graft vasculopathy in the setting of “chronic rejection.” Despite the term, which suggests a late occurrence, the forerunners of chronic rejectionlymphocytic endothelialitis (24) and smooth muscle cell migration from the media into the intima of coronary arteries-appear as early as the acute rejection episodes, and the stenoses of the coronary arteries may already develop and cause fatal myocardial ischemia in short-term survivors. Conversely, fatal acute rejection may appear, although rarely (25) in long-term survivors, especially in those who voluntarily discontinued the immunosuppressive therapy (7). In the present series, fatal acute rejection had the highest frequency (18%) in the early period (>l 43 months) and was considered to be both the prime and the immediate cause of death in most patients. Fatal infections are a frequent occurrence in short-term survivors (17), but the distribution of the microbiologic agents varies in different periods (4,26): whereas bacterial infections are more common in the first three postoperative months, saprophytes predominate later. In our series, the preponderance of bacterial infections is limited to the first postoperative month (Table l), whereas saprophytic infections, and mainly fungal pneumonia, were significantly more common in the subsequent periods (Table 1). The relatively high prevalence of fatal mycotic infections is consistent with the low mortality from acute rejection and warns against the risk of an excessive immunosuppressive treatment of recipients (12). Viral infections, finally, seem to play an initiating role because they were slightly more common as prime than as immediate cause of death, whereas the opposite is true for saprophytic infections, which often were the last link in a long chain of pathologies.
Conclusions Whereas long-term results of heart transplantation are satisfactory, short-term mortality is still comparably high: half of deaths occur in the first postoperative month. Deaths are mainly attributable to acute graft failure, postoperative complications, noncardiac emergencies, and bacterial infections in the first postoperative month and to acute rejection and saprophytic infections in the subsequent months, but myocardial dysfunction and ischemic necrosis secondary to graft vasculopathy occur before the end of the sixth postoperative month. The analysis of the immediate causes of death in shortterm survivors adds weight to a list of strategies that could dramatically improve the survival of cardiac transplantation
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recipients. Recipients should be accurately selected to avoid excessive pulmonary hypertension and transplanted when still in acceptable condition, before multiorgan failure ensues. Also, donors should be adequately selected in order to exclude the preexistence of coronary stenoses-which are going to be more and more frequent with the growing age of acceptable donors-and to minimize both distant procurement and volume mismatch with the recipient heart. The adequate selection of both donors and recipients should accordingly reduce the need for mechanical or inotropic support to limit early ischemic damages that may precipitate acute graft failure. Surgeons should be warned against the risk of arterial dissection when transplanting a heart into an atherosclerotic patient. Finally, the dosage of immunosuppressive drugs should be accurately stated and monitored to limit an excessive risk of saprophytic infections. We wish to acknowledge the assistance of Drs. M. Bramerio, P. Cocco, M. Grasso, and F. Italia in collecting the information about the case material.
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after
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Immediate Causes of Death in Short-term Surviving Heart Transplant Recipients Pietro Gallo, MD? Lucia Agozzino, MD,? Eloisa Arbustini, MD,* Giovanni Bartoloni, MD:* Giorgio Baroldi, MD,?? Edgardo Bonacina, MD,?? Cesare Bosman, MD,** Gualtiero Catani, MD,*** Cira di Gioia, MD,* Teresio Motta, MD,??? Angela Fucci, MD,*** Maurizio
Rocco, MD,**** and Gaetano Thiene, MD,????
Sections ofCardiovascular Pathology, Cardiac Tmnsplantation Units of *Rome (“La Sapienza” University), TNaples, $Pavia, **Catania, ttMilan, $*Rome (“Bambino Gesli” Hospital), ***Cagliari, tt+Bergamo, ***Turin, ****Udine, and *+++Padua,Italy.
From 1985 to 1992,1068 cardiac transplants have been performed in the Italian units. The immediate causes of death of 142 of the 148 orthotopic cardiac transplantation recipients who died within the first 6 postoperative months were surveyed. Deaths were grouped into three periods: perioperative (
From 1985 to 1992, 1068 cardiac transplants have been performed in the Italian units. Long-term results are satisfactory (the 7-year actuarial survival rate being 74%) and are fully comparable with those of other outstanding transplant centers (l-6). However, short-term mortality is comparatively high, as demonstrated by the fact that nearly three fourths of the deceased recipients died within the first 6 postoperative months. The purpose of the present paper is to describe the pathology of these short-term survivors.
Supportedin part by a grant of the Italian Ministry of Health and of the Fkgione Lazio. Manuscript received October 19, 1993; accepted February 15, 1994. Address for reprints: Prof. Pietro Gallo, Cattedra di Anatomia Patologica Canii ovasa~la~, Diwto di Medicina Sperkentale, Ft&linic~~ Umberto I, Viale Regina Elena 324, I-00161 Roma, Italy; telephone and fax: 39-64461484. Q 1994 by Elsevier Science Inc
In a recent paper (7), the prime causes of death of our transplant recipients were reported When a survey on large autopsy series is performed, prime and immediate causes of death should be studied separately (8-11). In fact, death is usually the result of a chain of morbid events, originated by a primary underlying disease and eventually leading to a final disorder: the immediate cause of death. Obviously, the prime and immediate causes of death may also coincide, as in the case of most transplant recipients dying of acute rejection. The immediate causes of death of long-term survivors are usually a matter of little practical importance compared with serious primary diseases, such as graft arteriopathy or tumors. On the contrary, a survey of the immediate causes of death seemed to be more appropriate in short-term survivors. In this period, indeed, death is not so much caused by major intervening pathologies as by an ominous complex of emergencies that might be treated or prevented. For instance, know1054.8807/94/$7.00
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Table 1. Absolute Frequency and Percentage Distribution of Immediate Causes of Death among
Short-term Surviving Orthotopic Transplant Recipients Timine of Death Ultimate Cause of Death Graft failure Pump failure Myocz&ial ischemia Arrhythmia Massive graft thrombosis Total Dissection of thoracic arteries Noncardiac emergencies Stroke Pulmonary embolism DIC DAD Acute pancreatitis Renal failure GI hemorrhages Ischemic enteritis Total Acute rejection Infections Pneumonia Bacterial Fungal Viral Protozoal Myocarditis Fungal Protozoal Encephalitis Sepsis Total Others
Perioperative (1 Month (n = 97)
Early >1-<3 Month (n = 33)
Advanced >3-(6 Month (n = 12)
Total (n = 142)
42 (43) 5 (5) 1 (1) 48 (49)
7 (21) 2 (6) 1 (3) 10 (30)
1 (8) 3 (26) 10 5 (42)
50 (35) 10 (7) 2 (1) 1 (1) 63 (44)
4 (4)
-
-
4 (3)
9 (10) 4 (4) 3 (3) 2 (2) 2 (2) 1 (1) 1 (1) 22 (23)
2 (6) 1 (3) 3 (9)
1 (8) _ 1 (8) 2 (16)
12 (9) 4 (3) 3 (2) 2 (1) 2 (1) 1 (1) 2 (1) _J_.@_ 27 (19)
8 (9)
6 (18)
5 (5) 3 (3) 1 (1) -
1 (3) 7 (21) 3 (9) -
1 (8) 3 (26) 1 (8)
7 (5) 13 (9) 4 (3) 1 (1)
1 (1) 1 (1) 2 (2) 1 (1) 14 (14)
1 (3) 12 (36)
_ 5 (42)
1 (1) 2 (1) 2 (1) 1 (1) 31 (22)
1 (1)
2 (7)
-
3 (2)
14 (10)
Note: Numbers enclosed within parentheses refer to percentages. DIC, disseminated intravascularcoagulation; DAD, diffuse alveolar damage; GI, gastrointestinal
ing that in a particular center many recipients died of saprophytic infections (immediate cause of death) after having been treated for acute rejection (prime cause of death) is extremely valuable to refining the dosage of immunosuppressive treatment: if deaths had been erroneously attributed to rejection, immunosuppression dosage should have been further augmented, with ominous results. Data about the immediate causes of death in short-term survivors may also contriiute to a better treatment of recipients, singling out categories at risk for definite postoperative complications.
Materials and Methods We studied 1068 heart transplants pertbrmed in the 11 Italian transplant units from November 1985 to April 1992. Most patients underwent orthotopic transplantation (1029/
1068,96.4%), but 13 heterotopic (1.2%), 12 hear-lung (l.l%), and 14 orthotopic retransplants (1.3%) were also performed. In 4 orthotopic transplants the donor’s heart was obtained through a domino procedure. Because orthotopic transplants represent the large majority of our series, and heterotopic and heart-lung transplants raise peculiar problems, the study of the causes of death was limited to orthotopic transplantation only, so that we could obtain a more homogeneous group without losing considerable information. The analysis of mortality data was also limited to shortterm survivors: i.e., to the recipients who died within the first 6 months after transplantation. All the recipients have been treated with a similar immunosuppressive procedure (triple therapy with cyclosporine A, prednisone, and azathioprine) and monitored with a sched-
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ule of endomyocardial biopsies (12). The present multicenter study has the advantage of reporting a large series that was collected from a homogeneous population, undergoing the same monitoring procedures. Further details about the characteristics of the study population and of data collecting and analysis have been reported elsewhere (7,12). Actuarial survival rates were computed according to Kaplan and Meier’s estimate (13). The &i-square method was used for comparison of percentage ratios. A p < 0.05was considered statistically significant.
Results Survival in the whole group of orthotopic transplant recipients. During the first 6.5 years of the Italian Units experience, 1029 patients have undergone orthotopic transplantation (14 recipients were transplanted twice), and 195 of them died (crude death rate 18.9%). Half of the 195 deaths (49.7%) occurred by the first postoperative month, 136 (69.7%) by 3 months, and 148 (75.9%) by 6 months. The actuarial survival rate is 89 % at the end of the first postoperative month, 85 % and 84 % at 3 and 6 months, respectively, and 83 % at 1 year. After the first year, the survival percentage slightly but steadily falls at a mean rate lower than 2 % per year, reaching 74% at 6.5 years. Short-term surviving orthotopic transplant recipients. The present analysis has been limited to the 148 short-term survivors who had received an orthotopic transplantation. The data were mainly drawn from the postmortem examination, which was performed in 127/148 patients (85.8%). In the remaining cases, autopsy was impossible because the patient died suddenly at home or consent was denied. The immediate cause of death could be definitively determined on pathological or clinical grounds in 142/148 cases.
Figure 1. Histologicalpicture of the heart of a recipientwho died in the operatingmom of immediate graft failure. The only obvious feature is represented by myecardial interstitial edema. (Hematoxylin-eosin stain, x loo.)
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The distribution of pathologies observed at the postmortem examination substantially varies according to the survival interval. We consequently subdivided the 142 short-term survivors, whose immediate cause of death was determinable, into three groups (Table 1): perioperative deaths (within the first month after transplantation: 97 patients, 68.3 %), early deaths (after the first month but before the end of the third month: 33 patients, 23.2%), and advanced deaths (>3 <6 months; 12 patients, 8.5%). Distribution of the immediate causes of death by survival intervals. A different spectrum of pathologies occurred according to the time elapsed from transplantation to death (Table 1). Graft failure was the most frequent cause of death (49 %) in the perioperative period. In spite of its wide use in the literature, this term actually covers several different conditions. Immediate graft failure usually occurs in the operating room and may be caused by ischemic damage to the donor heart, to surgical problems, or to severe pulmonary hypertension. It manifests itself with acute right ventricular dilation and pump failure. The pathological picture is usually poor (Figure 1)and consists of myocardial interstitial edema and hemorrhage, sometimes with fibrin thrombi in the arterioles. Untreatable pump failure, eventually leading to congestive heart decompensation, may also ensue later in the postoperative course and is usually caused hy multiorgan failure or pulmonary hypertension (Figure 2). A frequent pathological feature in recipients who died of acute graft failure in the postoperative period is the presence of myocardial ischemic necrosis. This may be so extensive
as to be considered the immediate cause of death (even subendocardial infarctions were observed) or it may consist of focal areas of myocardial ischemic necrosis, named “early” or “A type” ischemic damage according to the working formu-
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Figure 2. The trunk and main branches of the pulmonary artery
of a recipient who died of acute graft failure (dilation of the rightsided chambers and passive congestion of liver and spleen) on the fifth postoperative day. The recipient artery is dilated and disseminated of atherosclerotic plaques (the presence of hypertensive pulmonary vascular disease was histologically confirmed in the lungs). The suture with the donor pulmonary trunk is evident at the bottom of the figure.
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lation nomenclature (14,15). Patchy ischemic damage is usually attributable to the reperfusion injury (Figures 3 and 4), especially after a distant procurement of the donor heart, or to the infusion of high doses of catecholamines (Figure 5) either to the donor prior to heart removal or to the recipient during the early postoperative period. Finally, two transmural infarctions-which had been observed 1 day and 2 months, respectively, after transplantation-were attributable to the unexpected pre-existence of atherosclerotic stenoses in the coronary arteries of the donor heart. If ischemic damage (which appears also later as a consequence of graft vasculopathy) is left out, graft failure is significantly @ < 0.02) more frequent in the perioperative period than in the later ones. Except for gastrointestinal hemorrhages, which are probably a side effect of steroid therapy and develop later, all the other noncardiac emergencies (dissection of thoracic arteries, strokes, pulmonary embolism, disseminated intravascular coagulation, diffuse alveolar damage, acute pancreatitis, acute renal failure, and ischemic enteritis) were significantly more frequent @ < 0.02) in the perioperative period. Hyperacute rejection was never observed in our series. The frequency of both untreatable acute rejection (9%) and infections (14 X) in the perioperative stage was lower than in the later periods (13% and 38 % , respectively), but such difference is statistically significant (p < 0.01) for infections only. Conversely, the early and advanced periods were characterized by the appearance of gastrointestinal hemorrhages, by the sharp fall of the other noncardiac emergencies, and mostly by the gradual rise of fatal infections (36% and 42% in the early and advanced periods, respectively). In these stages, infections were not only more frequent but also showed a different pattern of pathogens, with a significant @ < 0.01) rise of saprophytic infections, increasing from 5 % of the immediate causes of death in the perioperative period to 27% in the subsequent stages.
Figure 3. Patchy reperfusion injury of the left ventricular myocardium in a recipient who died of acute graft failure a few days after transplantation. A focal, sharply circumscribed area of coagulative necrosis, with a hemorrhagic component, is present in the left half of the figure. (Hematoxylineosin stain, X40.)
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4. Reperfusion damage. Higher magnificationof the same lesion as in Figure 3. Coagulative necrosis of myocytes (left) and hemorrhagic infiltrationof the interstitium(right) are evident. (Hematoxylineosin stain, x250.)
Figure
In spite of the similarities in the distribution of many of the immediate causes of death, early and advanced periods differ as to prevalence of rejection. As a cause of death, acute rejection (Figures 6 and 7) had the highest frequency in the early period (18 %) and was not present in the advanced one. Chronic rejection was a prominent cause of death in the advanced period (26%), in the form of graft vasculopatby (Figures 8 and 9) and myocardial ischemic damage (“late” or “B type” ischemic necrosis). Immediate causes of death versus underlying primary dkeases. The prime causes of death in the present series have been analyzed elsewhere (7). In the perioperative period, graft failure was considered to be the underlying disease in 64 % and the immediate cause of death in 49 % of patients. As a primary disease, graft failure was attributed to a combination of causes: mainly to the poor state of the recipient (arriving at the grafting procedure
Fiie 5. A small, patchy area of ischemic necrosis, probably attributable to catecholamine effect (the patient died of HSV pneumoniaon the 5 1st postoperative day and had been treated for postoperative low cardiac output syndrome). Empty sarcolemmal sheaths are still visible, with a scant mononuclear infiltration. (Hematoxylin-eosin stain, x250.)
in condition of severe pulmonary hypertension or multiorgan failure syndrome), rarely to the poor preservation of the donor heart, and sometimes (especially in pediatric transplants) to the excessive volume mismatch between donor and recipient hearts. Graft failure was considered to represent the ultimate disorder in a smaller number of patients, because of the intervening onset of saprophytic infections or noncardiac emergencies that might be potentially treatable or preventable. Severe surgical complications, often attributable to the preexistence of diffise atherosclerotic changes in patients undergoing transplantation for ischemic heart disease, were the original disorder in a minority of patients (10X), whereas many immediate causes of death (pulmonary embolism, disseminated intravascular coagulation, diffuse alveolar damage, and acute pancreatitis) might have been the result of any major surgery. Fatal acute rejection was considered to be both the prime
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Figure 6. The right ventricular cavity of a recipient (note the suture line on the pulmonary trunk) who died of acute rejection on the 39th postoperative day. Mural myocardium has a marbled appearance because of heavy mononuclear infiltration.
and immediate cause of death in 13 of 15 cases. In one more patient, acute rejection was the underlying disease, causing pump failure and requiring assisted circulation: as a consequence, disseminated intravascular coagulation ensued, and
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that was the immediate cause of death, whereas the cardiac condition was improving. In another patient the underlying disorder was prolonged postoperative bleeding: it demanded manitbld transfusions and accordingly prevented adequate control of the cyclosporine hematic level, so that acute rejection arose and was the immediate cause of death. As far as infections are concerned, bacterial diseases were usually considered to be both the prime and immediate cause of death. Viral infections were more common as prime than as immediate cause of death (5 % vs. 3 % of patients, respectively), whereas the opposite was true for saprophytic infections (5% vs. 12%). Distribution of the immediate causes of death by reasons for transplant. The death risk of cardiac transplantation recipients varies according to the pathology that required the grafting procedure. In our series, patients transplanted for cardiomyopathies are significantly @ < 0.01)more numerous among alive than among deceased recipients (56.2 vs. 43.1%) and their percentage rate further falls to 40.3 % among short-term recipients (Table 2). The pathology requiring transplantation, though affecting the overall survival, does not significantly influence the percentage distribution of the immediate causes of death (Table 2). However, it is noteworthy that an ominous complication such as the dissection of the aortic arch (3 patients), the innominate artery (1 patient), or the common iliac artery (1 patient) was exclusively observed in atherosclerotic patients transplanted because of ischemic or valvular heart disease (Table 2).
Discussion In the first decades of the history of human heart transplantation, the main goal was to control acute rejection. This has been almost entirely achieved, thanks to the development
F&u12 7. The right ventricular myocardium of a recipient who died of acute rejection two months after transplantation. There is perivascular and diffuse interstitial mononuclear in8ltration with cytotoxic myocellular damage (diffise, borderline-severe, acute rejection: grade 3B, according to the working formulation). (Hematoxylin-eosin stain, X100.)
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F&ure 8. Short-axis view of the recipient heart of a patient who died of graft vascular disease. The myocardium is disseminated of gray areas of ischemic damage in different stages of organization.
Fcgure 9. Colliquative myocytolysis of the subendocamial right ventricular myocanhum of a recipient who died of graft vascular disease. (Hematoxylin-eosin stain, x250.)
of the endomyocardial biopsy technique and to the consequent assessment of monitoring strategies. The main obstacle to long-term survival is now represented by graft vasculopathy, and much research effort is devoted to this particular subject (16). However, in the world series (17)) as well as in ours, half of deaths still occur in the first postoper-
ative month. As a consequence, knowledge of the spectrum of immediate causes of death occurring in short-term survivors is mandatory in order to prevent them: reducing perioperative mortality could dramatically improve the overall survival of heart transplant recipients. In the present study, we collected mortality data about or-
Table 2. Distribution of Reasons for Transplant in Alive Patients and in Short-term Survivors (Subdivided by Immediate Cause of Death) Percentage
Pathology Cardiomyopathies Ischemic HD Valvular HD Others HD = heart disease.
Percentage
Distribution
Distribution
In Alive Patients
In Short-term Survivors
Graft Failure
Arterial Dissection
Acute Rejection
56.2 34.1 5.2 4.5
46.3 40.5 9.5 9.7
45.6 45.0 57.1 50.0
0.0 6.7 7.1 0.0
12.3 6.7 0.0 21.4
of Immediate
Causes of Death
Saprophytic Infections 10.5 16.7 7.1 7.1
Bacterial Infections
Other
5.3 6.7 7.1 7.1
26.3 18.2 21.6 14.4
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thotopic heart transplant recipients who died before the end of the sixth postoperative month, out of the 1054 patients who were transplanted in Italy from 1985 to 1992. Thanks to an autopsy rate that is high compared with that of other units (18), we could collect information from 142 of 148 such patients. In a recent paper (7) we surveyed the prime causes of death in our series. For the subset of short-term survivors, however, being aware of the immediate causes of death is almost as important as knowing the underlying diseases. Acute graft failure was the most frequent (44 %) immediate cause of death among our short-term survivors (Table 1). Postoperative pump failure may be associated with a poor preservation of the donor heart, especially with distant procurement of the organ (19), surgical problems, severe pulmonary hypertension, or the need for mechanical or inotropic support (17) of recipients, who are sometimes transplanted when already affected by multiorgan failure. When graft failure ensued during or immediately after surgery, the pathological findings were usually poor at the myocardial level; when pump failure was less immediate, Yarly” ischemic myocardial necrosis was often seen, even in the form of subendocardial infarction. After the first three months, graft failure was mostly attributable to “late” ischemic necrosis, as an effect of graft vasculopathy. Finally, we observed that two patients died of transmural myocardial infarctions caused by the unexpected pre-existence of severe atherosclerotic stenoses in the donor coronary arteries. Undetected pathologies in the donor heart have been observed in other series (2421) and are no longer surprising. In fact, after showing a sharp rise from 1981 to 1986, the world-wide number of heart transplants has gone up only slightly in the last few years (17), because of organ shortage. Consequently, the maximum age of acceptable donors is being raised (4); the presence of native atherosclerotic lesions in the grafts is accordingly going to become more and more frequent with the growing age of donors (4). Patients transplanted for cardiomyopathies have a significantly better outcome (7) than patients transplanted for ischemic, valvular, or congenital heart disease (22,23); this is usually ascribed to the fact that they suffer from a disease limited to the heart and are not expected to have undergone any previous surgery. However, acute graft failure had a similar frequency in our short-term survivors transplanted for cardiomyopathies as well as for ischemic or valvular heart disease (Table 2). The only noticeable difference applies to an infrequent but ominous postoperative complication: the dissection of an atherosclerotic artery (Table 2). Surgeons should be alerted when transplanting a new heart into a patient suffering diffise atherosclerotic changes. The relatively high frequency of strokes in short-term survivors (9%) may be related to a large number of causes, including the presence of pretransplant atherosclerosis of cerebral arteries and systemic hypertension, postoperative low-output syndrome, and the side effects of immunosuppressive treatment. Steroid therapy is usually held responsible for the occurrence of gastroenteric hemorrhages in the early and
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advanced periods (1% of our short-term survivors), Other noncardiac emergencies (Table l), such as pulmonary embolism, disseminated intravascular coagulation, diffuse alveolar damage, and acute pancreatitis, exclusively occurred in the perioperative period and are common to major surgery of any type. In three recipients who died in the advanced period (>3 <6 months), the immediate cause of death was myocardial ischemic necrosis attributable to graft vasculopathy in the setting of “chronic rejection.” Despite the term, which suggests a late occurrence, the forerunners of chronic rejectionlymphocytic endothelialitis (24) and smooth muscle cell migration from the media into the intima of coronary arteries-appear as early as the acute rejection episodes, and the stenoses of the coronary arteries may already develop and cause fatal myocardial ischemia in short-term survivors. Conversely, fatal acute rejection may appear, although rarely (25) in long-term survivors, especially in those who voluntarily discontinued the immunosuppressive therapy (7). In the present series, fatal acute rejection had the highest frequency (18%) in the early period (>l 43 months) and was considered to be both the prime and the immediate cause of death in most patients. Fatal infections are a frequent occurrence in short-term survivors (17), but the distribution of the microbiologic agents varies in different periods (4,26): whereas bacterial infections are more common in the first three postoperative months, saprophytes predominate later. In our series, the preponderance of bacterial infections is limited to the first postoperative month (Table l), whereas saprophytic infections, and mainly fungal pneumonia, were significantly more common in the subsequent periods (Table 1). The relatively high prevalence of fatal mycotic infections is consistent with the low mortality from acute rejection and warns against the risk of an excessive immunosuppressive treatment of recipients (12). Viral infections, finally, seem to play an initiating role because they were slightly more common as prime than as immediate cause of death, whereas the opposite is true for saprophytic infections, which often were the last link in a long chain of pathologies.
Conclusions Whereas long-term results of heart transplantation are satisfactory, short-term mortality is still comparably high: half of deaths occur in the first postoperative month. Deaths are mainly attributable to acute graft failure, postoperative complications, noncardiac emergencies, and bacterial infections in the first postoperative month and to acute rejection and saprophytic infections in the subsequent months, but myocardial dysfunction and ischemic necrosis secondary to graft vasculopathy occur before the end of the sixth postoperative month. The analysis of the immediate causes of death in shortterm survivors adds weight to a list of strategies that could dramatically improve the survival of cardiac transplantation
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recipients. Recipients should be accurately selected to avoid excessive pulmonary hypertension and transplanted when still in acceptable condition, before multiorgan failure ensues. Also, donors should be adequately selected in order to exclude the preexistence of coronary stenoses-which are going to be more and more frequent with the growing age of acceptable donors-and to minimize both distant procurement and volume mismatch with the recipient heart. The adequate selection of both donors and recipients should accordingly reduce the need for mechanical or inotropic support to limit early ischemic damages that may precipitate acute graft failure. Surgeons should be warned against the risk of arterial dissection when transplanting a heart into an atherosclerotic patient. Finally, the dosage of immunosuppressive drugs should be accurately stated and monitored to limit an excessive risk of saprophytic infections. We wish to acknowledge the assistance of Drs. M. Bramerio, P. Cocco, M. Grasso, and F. Italia in collecting the information about the case material.
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after