Between February 1983 and July 1987, twelve patients underwent heart-lung transplantation at theUniversity of Cape Town and the University of Munich.
1 7th Annual Symnposium
Initial Experience with Heart and Lung Transplantation
Hernann Reichenspumer, MD John A. Odell, MB, ChB David K.C. Cooper, MD Dimitri Novitzky, MD Alan G. Rose, MB, ChB Wemer Klinner, MD Bruno Reichart, MD
Between February 1983 and July 1987, twelve patients underwent heart-lung transplantation at the University of Cape Town and the University of Munich. The patients included eight men and four women, whose ages ranged from 15 to 49 years (mean, 27 years). The underlying pathologic condition was idiopathic primary pulmonary hypertension in five cases, Eisenmenger's syndrome in four cases, idiopathic pulmonary fibrosis in one case, diffuse fibrosing alveolitis in one case, and chronic emphysema in one case. The immunosuppressive regimen consisted of cyclosporine A, azathioprine, and rabbit antithymocyte globulin (RATG) during the first 2 postoperative weeks; RATG was subsequently replaced by methylprednisolone. Pulmonary rejection frequently occurred in the atbsence of cardiac rejection; in one case, however, this situation was reversed. Two patients required retransplantation, which was undertaken for caseating pulmonary tuberculosis with obliterative bronchiolitis after 1 year in one case and for early pulmonary insufficiency after 2 days in the other case. There were no operative deaths, but three early deaths occurred, owing to respiratory insufficiency of unknown origin (10 days postoperatively), multiorgan failure (10 days postoperatively), and acute liver dystrophy (11 days postoperatively). Five weeks after operation, a fourth patient died of multi-organ failure. There were five late deaths, all of which resulted from infectious compllcations. Three patients, including one who underwent retransplantation, remain alive and well, 10 to 36 months postoperatively. (Texas Heart Institute Journal 1988; 15:3-6)
Key words: Heart-lung transplantation; pulmonary Insufficiency; Immunosuppressive therapy; infection; pulmonary tuberculosis
From: The Department of Cardiothoracic Surgery and Pathology, University of Cape Town Medical School (Drs. Reichenspurner, Odell, Rose, and Reichart), Cape Town, Republic of South Africa; Oklahoma Baptist Medical Center (Drs. Cooper and Novitzky), Oklahoma City, Oklahoma, USA; and the Department of Cardiac Surgery, University of Munich (Dr. Klinner), Grosshadern D-8000 Munich 70, FRG Presented at the annual
symposium celebrating the 25th anniversary of the Texas Heart Institute titled
"Cardiology and Cardiovascular Surgery. Interventions, 1987,"held 7-10 October 1987 at the Westin Galleria Hotel, Houston.
Address for reprints: H. Reichenspurner, MD, Department of Cardiothoracic Surgery, University of Cape Town Medical School, Observatory 7925, Cape Town, Republic of South Africa
Te-cas Heati Institutejoumal
he first successful clinical heart-lung transplant was performed at Stanford University in 1981 by Reitz and colleagues,' who had previously carried out extensive experimental investigations of this procedure.2 This article describes our own experience with heart-lung transplantation at the Universities of Munich and Cape Town.
T
Patients and Methods Patient Population Between February 1983 and August 1984, two heart-lung transplantations were done at the University of Munich; and between September 1984 and July 1987, ten patients underwent heart-lung transplantation at the University of Cape Town. All told, there were eight men and four women; their ages ranged from 15 to 49 years (mean, 27 years). The underlying pathologic conditions included idiopathic primary pulmonary hypertension (five cases), Eisenmenger's syndrome (four cases), idiopathic pulmonary fibrosis with cor pulmonale (one case) (Fig. 1), fibrosing alveolitis (one case), and chronic emphysema (one case). The waiting period for a suitable donor organ ranged from 1 day to 9 months (mean, 3.2 months). One patient underwent retransplantation after 2 days, owing to early dysfunction of the donor lung. In another case, retransplantation was necessary after 1 year because of chronic rejection (which presented as obliterative bronchiolitis) and caseating tuberculosis (Fig. 2).
Surgical Tecbnique Our surgical approach was based on a slight modification of the technique described by Jamieson and coworkers.3 In brief, after a midline stemotomy had been performed and a vertical incision had been made in the pericardium, Heart-Lung Transplantation
3
the donor heart and lungs were removed as a single unit. The recipient's ventricles, as well as each lung, were excised separately, with care not to injure the phrenic or vagal nerves. Implantation ofthe donor organ involved anastomosing the donor's and recipient's tracheae, right atria, and aortae.
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Fig. 1 Cross-section of the heart showing cor pulmonale in a patient with idiopathic pulmonary fibrosis.
Immunosuppressive Regimen For the first 2 postoperative weeks, immunosuppression was achieved with cyclosporine A (3 to 8 mg/kg/day, sufficient to maintain a blood trough level of 400 to 500 ng/ml, as measured by radioimmunoassay); azathioprine (0 to 2 mg/kg/day, sufficient to keep the leukocyte count between 5000 and 7000 cells/mm3); and rabbit antithymocyte globulin (RATG) (1 to 3 mg IgG/kg/day, sufficient to maintain the peripheral T-lymphocyte level at approximately 50 to 150 cells/mm3). After the first 2 weeks, RATG was replaced with methylpredniso-
lone (0.3 mg/kg/day); depending on the patient's progress, this dose was gradually reduced to 0.2 mg/kg/day.
Diagnosis of Rejection The diagnosis of cardiac rejection was based on cytoimmunologic monitoring of peripheral blood samples,4 radionuclide scanning of the transplanted heart,5 and endomyocardial biopsy. The diagnosis of pulmonary rejection was somewhat more difficult and was based on close observation of the patients' clinical status and chest radiograms, as well as cytoimmunologic monitoring. In the presence of dubious results, an endobronchial or open lung biopsy was immediately performed. Treatment of Acute Rejection Episodes of acute rejection were treated with three courses of intravenous methylprednisolone (1 g/day). When severe rejection was present or corticosteroids were contraindicated, RATG was given in addition to (or instead of) methylprednisolone, in a dosage sufficient to reduce the circulating T-lymphocyte level to less than 200 cells/cu mm.
Results Eight of the twelve patients were successfully weaned from ventilatory support. Six patients were discharged from the hospital between 28 and 75 days after surgery (mean, 37 days). Four patients died during the first 5 postoperative weeks. There were five late deaths. The remaining three patients are still alive 10 to 36 months after surgery.
t'~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ Fig. 2 Lung section indicating caseating tuberculosis 1 year after heart-lung transplantation. The patient underwent successful retransplantation.
4 Heart-Lung Transplantation
Volume 15, Number 1, 1988
TABLE 1. Heart-Lung Transplant Recipients: Primary Diagnosis and Clinical Outcome No.
Age (y)
Sex
1
27
2 3
Diagnosis
Outcome
M
PPH
21 29
M F
PPH PPH
4
27
F
Fibrosing alveolitis
5
19
M
PPH
6
16
F
7
15
M
Status post correction of truncus arteriosus, type 1; ES Double inlet ventricle
Died on 1 1 th postop day, of acute liver dystrophy Al ive Underwent retransplantation after 1 yr, owing to chronic obliterative bronchiolitis; alive Died 2 years postop, owing to aspergillus septicemia Died after 143 days, of bilateral CMV pneumonia (which began on the 35th postop day) Died on 32nd postop day, owing to an esophageal fistula and renal insufficiency
8
43
M
(correction attempted); pulmonary banding & later debanding; ES Lung emphysema
9
29
F
Status post VSD closure; ES
10 11
43 44
M M
Lung fibrosis VSD, ES
12
49
M
PPH
Died on 1 97th postop day, owing to tuberculous pneumonia
Died 4 months postop, of a ruptured false aortic aneurysm Underwent retransplantation after 2 days, owing to lung dysfunction; died 10 days later Alive Died 5 weeks postop, of multi-organ failure Died 10 weeks postop, of multi-organ failure
CMV = cytomegalovirus; ES = Eisenmenger's syndrome; postop = postoperative(ly); PPH = primary pulmonary hypertension; VSD = ventricular septal defect
Causes of Death The causes of death are listed in Table I. Two days after operation, one patient underwent retansplantation because of respiratory insufficiency but died 10 days later, owing to respiratory inadequacy of unknown origin (permission for postmortem examination was refused). Another patient died of multiorgan failure 10 days after surgery. A third patient died on the eleventh postoperative day, of acute liver dystrophy (he was initially given cyclosporine A, 18 mg/kg/day, according to the old Stanford protocol). Another patient died of multi-organ failure 5 weeks after transplantation. Five deaths resulted from infectious complications. In one case, mediastinal sepsis led to tracheal dehiscence, followed by overwhelming systemic sepsis that resulted in death 32 days after transplantation. In the second case, mediastinitis associated with Stapbylococcus aureus resulted in a false aortic aneurysm, which ruptured 4 months after transplantation. The third patient died of tuberculous pneumonia, after having an episode of cytomegalovirus (CMV) pneumonia that had been successfully Texas Heart Institutejoumal
treated with CMV hyperimmunoglobulin (Biotest, Inc., FRG). The fourth patient died of severe bilateral CMV pneumonia before CMV hyperimmunoglobulin or DHPG (Syntex, Inc., United Kingdom) became available. The fifth patient did well for 26 months but then died of acute aspergillus pneumonia and septicemia. Acute Rejection In seven of the twelve patients, at least one episode of acute pulmonary rejection was verified All required increased doses of methylprednisolone (1 g/day for 3 days) and/or RATG therapy. In no case was lung rejection accompanied by cardiac rejection. Although one case of acute cardiac rejection was confirmed by means of an endomyocardial biopsy, the patient had no evidence of a pulmonary graft reaction. No deaths resulted from either pulmonary or cardiac rejection.
Chrnic Rejection (Obliterative Bronchiolitis, Chronic Cardiac Rejection) In two cases, chronic pulmonary rejection manifested as obliterative bronchiolitis. One of these patients, Heart-Lung Transplantation 5
who also had caseating tuberculosis, underwent successful retransplantation after 1 year. At that time, however, chronic cardiac rejection, manifesting as severe coronary artery stenosis, was also found. In the second case, obliterative bronchiolitis was successfully treated with increased doses of methylprednisolone (up to 1 mg/kg/day), but the patient died of aspergillus septicemia (as mentioned above) 2 years after surgery.
Comments We have described our initial experience with 14 heart-lung transplantations in twelve patients, three of whom remain alive 10 months to 3 years after surgery. There were no surgically related deaths. Although heart-lung transplantation has not yet reached the same level of success as cardiac transplantation alone, the results can probably be improved with more careful recipient selection. Candidates for this procedure (particularly those with tricuspid insufficiency) should not have any major dysfunctions of other organs such as the kidneys or liver. Early diagnosis and treatment of infectious diseases such as CMV pneumonia and tuberculosis is mandatory. The diagnosis of acute lung rejection is difficult. Important diagnostic clues are provided by the patient's clinical status and chest radiograms, as well as by cytoimmunologic monitoring of peripheral blood samples,4 which is helpful for differentiating between pulmonary rejection and pneumonia, particularly viral pneumonia. In the presence of dubious results, endobronchial or even open-lung biopsy is justified. Broncheo-alveolar lavage has been deemed useful for detecting infection and rejection,6'7 but the routine clinical use of this technique is not warranted.
6 Heart-Lung Transplantation
There is increasing evidence that cytomegalovirus and tubercle bacillus may be transferred with donor organs. Because pulmonary tuberculosis appears to be more frequent in immunosuppressed patients in South Africa than elsewhere, all of our heartlung transplant patients now routinely receive prophylactic antituberculosis therapy. Although heart-lung transplantation is still in the early stages, we believe that it is clinically justified in patients with end-stage pulmonary vascular or parenchymal disease who do not respond to conventional therapy.
References 1. Reitz BA. Heart and lung transplantation. J Heart Transplant
1981; 1:80. 2. Reitz BA, Burton NA, Jamieson SW, Bieber C, Pennock JL, Stinson EB, Shumway NE. Heart and lung transplantation. Orthotransplantation and allotransplantation in primates with extended survival. J Thorac Cardiovasc Surg 1980;
80:360. 3. Jamieson SW, Stinson EB, BaldwinJC, Shumway NE. Operative technique for heart-lung transplantation. J Thorac Cardiovasc
Surg 1984; 87:935. 4. Reichenspumer H, Ertel W, Hammer C, Lersch C, Reichart B, Uberfuhr P, Welz A, Reble B, Kemkes BM, Gokel M. Immunologic monitoring of heart transplant patients under cyclosporine immunosuppression. Transplant Proc 1984; 16:1251. 5. Novitzky D, Boniaszczuk J, Cooper DKC, Isaacs S, Rose AG, Smith JA, Uys Cj, Barnard CN, Fraser R. Prediction of acute cardiac rejection using radionuclide techniques. S Afr MedJ 1984; 65:5. 6. Griffith BP, Hardesty RI, Trento A, Paradis IL, Duquesnoy RJ, Zeevi A, Dauber JH, Dummer JS, Thompson ME, Gryzan S, Bahnson HT. Heart-lung transplantation: Lessons leamed and future hopes. Ann Thorac Surg 1987; 43:6-16. 7. Hoefter E, Reichenspumer H, Krombach F, Kemkes BM, Fiehl E, Kugler C, Ertel W, Osterholzer G, Gokel JM, Hammer C. Morphology and function of free lung cells following combined hetero-orthotopic heart-lung transplantation in the dog. Transplant Proc 1987; 19:1045-1048.
Volume 15, Number 1, 1988
