Human heart transplantation

HUMAN HEART TRANSPLANTATION JACK G. COPELAND, M.D. EDWARD B. STINSON, M.D.

A Note

from

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TABLE

OF CONTENTS . .

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4

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6

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8

RECIPIENT SELECTION ..............

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8

DONOR SELECTION

.

SELF-ASSESSMENT AN OVERVIEW PRECLINICAL INITIAL

QUESTIONS

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................ HEART TRANSPLANTATION

EXPERIENCE

DONOR MANAGEMENT

IN HUMAN

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HEART TRANSPLANTATION

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. 12

. . . 15

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ORTHOTOPIC CARDIAC TRANSPLANTATION

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. 17

HETEROTOPIC HEART TRANSPLANTATION

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. 41

OUTLOOK FOR CARDIAC TRANSPLANTATION

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44

SELF-ASSESSMENT

QUESTIONS

1. What is the approximate number of heart transplants that have been done? 2. What are the (a) l-year and (b) &year survival rates for heart recipients? 3. When and by whom was the current technique for orthotopic cardiac transplantation devised? 4. What are the histologic changes in (a) acute cardiac rejection? (b) chronic rejection? 5. How is cardiac rejection graded histologically? 6. When was the first human heart transplant performed that led to long-term survival? 7. What are the primary selection criteria, absolute contraindications, and matching requirements with the donor for a potential cardiac recipient? 8. Name 4 major points in diagnosing brain death. Is a flat EEG necessary? 9. What single ECG finding is considered grounds for refusal as a heart donor? 10. How do fall in QRS voltage, myocardial blood flow and cardiac function relate to acute rejection? 11. What is a T-lymphocyte? How do T-lymphocyte levels behave in cardiac recipients? 12. What is the current therapy for (a) acute rejection? (b) chronic management of cardiac recipients? 13. Name 3 indications for retransplantation of the heart? 14. What are the 2 major causes of death after cardiac transplantation? 15. Discuss the problems facing cardiac transplantation in the next decade.

Answers appear on the following 1. 2. 3. 4. 5.

p, 5 p.5 p. 6 pp. 7-8 pp. 7-8

6. 7. 8. 9. 10.

pages.

p. 8 pp. 12-15 pp. 15-16 p. 20 pp. 19-20

11. 12. 13. 14. 15.

pp. 24 -25 pp. 19-34 p. 35 pp. 30,38-41 pp. 44-47

is Associate Professor and Section Chief of Cardiothoracic Surgery at Arizona Health Sciences Center, Tucson, Arizona. After graduating from Stanford Medical School, he trained at University of California, San Diego (1969-71), National Heart, Lung and Blood Institute (as Surgical Clinical Associate, 1971- 73) and Stanford University (1973-77). His interests include cardiac transplantation, cardiovascular pathology and physiology, and surgical correction of congenital cardiac lesions.

is Thelma and Henry Doelger Professor of Cardiovascular Surgery at Stanford University and has been closely involved with the Stanford cardiac surgery program since its start in 1968. After graduating from Stanford Medical School and completing a rotating internship at Hennepin County General Hospital, he returned to Stanford to complete his cardiovascular surgical training and become a member of the surgical staff. Dr. Stinson also worked in the National Heart, Lung and Blood Institute, performing in both research and clinical capacities. His major interests include cardiac transplantation and cardiovascular mechanics, pharmacology and electrophysiology.

AN OVERVIEW MAJOR ADVANCES IN HEART TRANSPLANTATION over the past 2 decades have established a scientific basis and clinical value for the procedure. In a few centers, excellent results indicate that human heart transplantation may be considered therapeutic rather than experimental. Ten years elapsed between description of the technique for orthotopic cardiac transplantation’ and the first human cardiac allograft.* During the ensuing 4

12 years more than 400 human heart transplants have been performed (Fig 1). This clinical experience has led to many refinements in diverse areas3 of cardiac transplantation technology. Selection criteria, strongly influenced by therapeutic limitations of the procedure, have defined a group of patients in whom cardiac replacement prolongs life. Availability of donor hearts has improved by virtue of wide acceptance of a definition of brain death4p5 and enlargement of the “donor pool” through air transport of allografts from distant cities.6 Improved specificity in the diagnosis of rejection’ and the use of rabbit antithymocyte globulins,9 for the treatment of rejection have contributed significantly to the current favorable survival results, i.e., a survival rate of 67% at 1 year and approximately 50% at 5 years. Chronic rejection, in the form of progressive graft arteriosclerosis, similar histologically to coronary arteriosclerosis seen in the general population, has been identified and treated prophylactically and, in recent experience, it has been reduced in severity.‘” Retransplantation with a second allograft heart in cases of graft failure from intractable rejection or progressive arteriosclerosis has proved feasible and has salvaged a small number of recipients.” Finally, rehabilitation to “normal function” has been documented in 90% of l-year survivors.12 The Stanford University cardiac transplantation program has led the world in number of heart transplants (190) and has produced advances in diagnosis and therapy resulting in survival rates that compare favorably with graft survival in kidney transplantation.‘3-‘8 Three other institutions have conducted major heart transplantation programs:3> I4 the Medical College of Virginia,‘S$ 2o the Groote Schuur Hospital in Capetown, South Africa,21-23 and Hopital de la Pitie in Paris, France,24 each having performed more than 25 heart transplants. Renewed and continued interest in heart transplantation is reflected by newer and/or smaller programs in the following locations: ColumbiaPresbyterian Hospital, New York, NY, University of Wisconsin, Fig l.-Number

of human

heart

transplant

operations

since

1967.

58 1q 5: 50c8-g 403020; f loz’

0

II

III

11

11

1

’

1967 1968 1969 1970 1971 1972 1973 1974 1975 1976 1977

Year

Madison, WI, University of Arizona, Tucson, AZ, and Downstate Medical Center, Brooklyn, NY. Estimates of the number of potential heart transplant recipients in the US. have ranged from 10,000 to 75,00013 per year. These estimates, however, grossly exaggerate the number of patients for whom the current %tate of the art” offers a high expectation of success; at present, the total number of fully suitable candidates for heart transplantation in this country probably ranges from several hundred to 3,000 annually. Currently, about 60 heart transplants are performed each year in the world. PRECLINICAL

HEART

TRANSPLANTATION

The first heart transplant procedure was accomplished by Carrel and Guthriez5 in 1905, when they anastomosed a canine donor heart to the neck vessels of another dog. This heterotopic (outside the normal intrathoracic position) graft beat for approximately 2 hours before clotting. During the next 55 years, heterotopic cardiac transplants were placed in the neck, abdomen, and thorax by a number of surgeons.26 In 1960, Lower and Shumwayl made the contribution that was essential for further development of the concept of total heart replacement. They described a simple technique for orthotopic (placement in the normal position) transplantation of the canine heart. Their technique simplified the procedure by excision of the recipient heart at the level of the atrioventricular groove (Fig 2), leaving in situ the majority of the left and right atria of the recipient. The donor heart was then implanted by joining the atria1 walls and septum to the corresponding recipient structures with a single continuous suture. Previous techniques had completely removed the recipient heart, thus obliging the surgeon to construct multiple posterior anastomoses (2 caval, 4 pulmonary venous) before proceeding to the aortic and pulmonary artery anastomoses. The new technique was faster, simpler and more hemostatic. They also used cold saline (4 C) to cool topically the donor heart after excision to a myocardial temperature of 12- 15 C, thus decreasing the metabolic rate and protecting the ischemic organ until coronary perfusion was reestablished. In a series of 8 consecutive canine transplants, 5 of the recipient animals lived for 6-21 days. Work with the canine model of orthotopic cardiac transplantation over the next several years formed the basis for launching human heart transplantation trials in the late 1960s. Attempts to prolong life in recipient dogs produced several discoveries.27-29 A progressive fall in QRS voltage, usually starting several days before death from rejection, was noted on serial ECGs. When “pulse” immunosuppressive therapy with methylprednisolone and azathioprine was administered according to 6

Fig 2.-Lines of transection donor heart removal (dotted

in lines).

fluctuations in QRS voltage, survival for as long as 1 year was obtained.30 Immunosuppression was used only after the amplitude of the QRS voltage (particularly lead II) fell and was continued only until the voltage returned to baseline levels. In contrast, continuous immunosuppressive therapy caused death from “drug toxicity” (primarily infection) after prolonging survival slightly beyond that of untreated control animals (6 - 7 days). Autotransplantation of the heart (removal followed by implantation of the same heart) resulted in a completely denervated heart free of rejection .31,32 Animals with autotransplanted hearts were found to have normal hemodynamics, but slowed heart rate responses to-exercise. Cardiac failure due to absence of innervation per se was not observed. Reinnervation, both sympathetic and parasympathetic, was found after several months to 2 years,3, 33 but was not consistent. Evidence for similar reinnervation following allotransplantation (from one individual to another) is questionable. Two histologically distinct patterns of rejection, acute and chronic, have been studied in detail in the canine mode1.34 In acute rejection, the first abnormalities were found to occur at the host-graft interface, the capillary endothelium. Endothelial cells were enlarged with numerous pinocytotic vesicles and became closely related to marginated monocytes; some were occluded with thrombi and ruptured, permitting hemorrhage, or became shrunken and necrotic. Grossly, the heart was noted to be edematous and focally hemorrhagic. Interstitial edema, exudation of monocytes, and myocytolysis (lysis of muscle cells) were next seen, followed by phagocytosis of necrotic myocytes by

monocytes and polymorphonuclear cells. Chronic rejection took the form of destructive arteritis and proliferative intimal fibrosis leading to luminal narrowing and, ultimately, foci of myocardial infarct+ INITIAL HEART

EXPERIENCE IN HUMAN TRANSPLANTATION

In January 1964 the first attempt at biologic replacement of the human heart was made.35 A xenograft heart taken from a 96lb chimpanzee was orthotopically transplanted into a 68yearold man with terminal ischemic heart disease. The heart failed 1 hour after transplantation and the patient died. No other cardiac xenograft has been orthotopically transplanted in man. Subsequent cardiac transplant procedures have been performed with human donor hearts. Nearly 4 years later, in December 1967, Dr. Christiaan Barnard performed the first human heart transplant in a 54-yearold man2 this patient died 18 days postoperatively of Pseudommas pneumonia. Also in December 1967, Dr. Adrian Kantrowitz transplanted a heart into an infant with tricuspid atresia, but the patient died within the first 12 hours. Dr. Barnard’s second human heart transplant on January 3, 1968 led to long-term survival. The first heart transplant procedure at Stanford was performed on January 6, 1968 in a 54-year-old man with a cardiomyopathy;36 the recipient died on the 15th postoperative day of gastrointestinal bleeding and gram-negative sepsis. The second recipient in the Stanford series, a 40-year-old-man, received a transplanted heart on May 1, 1968, and died 3 days later of hypoxemia. Thus, in spite of encouraging preliminary data from the laboratory, it was apparent that significant improvements would be necessary. Improvements in many areas followed quickly, as will be briefly described in the following sections. RECIPIENT

SELECTION

The selection process of potential recipients may be one of the most difficult in the field of cardiac transplantation. If the patient is too sick, he may die during or shortly after transplantation, thus deriving no benefit from a costly and time-consuming effort. If, on the other hand, he is not “sick enough,” he may die prematurely, the victim of a %uccessful” heart transplant. The selection criteria have changed as therapy and survival statistics have become clarified. For example, it was stated in 1972 that a recipient might be accepted “only if it is agreed that he faces death in a matter of weeks,“26 whereas the most recent summary from Stanford states that “they [recipients] should 8

have a poor prognosis for surviving the next 6- 12 months and generally are limited by functional class IV congestive heart failure.“13 The selection criteria are of critical importance because they exert a crucial influence on the survival statistics obtained. They may vary from one center to another. At Stanford, for instance, no recipient being maintained on an intra-aortic balloon pump has been accepted, whereas at Columbia-Presbyterian Hospital, 5 of 9 patients have received heart transplants during aortic balloon counterpulsation.37, 38 The discussion that follows outlines selection criteria, contraindications and matching requirements derived primarily from the Stanford experience and, therefore, serves only as a general guideline (Table 1). The first requirement is thatthe patient have terminal heart disease such that improvement and prolonged survival cannot be realized with further standard medical or surgical therapy. Although there may be controversy, especially with regard to surgical therapy, it is generally believed that an operation that has a reasonable chance of success, with an acceptable operative mortality, should not be withheld in favor of heart transplantation. The prognosis should predict less than 1 year survival. Documentation of progressive and recent decline in the patient’s cardiac function usually facilitates such a projection. Ischemic cardiomyopathy has been the presenting diagnosis for 55% of the patients in the Stanford series;13 the remainder have had idiopathic, viral or rheumatic cardiomyopathies. Patients usually present with symptoms of low cardiac output and left ventricular failure. A weak pulse, narrow pulse pressure, pulsus alternans, cool extremities, pale-to-cyanotic (with exercise) TABLE

1. -RECIPIENT SELECTION CRITERIA AND MATCHING REQUIREMENTS WITH DONOR

Primary selection criteria Irremediable terminal cardiac disease Age under 55 Noncardiac organ function: normal or reversible dysfunction Absence of systemic illness that would limit recovery or survival Absolute contraindications Active infection Recent pulmonary infarction Diabetes mellitus (requiring insulin) Pulmonary vascular resistance of more than 8 Wood units Psychosis or mental deficiency unrelated to low cardiac output or metabolic status Drug addiction Matching requirements with donor AI30 compatibility Absence of donor-specific lymphocyte cytotoxicity Appropriate size match HLA-A, compatibility 9

skin, jugular venous distention, hepatomegaly, pulmonary rales and a greatly enlarged heart with a lateral impulse, S, and S, gallops and a mitral regurgitant murmur are common findings. Digitalis, high-dose furosemide, afterload reduction, antiarrhythmic agents and anticoagulants constitute the major elements of the medical regimen for many such patients. At present, selection criteria require that patients be under the age of 55 years. Older patients have a poor record of survival (15% 3-year survival) in comparison to recipients in younger age groups (41- 50: 25% 3-year survival; 11 - 40: 55% 3-year surviva1).39 Infection has been responsible for the majority of deaths in older recipients; thus, such patients seem to be more intolerant of the effects of immunosuppression than their younger counterparts. The age criterion is not absolute, however, and must be evaluated individually. For example, the effects of prolonged heart failure, especially over several years, may result in a prohibitive degree of cardiac cachexia in a 40-year-old patient, whereas a previously fit man of 55 years with a recent massive myocardial infarction may, in comparison, be a highly favorable candidate. Irreversible damage to one or more vital organs, such as kidneys, liver and lungs, and the presence of systemic illness that might limit recovery or survival are relative contraindications. The ideal candidate should have no extracardiac disease. Absolute contraindications to acceptance as a cardiac recipient have evolved from experience with posttransplantation morbidity and mortality. Patients with active infections cannot be accepted for cardiac transplantation until complete resolution of the infectious process. In cases complicated by deep tissue infections at the time of transplantation, the outcome has been uniformly fatal. Sixty percent of recipients who have sustained a pulmonary infarction just before transplantation have developed fatal pulmonary infections arising in the area of the previous pulmonary damage.3 Since pulmonary embolism is a common complication of the low cardiac output state characteristic of potential recipients, care must be taken to prevent this complication. This is done by prophylactic treatment with sodium warfarin, examination of the potential recipient upon initial presentation for evidence of silent pulmonary embolism and by waiting for at least 6 weeks or until complete healing of the lung before reconsideration of the patient as a potential recipient. Four patients in the Stanford series have died of acute right heart failure after orthotopic transplantation of a normal heart into a recipient with high pulmonary vascular resistance (greater than 8 Wood units).3 A normal right ventricle is unable to function against such high resistance. This may be an indication for heterotopic (“piggyback”) transplantation, which leaves 10

the recipient heart in situ (see Fig 13). It is therefore imperative that an accurate determination of pulmonary vascular resistance be made for all patients referred for transplantation. Diabetes mellitus requiring insulin has traditionally been considered an absolute contraindication to heart transplantation because corticosteroids exacerbate glucose intolerance and because of the increased susceptibility of these patients to infection. Finally, psychosis, drug addiction or a history of inadequate medical compliance in the recipient are contraindications to cardiac transplantation.40 Obviously, additional criteria of selection have been used3 since 90% of referrals to the Stanford program have been refused. In a sample year when 234 referrals were made, 23 patients were finally accepted as potential recipients. “Psychosocial problems” and “other medical contraindications” accounted for about 25% of the rejections. Also of interest, 41 patients died during the selection process or after being selected, whereas 7 were considered premature referrals and 14 had other therapy attempted. The matching requirements for the donor-recipient pair are simple. They must be compatible by the ABO blood grouping system. The “ABO barrier” has not been crossed in the Stanford experience. A second test, the lymphocyte cytotoxicity test (donor lymphocytes with recipient serum) is used in order to avoid transplanting a donor heart into a recipient who possesses preformed antibodies against donor histocompatibility antigens. Donor-specific lymphocytotoxicity assays may not always be necessary since another screening test (random lymphocyte panel) is available well in advance of the time of transplantation to check for preformed antibody against a battery of over 60 tissue isoantigens. If the-results of this screening are uniformly negative, it is highly unlikely that the recipient’s serum will exhibit cytotoxic activity against any donor lymphocytes. Matching donor and recipient for size is crucial in only one direction. It would be contraindicated to transplant a small donor heart into a large man. On the other hand, there may be some, as yet unproved, benefit in transplanting a large donor heart into a small recipient. A final matching requirement, which may be of some value, is for the HLA-A, antigen. A preliminary study matching for this antigen has correlated with a decrease in the time-related incidence of graft arteriosclerosis .41HLA matching for other serologitally defined antigens has revealed no relationship with surviva1.42 A complete recipient evaluation might include the information listed in Table 2. The psychosocial evaluation is important. A stable social situation may help a patient considerably in ad11

TABLE

2. -CARDIAC

RECIPIENT

EVALUATION

PROCEDURES

History and physical examination Routine laboratory testing, blood type, HLA type PulmonarjMmction Skin testing Cardiac catheterization and angiography Psychosocial evaluation by follow-up team (social worker, psychiatrist) Financial evaluation and counseling

justing to the strict medical regimen required for a cardiac recipient. A frank discussion of finances for the proposed procedure and follow-up care should also be covered in advance of the transplantation date. Preoperative recipient management consists simply of continuation of the patient’s medical therapy until the time of the transplantation. Sodium warfarin administration is continued until a donor heart becomes available. Its anticoagulant effect can be counteracted by administration of fresh frozen plasma immediately after the transplant operation. A single loading dose (4 mg per kilogram) of azathioprine is given just prior to transplantation. No other preoperative immunosuppression is used routinely. DONOR

SELECTION

It is well known that irreversible functional and structural changes occur in the normothermic heart after 20- 30 minutes of anoxia43 and that severe metabolic changes occur in the dying patient. Removal of a donor heart after cessation of the heartbeat would yield a damaged organ, thus jeopardizing survival of the recipient. Clearly, the recognition and acceptance of the concept of brain death by the medical profession,4l 5*44 the court~~~~46 and the public has been a prerequisite to successful heart transplantation. The Harvard criteria, a product of the Ad Hoc Committee of the Harvard Medical School to Examine the Definition of Brain Death, were outlined in August 19684 and have been accepted widely in the past 11 years. Other definitions have been proposed, 5~44 but there is not much deviation from these major points: (1) unreceptivity and unresponsivity; (2) no movements or breathing; (3) no reflexes, and (4) flat EEGs 24 hours apart. Such guidelines for the definition of brain death were used in the 2 major court decisions involving cardiac donors. In Tucker vs. Lower,45 a 1972 case brought by the donor’s brother against transplant surgeons, it was alleged that the cause of death was the removal of the heart and kidneys. After hearing expert testimony regarding the definition of brain death, the jury was instructed to consider the time of complete 12

and irreversible loss of function of the brain to be the time of death. The surgeons were found not guilty of causing wrongful death. In People us. Lyons 46 it was alleged that cardiectomy performed by Stanford surgeons resulted in the death of a homicide victim rather than a gunshot wound to the head. Again, after an overwhelming medical testimony supporting the definition of brain death, the jury was instructed that “the victim was legally dead before removal of organs.” Finally, 18 state governments have passed legal definitions of death. Several types of definitions have been made; all accept brain death. All 50 states have passed the Uniform Anatomical Gift Act, which permits arranging for tissue and organ donation prior to death, but does not state a definition of death. The initial requirement for a cardiac donor, therefore, is that he/she meet some accepted criteria for brain death. The Harvard criteria4 are considered by many to be conservative and too restrictive in view of subsequent studies.47 An example of a set of current criteria, which is used at the University of Arizona Health Sciences Center, is listed in Table 3. Conflict of interest is avoided in making the determination of brain death by stipulating that the decision be made by physicians entirely separate from the transplant team. Not all patients who meet the brain death criteria are suitable donors. In a previous study of cardiac donors,48 2 factors found to correlate with poor graft function were increasing donor age and a history of transient, severe hypotension after injury. These factors should be weighted carefully. Male cardiac donors should probably be under the age of 35 and female donors, under 40 years. In older potential donors, even with negative cardiac histories and findings, coronary arteriography is recommended to rule out coronary artery disease. Most often, donors have traumatic head injuries 48 (blunt trauma, gunshot wound). Initial evaluation should include a survey for evidence of thoracic or cardiac trauma, including intracardiac injections during resuscitative procedures. A careful history of events from the time of injury until the time of donor referral is essential to define periods of cardiorespiratory arrest and hypotension that may have damaged the heart. A careful cardiac history from relatives and direct examination are followed by ECG, chest roentgenogram and CPK-MB serum enzyme determination. ECG abnormalities were found in all 22 cardiac donors reported by Griepp.48 Abnormalities of ST segments (elevation and depression) were most common, followed by atria1 arrythmias, prolonged QT interval, left ventricular hypertrophy and intraventricular conduction delay. All of these abnormalities were considered to be compatible with intracranial catastrophe, the effect of vasopressors or hypothermia. ECG diagnosis of previous myocardial infarction on the basis of pathologic Q waves was 13

TABLE

3. -CRITERIA FOR BRAIN DEATH AT THE UNIVERSITY ARIZONA HEALTH SCIENCES CENTER

OF

1.0 It is general1 recognized that when satisfactory scientific evaluation has established t x at the brain is dead, that person is, in fact, dead whether the heart or other vital organs continue to function or not. The following criteria for determining brain death have been adopted by the medical staff: 1.1 Deep coma with unresponsivity and unreceptivity; deep tendon reflexes, integrated at a spinal level, may be preserved. 1.2 No movement (except deep tendon reflexes), and no breathing. The absence of respiratory effort can be established when no such effort is observed when the respirator is disconnected for three minutes. An alternative method is to show that there is no respiratory effort when the Pace, is 50 mm Hg or above. 1.3 No brain stem reflexes. All brain stem reflexes are absent. 1.3.1 The pupils are fixed in diameter and do not respond to sharp changes in the intensity of incident light. 1.3.2 There is no cornea1 reflex. 1.3.3 The vestibulo-ocular reflexes are absent. 1.3.4 No motor responses within the cranial nerve distribution can be elicited by adequate stimulation of any somatic area. 1.3.5 There is no gag reflex or reflex response to bronchial stimulation by a suction catheter passed down the trachea. 1.4 The diagnosis of a condition which can cause brain death must have been established; if there is any suspicion that criteria 1.1 through 1.3 are due to depressant drugs or profound metabolic disturbance (acidbase balance, blood glucose, or serum electrolytes), a diagnosis of brain death cannot be made. Body temperature must be greater than 90F (32.2C). It may be obvious within hours of a primary intracranial event, such as severe head injury, spontaneous intracranial hemorrhage or following neurosurgery, that the condition is irremediable. However, when a patient has suffered primarily from cardiac arrest, hypoxia or severe circulatory insufficiency with an indefinite period of cerebral anoxia, or is suspected of having cerebral air or fat embolism, then it may take much longer to establish the diagnosis and to be confident of the prognosis. In some patients the primary pathology may be a matter of doubt and confident diagnosis may only be reached by continuity of clinical observation and investigation. 2.9 Repetition of Tests 2.1 The responsible physicians should repeat tests 1.1 through 1.3.5 at intervals to exclude observer error. The interval between tests must depend upon the primary pathology and the clinical course of the disease. Paragraph 1.4 indicates some conditions in which it would be unnecessary to repeat them since a prognosis of imminent brain death can be accepted as being obvious. 2.2 In some conditions the outcome is not so clear-cut and in these it is recommended that the tests should be repeated. The interval between tests depends upon the progress of the patient and might be as long as 24 hours. This is a matter for judgment and repetition time must be related to the signs of improvement, stability, or deterioration which present themselves. 3.9 Ancillary Studies 3.1 The electroencephalogram is not necessary for diagnosis of brain death; however, in most cases a flat EEG provides confirmatory evidence and is recommended. 3.2 Cerebral angiography demonstrating cessation of cerebral blood flow 14

TABLE

3. -Continued

for at least 30 minutes is acceptable evidence of brain death; angiography is not recommended for routine determination of cerebral death, however. 4.0 A proper note should be made in the progress note of the patient indicating that the next of kin or patient’s representative has been fully advised of the condition of the patient and that a pronouncement of death is planned because of brain death. Such a note should also be accompanied by a statement that these people did not object (if this is true). 5.0 The responsible physician shall obtain a confirming consultation from the patient’s‘ attending physician before declaring the patient dead. 6.0 To avoid conflict of interest, the following procedures shall be followed: 6.1 The donor must have a medical history of findings indicating a catastrophic intracranial event from which death is known to occur. 6.2 Independent evaluations by 2 (two) specialists from Neurosurgery or from Neurology are to be made. If the attending physician is a neurosurgeon or neurologist the note may substitute for one of the 2 (two) University Hospital attendings. The decision regarding brain death must be noted by both of these individuals in the patient’s chart. 6.3 Clinical criteria for brain death are as indicated above. 6.4 After diagnosis of brain death is made as noted above, and the patient’s family has signed permission for removal of organs, the patient is to be transferred to the care of the Surgery Service and county medical examiner notified. 6.5 At the time of organ removal, the donor will be transported to the operating room. His management will be supervised by the attending anesthesiologist. After administration of heparin, organs listed on the permit slip will be removed. After organ removal, the respirator and all other supportive means will be discontinued. This will be followed by renotification of the county medical examiner and a complete autopsy.

considered grounds for donor rejection. No other change was an absolute contraindication to acceptance of the donor heart. In potential donors with possible cardiac abnormalities and equivocal cardiac findings, as in older potential donors (men over 35, women over 40), a complete cardiac catheterization with contrast studies is advisable. If the potential donor appears to have a normal functioning heart, has no infection or carcinoma, is ABO compatible with the recipient, has a negative lymphocyte crossmatch with recipient serum and is a reasonable size match for the recipient, he/she is accepted. DONOR

MANAGEMENT

The period of time between pronouncement of brain death and cessation of heartbeat even with maximal medical support has most often ranged from 6 hours to several days and rarely exceeded 1 week.5 Brain death is usually accompanied by loss of vasomotor tone with a tendency for systolic blood pressure to fall drastically within 1 - 6 hours. 48Homeostatic temperature control 15

is lost and the donor becomes hypothermic with a marked tendency for ventricular arrhythmias when the core temperature falls below 30 C. High-volume urine output from diabetes insipidus may rapidly result in hypovolemia. Neurogenic pulmonary edema occurs commonly and pneumonia is a constant threat. Supportive measures are directed toward thorough monitoring and maintenance of as normal a cardiovascular status as possible. Once the donor is available, transplantation is conducted within 6- 12 hours. Blood pressure maintenance is achieved by adequate volume replacement and use of a-adrenergic agents such as metaraminol. The core temperature is maintained within the normal range by a heating blanket. Intramuscular administration of vasopressin, 10 units every 4 hours, has been found to be satisfactory in controlling diabetes insipidus. Vigorous pulmonary care with frequent suctioning and position change and positive end-expiratory pressure are used to treat the inevitable pulmonary congestion. After obtaining a tracheal aspirate and blood and urine cultures from the donor, high-dose broadspectrum antibiotic coverage is started. The procedural aspects of donor heart removal are organized in one of 2 ways. The donor’s heart may be removed in an adjacent operating room in timing with the recipient procedure so as to result in the shortest possible cardiac ischemia time (30 - 45 minutes). The second technique, which was not used until 1977,4s involves donor cardiectomy at a distant hospital, myocardial preservation using topical or coronary flush cooling, and rapid air transport to the transplanting hospital. The latter technique increases the effective “donor pool” and is a major step toward reducing the waiting period for potential recipients after acceptance into a heart transplant program. Richmond has reported 6 transport cases, 4s there have been more than 15 at Stanford50 and 2 at the Arizona Health Sciences Center in Tucson. The longest time interval between donor heart removal and reinstitution of coronary arterial perfusion has been 320 minutes.4s The safe period for cardiac storage is currently not known. Several laboratory experiments have used coronary cooling with ‘textracellular”51 or “intracellular”52 solutions to extend the preservation time to more than 24 hours, and, after successful transplantation of the preserved hearts, the animals operated on have survived to rejection. Currently, the results of extended in vitro preservation are not sufficiently reliable for application to human transplantation. Surgical removal of the donor heart from the heparinized donor (see Fig 2) maximizes the lengths of great vessels and atria1 cuffs in order to facilitate subsequent implantation. After instituting inflow occlusion by ligation of the superior and inferior venae cavae, cold “cardioplegic” solution (buffered saline to pH 7.40, with mannitol to osmolality of 360, and KC1 40 mEq/l; vol16

ume, 500 cc; temperature, 4 C) is flushed under pressure into the ascending aorta. When the heart arrests, the aorta is occluded until the entire volume of cardioplegic solution has flushed through the coronary circulation. The heart is then removed. The superior vena cava is transected above the ligature (approximately 1% in. above the caval-atria1 junction), thus insuring that the sinus node will not be damaged. The other transection lines include the inferior vena cava just inside pericardium, the left atrium at pulmonary vein orifices, the aorta at the innominate artery origin and the pulmonary artery at its bifurcation. The heart is immediately placed in a bath of saline at 4 C and is either transported to a nearby operating room for transplantation or placed in a sterile iced container for transPO&. ORTHOTOPIC

CARDIAC

TRANSPLANTATION

The technique of orthotopic cardiac transplantation has changed little since its description by Lower and Shumway in 1960.’ The preoperative preparation includes placement of a central venous line in the left internal jugular vein; the right internal jugular vein, a route of entry for the endomyocardial bioptome after transplantation, remains undisturbed. Preoperative broad-spectrum antibiotics are administered before the initial incision. Anesthetic management must be gentle, avoiding cardiac depression. Sterile technique is followed in endotracheal tube placement. An arterial line and 1 or 2 peripheral intravenous lines are used. Foley catheters are avoided and suprapubic bladder catheterization is preferred as an aseptic technique of bladder drainage. The operation proceeds as indicated in Figure 3. Cannulae for venous return are placed in the cavae via the right atrium. Total cardiopulmonary bypass occluding venous inflow to the heart with choker tapes constricting the cavae around the canulae provides a nearly bloodless field. After fibrillating the recipient heart and clamping the ascending aorta, the heart is removed. Some blood returns to the left atrium via bronchial artery collaterals. The donor heart is prepared for implantation and a control biopsy of right ventricular endocardium is taken. Anastomoses of the atria1 cut%, first left, then right, are completed with a continuous suturing technique. Cold (4 C) saline is then flushed continuously through the left atrium and out the aorta for the dual purpose of removing air from the left heart and maintaining a low myocardial temperature. After completion of the end-to-end aortic anastomosis, cooling is discontinued, the aortic cross clamp is removed and, after a short period of coronary reperfusion, the heart is defibrillated. The end-to-end pulmonary arterial anastomosis is then completed. After 30 min17

Fig 3.-Heart transplantation surgical technique. A, cannulation technique and lines of cardiectomy for recipient heart. 6 (upper drawing), after cardiectomy, the remaining portions of the recipient heart include the posterior portions of both atria and the supravalvular portions of the great vessels. Lower drawing, the initial donor-recipient suture line runs / down the lateral left atrial wall. C f/eftJ, after completion of the aortic anastdmosis, the aortic cross-clamp is removed, resulting per.-...in coronary fusion, while the pulmonary artery anastomosis is completed. Rlghr, appearance after completion of transplantation. Note the ligated donor superior vena cava anterior to the aorta and the atrial pacing wire just below.

utes of resuscitation of the beating donor heart, cardiopulmonary bypass is discontinued. Hemostasis of all suture lines is rechecked several times and fresh frozen plasma is administered to patients taking warfarin up to the time of operation. A temporary pacing wire is placed on the right atrium and exited from the chest under the right costal margin. The remainder of the procedure consists of routine chest tube placement and median sternotomy closure. A diluted drip of isoproterenol(4 pg per milliliter at’1 pg per minute) or dopamine (800 pg per milliliter at 5 pg per kilogram per minute) is started to augment the cardiac output. Postoperatively, extubation is carried out in recipients as soon as they are awake and their cardiovascular status is stable. Chest tubes are removed when the volume of drainage decreases to less than 100 ml for 8 hours. Full reverse isolation is maintained for l-3 weeks in the intensive care unit. Immunosuppressive therapy is continued (initiated with azathioprine by mouth preoperatively) with 500 mg of methylpiednisolone intravenously immediately after discontinuation of cardiopulmonary bypass, and 125 mg intravenously every 8 hours until the 18

patient starts taking oral medications. At this time (usually first postoperative day), prednisone administration (100 mg per day) is started. The prednisone is tapered by 5 mg per day until reaching 1 mg per kilogram a day, a maintenance dose for the first 4-8 weeks. Azathioprine, about 2 mg per kilogram, is started when the patient begins oral intake and continued at that level indefinitely, if bone marrow or hepatic toxicity is not encountered. If the white blood cell count is suppressed below 4,000 per cu mm, the azathioprine dose is adjusted accordingly. Rehabilitation efforts are begun during the first postoperative week. Physical therapy goals include maintenance of muscular strength, progressively increasing exercise tolerance and formation of an exercise habit to be continued after discharge. Occupational therapy focuses on the maintenance of fine hand-eye coordination and providing the patient with an avocation, if he has none, during his initial convalescence period. Psychosocial counseling with the patient and his family is continued and coping strategies are stressed from the beginning. ACUTE REJECTION

The pathophysiology of cardiac rejection had been demonstrated in the laboratory prior to clinical heart transplantation. Rejection was heralded by decreases in QRS voltage2* and histologic findingss4 consisting of myocardial edema and cellular infiltration, as has been outlined in the section, Preclinical Heart Transplantation. Further studies revealed that the cardiac output of canine transplant recipients did not fall significantly until 24- 12 hours prior to death from rejection.53 This fall was due to reduction in stroke volume, the heart rate being constant. Blood pressure did not fall until several hours before death. Additional studies using direct measurement of circumflex coronary artery blood flow and reactive hyperemic response,53 and indirect measurement of myocardial blood flow with radioactive microspheres during the rejection process54 have documented a fall in coronary blood flow and more marked restriction of reactive hyperemia beginning about 24 hours prior to death, and a 50% decrease in blood flow to the left ventricle correlated with decline in QRS voltage. Furthermore, the drop in myocardial blood flow was more marked in the subendocardial layers. Several conclusions of practical importance may be drawn from these studies, as follows. 1. A progressive fall in the QRS voltage occurs before hemodynamic decompensation. 2. Decreased myocardial blood flow or ischemia is an important mechanism in the progressive decline of cardiac function. 3. Immunologic injury of the capillary endothelium and myocardium leads to edema, capillary microthrombosis, loss of per19

fusion, increased vascular resistance and, ultimately, ischemic injury. 4. The subendocardium is more severely involved than more superficial myocardial layers. ECG abnormalities in patients with allograft rejection were studied in the late 1960s.55 A decrease in QRS voltage was the most reliable finding. Fortunately, it preceded the onset of clinically apparent heart failure, permitting treatment at a time when the rejection process could be stopped and voltage reverted to normal. Other ECG abnormalities associated less consistently with rejection were (1) the onset of atria1 arrhythmias; (2) right axis deviation; and (3) first-degree heart block progressing to nodal rhythm. A laboratory correlate of the 1st and 3d findings was the appearance of histologic abnormalities, particularly in the atrioventricular node in animals noted to have had arrhythmias or conduction delays prior to death from rejection.% The ECG findings continue to be extremely valuable in diagnosing rejection. Currently, we use the sum of the peak-to-peak QRS voltage for leads I, II, III, V, and V,. A fall of 20% or more is an indication for heart biopsy. Decreases in voltage 3 months or more following transplantation are treated first with an increase in the prednisone dosage. Failure of the voltage to rise indicates that a biopsy examination should be done. Experience has demonstrated that ECG voltage, although highly sensitive, is not entirely specific for rejection. Technical factors such as lead placement and variability in electrode contact may account for voltage drops. Changes in thoracic impedance from pneumonia, pneumothorax and pleural or pericardial effusion may lower QRS voltage in surface leads. Finally, systemic changes such as a fall in hematocrit, a sudden rise in body weight (from fluid retention) and sepsis with fever can decrease voltage. An S, gallop, indicative of decreasing left ventricular compliance, is a useful clinical sign, but often this finding follows a progressive drop in QRS voltage by 2 or 3 days. Also, observer detection of gallops varies. Therefore, clinical examination, if positive for early signs of left ventricular failure, may be helpful in confirming the impression of rejection, but is generally of secondary value for initial detection. Biopsy

A technique for serial percutaneous right ventricular endomyocardial biopsy was modified for use in cardiac transplantation and described first by Caves and Billingham in 1973.5’ Subsequent application to a large series of transplant recipients led to the conclusion that “cardiac biopsy seems to have been wholly accurate in the detection of acute graft rejection.“58 In cases with abnormal histology, even in the presence of normal baseline ECG voltage, the development of other signs of rejection soon 20

followed. Histologic changes of rejection were always present at least 2 days before a decrease in ECG voltage. Since that time, serial cardiac biopsy has become the standard for diagnosis of rejection. More than 1,200 biopsies have been completed at Stanford3 with no mortality or major morbidity. The technique (Fig 4), which requires lo- 15 minutes and local anesthetic only, used cannulation of the right internal jugular vein with a 7 or 8 French catheter sheath, passage of the bioptome* into the right ventricle with fluoroscopic visualization and removal of a specimen of right ventricular endocardium. Three pieces, requiring 3 passes of the bioptome, are routinely taken. These vary in size from 1 to 3 mm in diameter. Most of the tissue is sent for routine processing with hematoxylin-eosin and methylgreen pyronin staining. Frozen section studies have not been helpful. Biopsy examinations are generally done on a weekly basis for the 1st month, and then as indicated by ECG voltage or other clinical. findings. The histologic grading of these biopsies is based on the work of Kosek,34 Billingham and Bieber.59 Table 4 summarizes the grading system.60 Accompanying photographs (Fig 5- 8) illustrate the spectrum from normal to severe rejection. The methylgreen pyronin stain has been particularly helpful in mild rejection when changes seen on hematoxylin-eosin staining are subFig 4.-illustration

of endomyocardial

biopsy

nrerflal

technique

jugular

(see

text)

vein

*Schultz Mark IV cardiac bioptome Werner Schultze, 24112 Birch Street, Willitz, CA 95490. 21

TABLE Mild

4. -GRADING OF HISTOLOGIC CHANGES SEEN IN BIOPSY SPECIMENS OF ACUTELY REJECTING ALLOGRAFTS Blood vessels - Endocardium Myocytes Interstitium Blood vessels

Moderate

Endocardium Myocytes Interstitium Blood vessels

Severe

Endocardium Myocytes Interstitium

Endothelial swelling Edema Fibrillar separation; perinuclear vacuolixation Mild fibrinous exudate; few lymphocytes Perivascular infiltrate of small lymphocytes and large pyroninophilic mononuclear cells Fibrinous exudate in subendocardium Continued fibrillar separation and prominent perinuclear vacuolixation Fibrinous exudate; cellular infiltrate Heavy perivascular infiltrate; marked endothelial swelling Heavy cellular infiltrate including polymorphonuclear forms Degenerative changes progressing to myocytolysis in focal areas Marked polymorphous cellular infiltrate, hemorrhage and heavy fibrinous exudate

tle. This stain identifies “turned on” lymphocytes in the myocardial interstitium by staining increased RNA in the cytoplasm. Endomyocardial biopsy seems to have been well received by other institutions performing heart transplants. It is practiced at the Medical College of Virginia,1s in the Union of South Fig

5.-Photomicrograph

showing

normal

histology.

Fig 6.-Photomicrograph

showing

moderately

severe

rejection.

Africa,Gl at H6pital de la Pit% (Paris)62 and at Arizona Health Sciences Center. Criticism of the technique has focused primarily on the possibility of sampling error and the subtlety of the histologic changes in diagnosing rejection.lg In an attempt to validate the technique, Rose et al.s1 examined biopsy samples Fig 7.-Photomicrograph

showing

severe

rejection

(see

Table

4).

23

Fig 8.-Photomicrograph

showing

severe

rejection

(see

Table

4).

taken with a bioptome from formalin-fixed transplanted hearts from human transplant recipients and compared these in a blind fashion with standard histologic sections taken from the same hearts. Using a scoring technique to grade severity of rejection, they found agreement of results between the bioptome biopsies and routine sections in 86% of cases. More important was the fact that in 285 biopsy samples, only 2 false negative results were obtained. Immunologic

Monitoring

Diagnosis of impending graft rejection should, in theory, be most readily made by monitoring activity of the recipient’s immune system since immunologic recognition and activation are prerequisites to rejection. Currently, the most helpful form of immunologic monitoring is measurement of the T-lymphocyte level. T-lymphocytes are identified in humans by spontaneous rosetting of sheep red blood cells around the T-lymphocytes.BO These lymphocytes are thymic-derived during fetal and neonatal development and play a central role in the recognition and effector phases of cell-mediated immunity, including allogr& rejection. They do not produce antibodies, which is the role of B-lymphocytes. Their numbers (normal, l,OOO- 2,000 per cu mm) as measured by T-cell rosette test are markedly depressed (5- 20 per cu mm) within hours after the administration of antithymocyte globulin (ATG). During the first 30 days after transplantation, in patients treated with rabbit ATG, a sudden, large rise in T-lymphocyte numbers has been closely correlated with biopsy24

proved rejection in the subsequent 72 hours.8 Further, the longer the interval between T-lymphocyte rises, the less likely the patient is to sustain frequent or severe rejection episodes.* Another measurement that provides similar prognostic information and with which the T-lymphocyte level is inversely correlated is the half-life of circulating rabbit globulin (RATG T,,,). Prolonged RATG Tllz (11.4 + 1.6 days) correlates with decreased frequency and severity of rejection episodes and low T-cell counts. After the first 30 postoperative days, the incidence of false positive T-lymphocyte elevations increases, so that it is no longer helpful in predicting rejection.* Indeed, it is usual for recipients, several months after transplantation, to have baseline levels of T-lymphocytes that are much higher than the immediate postoperative levers, although often still subnormal. Other immunologic tests for the detection of rejection have been less valuable. The modified reactive leukocyte blastogenesis (MRLB) test measures in vitro spontaneous uptake of tritiated thymidine by peripheral blood leukocytes,63 and correlates well with the clinical or biopsy diagnosis of cardiac rejection; elevations occur approximately 3 - 5 days before rejection can be diagnosed by nonimmunologic means. Unfortunately, however, the assay incurs a 20- 25% false positive rate and, therefore, cannot be used alone for clinical decisions. Its potential use, however, may be to alert physicians to the possibility of impending rejection and encourage aggressive attempts to make a definitive diagnosis. Thomas has reported several other tests monitoring different immune functions: B-cell levels, ATG-coated lymphocyte levels, T-cell reactivity to mitogens, B-cell reactivity to a staphylococcal strain, spontaneous lymphocyte blastogenesis, “K”-cell cytotoxicity, and mixed lymphocyte culture.64 He and the group at Richmond have shown- that false negative T-cell counts using the rosette technique may occur while other tests suggest rejection. None of these tests, however, has emerged as entirely reliable or superior to ECG monitoring combined with endomyocardial biopsy. With current therapy about 3 rejection episodes can be expeded during the first 3 postoperative months and 1 in 10 patients will experience no rejection. In subsequent months, approximately 1 acute rejection episode per year is expected. If the rejection reaction of individual recipients could be accurately predicted, more intensive immunologic testing, more aggressive cardiac biopsy scheduling and a longer initial hospital stay could be planned for the “high-risk” patient. With present techniques, however, this is not yet possible. Recipients with a history of blood transfusion prior to heart transplantation were found in one Stanford study65 to be at lower risk than nontransfused patients. In 1973 it was noted that 25

the l-year survival rate after cardiac transplantation in patients who had previously received blood transfusions was 75%, as compared to 30% for nontransfused patients.65 All of these patients were treated postoperatively with horse antithymocyte globulin. In contrast, among recipients undergoing transplantation since 1973, all of whom were treated with RATG, the l-year survival rate for previously transfused patients (60%) was less than for the nontransfused group (67%). Therefore, high- and low-risk groups cannot be reliably identified by this variable. One promising predictor evolved from the studies of Coulson on mixed lymphocyte cultures,@ in which he showed that the serum of 2 patients in 10% dilution depressed the uptake of tritiated thymidine into antigen-stimulated recipient lymphocytes. These 2 patients survived without any rejection episodes. Using concanavallin A stimulation in a mixed lymphocyte culture, Biebe+ has found that recipient’s serum has a spectrum of effects in enhancing suppressor activation of peripheral mononuclear cells, effects that may relate to prognosis after transplantation. In those recipients (n=34) whose serum causes more suppressor cell activation (less tritiated thymidine uptake) than the mean, the l-year survival rate has been 82 t lo%, compared to a 36 ? 11% l-year survival rate for those with less suppressor activation than the mean (n=27). Evaluation of this test in the prospective identification of high- and low-risk groups is currently underway. Postoperative Immunosuppression There is no adequate treatment of allograft rejection with specific immunosuppressive medication in any form of organ transplantation. Rather, we have available nonspecific immunosuppressive agents whose major toxicity is increased susceptibility to infectious disease. The current dosages and administration of the immunosuppressive drugs used in cardiac transplantation are listed in Table 5. Limited initial immunosuppression after cardiac transplantation, high-dose treatment of acute rejection only when the diagnosis is definitively proved by cardiac biopsy and downward titration of oral prednisone dosage in an attempt to find the lowest possible chronic dose at which the patient can be maintained free of rejection constitute empirical means of establishing a balance between over- and underimmunosuppression. Azathioprine is the other major medication used on a chronic basis for immunosuppression. It is generally given in a dose of 2 or 3 mg per kilogram per day and is tapered only when the white blood cell count falls below 4,000 per cu mm or other toxic side effects are encountered. The effects of corticosteroids on inflammation include: limitation of increases in capillary permeability and, therefore, a decrease in edema and protein leak in areas of inflammation; inhibition of white blood cell adhesion to capillary endothelium and 26

TABLE

5.-USE OF IMMUNOSUPPRESSIVE IN CARDIAC TRANSPLANTATION

Immediate Postoperative Methylprednisolone

Period

Rabbit antithymocyte

globulin

When oral intake starts Prednisone

Azathioprine Dipyridamole Aspirin Treatment of acute rejection Methylprednisolone Prednisone Rabbit antithymocyte Heparin Actinomycin D IV = intravenously;

globulin

500 mg 125 ma 200 mg 50- 100 doses

DRUGS

IV immediately postoperatively IV everv 8 hours x 3 doses IM every other day x 6 doses mg IV, alternated with IM x 6

100 mg PO per day, tapered at rate of 5 mg per day until dose of 1 mg/kg/day is reached and maintained for 1- 2 months; then, gradual tapering to final maintenance dose of 0.25-0.5 mglkgl day to be attained between 4 - 6 months postoperatively 200 mg/day to be regulated according to bone marrow and hepatic tolerance 400 mglday 325 mg/day 1 gm IV daily x 3 days Dose raised to 100 mglday and tapered as above 200 mg IM every other day to suppress T-cells to 10% or 50 per cu mm 250 - 500 pg over 2 or 3 days (optional)

IM = intramuscularly;

PO = orally.

decreased diapedesis of these cells through capillary endotheliurn; interference with phagocytosis of antigens; stabilization of lysosomal membranes; and lympholysis that results in depression of T-lymphocytes to a much greater extent than of the Blymphocytes. 68 When corticosteroids are administered intravenously there is a rapid fall in total lymphocyte and T-lymphocyte counts to nearly zero within 4 hours and a gradual rise to baseline levels within 24 hours.68 Chronic administration tends to have a chronic suppressive effect on lymphocyte numbers. Prednisone, the corticosteroid given on a long-term basis to cardiac transplantation patients, has an anti-inflammatory potency 3Y3 times that of hydrocortisone and a moderate sodium-retaining influence. Methylprednisolone, the corticosteroid used in very large doses for short periods of time in the treatment of acute rejection, has an anti-inflammatory potency 5 times greater than that of hydrocortisone and little sodium-retaining influence. The plasma half-life of both of these corticosteroids is 200 minutes or greater and the biologic half-life as measured by inhibition of the inflammatory response extends for 18-36 hours.68 Doses as small as 7%- 10 mg per day of either one of these medications causes suppression of the hypothalamic-pituitary27

adrenal ax&G” making the patient susceptible to addisonian crisis in the event of sudden withdrawal of steroid medication. Prednisone has generally been administered on a twice per day basis to cardiac transplantation patients. No extended attempt to maintain the function of the hypothalamic-pituitary-adrenal axis by every-other-day therapy has been made. Unfortunately, the side effects of corticosteroids are multiple and have been clearly associated with mortality in the Stanford heart transplant series. Early in the Stanford experience it was apparent that patients who were repeatedly treated with highdose intravenous methylprednisolone for acute rejection became highly susceptible to infection and often died from this complication. Other side effects, although not as immediately devastating, have been severe and potentially fatal. Osteoporosis and osteonecrosis have been associated with vertebral compression fractures and severe back pain, as well as with hip dysfunction and a requirement for prosthetic hip replacement in some patients. Gastric ulcers and perforation have occurred on several occasions. A tendency for fluid retention, hyperglycemia, glycosuria and muscle wasting has been observed commonly, as well as the typical cushingoid appearance, including moon facies, “buffalo hump,” central obesity, supraclavicular fat pads, striae, thinning of the skin, ecchymoses and acne. Several acute psychotic episodes have been documented and one death from suicide has occurred. This experience is similar to other reports of corticosteroid toxicity, in which mental disturbances, including depression and suicidal tendencies, gastric ulcers, infections, compression fractures and progressive arteriosclerosis have been frequently observed.68 Azathioprine is the other drug currently necessary for chronic immunosuppression. It is metabolized to 6-mercaptopurine and acts as a false purine, interrupting synthesis of DNA and RNA. It has been shown to suppress antibody formation6g and it also exerts an anti-inflammatory effect. The dosage used for chronic maintenance treatment in the heart transplantation program has ranged from 1 to 3 mg per kilogram per day. The dose-limiting effect has been bone marrow toxicity (leukopenia, thrombocytopenia and anemia), which may persist for days or weeks after the drug is discontinued. Hepatic toxicity of hepatocellular and cholestatic types has occasionally been noted. The role of this drug in carcinogenesis may be quite important. A relatively high incidence of malignancy, particularly lymphoma, has been reported in patients taking this medication. The RATG, a potent T-lymphocyte suppressor, has been used in the Stanford transplant program since 1973. It is produced by inoculating rabbits with human thymocytes. After giving a booster dose of thymocytes and waiting for several weeks, the animals are bled and the IgG fraction from the serum is isolat28

ed. A dose of 3 mg per kilogram of this substance has been used for intramuscular administratiom70 the intravenous dose has been somewhat lower. Initial treatment has included every-other-day intramuscular alternating with every-other-day intravenous administration. Pretreatment of patients with 625 mg of aspirin and 50 mg of dyphenhydramine, as well as their daily dosage of corticosteroids prior to administration of antithymocyte globulin, has helped to reduce some side effects. Reactions after intravenous administration of antithymocyte globulin, even when it is given in 100 ml of normal saline over 1 hour, can be quite striking; they consist of chills, fever and hypotension. Serum sickness has not occurred commonly; however, its possible occurrence with characteristic findings of urticarial rash, facial edema, arthritis and arthralgia and occasional pericarditis and mononeuritis should be kept in mind. The most common reaction to intramuscular RATG is severe local inflammation at the site of infection. This area becomes red, swollen, tender and occasionally ecchymotic. The RATG injections are given initially until the peripheral T-cell count, as measured by the sheep red blood cell rosette technique, has decreased to 10% or less of normal. Then, RATG is discontinued and used again during episodes of acute rejection. Since the replacement of horse antithymocyte globulin by RATG in the Stanford program, a significant improvement in overall survival has been obtained (50% 5year survival rate as compared to 20% 5-year survival rate with horse antithymocyte globulin). The posttransplantation rejection-free interval (i.e., the period of time during which the patient is entirely free of rejection after transplantation) has averaged 24 days with RATG treatment versus 13 days with horse antithymocyte globulin. Furthermore, the frequency of rejection episodes during the first 100 days has been reduced significantly with RATG therapy. It thus appears that RATG is a potent immunosuppressive agent and has made an important contribution to control of the immune response after cardiac transplantation. Dipyridamole was added to the pharmacologic regimen in 1973 for its antiplatelet aggregation effect to be discussed in the section, Chronic Rejection. Aspirin in low dosage (325 mg per day) has been added to the regimen at Arizona Health Sciences Center on the basis of recent laboratory reports that indicated prolonged heart graft survival with a dose of 200 mg per kilogram sodium salicylate in rats. 21 At low dosage, the antiplatelet aggregation effect of aspirin may be of some value. Since transplant recipients seem to be at increased risk for gastric ulceration and perforation, at the present time it does not seem justifiable to raise the dosage to higher levels. A number of other agents have been or are being evaluated for immunosuppression in animal heart allograft models. The 29

most promising of these appears to be cyclosporin A. This cyclical polypeptide extracted from 2 species of fungi has resulted in survival of porcine cardiac allograft recipients for more than 2 months with &other immunosuppressive medication.71 It was tried in 7 recipients of mismatched human cadaver kidneys, with notable results.72 None of the patients received steroids. Five patients, who were also receiving a cyclophosphamide analogue, were discharged from the hospital with functioning allografts. One died of a fungal infection and one required allograft nephrectomy for pyelonephritis. Hair loss, nephrotoxicity and hepatotoxicity were the main side effects of this fat-soluble drug, which had to be dissolved in olive oil to promote absorption. The great promise of this drug is that it may permit immunosuppression without the toxic effects of corticosteroids. The treatment of acute rejection episodes has changed little in the last decade74 (Table 5). Heparin may be administered for 5- 7 days to prevent microvascular thrombosis. At the Arizona Health Sciences Center we have chosen not to administer heparin during acute rejection to patients taking both aspirin and dipyridamole and have encountered no problems thus far. Acute rejection therapy must be evaluated as treatment proceeds. Reversal of 95% of rejection episodes has been documented. With reversal, QRS voltage usually returns to baseline levels and the histologic appearance of right ventricular endomyocardial biopsies returns to normal. Routine posttreatment biopsy studies provide a valuable method for assessing the adequacy of therapy. If rejection persists, therapy is continued and graft histology is reevaluated again. Infection

Following

Cardiac

Transplantation

Infection is the most common cause of death after cardiac transplantation, accounting for 62% (n=31) of all deaths in the first 3 postoperative months and 46% (n=26) of deaths after the first 3 months in the Stanford experience. The mean incidence of infectious episodes is 3 per patient. After 1 year, the incidence of infection drops markedly to 1 episode per 455 patient-days.13 Pulmonary infections have been most common (47%), but nearly every organ system has been involved. In decreasing order of frequency, other sites of involvement have included bloodstream (lo%), urinary tract (6%), central nervous system (4%), disseminated viral (2%), pleural cavity (2%), disseminated fungal (2%), liver (lo/o), retina (l%), bone (0.2%) and a number of other rarely involved sites (25%). Bacterial organisms have predominated, followed by viral, fungal, protozoan and nocardial (Table 6). Aspergillus and the gram-negative bacteria (E. coli, Klebsiella and Pseudomonas) have been most commonly associated with a fatal outcome (see Table 6). Early after cardiac transplantation, when immunosuppression is most intense, the risk for infection is highest. As time passes, 30

TABLE 6. -MICROORGANISMS INFECTIONS IN CARDIAC!

Bacterial Anaerobic, mixed Arizona Atypical, AFB Citrobacter Clostridia Enterobacter Enterococcus E. coli Hemophilus parainfluenzae Herellea Klebsiella Listeria Mima Pneumococcus Proteus mirabilis Proteus morganii Pseudomonas Salmonella Serratia Staphylococcus Streptococcus Viral Cytomegalovirus Hepatitis Herpes simplex Herpes zoster Influenza A Undefined Fungal Aspergillus Candida Coccidioides cryptococcus Mucor Rhizopus Protozoan Pneumocystis Toxoplasma Trichomonas Nocardial

ASSOCIATED TRANSPLANTATION

36 2 11 5 2 14 15 49 13 4 44 4 1

WITH

PULMONARY PATIENTS

i 2 28 1 17 30 15

30 2 9 5 2 12 14 40 8 4 42 4 1 5 3 2 22 1 16 25 11

9 4 48 30 3 3

9 4 42 29 2 3

2 1 1 3

39 12 1 10 1 2

39 12 1 9 1 2

20 6

22 6 1 22

21 6 1 22

6 5 1 3

1 7 6 18 1 21

1 1 1 11 5 8 3

1

3 1

the accommodation between the recipient and his/her allograft permits lower doses of corticosteroids and is associated with a much reduced incidence of infection. However, even in 3-month survivors, when acute rejection is treated with intravenous methylprednisolone (usual dosage: 1 gm per day for 3 days) and antithymocyte globulin, there is a threefold increase in the incidence of serious infection (from 1.3 infections per 1,000 pa31

tient-days to 3.6 per 1,000 patient-days after treatment).75 If the rejection is graded mild or moderate, rather than severe, and survivors of 3 months or more are treated with increased doses of prednisomzuather than intravenous methylprednisolone (maintenance dose doubled or raised to 100 mg per day), there is no significant increase in the incidence of infection above that expected without treatment for rejection. As treatment for rejection becomes more specific, it may be anticipated that the incidence of infection and its attendant mortality will be markedly decreased. In the interim, efforts are directed at prevention of infection, early detection and intensive therapy. A careful preoperative history may be of some use in identifying patients who have had tuberculosis (which may reactivate) or recurrent chronic infections (urinary tract) or those who have ongoing increased risk from exposure (endemic coccidioidomycosis areas). Preoperative sputum and urine culture tests are routine. Skin testing for coccidioidomycosis, histoplasmosis, tuberculosis and serologic testing for cytomegalovirus (CMV) and herpesvirus give some baseline information that may be relevant later in the patient’s course. Rand76 found that cardiac transplant patients who were preoperatively seronegative for CMV had a higher incidence of pulmonary infections postoperatively than those who were seropositive preoperatively. In all cases, the pulmonary infections occurred in the 2d and 3d months after transplantation, at a time when new or recurrent CMV infections were serologically detected. It was proposed that pulmonary infections (bacterial, fungal, nocardial) occur as superinfections following CMV pneumonitis. Preventive measures commonly used in the postoperative period include prophylactic antibiotics, reverse isolation, minor adjustments in room ventilation and special nursing care. Prophylactic antibiotics (cephalosporin and gentamycin) are administered 1 hour prior to transplantation and for 48 hours postoperatively. Strict reverse isolation serves to reduce traffic into the patient’s room to a minimum. Good hygiene is stressed with the patient, his family and the nursing and physician staffs. Additional room cleaning precautions are in force before the patient is brought to his room and on a daily basis. We have used increased-pressure air conditioning in transplant rooms (to prevent air inflow through the door) and high-grade medical filters for the inflow ducts into the room. The use of more expensive laminar airflow rooms has not been proved beneficial. Intravenous lines are cared for daily and removed as soon as possible. We use alternating tetracycline and amphotericin B (50 mg/25 ml water) mouthwashes for the first several weeks. Oral nystatin is administered 3 times daily, because of the previously described propensity of recipients to Candida and other yeast recovered from sputum, urine and stool cultures.77 When the patient is in 32

the hospital outside of his room, wearing a mask serves as a reminder to avoid sources of respiratory contamination. We have limited laboratory and roentgenographic testing to a minimum. Cultures and titers, aside from baseline tests, are obtained only when clinically indicated. Chest roentgenograms are obtained daily for about 2 weeks, then 2 or 3 times per week until discharge. Patients are taught to take and record their temperatures daily and are instructed in the benefits of early detection of infection. When infiltrates have been noted on chest roentgenograms and/or the patient has become febrile, transtracheal aspiration has often yielded a culture positive for the infecting organism. In the presence of an infiltrate and nondiagnostic transtracheal aspirate, percutaneous pulmonary needle aspiration has produced a diagnosis in at least 75% of cases. At Stanford, bronchoscopy (which itself may cause bacteremia) has not been used, although this technique is favored over lung aspiration by the Richmond group. ls The treatment of these infections differs little from their treatment in any patient population. However, a tendency to treat with higher doses, multiple drugs and for more prolonged periods has been a natural outgrowth of witnessing the devastating results of infection in transplant recipients. CHRONIC

REJECTION-GRAFT

ARTERIOSCLEROSIS

The first long-term survivor in the Stanford program died 21 months after heart transplantation.‘O Postmortem examination of his coronary arteries revealed intimal hyperplasia and atheromatous plaques nearly identical to the abnormalities seen in spontaneous coronary artery disease. Similar changes had previously been described by Kosek34 in canine heart allografts, and later by Bieber and Kosek in human heart transplants.599 78 Recipients with high-grade arterial narrowing resulting in myocardial infarction and congestive heart failure have not had angina pectoris since they lack cardiac innervation. Close clinical followup and serial coronary arteriograms have been used to detect this serious complication. In 1973, nearly all long-term survivors were found to have narrowing of 20% or more in the luminal diameterlO of at least one coronary artery on angiography. This group of 9 patients who received heart transplants between August, 1968 and December, 1969 had all survived beyond the initial 3 months. In 1970, a prospective treatment program was begun, which included the following alterations in therapy: (1) anticoagulation with warfarin; (2) dipyridamole, 400 mg daily; (3) weight control with exercise and caloric restriction; and (4) a diet low in saturated fat and cholesterol. The progression of graft arteriosclerosis 33

was assessed with yearly coronary arteriograms. After a 4-year follow-up, the treated group of patients had only a 22% incidence of graft arteriosclerosis as defined above. The statistical difference in iru$dence between the 1968- 69 untreated group and the 1970 - 74 group was striking (p < O.OOOOO1)lo(Fig 9). A very significant decrease in time-related incidence of graft arteriosclerosis was documented. Considerable care was taken to show that these 2 groups were similar in terms of preoperative and postoperative variables, such as age, serum cholesterol, number of HLA antigen mismatches, prednisone doses and h-equency of rejection, Only 3 significant differences were found. The second group was found to have a slightly lower mean age, a lower incidence of smoking and a delay in onset to rejection (7 days for first group, 16 for second). On the basis of this study, it was reasoned that dipyridamole might have exerted significant benefit in preventing rapidly progressive graft arteriosclerosis, since dietary restrictions and weight control were not uniformly attained and since sodium warfarin anticoagulation had failed in other studies to benefit patients with known arteriosclerosis.10 Limitations of this study, such as the sequential rather than concurrent relation of the 2 groups and the use of cardiac biopsy and RATG only in the latter group, however, do not permit definite conclusions about the role of dipyridamole in preventing graft arteriosclerosis. The study does document a rapidly progressive form of arteriosclerosis and marked reduction in incidence from the early (1968-69) to the later (1970- 74) group. At present, we are using both dipyridamole (400 mg per day) and aspirin (325 mg per Fig 9.-Comparison of incidence of graft arteriosclerosis on coronary arteriography in group I (9 recipients surviving 3 months during 1968-69) and group II (44 recipients surviving 3 months from 1970-1974) treated with prophylactic regimen (see text).

34

day) because we believe that platelet aggregation in coronary arteries plays an imnortant role in producing intimal proliferation and, ultimately, obstructive atherosclerotic plaques. RETRANSPLANTATION

Retransplantation presents an alternative available to heart recipients with allograft failure. In the absence of a mechanical heart for interim support in the patient with a failing allograft, early diagnosis of impending failure followed by retransplantation is mandatory for recipient survival. Three indications for retransplantation have emerged from the Stanford series: (1) graft arteriosclerosis (8 patients); (2) unremitting rejection (4 patients); and (3) poor donor heart function (2 patients). Patients with graft arteriosclerosis resulting in 7% or greater luminal narrowing of major coronary arteries have been considered candidates for retransplantation because of the rapidly progressive course of this entity and the threat of fatal myocardial infarction or ventricular arrhythmia. Yearly coronary arteriograms are performed in all transplant recipients in order to evaluate coronary arterial anatomy. Serial ECGs for evaluation of ischemic changes and clinical evaluation have been of limited value. Treadmill stress testing and exercise thallium scans may in the future be of some value in earlier identification of recipients at high risk. Five percent of acute rejection episodes prove refractory to immunosuppressive therapy. Smouldering acute rejection, treated with high-dose methylprednisolone (in doses reaching lo- 13 gm in 4-6 weeks) is likely to lead to death from rejection or infection.14 Further, the persistence of histologic evidence of acute rejection, progressive fall in the amplitude of QRS voltage and the presence of clinical findings of low cardiac output and heart failure are conclusive evidence of impending death. Computer analysis7g of the movement of intramyocardial markers to derive information about left ventricular function has demonstrated progressive deterioration during persistent acute rejection” (Fig 101. Serial echocardiography, both M-mode and 2-dimensional, has the potential for providing similar information. Poor donor heart function, if not immediately fatal, is a third indication for retransplantation. A 43-year-old man became the recipient of a third heart transplant 3 days after the second because of left ventricular failure of the second donor heart.s0 Early graft failure may result from direct traumatic damage, injury during the resuscitation process or inadequate preservation during harvesting and transportation. At present, 6 of 14 patients have survived 6 months or more after retransplantation. The mechanics of the second operation 35

“Ejection Fraction” Pednt Diameter Shortening

0.8 1 0.6 : 0.4 -

I

oi;-

I I

I

15-

Velocity (circslsec) T 10 20 30 40 50 60 70 80 90 PM1 W3W)

Postoperative

Days

Fig IO.-Serial measurements of cardiac function by noninvasive cinefluoroscopy in the RAO projection of intramyocardial markers. In this case the recipient showed progressive deterioration in function. Following retransplantation on postoperative day 57 (dotted line), improved function was noted.

have posed no problems.

Postoperative infection (with Candida, or multiple bacterial) has been common and probably constitutes the major risk of retransplantation. Rejection episodes after retransplantation have been noted, but appear to be less frequent than would be expected after a first transplant. Nocardia,

Pneumocystis

SURVIVAL

Survival rates at Stanford have improved significantly since initiation of the program. One-year survival rates have increased from 22% in the first year of the program (1968) to the TABLE 7. - STANFORD PROGRAM: JANUARY

1968 1969 1970 1971 1972 1973 1974 1975 1976 1977 1978 1979

(through TOTAL

36

8/79)

CARDIAC TRANSPLANTATION 6, 1968-AUGUST 31, 1979

9 9 8 12 13 15 13 18 20 19 25 14 175

10 9 8 12 14 15 15 19 21 20 31 16 190

22 44 50 42 54 47 62 67 70 58 60

TABLE RATES:

8. -STANFORD JANUARY

OVERALL 6, 1978-AUGUST

1 2 3 4 5

56 49 43 34 31

SURVIVAL 31, 1979

78 69 61 48 44

range of 60 - 70% during the last 5 years (Table 7). The overall survival rates for the entire experience are shown in Table 8. A marked differential in survival rates is apparent for the group of recipients who have survived the first 3 months, a period known to be associated with the greatest risk for rejection and infection. A more accurate appraisal of the current prognosis for a patient receiving a heart transplant comes from the experience of the last 5 years (Fig 11). The &year actuarial survival rate for recipients receiving transplants between January 1974 and August 1979 is 48%. This represents a more than double increase in survival as compared to the 1968- 73 subgroup, in which an 18% &year survival rate was recorded. When the current 5-year survival rate is compared to the natural history of the recipient group without transplantation (Fig ll), the rationale for heart transplantation is clear. Thirty-five patients selected as potential recipients have died while awaiting a donor heart- a validation argument for the severity of cardiac disease present in such patients. One-year survival rates from 1968 to 1973 were in the 45-50% range, as compared to l-year survival rates of 58- 70% for the years 1974-78 (Fig 12). Advantages unique to the later group and which may have accounted for the improvement include the performance of endomyocardial biopsy study for diag-

l6

Fig ll.-Actuarial survival curves for Stanford cardiac transplantation program. Closed circles include all patients treated from 1966 through 1979. Open circles include patients treated from 1974 to 1979. Open triangles include patients from 1968 to 1973. Closed triangles include all patients chosen as potential recipients but not receiving a heart transplant.

Years Post Transplant 37

Fig 12.-A plot of l-year survival rates for each year of the Stanford program; solid lines indicate plateau periods in survival rates.

a”

‘OL68

6970717273747576777879

Year nosis of acute rejection and administration of RATG for the treatment of acute rejection. Further, improved survival beyond 1 year is probably due to (1) more specific diagnosis and treatment of rejection during the first postoperative year; (2) a prophylactic regimen against graft arteriosclerosis; and (3) more frequent use of retransplantation for graft failure. Since 1974, l-year survival rates have ranged between 58 and 70%. During that time, patient care, overseen by a consistent protocol and senior staff, has been directly in the hands of 8 chief residents. In spite of their varying backgrounds, skills and motivations, they have obtained results that have not varied greatly. Such consistency within one institution suggests that similar results could be duplicated if the same technology could be transferred to other interested physicians in distant centers. At the time of this writing, 175 patients have had transplants and 69 are alive; the longest survivor is alive 9V2 years after transplantation. Causes of early and late postoperative deaths are summarized in Table 9. TABLE

9. -CAUSES OF POSTTRANSPLANTATION

Acute rejection Infection Graft arteriosclerosis Proliferative Arteriosclerotic Malignancy CVA Suicide No. of deaths 38

12 31 (chronic

EARLY

AND DEATH

10 26

22 57

5 8 6

5 8 6 2 1 106

rejection)

2 50

LATE

1 56

Rehabilitation in 56 patients surviving 6 months or longer after heart transplantation was documented in 91% of cases by Christopherson et a1.12 Competitive employment (26 recipients), active retirement (13), student (8) and homemaker status (4) were the categories into which rehabilitated patients were classified. Among those patients unable to lead active lives and classified as disabled (5), 4 had physical limitations resulting from postoperative complications and 1 had severe psychiatric dysfunction. PHYSIOLOGY

OF THE TRANSPLANTED

HEART

Immediately after cardiac transplantation, function of the donor heart is depressed .53,*I In a group of 10 allograft recipients, the mean stroke index (SI) (21.4 ? 1.7 cc per sq m) and cardiac index (CI) (1.83 5 .16 L per minute per sq m) were depressed on postoperative day 1 and remained subnormal until the 4th postoperative day when the SI rose to 29.5 + 2.0 cc per sq m and the CI to 2.44 5 .ll L per minute per sq m.*l The mechanisms for this depression have not been defined, but empirical treatment with isoproterenol (1 - 4 pg per minute) or dopamine (2- 5 pg per kilogram per minute) has been adopted as routine; positive myocardial inotropic support has been documented to normalize early graft function. StinsorP has reported cardiac catheterization data in 8 patients 1 year after cardiac transplantation and in 2 of these again at 2 years. The functional level of the patients 1 year postoperatively was normal, Intracardiac pressures at rest were normal. The average cardiac index was slightly decreased at 2.3 L per minute per sq m and the AVo, difference was minimally elevated at 5.42 vol %. A lo-minute period of supine exercise produced the following changes: (1) heart rate increased gradually, reaching a plateau 5-6 minutes after the start of exercise and not falling to normal until 20 minutes after termination of exercise; (2) left ventricular end-diastolic pressure rose to abnormal levels initially and then tended to decrease late in the exercise interval; (3) cardiac index rose progressively and late in the exercise period reached levels nearly twice the baseline values; (4) stroke volume increased by average 44% late in the exercise period; (5) systolic pressure rose and was paralleled by increase in maximum left ventricular dp/dt; and (6) the exercise factor (increase in oxygen consumption/increase in cardiac output) was normal. In the 2 patients studied with exercise 2 years after transplantation, the values for cardiac output, oxygen consumption and stroke volume in response to the same amount of exercise were decreased as compared to the previous year. In both patients severe graft arteriosclerosis was subsequently documented. 39

In both l- and 2-year posttransplantation studies, donor heart rates were not influenced by amyl nitrite inhalation or atropine injection, while the residual recipient atria1 cuffs increased their rates with bot.h,stimuli. In summary, it appeared at 1 year after transplantation that the cardiac allograft responded adequately, but atypically when recipients were subjected to the stress of muscular exercise. Dependence on the Frank-Starling mechanism and the slow rise and fall of heart rate (suggesting response to humoral factors) are expected in the denervated heart. Indeed, no evidence of cardiac innervation following human cardiac allografting has been found.16 Studies of the electrophysiology of the transplanted heart have demonstrated the persistence of p-adrenergic receptors that can be stimulated and blocked,83 normal sinus node function,84 absence of an acute neurally mediated digitalis effect on either the sinus or atrioventricular nodes (a direct effect with chronic administration, however, is retainedY4 and depressant effects of quinidine on the sinus node (increased cycle length) and AV node (increased conduction time), in contrast to the net effects of quinidine on autonomically innervated hearts.85 In summary, the cardiac allograft in humans is permanently denervated. Patients do not experience angina pectoris. The direct effects of the autonomic nervous system which normally exerts a major role in regulating the response to exercise and most cardioactive drugs are lacking. Substantial humoral control, however, remains. The response to exercise, therefore, is atypical, but directionally appropriate, and allows transplant recipients to achieve normal functional status. OTHER LONG-TERM COMPLICATIONS MALIGNANCY. -Six deaths in the Stanford series, all in recipients surviving for more than 3 months, have been attributed to malignancy. Krikorians6 reported an incidence of malignancy in this series of 3% at 1 year after transplantation and 25% at 5 years. Andersona in a review of lymphomas from the Stanford transplant series, found a 30-fold increase in risk of lymphoma in the heart transplant population in comparison to normal. He also reported that lymphomas were found exclusively in patients who had been referred for transplantation with a diagnosis of idiopathic cardiomyopathy and who were under the age of 40. There have been 6 cases of lymphoma (3 involving the central nervous system), 3 of skin cancer (2 squamous cell, 1 basal cell), 1 of acute myelogenous leukemia and 1 of adenocarcinoma of the colon with metastasis to the liver. This experience is similar to that encountered in kidney transplantation. One mechanism has been proposed as predisposing to lymphoma. It was found in the idiopathic cardiomyopathy patients 40

that a defect in mitogen-induced mononuclear suppressor cell activity was present. 87 This defect was absent in patients referred for transplantation with ischemic cardiomyopathy and in controls. These findings suggest an excessive risk of postoperative lymphoma in suppressor cell-deficient patients. At greater risk were those under 40 years of age with idiopathic cardiomyopathy. Six of the 11 malignancies in the Stanford series have been fatal. Early diagnosis and treatment have thus far salvaged the others. PERIPHERAL ARTERIOSCLEROSIS. -Coronary artery disease with associated ischemic cardiomyopathy has constituted the underlying etiologic diagnosis in 55% of the patients in the Stanford heart transplantation series. A predisposition to peripheral arterial disease is expected in this group. Two patients have presented with symptomatic abdominal aortic aneurysms and had successful aneurysmectomies. 88 Two amputations for lower extremity vascular insufficiency have been required. ORTHOPEDIC PROBLEMS.-Two varieties of orthopedic problems have plagued long-term heart transplant survivors, Vertebral compression fractures resulting in back pain have occurred in several patients. Osteonecrosis of the femoral head associated with corticosteroid administration has led to bilateral total hip arthroplasty in 2 patients. 8g Postoperatively, both of these patients regained normal hip function and there have been no problems with infection of the implanted prostheses.

HETEROTOPIC

HEART

TRANSPLANTATION

Heterotopic heart transplantation, which refers to transplantation of an allograft heart to any position except that normally occupied by the recipient heart, has been advocated by the Capetown transplant team since November 1974.go, g* In the first 2 heterotopic transplant procedures done in Capetown, a left heart assist was established. The transplanted heart was connected in parallel with the left heart of the recipient, left atrium to left atrium, aorta to aorta, with the donor pulmonary artery anastomosed end-to-side to the recipient right atrium. Since then, 7 other heterotopic transplants have been completed. In these procedures, parallel right and left heart connections between the donor and recipient were established (Fig 13). The donor heart was implanted on the right side of the recipient heart with the left and right atria, aorta and pulmonary artery (with graft) anastomosed to the equivalent recipient structures. In the entire heterotopic series, 4 patients died of infection, 4 are alive 1 year postoperatively, and 1 less than 1 year. The mean pulmonary vascular resistance in these recipients 41

Artery

Fig 13.-Capetown heterotopic heart transplantation technique. heart is on the left side of the illustration (patient’s right side). The trates that the donor heart is connected in parallel with the recipient’s

The donor insert illusheart.

has been 5 ? 1 Wood units. The original purpose of this technique was to permit heart transplantation in patients with high pulmonary vascular resistance in whom an orthotopic transplant would lead to right heart failure and death. Implicit in this rationale was the assumption that a substantial percentage of potential recipients with pulmonary hypertension had reasonable right ventricular function and not global cardiomyopathies. After the initial experience with this technique, it was used in all subsequent recipients. In fact, this was rationalized on the basis of experience with a 25-year-old man who sustained severe rejection of his heterotopic heart 10 months postoperatively; the recipient heart supported circulation during severe functional depression and a short period of fibrillation of the donor heart.g2 After rigorous immunosuppression, the donor heart recovered and the patient returned to an active life. A backup function was thus demonstrated by the recipient heart. Theoretical disadvantages of this heterotopic technique, such as inadequate intrathoracic space for a second heart and the potential for embolism from the recipient heart, have not been observed in practice. Bronchograms in one patient revealed the donor heart situated to the right of the recipient heart and anterior to the lung, causing no right lung collapse. Sodium warfarin and dipyridamole have been used in this series of patients, and no emboli have been noted. Another potential problem has been the lack of coordination between the heterotopic and recipient hearts. With synchronous 42

contraction of both hearts, the stroke volume of the diseased recipient heart is minimal. As maximal isovolumic pressure increases in the recipient left ventricle, stroke volume decreases.s3 Function of the recipient left ventricle is therefore optimal when the 2 hearts contract in an alternating pattern. An ingenious double atrial-triggered standby pacemaker was recently used in a 35-year-old recipient of a heterotopic heart to insure alternate contraction.s4 Using 2 interconnected pacemakers, the alternating atria1 stimulation was controlled by the faster of the 2 atria1 rates (donor or recipient). Obviously, as arrythmias occur in either or both hearts, such a system will be tested. Even with uncoordinated contractions between the donor and recipient hearts, the hemodynamic function of the donor heart alone has been adequate to support normal patient activity. and clinicals5 studies of hemodynamic perforExperimentaP mance of the donor hearts have consistently shown adequate mechanical function. In one case,s5 a large portion of the recipient left ventricle was resected, the mitral and aortic orifices were closed and the donor heart assumed full left ventricular function without apparent difficulty. One heterotopic transplantation was completed by the Richmond team.s6 That patient was not a long-term survivor; death was due to infection with concomitant severe rejection. The potential value of the heterotopic technique derives from the benefit of having backup cardiac function analogous to the backup provided by dialysis for renal transplant patients. Theoretically, it could also be used in the potential recipient with pulmonary vascular resistance greater than 10 Wood units. In view of the fact that large donor pools are available through air transport and hypothermic preservation of donor hearts, retransplantation is now commonly practiced, and orthotopic allografts usually fail slowly over a period of days, the concept that orthotopic transplantation is irrevocable is now less applicable than in 1974, when heterotopic transplantation was initiated. Hence, the argument in favor of backup function, although still valid, has been weakened. Other criticisms of heterotopic transplantation must be answered before it is acceptable for widespread use. Cardiac biopsy is more difficult, with isolated left-sided anastomoses requiring an arterial access site and retrograde entrance across the aortic valve into the left ventricle, making heterotopic donor heart biopsy much more difficult than orthotopic and less easily used in day-to-day management. Heterotopic transplantation into a small person, with the attendant space limitations, has not yet been accomplished.s3 The number of heterotopic transplants is small and the possibility of embolism from the recipient left ventricle still not yet observed may, in fact, be a problem. In many patients with cardiomyopathy, ischemic or idiopathic, the right ventricle is as severely 43

involved as the left; If such a patient had severe pulmonary hypertension, the burden might prove too great even for a heterotopic right ventricle aided by the recipient ventricle. Finally, there is as yet no proved advantage to heterotopic transplantation in terms 01 patient survival. OUTLOOK

FOR CARDIAC

TRANSPLANTATION

FACTORS THAT FAVOR MORE WIDESPREAD APPLICATION.- The encouraging results reported by Stanford University and the groups at Richmond, Hopital de la Pitie (Paris), and Capetown have established cardiac transplantation as a valuable therapeutic technique, which prolongs life in selected patients. The current survival results, 67% at 1 year, with an expectation of 50% &year survival after heart transplantation, rival those presented for cadaver kidney transplantation18 and surpass those presented for liver, pancreas and lung transplantation.g7 These results, in addition to the previously mentioned surplus of potential transplant recipients,13 indicate that more widespread clinical trials of cardiac transplantation are needed. The protocols that have produced these good results are available, outlining details ranging from the selection of potential recipients to chronic management. The establishment of a new cardiac transplantation program in an appropriate setting does not require major capital investment. Most university medical centers with active cardiovascular surgery programs have the necessary equipment and building facilities. Ancillary support for the care of patients in the eventuality of complications are generally available. Also, most university centers draw referrals from a large population base, in which it is likely that potential recipients and donors will be readily found. PROBLEMS FACING CARDIAC TRANSPLANTATION IN THE FUTURE ANDOPPOSINGMORE WIDESPREADAPPLICATION. -The major obsta-

cle to widespread use of cardiac transplantation and broadened indications for selection of recipients is the inability to specifically suppress graft rejection. A major portion of the effort expended in cardiac transplantation is directed toward titration of nonspecific chemical immunosuppression in order to avoid drug toxicity and infection, the major cause of death, while maintaining the recipient free of rejection. Clearly, deeper understanding of allograft rejection and knowledge of its control are needed. Side effects from the current chemotherapy are inevitable and costly in terms of hospital bills, physician time, and patient morbidity and mortality. The cost for cardiac transplantation in the past’ has been high. At Stanford University it has ranged around $60 - 70,000 for the 44

initial hospitalization in the past 2 years. In Richmond, Virginia, the cost is apparently slightly less. At the Arizona Health Sciences Center, where we have undertaken a new program and endeavored to hold cost down as much as possible, the average cost for initial hospitalization in 3 transplant patients has been $21,600. Further costs after the initial hospitalization can also be considerable. This depends entirely on the complications encountered by the individual patient. Reimbursement for these costs by insurance has covered approximately 60% of patient care charges in the Stanford experience. Medicare, declaring that cardiac transplantation is an experimental procedure, has refused to pay for the initial hospital stay of cardiac recipients, until it can be demonstrated that cardiac transplantation is not experimental outside Stanford; this viewpoint will have a restrictive effect. Most patients cannot afford to fund cardiac transplantation from their own financial resources; therefore, it is self-evident that wider application of cardiac transplantation will be limited by lack of third-party coverage of patient care expenses. Factors that may improve this situation in the future include reproduction of the Stanford results at other institutions and more cost-efficient use of laboratory testing and hospital facilities for carrying out cardiac transplantation procedures. A factor that favors a university setting for cardiac transplantation is the tremendous commitment, both psychological and in terms of time invested, required of the physician or physicians in charge of cardiac transplant programs. This includes constant availability for patient care, a willingness to put aside other matters in favor of care of the cardiac transplant patient and a persistence in following up acute problems and maintaining assiduous chronic care. For those who have personally observed the cardiac transplant program in action at Stanford University, the total commitment to obtaining optimal results in every recipient from the time of his selection is quite obvious. Without this commitment, which sometimes borders on religious zeal, a program with the complexity and risk of cardiac transplantation should not be undertaken. Even if financing and total physician commitment are available, there are 2 other factors which currently seem critical to the success of cardiac transplantation, i.e., availability of RATG and that of donor hearts. Currently, there is no commercial source for RATG. Production of this potent immunosuppressive medication in large quantities is time consuming and expensive. Techniques are available for production of this substance, but the means for obtaining the highest-potency globulin and the ability to quantify its potency objectively are less readily apparent. Initiation of a new program of cardiac transplantation in the absence of a source of RATG is currently inadvisable. Improvement 45

TABLE

lO.-REQUIREMENTS TRANSPLANTATION

FOR A CARDIAC PROGRAM

1. Clearance and education a. HospitaIadministration b. Hospital staff Surgery, neurosurgery, neurology, anesthesia c. Nursing d. Psychiatry, social service goals, counseling techniques e. Physical Resources Room cleaning, room modifications f. County coroner 2. Explicit protocol a. Donor-brain death criteria b. Recipient Preoperative identification Postoperative care Antithymocyte globulin availability c. Nursing care Isolation techniques 3. Transplant team experience and background a. The operation Surgeons’ experience Operating room personnel b. Heart biopsy Technique Histologic criteria of rejection c. EKG monitoring d. Treatment of rejection e. Continuous availability of physician for clinical care f. Heart procurement In hospital Long-distance transport 4. Community a. Education of referring physicians Donors Recipients b. Education of lay public Organ donation c. The press Hospital news bureau Protection of privacy Patients Physicians

of recipients

in the effectiveness of an alternate preparation that is commercially available (e.g., the horse isolate) and the development of other, more specific agents may obviate this problem in the future. Theoretically, the availability of donor hearts should be much less a problem than in previous years, before brain death was defined and accepted and legal precedents were set for removal of the beating heart from brain-dead patients. The death of 35 of the patients chosen as potential recipients in the Stanford program, however, does not support this contention. Although the 46

cardiac transplantation program at Stanford University has been widely publicized both locally and internationally, and in spite of the excellent results that have been obtained, difficulty in procuring donor hearts at appropriate times has been a major problem. In recent years, most of the hearts used in the Stanford program have been obtained by distant heart procurement. NEW PROGRAMS IN CARDIAC TRANSPLANTATION. -Initiation of new cardiac transplantation programs should be undertaken only after serious consideration of the current state of the art. The major problems have been previously mentioned, but a large number of details have been omitted. The most important single factor in beginning such a new undertaking at an institution lacking in previous experience with cardiac transplantation should be a detailed protocol outlining each step in the entire process. If results similar to those obtained at Stanford are expected, it would seem logical to rely heavily on the techniques mentioned in this and other articles for the construction of such a protocol. Observation of a successful transplantation program and acquisition of skills in the techniques of orthotopic cardiac transplantation and percutaneous endomyocardial biopsy should also be absolute requirements. Communication, education and discussion with the hospital administration, the hospital staff, nursing staff ,and ancillary personnel constitute important groundwork, which should be covered well in advance of the initial transplantation procedure. A checklist of requirements for a cardiac transplantation program is given in Table 10 and is the product of a program initiated within the past 6 months. REFERENCES

5. 6.

7. 8.

9.

10.

Lower, R. R., and Shumway, N. E.: Studies on the orthotopic homotransplantation ofthe canine heart, Surg. Forum 11:18,1960. Barnard, C. N.: The operation, South Afr. Med. J. 41:1257,1967. Baumgartner, W. A., Reitz, B. A., Oyer, P. E., Stinson, E. B., and Shumway, N. E.: Cardiac transplantation, Curr. Probl. Surg. 16:6, 1979. A definition of irreversible coma: report of the Ad Hoc Committee of the Harvard Medical School to Examine the Definition of Brain Death, J.A.M.A. 205:85, 1968. Black, P. M.: Brain death, N. Engl. J. Med. 299:338,1978. Watson, D. C., Reitz, B. A., Baumgartner, W. A., Oyer, P. E., Stinson, E. B., and Shumway, N. E.: Distant vs. local organ harvest for orthotopic heart transplantation, Sot. Univ. Surg. (abst.) p. 18, Feb. 1979. Caves, P. K., Billingham, M. E., Stinson, E. B., and Shumway, N. E.: Serial transvenous biopsy of the transplanted heart, Lancet 1:821,1974. Baumgartner, W. A., Reitz, B. A., Bieber, C. P., Oyer, P. E., Shumway, N. E., and Stinson, E. B.: Current expectations in cardiac transplantation, J. Thorac. Cardiovasc. Surg. 75:525, 1978. Bieber, C. P., Griepp, R. B., Oyer, P. E., Wong, J., and Stinson, E. B.: Use of rabbit antithymocyte globulin in cardiac transplantation, Transplantation 22~478, 1976. Griepp, R. B., Stinson, E. B., Bieber, C. P., Reitz, B. A., Copeland, J. G., 47

11.

12. 13. 14. 15. 16.

17. 18. 19. 20. 21. 22. 23.

24.

25. 26.

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