Human heart transplantation∗

Human Heart Transplantation* CHRISTIAN CABROL,M.D. and ASSOCIATES~ Paris,

France

T

HE LEssoNs,taught by faiIure are o&en the most profitable. This is the principal reason justifying a report of our first attempt at human heart transplantation. CASE HISTORY A 66 year old retired factory foreman entered the Cardiology Department of Salpetriere Hospital on April I7, 1968,. because of rapidly progressing heart failure. Suffeoing from atria1 fibrillation of 10 years’ duration, he had started to experience considerable dyspnea on effort in 1963. The dyspnea gradually became more pronounced and by July 1967 was complicated by a severe attack of acute pulmonary edema. Subsequently his condition remained relatively satisfactory until January 1968, when severe exacerbation set in despite prompt cardiotonic treatment combining digitalis and diuretics. His past history disclosed no rheumatic fever, arterial hypertension, or angina pectoris; pneumonia occurred at age 20 years; he had had psoriasis since age 17. On admission the patient was extremely fatigued, dyspneic and covered with perspiration. He was incapable of standing up for more than a minute or two and could tolerate only a half-reclining position in bed. Physical examination showed a tachyarrhythmia of 150 beats/min., a systolic murmur at the apex, grade 3/6, and a diastolic gallop. There was moderate enlargement of the liver and bilateral ankle edema. Chest roentgenograms showed marked dilatation of the left vetnri’cle and remarkably weak and hardly visi~blecardiac and aortic pulsations. The electrocardiogram showed, in addition to atria1 fibrillation, low voltage ventricular complexes and incomlplete left bundle branch block, numerous multifocal ventricular extrasystoles and short periods of ventricular tachycardia. Continuous electrocardiographic monitoring also revealed on two occasions a return to sinus rhythm with

severe changes possibly indicating an anterolateral infarct. Right heart catheterization showed a mean right atria1 pressure of 10 mm. Hg, a right ventricular pressure of 47/4 mm. Hg (mean 12), a pulmonary arterial pressure of 46/25 mm Hg (mean 35) and a brachial artery pressure of 98/66 mm. Hg (mean 74). Cardiac output was reduced to 1.6 L./min. with a cardiac index of 0.865 L./min./M? Circulation time was 66 seconds. Laboratory investigation disclosed the blood volume and hematocrit to be normal, as were serum electrolytes. The blood urea of 160 mg. per cent on admission fell to 70 after several days. Liver function tests were practically unchanged, as were lung function tests, which showed only a slight decrease (30 per scent) in vital capacity. Medical treatment was undertaken immediately based on Cedilanidm intravenously for the first three days, then various antiarrhythmic agents. Despite these measures, we observed progressively exacerbated shortness of breath and rapid deterioration of the patient’s general condition. In view of the persistence of the alarming clinical picture, in which a fatal prognosis within a short period of time seemed inevitable, and since classic treatment had failed, the decision to perform a heart transplant operation was made on April 26, after approval of the attending physician, the patient and his family had been obtained. THE DONQR On April 25, the Neurosurgical Department had an emergency admission of a 23 year old man transferred from the HBpital Saint-Denis for grave cranial injuries following an automobile accident. Coma was immediate, with convulsions and episodes of apnea. Upon arrival in Neurosurgery, there was deep coma. There were indications of decerebration, but no localizing signs with the exception of a right mydriasis. A carotid arteriogram taken im’mediately revealed a severe right Itemporal contusion with extradural hematoma et the base

* From the Service of Professor M. Mercadier, Department No. 8, HBpital de la Pitie, Paris, France. t Drs. G. Guiraudon, J. C. Fabre. A. Cabrol, J. Luclani, M. H. Cappe, J. P. Berges, P. Dahan, J. Facquet, A.

haud, L. Schwarzenberg, J. L. Amiel and C. Jacobs. Address for reprints: Christian Cabrol, M.D., Service d’Anatomie, l’Hbpita1, Paris 13, France.

VOLUME22, DECEMBER1968

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Secteur

Pitie-Salpetriere,

105 Boulevard

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and a right temporal fracture line. Neurosurgical operation was undertaken the next day. Postoperatively, spontaneous respiration persisted, but the coma deepened. Bilateral mydriasis appeared, and at 12 noon on April 27 there occurred a cardiac arrest which was overcome by external cardiac massage and artificial ventilation. Arterial pressure remained low (60 mm. Hg systolic) and required administraftion successively of isoproterenol (Isuprel@) followed by metaraminol (Aramine@) in conjunction with transfusions to bring it up to 100 mm Hg. An electroencephalogram taken right after the accident showed a flat ‘tracing. This was confirmed by four repeat tracings at one hour intervals. The diagnosis of cerebral death was then confirmed in accordance with the three following criteria: anatomic damage ascertained at operation, the neurologic clinical examination and serial electroencephalograms. In agreement with the neurosurgeons, we considered this patient a possible donor since he met the established criteria: youth (age 23 years); absence of infection and of known transmittable general disease; and sound condition of the cardiovascular system, as established by interviews with the family, clinical examination of heart and vessels, normal electrocardiogram and frontal chest roentgenogram. Consequently, resuscitation was continued and antibiotic therapy increased. The skin of the operative area was prepared. The histocompatibility of the recipient and possible donor was studied, ‘taking into account two presently known groups of histocompatibility, i.e., the ABO group, determined by the erythrocyte study, and the HL-A group, determined by the leukocyte study. Both subjects belonged to blood group 0. Leukocyte antigens were studied by the Van Rood leukoagglutination method and the macromethod cytotoxicity technic. The antisera used were multiparous sera studied and identified at the Institute for Cancerology and Immunogenetics and kindly made available by Professor Dausset, Dr. Payne and the antiserum “bank” at Bethesda. The antigens of the recipient were l-3 (Dausset nomenclature) or LA,, 4a (Van Rood nomenclature). The antigens of the donor were 1, 3, 5, 12 (LA,, LA,, 4 a-c). Accordingly, there existed considerable compatibilities but also certain incompatabilities (12, 5 or LA,, 4~). In the scheme proposed here, these incompatibilities did not disqualify the donor for a kidney transplantation. Consequently, the transplantation was decided upon. OPERATIVE

PROCEDURE

Approval of the donor’s family was obtained and operation on the recipient was started at 10: 15 P.M. After premeditation ‘with atropine, 0.25 mg., anesthesia was started with Yentothal-Caelocurine@.

The patient was intubated and ventilated by means of an Engstriim apparatus. The radial artery was catheterized for monitoring of intra-arterial pressure, and a catheter for perfusion and for recording venous pressure was inserted in the left basilic arm vein. The thorax was opened by means of a vertical median sternotomy. Vertical incision of the anterior surface of the pericardium showed a large heart which was globularly dilated without specific distention of any cavity. After general heparinization (3 mg./kg.) two catheters were inserted into the two venae cavae through the right atrium, and the arterial catheter was inserted into the right femoral artery. These catheters were attached to an extracorporeal circuit comprising three Sarns pumps, a Kay-Cross 25 inch oxygenator, a plate heat exchanger, a bubble trap filter, two low pressure aspirators and one coronary transfusion line branched directly on the arterial transfusion line and equipped with a manometric control system, as previously described.1 The circuit was then freed from air bubbles wi,th glucose solution and filled with 1,390 ml. glucose solution, 260 ml. hypertonic bicarbonate solution, 3,000 ml. of titrated blood taken the day before and heparinized (20 mgJ500 ml. bottle) and recalcified (0.7 M calcium gluconate/bottle). Meanwhile, the donor was brought to the adjacent operating room. His circulajtion was maintained with artificial respiration, blood transfusion and vasopressor agents. His electrocardiogram began to show signs of deterioration (slight S-T shifts and QRS widening), and the requiremenst for vasopressor agents increased. The thorax was opened by median vertical sternotomy, and the heart exposed by vertical incision of the anterior surface of the pericardium. The heart was small and beat strongly. The two venae cavae were dissected, as were the two right pulmonary veins, the pulmonary artery, the ascending aorta and the innominate artery. When everything was ready to start ‘the extracorporeal circulation of the recipient, the donor was heparinized by intravenous administration of 150 mg. of heparin (3 mg./kg.). Electrical fibrillation of the donor’s ventricles was started at 11:42 P.M.; they were removed after ligature of the two venae cavae flush with their atria1 entry. The donor’s spleen was also removed through a left phrenotomy for the preparation of the antilymphocyte serum. The removal of the heart was fully completed at 11:44 P.M. The venae cavae were severed immediately above their ligature with their ends thus resting on the heart. The four pulmonary veins were similarly severed just before their entry into the atrium, the pulmonary artery at the level of its bifurcation and the aorta below the left common carotid artery. This artery and the innominate artery were cut 2 cm. from their origin. Immediately after removal, at 11:46 P.M., the THE

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heart was immersed in isotonic salt solution of 4” C. and was taken to the recipient’s operative field. There it was prepared for grafting. A slit was made

on the posterior surface of the right atrium be-

tween the two venae cavae 5 mm. from the interatria1 groove. The posterior surface of the left atrium was prepared by interconnecting the four pulmonary veins, thus leaving most of the heart intact, according to precautions indicated by Barnard.2 The pulmonary artery and aorta were carefully cleared of extrinsic fat, and a No. 20 radiopaque catheter was inserted into the ascending aorta through the lnnominate artery and held in place by a ligature. The heart so prepared was now left in the 4O C. solu.tion. The extracorporeal circulation of the recipient was then started at 12:05 A.M. The nooses of the venae cavae were tightened. The heart was electrically fibrillated, and the aorta was clamped just above the innominate artery. The diseased heart was then removed by severing the aorta immediately above the coronary orifices, and the pulmonary artery at the level of its valve. The atria were cut at the atrioventricular groove. Thrombosis of the left atrium made resection necessary. On the cut section of the right atrium at the median part elf the external surface there was an i.nfarcted zone 3 cm. long, with associated mural thrombi. This zone was also resected. The recipient’s pulmonary arl:ery and aorta were then prepared in accordance with those of the transplanted heart. The latter was then placed into the empty cavity of the pericardium. Its perfusion catheter was attached to the coronary line, and perfusion began, after the aorta had been freed of air and clamped immediately below the innominate artery, at 12:37 A.M. By this time, anoxia had lasted 53 minutes. The atria1 anastomoses were carried out with double continuous over-and-over sutures of 0 silk and in the following sequence: interatrial septum, right atrium from top to bottom and left atrium from below to above. The recipient’s right atrium was much larger than that of the transplanted heart. This made it necessary to make a horizontal incision, starting from the initial incision on the right atrium of the transplanted heart and leading to the interatrial groove. At the level of the left atrium, the extremely fragile tissue of the recipient required numerous additional sutures. Anastomosis of the pulmonary artery was carried out by means of two simple continuous over-andover sutures with 4-O Tevdek.@ At 12:40 A.M., during suturing, ‘the atria of the transplanted heart began to beat; then the ventricles fibrillated and at I:20 A.M. resumed sinus rhythm, as shown by the electrocardiogram. The strength of their contraction was closely dependent on the quality of the coronary perfusion, -which was fixed at a relatively low pressure of 50 cm. H,O. Any interference with VOLUME

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this perfusion through cardiac manipulations was reflected in the strength of the contraction and in the eleotrocardiogram. To perform the aortic anastomosis, the coronary perfusion was interrupted for three minutes. The aorta of the transpla,nted heart was severed 15 mm. above the innominate artery. The section was oblique toward the posterior surface to adapt it to the largest opening of the recipient’s aorta. Perfusion of the coronary arteries in accordance with our usual technics was performed through a second aortic incision. Cardiac contractions remained normal, and the aortic anastomosis was made with a continuous everting mattress stitch with 0 silk (Blalock stitch) then re-enforced by a simple continuous over-andover stitch, all over two strips of Teflon@ felt. The aortic counterincision was closed in the same manner after removal of the coronary perfusion catheters and after electrical fibrillation of the transplanted heart. Such induced fibrillation protected against air embolism from the cardiac chambers. Actually, the air in these cavities was carefully let out by drainage cannulas and aspiration. At 3:40 A.M. the clamps were removed from the aorta. Electrical fibrillation was stopped, but the heart continued to fibrillate strongly. It was defibrillated at the first electrical shock and resumed sinus rhythm. Thereupon, a careful inspection of all the sutures was undertaken. Some additional stitches were required to complete the left atria1 suture. During that time the body temperature, which had been lowered to 30’ C. at the start of perfusion, was raised to 35O C. The previously placed vent in the left ventricle prevented left ventricular distention. This catheter had been inserted first through the left atrium of the donor and then, after completion of the left atria1 suture, through the right edge of the left atrium of the recipient. This catheter was now removed. Likewise, a right ventricular catheter had been inserted through the right atrium during suturing of the pulmonary artery. Since the heart seemed strong and in sinus rhythm, the extracoporeal circulation was stopped at 4:20 A.M. The perfusion had been carried out so as to assure a flow of approximately 4 L./min. and an average arterial pressure of 90 mm. Hg. It lasted 4 hours and 15 minutes. From the start, the heart assured an absolutely normal circulatory state, with an arterial pressure of 120/80 mm. Hg and a sinus rhythm of 80 min. The heart, small and not distended, showed no sign of distress. The patient showed signs of waking up. The catheters were removed, and in the end of the catheter of the superior vena cava an obviously old clot was discovered, 3 cm. long and 5 mm. thick. Protamine was injected, and the femoral arteriotomy was sutured with interrupted Tevdek stitches. Hemostasis was normal. There was no alarming symptom, when suddenly one hour after the end

Cabrol of the perfusion, the electrocardiogram, until then normal, showed dome-shaped waves, and at the same time the arterial pressure dropped. The heart showed general distention. Venous pressure, so far at 10 cm. H,O, rose to 30 cm. Injections of vasopressors (Isuprel, then Aramine) were ineffective, and we had to massage the heart directly to maintain an arterial pressure of 60 mm. Hg. The arterial cannula of the extracorporeal circuit was reinserted into the femoral artery for direct interarterial perfusion. As a result of all these resuscitative measures, the arterial pressure rose little by little to a systolic level of 100 mm. Hg, but the collapse had lasted 35 minutes, the pupils were dilated, and severe metabolic acidosis developed (pH 7.25); with great difficulty this was restored to 7.4 with the injection of 1 L. of THAM). POSTOPERATIVE

COURSE

At 7:15 A.M. the patient was wheeled into the recovery room especially prepared for that purpose, an isolated room in a previously disinfected unit which had been sterilized with ultraviolet rays. Bed linen and clothing of the supervisory personnel had been sterilized. As he left the operating room, the patient was not yet awake, but was in a deep coma with bilateral mydriasis without localizing signs. Respiration was spontaneous but impaired, requiring continued intubation and artificial respiration. He reacted to pinching, and periosteal and tendon reflexes were present in his lower limbs. The cardiovascular status was satisfactory. Rhythm was regular at llO/min. and arterial pressure maintained at 120/80 mm. Hg with the use of vasopressor agents. Temperature was 37O C., and there was no bleeding. The patient’s condition remained unchanged during the first 24 hours. The edema spectacularly disappeared; the pupils remained dilated and the electroencephalogram was generally disturbed without localized signs. But the patient’s condition deteriorated little by little. The coma deepened. Urinary output which had been extremely reduced the first day (ZOO ml.) stopped, and peritoneal dialysis was carried out. Clotting disturbances appeared, with fbleeding through the gastric aspiration tube. The dose of vasopressor agents had to be increased to maintain the arterial pressure and the patient died in the fifty-sixth hour. He had shown no disturbances in cardiac rhythm until an hour before death. Treatment, in addition to the usual antibiotics (Keflin,@ 6 gm. intramuscularly daily), consisted of vasopressor agents (Aramine, then noradrenaline) and Isuprel. The infusions needed for the vasopressor and immunosuppressive treatment were carried out as follows:

Two hours prior to the operation, the patient received the following. Imuran@, 320 mg., and Melphalan@, 2 mg., orally; 8 mg. of Soludecadron@ intravenously and 20 ml. of antilymphocyte serum (Prof. Mathe, Dr. Choay’s Laboratory) by deep intramuscular injection. On the first postoperative day he received Imuran, 210 mg.; Melphalan, 2 mg.; Soludecadron, 8 mg.; and antilymphocyte serum, 10 ml. On the second day he received 20 ml. of antilymphocyte serum. Administration of Imuran and Melphalan had been stopped because of the anuria and the gastric disturbances pending delivery of the injectable Imuran. AUTOPSY

FINDINGS

Autopsy was carried out by Professor Chomette. There was no anomaly of the operative site; the cardiac surgical sutures were intact. The atria1 and ventricular cavities of the transplanted heart were normal. The right ventricle in particular was tonic. The valves were normal, and the coronary arteries showed no disease. However, histologic examination of the myocardium revealed numerous anoxic zones, some minor, some more important (acidophilic necrosis), especially in the posterior column of the mitral valve. These changes were probably secondary to the postoperative collapse. The viscera showed signs of chronic stasis due to the old cardiac insufficiency (liver and spleen) and recent stasis due to the acute collapse (severe congestion, almost infarctoid intestinal lesions, gastric hemorrhagic erosion). Anoxic lesions, probably secondary to the collapse, were present: small hepatic infarcts, renal microinfarcts, diffuse and microinsular necrosing pancreatitis. The lungs presented, on the whole, signs of chronic bilateral stasis as well as more recent lesions of doubtlessly anoxic nature. In addition, there existed pulmonary arterial emboli, one old one (7 to 8 days) with an infarction already formed in the lingula and several new ones, particularly in the right pulmonary artery, where recent emboli encroached on the lumen, obstructing all the lobar and segmentary branches. There were diffuse palmonary artery atheroma with thickening. Examination

of the veins

of

the

lower

limbs

disclosed, on the right, multiple organized thromboses, already somewhat adherent to the calf veins; thromboses also obliterated the lower popliteal and femoral veins. On the left side there were multiple thromboses, also recent and obliterating the calf veins, the companion veins to the posterior tibia1 veins and also the large intramuscular supply veins. The assumed cause of death was multiple pulmonary embolism arising from phlebothromboses of the two lower limbs. Examination of the operatively removed recipient’s heart revealed neither coronary atheroma nor

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valvular lesions, but there was marked hypertrophy and dilatation of the left ventricle and hypertrophy of the right ventricle with biatrial thrombosis of recent date. H,istologic examination showed diffuse fibrous lesions with well characterized fibroplastic endocarditis, predominantly of the left ventricular cavity. DISCUSSION

This case suggests a few brief comments. 1. The recipient was elderly, in a stage of advanced circulatory failure and destined to die shortly, all conditions not very promising for the success of a major operation. However, our knowledge oi: cardiac transplantation was at that time such that it seemed impossible to propose such an intervention to a patient who still might have a few months to live. Since the start of this program last January, only patients of this type (3 altogether) had been reserved for {this procedure. All 3 died spontaneously within 48 hours after the operative recommendation, before transplantation could be performed. 2. As far as the donor is ,concerned, we have respected the latest legal dispositions concerning death and the removal of organs. 3. In the operative procedure we took into account the teachings of our predecessors. The patient’s heart was excised in accordance with the Shumway technic,4 thereby leaving the atria in place so as to avoid having to make six venous anastomoses. The donor’s heart was removed according to Barnard’s method.2 It was removed in ‘its entirety so as to keep the inltrinsic nervous system of the heart as intact as possible, a procedure that alone assures the regular autonomous functioning of the transplanted organ. The heart was initially preserved by immersion in iced serum, as recommended by Shumway, then directly perfused with the blood of the extracorporeal circulation as done by Barnard. Since we wished to maintain the continuity of cardiac vascularization, we even carried out a direct coronary perfusion during aortic suturing.

VOLUME 22, DECEMBE.R1968

Transplantation 4. The immediate cause of death was a familiar complication, i.e., pulmonary embolism. The migration of ‘the venous thrombi from the phlebothromboses of ,the lower limbs one hour after ‘completion of the transplant was probably the cause of the shock observed at that moment in the operating room. Severe .tissue anoxia caused by the shock was responsible for the neurologic lesions and for the secondary irreversible deterioration of the patient. CONCLUSION

In defining the indications for a heart transplantation in the future, one must discuss the treatment of certain cardiopathies which at present defy classic treatment. The best indications seem to be diseases of the heart muscle proper or diffuse and serious disease of the coronary artery system, preferably in a fairly young subject in good bodily condition. Preservation of myocardial vitality for the anastomoses by means of continuous perfusion is certainly a more drawn out method than simple local hypothermia, but here it has proved to be sure and effective. Finally, the occurrence of a pulmonary embolism, which in our case was fatal, is a formidable complication which always threatens, and every effort must be made to prevent this in patients with severe heart disease, who often have been bedridden for many months, REFERENCES 1. CABROL, C., CABROL A., CONSO, J. F., CONSO, C., PREGERMAN, M., BOSURGI, J. and PARIENTE, G. L’abord des valvules aortique et mitrale en chirugie experimentale. In: Actualites Cardiovasculaires Medico Chirurgicales, ed I., pp. 1%21. Paris, France, 1964. Masson et tie. 2. BARNARD,C. N. A human cardiac transplant: An interim report of a successful operation performed at Groote Schuur Hospital, Cape Town. South African M. J., 41:1271, 1967. 3. CABROL,C. and BERTRAND,M. Une methode de contention des canules de perfusion coronaire. Presse mtd., 73:2326, 1965. 4. LOWER, R. R., STOFER, R. C. and SHUMWAY, N. E. Homovital transplantation of the heart. J. Thorucic 6 Cardiovas. Surg., 41:196, 1961.