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Lung Transplantation
Symposium on Organ Transplantation
Lung Transplantation Frank J. Veith, M.D.':' To date, 38 patients have received lung transplants (Table 1). One patient survived 10 months and another survived six months. 6 • 21 Although both patients derived a significant palliative effect, there have been no unmitigated long-term clinical successes; interestingly, only two patients have received a lung transplant in the last two years. Does this mean that the possibility for achieving success in human lung transplantation has been ruled out? The present communication will support the position that this is not the case by examining the three problem areas that hampered results with human lung transplantation and by outlining investigative efforts presently being made to overcome some of the problems in these areas of donor lung procurement, bronchial anastomotic complications, and allograft rejection.
DONOR LUNG PROCUREMENT Suitable donor lungs are extremely scarce. In our own experiencfi!, we have had more than 19 potential recipients but have only been able to perform five lung transplants. The remaining patients died because no suitable lung donor could be found, even after waiting periods of up to six months. This occurred despite the fact that more than 100 kidney donors are identified in our region annually. There are several reasons that make lungs harder to get than other donor organsY· 19 Even minimal ischemia of a donor lung produces transient malfunction after transplantation. This malfunction is poorly tolerated by a recipient who is almost totally dependent on his transplanted lung. Thus, donor lung ischemia must be minimized, and this means that the donor and recipient must be located in the same institution. This often requires cooperation that is impossible to get from the donor's family and from other physicians. In addition, pulmonary edema and pneumonia are common in prospective donors, most of whom have had long periods of tracheal intubation. Lastly, the size of From the James Hilton Manning and Emma Austin Manning Laboratory and the Department of Surgery, Montefiore Hospital and Albert Einstein College of Medicine, New York, New York ''Professor of Surgery, Albert Einstein College of Medicine; Chief of Vascular Surgery, Montefiore Hospital and Einstein College of Medicine Supported in part by USPHS grants HL1 7417 and HL164 76 and the Manning Foundation. Surgical Clinics of North America- Vol. 58, No.2, April 1978
357
Table 1. Human Lung Transplants Performed as of August, 1977 CASE NO. AND MEDICAL TEAM
TYPE OF DATE
INDICATION FOR TRANSPLANT'''
TRANSPLANT
DURATION OF PATIENT SURVIVAL OF OR LOBE
1. J.D. Hardy 2. G. J. Magovern Shinol 3. K. 4. W. E. Neville
6/11/63 7/6/63
Carcinoma left lung, CLD CLD
Left lung Left lung
18 days 8 days
6/25/65 9/13/65
Left lower lobe Right lung
18 days 5 hr
5. J. J. White and L. D. MacLean 6. Y. Tsuji S. 7. E. Bucheri 0. Hayata 8. Y. 9. B. Gago and S. Morris J.D. 10. E. Bucheri
9/25/65
Bronchiectasis, tuberculosis Carcinoma right lung, left pneumonectomy Silicosis, chronic infection
Left lung
7 days
3/15/66
Carcinoma left lung, CLD
Left lower lobe
7 days
1/5/67 4/1/67 6/15/67
Toxic pneumonitis (HCl) Bronchiectasis Primary pulmonary hypertension
Left lung Left lower lobe Left lower lobe
1 hr 8 days 3 hr
11/5/67
Right lung
2 days
Left lung
8 hr
Left lung
13 days
11. J. J. Haglin
5/14/68
12. A. Logan
5/15/68
Posttraumatic pulmonary insufficiency, right pneumonectomy Carcinoma left lung, right pneumonectomy Toxic pneumonitis (paraquat)
13. A. C. Beall
8/31/68
COPD
Left lung
26 days
14. D. A. Cooley
9/15/68
Heart and lungs
14 hr
15. G. L. Hallman and D. A. Cooley 16. F. Derom
11/8/68
Pulmonary hypertension, congenital heart disease COPD
11/14/68
Silicosis
Left lung Right lung
6 days 10mo
17. J.D. Hardy
1/18/69
CLD, acute pneumonia
Left lung
29 days
18. F. J. Veith and S. K. Koerner 19. D. L. Ross
3/6/69
Carcinoma right lung, CLD
Right lung
14 days
3/26/69
COPD
Left lung
10 days
CAUSE OF DEATH
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OR FAILURE
ClJ
Renal insufficiency Respiratory insufficiency, pneumonia, rejection Rejection Respiratory insufficiency, ischemic damage Respiratory insufficiency, pneumonia, rejection Alveolar hemorrhage, rejection Respiratory insufficiency Rejection Respiratory insufficiency, lobe congested Respiratory insufficiency Respiratory insufficiency, bleeding insufficien~y, ? paraquat toxicity. Respiratory ?? rejection Respiratory insufficiencY, pneumonia, rejection Respiratory insufficiency Respiratory insufficiency, rejection Respiratory insufficiency, pneumonia, rejection Respiratory insufficiency, rejection Respiratory insufficiency, rejection Respiratory insufficiency, rejection
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20. A. C. Beall
4/9/69
COPD
Left lung
10 days
21. P. J. Vanderhoeft
6/1/69
COPD, tuberculosis
Left lung
11 days
22. D. R. Kahn
9/1/69
COPD
Left lung
4 days
23. C. W. Lillehei
12/31/69
COPD
Heart and lungs
8 days
24. J. J. Haglin
3/17/70
COPD
Left and right lungs
11 days
25. F. J. Veith and S. K. Koerner 26. P. Hugh Jones, A. MacArthur, and P. Cullum 27. D. R. Kahn
4/19/70
Right COPD, left destroyed lung (tuberculosis) Fibrosing alveolitis
Right lung
15 pays
Right lung
2mo
3/20/71
Left lung
1 mo
28. C. Barnard
3/20/71
Chronic restrictive lung disease COPD
29. F. S. 30. F. S.
1/7/72
COPD
Right lung
5/6/72
COPD
Left lung
15 days
31. M. Molins
3/30/67
Bronchiectasis, COPD
Right lung
6 days
32. M. Molins
9/28/67
Carcinoma left lung, COPD
Left lung
1 day
33. 34. 35. 36.
12/12/71 7/7/72 5/14/73 12/4/73
Toxic pneumonitis (paraquat) CLD CLD COPD
8/22/75
Posttraumatic pulmonary insufficiency; failed ECMO Respiratory burn
J. Veith and
3/26/71
Heart and lungs
23 days 6mo
K. Koerner
J. Veith and K. Koerner
K. Davidson M. Noirclerc M. Noirclerc F. J. Veith and S. K. Koerner
37. A. Thomas and W. F. Blaisdell 38. J. M. N elems, J. D. Cooper, and F. G. Pearson
5/13/77
5 days No survival 9 days 2 days
Left lung
10 days
Right lung
18 days
Respiratory insufficiency, pneumonia, rejection Respiratory insufficiency, rejection Respiratory insufficiency, cerebral damage Respiratory insufficiency, pneumonia Respiratory insufficiency, rejection, right bronchial disruption Bronchial dehiscence Peribronchial abscess, pulmonary arterybronchial fistula Respiratory insufficiency, pneumonia Right bronchial disruption, pneumonia Massive hemoptysis from eroded bronchial artery Aspiration pneumonia from necrotic bronchial mucosa Respiratory insufficiency, pneumonia Respiratory insufficiency, pneumothorax ? Paraquat toxicity Cardiac arrest Acute gastric dilation Respiratory insufficiency, ? hyperacute rejection, bleeding Sepsis, bronchial leak, space problem Bronchial leak
*CLD = chronic lung disease; COPD = chronic obstructive lung disease; and ECMO = extracorporeal membrane oxygenation.
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the donor lung, its hilar structures, and particularly its bronchus must approximate those of the recipient. 15• 19 The scarcity of donor lungs has had several secondary effects that have directly worsened the results of clinical lung transplantation to date. First, recipients have often come to operation in a cachectic, moribund state. Second, use of a poor donor lung has resulted directly in recipient death in at least two of the 38 patients (Cases 4 and 37 in Table 1). Of course, the nature of the donor lung defect was only recognized retrospectively. Third, the scarcity of donor lungs has produced a wide scattering of the human lung transplant experience. Results with other new procedures have shown that a concentrated experience in a short time at a single institution is necessary to define problems and permit development of solutions that lead to success. And fourth, the shortage of donor lungs means that ideal recipients cannot generally be transplanted. Donors simply cannot be found for patients with rapidly fatal pulmonary insufficiency. Many of these patients are young, free of sepsis, have other healthy organs, and will predictably die within a short time. An example of this situation is presented by some patients treated with extracorporeal membrane oxygenation. If the lungs of such patients continue to worsen after five days of oxygenator support, they will certainly die. 25 In many ways, they are ideal lung transplant candidates, and we have considered this possibility on at least seven occasions. In only one instance, a patient in whose care we collaborated with Drs. A. Thomas and W. F. Blaisdell of San Francisco,t 5 was it possible to find a donor lung. Lung transplantation allowed this patient to be removed from the extracorporeal support, and he survived for 10 days on the function of his transplanted lung. His ultimate death was due, in large part, to the transplantation of an excessively large donor lung. This situation would not have occurred if a more ideal lung had been available. Thus, for many reasons, greater availability of donors should facilitate the achievement of better results with clinical lung transplantation. Clearly, this donor scarcity and its resulting ill effects would be remedied if we had available a method that permitted a lung to be harvested in one institution, preserved up to 20 hours, and transported to another institution for transplantation. If such a method did not add to the minimal ischemic damage of the transplant procedure, it would permit donor procurement almost anywhere in the world. Until recently, no such system existed, and it had been found that lungs were more difficult to preserve without functional impairment than were other organs. 17 • 19 Recently, we have developed a method which permits donor lungs to be preserved up to 21 hours, transported, and then transplanted.17 This method includes flushing the inflated lung with a hypertonic, hyperkalemic solution against outflow resistance. With its vessels clamped, the lung is then immersed in this solution for storage. Transportation at 4° C is accomplished using a solid-liquid mixture of an organic chemical, 1-hexadecene. When left lungs so preserved are allo-
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LUNG TRANSPLANTATION
361
grafted into immunosuppressed dogs whose right pulmonary artery is immediately ligated, the function of the preserved transplant has been excellent and at least equal to the function of non preserved transplanted lungs. This is reflected in normal blood gas values and up to 40 days survival of the recipient animals whose only pulmonary function is provided by the preserved transplant. The adequacy of the method is also indicated by the· clarity of many of these preserved left lungs on chest roentgenograms, even in the early posttransplant period when ischemic damage is at its peak.n The experimental evaluation of this method is sufficiently promising that we believe it could be used in some clinical situations to help alleviate the shortage of donor lungs.
BRONCHIAL ANASTOMOTIC COMPLICATIONS Complications resulting from imperfect healing at the bronchial anastomosis are the second major problem area in lung transplantation. These complications can be considered the Achilles heel of human lung transplantation today since they have contributed directly to the death of most of the recipients who survived 10 days or more after operation.t 3 • 15 • 19 These bronchial complications include anastomotic disruption with air leakage, infection, bleeding, or stenosis and mucosal necrosis with aspiration pneumonia. These problems have generally been attributed to ischemia of the transplant bronchus which must be nourished retrograde by collaterals from the pulmonary artery. On this basis, some investigators have advocated revascularization of the transplant bronchial arteries by implanting a button of donor aorta containing their origin into the recipient aorta, 7· 13 and this procedure has been carried out in two patients.7 However, this technique is difficult and adds to the complexity of the transplant operation. We and others, therefore, have tried to minimize bronchial problems by simpler operative techniques, such as shortening the donor bronchial stump, reinforcing the anastomosis with surrounding vascularized tissue, and using an intussuscepting anastomotic method. 2 • 4 • 8 • 16 • 22 These techniques have almost eliminated bronchial problems in experimental lung transplants. 2 • 22 However, they continue to plague human transplant efforts, sometimes becoming manifest many weeks after operation. 19 • 21 This late occurrence suggests that the pathogenesis of these complications is more complex than previously thought and includes also rejection, high-dose corticosteroids, and size discrepancy between donor and recipient bronchi. In addition to the operative modifications already mentioned, po- · tential remedies to prevent bronchial problems include other technical improvements that are being developed, such as performing the anastomosis further within the lung where collateral vascular connections with the pulmonary artery and vein will be better.t0 Methods to evaluate the adequacy of collateral supply are also under study. At present, however, development of improved immunosuppression without the need for high-dose steroids will probably be most important in eliminating bronchial anastomotic complications.
362
FRANK]. VEITH
LUNG ALLOGRAFT REJECTION In evaluating the third major problem area in lung transplantation, namely allograft rejection, several specific questions must be addressed 1. How can rejection be manifest in an allografted lung? Several years ago, we postulated that rejection in lung allografts could be manifest in one of two ways. 18 • 23 The first was in a classic form in which perivascular cuffs of round cells were prominent along with alveolar exudates containing pneumocytes and round cells. Radiographically this classic rejection was associated with transplant opacification, and functionally it was associated with decreased transplant ventilation and perfusion. The second form of rejection, which we termed atypical or alveolar rejection, was observed in immunosuppressed animals and was characterized by the presence of fibrinous alveolar exudates with a relative paucity of round cells and no perivascular cuffing. Radiographically and functionally, this alveolar rejection was associated with transplant opacification and decreased ventilation without a corresponding reduction of blood flow. Thus, this atypical or alveolar form of rejection, which was never observed in autografts, could produce serious ventilation-perfusion imbalances and respiratory insufficiency such as had caused the death of several human lung transplant recipients. 14 • 19 • 24 Although the premise that this atypical or alveolar form of rejection was indeed rejection was at first disputed, its occurrence has been confirmed by several histological and functional studies from other laboratories. 3 • 5 • u, 12 2. Has rejection contributed importantly to the poor results with human lung transplantation? The importance of this alveolar form of rejection is apparent when one attempts to answer this second question. Because classic rejection had not been observed on histological examination of many of the failed human lung transplants, it was thought that rejection had not been the cause of death. 14 • 18 • 24 Other factors such as ventilationperfusion mismatching secondary to the presence of an emphysematous lung in parallel with a transplant were thought to be more important. On this basis, double lung transplantation was widely advocated for emphysematous recipients. Subsequent facts do not support the latter recommendation. Rejection, often in the atypical alveolar form, seems to have been a very important cause of the poor transplant function that has contributed to the disappointing results with clinical lung transplantation. 18 If rejection can be prevented, a single functioning lung transplant seems to be enough to provide adequate pulmonary function as it did for one emphysematous patient who survived for six months after receiving a single lung transplant. 21 When his allograft was not rejecting, he was greatly improved clinically and had a normal carbon dioxide tension and arterial oxygen tensions up to 71 mm Hg with minimal ventilation-perfusion imbalance.
LUNG TRANSPLANTATION
363
3. How can lung allograft rejection be diagnosed? Rejection in a lung allograft can best be diagnosed at present by the rapid appearance of an infiltrate on plain chest roentgenogram accompanied by fever, leucocytosis, a decrease in arterial oxygen tension, and, importantly, no change in the sputum bacteriology. 20 Serial Gram stain examination of the sputum is most helpful in evaluating the latter point. Obviously, better methods are needed to reliably differentiate rejection from pneumonia which can present in almost identical fashion. In the laboratory, in this regard, transthoracic needle biopsy has proved helpful whereas trans bronchial biopsy has not. 9 In addition, we are presently evaluating cytological examination of alveolar lavage fluid as a method to provide safely more reliable differentiation between pneumonia and rejection. 1 4. Can lung allograft rejection be reversed? In the majority of instances when it occurs, lung allograft rejection can be effectively reversed by the administration of large intravenous bolus doses of methylprednisolone. 20 This has been shown to be true with both clinical and experimental lung allografts. In the latter instance, the occurrence and reversal of rejection have been documented both radiographically and histologically. 5. Can lung allograft rejection be prevented? The answer to this most important question is, "Yes, but." Several patients, including the one who survived six months, had minimal evidence of any serious pathology in their graft. 19·2 1. This indicates that permanent changes secondary to rejection can, on occasion, be prevented with present immunosuppression. However, it cannot be prevented in all or even the majority of instances, either clinically or experimentally.18· 23 Furthermore, present nonspecific immunosuppression exacts a vicious toll in lung transplant recipients as it does in recipients of other organs. Clearly, therefore, there is a pressing need for more effective, safer immunosuppression if widespread successful clinical lung transplantation is to become a reality.
RELATIONSHIP BETWEEN LUNG TRANSPLANTATION AND LONG-TERM EXTRACORPOREAL MEMBRANE OXYGENATOR SUPPORT Recently, membrane oxygenators have been used successfully to provide supplementary oxygenation for patients with acute respiratory insufficiency for periods up to two weeks. The relationship of lung transplantation to such systems of subacute extracorporeal artificial oxygenation remains to be precisely defined. Almost certainly the two modalities of treatment will be complementary. Partial bypasses employing membrance oxygenators may be useful to support lung transplant recipients through critical periods of transplant functional insufficiency. Similarly, patients who cannot survive withdrawal of extracorporeal support after several weeks may be candidates for lung transplantation.
364
FRANK]. VEITH
REFERENCES 1. Achterrath, U., Bliimcke, S., Veith, F. J., eta!.: Alveolar lavage cytology in transplanted lungs. I. Staining methods and findings in dogs with auto grafts and allografts without immunosuppression. J. Thorac. Cardiovasc. Surg., 69:510, 1975. 2. Alican, F., I sin, E., Cockrell, J. V., eta!.: One-stage allotransplantation of both lungs in the dog. Ann. Surg., 177:193, 1973. 3. Anderson, W. R., Conlon, T. F., Kiesel, T. M., eta!.: Morphologic characteristics of rejection of the baboon lung allograft. Primates Med., 7:81, 1972. 4. Blumenstock, D. A.: Transplantation of the lung. Transplantation, 5:917, 1967. 5. Byers, J. M., Sabanayagam, P., Baker, R. R., eta!.: Pathologic changes in baboon lung allografts. Ann. Surg., 178:757, 1973. 6. Derom, F., Barbier, F., Ringoir, S., eta!.: Ten-month survival after lung homotransplantation in man. J. Thorac. Cardiovasc. Surg., 61:835, 1971. 7. Haglin, J. J., Ruiz, E., Baker, R. C., eta!.: Histologic studies of human transplantation. In Wildevuur, C. (ed.): Morphology in Lung Transplantation. Basel, Switzerland, S. Karger, 1973, pp. 13-22. 8. Huggins, C. E.: Reimplantation of lobes of the lung: An experimental technique. Lancet, 2:1059, 1959. 9. Koerner, S. K., Hagstrom, J. W. C., and Veith, F. J.: Trans bronchial biopsy for the diagnosis of lung transplant rejection: Comparison with needle and open lung biopsy techniques in canine lung allografts. Am. Rev. Res. Dis., 114:575, 1976. 10. Koerner, S. K., Pinsker, K., Torres, M., eta!.: Lobar bronchial anastomoses to improve bronchial healing in lung transplantation. Surg. Forum, 27:195, 1976. 11. Kondo, Y., Cockrell, J. V., Kuwaharo, 0., eta!.: Histopathology of one-stage bilateral lung allografts. Ann. Surg., 180:753, 1974. 12. Kreuzer, W., Salem, G., Keiler, A., eta!.: Hemodynamic of rejection in canine pulmonary transplantation. Bull. Soc. Int. Chir., 34:27, 1975. 13. Mills, N. L., Boyd, A. D., and Gheranpong, C.: The significance of bronchial circulation in lung transplantation. J. Thorac. Cardiovasc. Surg., 60:866, 1970. 14. Stevens, P.M., Johnson, P. C., Bell, R. L., eta!.: Regional ventilation and perfusion after lung transplantation in patients with emphysema. New Engl. J. Med., 282:245, 1970. 15. Thomas, A., Blaisdell, F. W., Veith, F. j., eta!.: Manuscript in preparation. 16. Trummer, M. J., and Berg, P.: Lung Transplantation. Springfield, Ill., Charles C Thomas Publisher, 1968. 17. Veith, F. j., Crane, R., Torres, M., eta!.: Effective preservation and transportation of lung transplants. J. Thorac. Cardiovasc. Surg., 72:97, 1976. 18. Veith, F. J., Hagstrom, J. W. C., Anderson, W. R., eta!.: Alveolar manifestations of rejection: An important cause of the poor results with human lung transplantation. Ann. Surg., 175:336, 1972. 19. Veith, F. J., and Koerner, S. K.: The present status of lung transplantation. Arch. Surg., 109:734, 1974. 20. Veith, F. J., Koerner, S. K., Siegelman, S. S., eta!.: Diagnosis and reversal of rejection in experimental and clinical lung allografts. Ann. Thorac. Surg., 16:172, 1973. 21. Veith, F. J., Koerner, S. K., Siegelman, S. S., eta!.: Single lung transplantation in experimental and human emphysema. Ann. Surg., 178:463, 1973. 22. Veith, F. J., and Richards, K.: Improved technique for canine lung transplantation. Ann. Surg., 171:553, 1970. 23. Veith, F. J., Sinha, S. B. P., Dougherty, J. C., eta!.: Nature and evolution of lung allograft rejection with and without immunosuppression. J. Thorac. Cardiovasc. Surg., 63:509, 1972. 24. Wildevuur, C. R. H., and Benfield, J. R.: A review of 23 human lung transplantations by 20 surgeons. Ann. Thorac. Surg., 9:489, 1970. 25. Zapol, W.: Personal communication. Montefiore Hospital 111 East 210th Street New York, New York 10467
Lung Transplantation Frank J. Veith, M.D.':' To date, 38 patients have received lung transplants (Table 1). One patient survived 10 months and another survived six months. 6 • 21 Although both patients derived a significant palliative effect, there have been no unmitigated long-term clinical successes; interestingly, only two patients have received a lung transplant in the last two years. Does this mean that the possibility for achieving success in human lung transplantation has been ruled out? The present communication will support the position that this is not the case by examining the three problem areas that hampered results with human lung transplantation and by outlining investigative efforts presently being made to overcome some of the problems in these areas of donor lung procurement, bronchial anastomotic complications, and allograft rejection.
DONOR LUNG PROCUREMENT Suitable donor lungs are extremely scarce. In our own experiencfi!, we have had more than 19 potential recipients but have only been able to perform five lung transplants. The remaining patients died because no suitable lung donor could be found, even after waiting periods of up to six months. This occurred despite the fact that more than 100 kidney donors are identified in our region annually. There are several reasons that make lungs harder to get than other donor organsY· 19 Even minimal ischemia of a donor lung produces transient malfunction after transplantation. This malfunction is poorly tolerated by a recipient who is almost totally dependent on his transplanted lung. Thus, donor lung ischemia must be minimized, and this means that the donor and recipient must be located in the same institution. This often requires cooperation that is impossible to get from the donor's family and from other physicians. In addition, pulmonary edema and pneumonia are common in prospective donors, most of whom have had long periods of tracheal intubation. Lastly, the size of From the James Hilton Manning and Emma Austin Manning Laboratory and the Department of Surgery, Montefiore Hospital and Albert Einstein College of Medicine, New York, New York ''Professor of Surgery, Albert Einstein College of Medicine; Chief of Vascular Surgery, Montefiore Hospital and Einstein College of Medicine Supported in part by USPHS grants HL1 7417 and HL164 76 and the Manning Foundation. Surgical Clinics of North America- Vol. 58, No.2, April 1978
357
Table 1. Human Lung Transplants Performed as of August, 1977 CASE NO. AND MEDICAL TEAM
TYPE OF DATE
INDICATION FOR TRANSPLANT'''
TRANSPLANT
DURATION OF PATIENT SURVIVAL OF OR LOBE
1. J.D. Hardy 2. G. J. Magovern Shinol 3. K. 4. W. E. Neville
6/11/63 7/6/63
Carcinoma left lung, CLD CLD
Left lung Left lung
18 days 8 days
6/25/65 9/13/65
Left lower lobe Right lung
18 days 5 hr
5. J. J. White and L. D. MacLean 6. Y. Tsuji S. 7. E. Bucheri 0. Hayata 8. Y. 9. B. Gago and S. Morris J.D. 10. E. Bucheri
9/25/65
Bronchiectasis, tuberculosis Carcinoma right lung, left pneumonectomy Silicosis, chronic infection
Left lung
7 days
3/15/66
Carcinoma left lung, CLD
Left lower lobe
7 days
1/5/67 4/1/67 6/15/67
Toxic pneumonitis (HCl) Bronchiectasis Primary pulmonary hypertension
Left lung Left lower lobe Left lower lobe
1 hr 8 days 3 hr
11/5/67
Right lung
2 days
Left lung
8 hr
Left lung
13 days
11. J. J. Haglin
5/14/68
12. A. Logan
5/15/68
Posttraumatic pulmonary insufficiency, right pneumonectomy Carcinoma left lung, right pneumonectomy Toxic pneumonitis (paraquat)
13. A. C. Beall
8/31/68
COPD
Left lung
26 days
14. D. A. Cooley
9/15/68
Heart and lungs
14 hr
15. G. L. Hallman and D. A. Cooley 16. F. Derom
11/8/68
Pulmonary hypertension, congenital heart disease COPD
11/14/68
Silicosis
Left lung Right lung
6 days 10mo
17. J.D. Hardy
1/18/69
CLD, acute pneumonia
Left lung
29 days
18. F. J. Veith and S. K. Koerner 19. D. L. Ross
3/6/69
Carcinoma right lung, CLD
Right lung
14 days
3/26/69
COPD
Left lung
10 days
CAUSE OF DEATH
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OR FAILURE
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Renal insufficiency Respiratory insufficiency, pneumonia, rejection Rejection Respiratory insufficiency, ischemic damage Respiratory insufficiency, pneumonia, rejection Alveolar hemorrhage, rejection Respiratory insufficiency Rejection Respiratory insufficiency, lobe congested Respiratory insufficiency Respiratory insufficiency, bleeding insufficien~y, ? paraquat toxicity. Respiratory ?? rejection Respiratory insufficiencY, pneumonia, rejection Respiratory insufficiency Respiratory insufficiency, rejection Respiratory insufficiency, pneumonia, rejection Respiratory insufficiency, rejection Respiratory insufficiency, rejection Respiratory insufficiency, rejection
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20. A. C. Beall
4/9/69
COPD
Left lung
10 days
21. P. J. Vanderhoeft
6/1/69
COPD, tuberculosis
Left lung
11 days
22. D. R. Kahn
9/1/69
COPD
Left lung
4 days
23. C. W. Lillehei
12/31/69
COPD
Heart and lungs
8 days
24. J. J. Haglin
3/17/70
COPD
Left and right lungs
11 days
25. F. J. Veith and S. K. Koerner 26. P. Hugh Jones, A. MacArthur, and P. Cullum 27. D. R. Kahn
4/19/70
Right COPD, left destroyed lung (tuberculosis) Fibrosing alveolitis
Right lung
15 pays
Right lung
2mo
3/20/71
Left lung
1 mo
28. C. Barnard
3/20/71
Chronic restrictive lung disease COPD
29. F. S. 30. F. S.
1/7/72
COPD
Right lung
5/6/72
COPD
Left lung
15 days
31. M. Molins
3/30/67
Bronchiectasis, COPD
Right lung
6 days
32. M. Molins
9/28/67
Carcinoma left lung, COPD
Left lung
1 day
33. 34. 35. 36.
12/12/71 7/7/72 5/14/73 12/4/73
Toxic pneumonitis (paraquat) CLD CLD COPD
8/22/75
Posttraumatic pulmonary insufficiency; failed ECMO Respiratory burn
J. Veith and
3/26/71
Heart and lungs
23 days 6mo
K. Koerner
J. Veith and K. Koerner
K. Davidson M. Noirclerc M. Noirclerc F. J. Veith and S. K. Koerner
37. A. Thomas and W. F. Blaisdell 38. J. M. N elems, J. D. Cooper, and F. G. Pearson
5/13/77
5 days No survival 9 days 2 days
Left lung
10 days
Right lung
18 days
Respiratory insufficiency, pneumonia, rejection Respiratory insufficiency, rejection Respiratory insufficiency, cerebral damage Respiratory insufficiency, pneumonia Respiratory insufficiency, rejection, right bronchial disruption Bronchial dehiscence Peribronchial abscess, pulmonary arterybronchial fistula Respiratory insufficiency, pneumonia Right bronchial disruption, pneumonia Massive hemoptysis from eroded bronchial artery Aspiration pneumonia from necrotic bronchial mucosa Respiratory insufficiency, pneumonia Respiratory insufficiency, pneumothorax ? Paraquat toxicity Cardiac arrest Acute gastric dilation Respiratory insufficiency, ? hyperacute rejection, bleeding Sepsis, bronchial leak, space problem Bronchial leak
*CLD = chronic lung disease; COPD = chronic obstructive lung disease; and ECMO = extracorporeal membrane oxygenation.
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the donor lung, its hilar structures, and particularly its bronchus must approximate those of the recipient. 15• 19 The scarcity of donor lungs has had several secondary effects that have directly worsened the results of clinical lung transplantation to date. First, recipients have often come to operation in a cachectic, moribund state. Second, use of a poor donor lung has resulted directly in recipient death in at least two of the 38 patients (Cases 4 and 37 in Table 1). Of course, the nature of the donor lung defect was only recognized retrospectively. Third, the scarcity of donor lungs has produced a wide scattering of the human lung transplant experience. Results with other new procedures have shown that a concentrated experience in a short time at a single institution is necessary to define problems and permit development of solutions that lead to success. And fourth, the shortage of donor lungs means that ideal recipients cannot generally be transplanted. Donors simply cannot be found for patients with rapidly fatal pulmonary insufficiency. Many of these patients are young, free of sepsis, have other healthy organs, and will predictably die within a short time. An example of this situation is presented by some patients treated with extracorporeal membrane oxygenation. If the lungs of such patients continue to worsen after five days of oxygenator support, they will certainly die. 25 In many ways, they are ideal lung transplant candidates, and we have considered this possibility on at least seven occasions. In only one instance, a patient in whose care we collaborated with Drs. A. Thomas and W. F. Blaisdell of San Francisco,t 5 was it possible to find a donor lung. Lung transplantation allowed this patient to be removed from the extracorporeal support, and he survived for 10 days on the function of his transplanted lung. His ultimate death was due, in large part, to the transplantation of an excessively large donor lung. This situation would not have occurred if a more ideal lung had been available. Thus, for many reasons, greater availability of donors should facilitate the achievement of better results with clinical lung transplantation. Clearly, this donor scarcity and its resulting ill effects would be remedied if we had available a method that permitted a lung to be harvested in one institution, preserved up to 20 hours, and transported to another institution for transplantation. If such a method did not add to the minimal ischemic damage of the transplant procedure, it would permit donor procurement almost anywhere in the world. Until recently, no such system existed, and it had been found that lungs were more difficult to preserve without functional impairment than were other organs. 17 • 19 Recently, we have developed a method which permits donor lungs to be preserved up to 21 hours, transported, and then transplanted.17 This method includes flushing the inflated lung with a hypertonic, hyperkalemic solution against outflow resistance. With its vessels clamped, the lung is then immersed in this solution for storage. Transportation at 4° C is accomplished using a solid-liquid mixture of an organic chemical, 1-hexadecene. When left lungs so preserved are allo-
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grafted into immunosuppressed dogs whose right pulmonary artery is immediately ligated, the function of the preserved transplant has been excellent and at least equal to the function of non preserved transplanted lungs. This is reflected in normal blood gas values and up to 40 days survival of the recipient animals whose only pulmonary function is provided by the preserved transplant. The adequacy of the method is also indicated by the· clarity of many of these preserved left lungs on chest roentgenograms, even in the early posttransplant period when ischemic damage is at its peak.n The experimental evaluation of this method is sufficiently promising that we believe it could be used in some clinical situations to help alleviate the shortage of donor lungs.
BRONCHIAL ANASTOMOTIC COMPLICATIONS Complications resulting from imperfect healing at the bronchial anastomosis are the second major problem area in lung transplantation. These complications can be considered the Achilles heel of human lung transplantation today since they have contributed directly to the death of most of the recipients who survived 10 days or more after operation.t 3 • 15 • 19 These bronchial complications include anastomotic disruption with air leakage, infection, bleeding, or stenosis and mucosal necrosis with aspiration pneumonia. These problems have generally been attributed to ischemia of the transplant bronchus which must be nourished retrograde by collaterals from the pulmonary artery. On this basis, some investigators have advocated revascularization of the transplant bronchial arteries by implanting a button of donor aorta containing their origin into the recipient aorta, 7· 13 and this procedure has been carried out in two patients.7 However, this technique is difficult and adds to the complexity of the transplant operation. We and others, therefore, have tried to minimize bronchial problems by simpler operative techniques, such as shortening the donor bronchial stump, reinforcing the anastomosis with surrounding vascularized tissue, and using an intussuscepting anastomotic method. 2 • 4 • 8 • 16 • 22 These techniques have almost eliminated bronchial problems in experimental lung transplants. 2 • 22 However, they continue to plague human transplant efforts, sometimes becoming manifest many weeks after operation. 19 • 21 This late occurrence suggests that the pathogenesis of these complications is more complex than previously thought and includes also rejection, high-dose corticosteroids, and size discrepancy between donor and recipient bronchi. In addition to the operative modifications already mentioned, po- · tential remedies to prevent bronchial problems include other technical improvements that are being developed, such as performing the anastomosis further within the lung where collateral vascular connections with the pulmonary artery and vein will be better.t0 Methods to evaluate the adequacy of collateral supply are also under study. At present, however, development of improved immunosuppression without the need for high-dose steroids will probably be most important in eliminating bronchial anastomotic complications.
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LUNG ALLOGRAFT REJECTION In evaluating the third major problem area in lung transplantation, namely allograft rejection, several specific questions must be addressed 1. How can rejection be manifest in an allografted lung? Several years ago, we postulated that rejection in lung allografts could be manifest in one of two ways. 18 • 23 The first was in a classic form in which perivascular cuffs of round cells were prominent along with alveolar exudates containing pneumocytes and round cells. Radiographically this classic rejection was associated with transplant opacification, and functionally it was associated with decreased transplant ventilation and perfusion. The second form of rejection, which we termed atypical or alveolar rejection, was observed in immunosuppressed animals and was characterized by the presence of fibrinous alveolar exudates with a relative paucity of round cells and no perivascular cuffing. Radiographically and functionally, this alveolar rejection was associated with transplant opacification and decreased ventilation without a corresponding reduction of blood flow. Thus, this atypical or alveolar form of rejection, which was never observed in autografts, could produce serious ventilation-perfusion imbalances and respiratory insufficiency such as had caused the death of several human lung transplant recipients. 14 • 19 • 24 Although the premise that this atypical or alveolar form of rejection was indeed rejection was at first disputed, its occurrence has been confirmed by several histological and functional studies from other laboratories. 3 • 5 • u, 12 2. Has rejection contributed importantly to the poor results with human lung transplantation? The importance of this alveolar form of rejection is apparent when one attempts to answer this second question. Because classic rejection had not been observed on histological examination of many of the failed human lung transplants, it was thought that rejection had not been the cause of death. 14 • 18 • 24 Other factors such as ventilationperfusion mismatching secondary to the presence of an emphysematous lung in parallel with a transplant were thought to be more important. On this basis, double lung transplantation was widely advocated for emphysematous recipients. Subsequent facts do not support the latter recommendation. Rejection, often in the atypical alveolar form, seems to have been a very important cause of the poor transplant function that has contributed to the disappointing results with clinical lung transplantation. 18 If rejection can be prevented, a single functioning lung transplant seems to be enough to provide adequate pulmonary function as it did for one emphysematous patient who survived for six months after receiving a single lung transplant. 21 When his allograft was not rejecting, he was greatly improved clinically and had a normal carbon dioxide tension and arterial oxygen tensions up to 71 mm Hg with minimal ventilation-perfusion imbalance.
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3. How can lung allograft rejection be diagnosed? Rejection in a lung allograft can best be diagnosed at present by the rapid appearance of an infiltrate on plain chest roentgenogram accompanied by fever, leucocytosis, a decrease in arterial oxygen tension, and, importantly, no change in the sputum bacteriology. 20 Serial Gram stain examination of the sputum is most helpful in evaluating the latter point. Obviously, better methods are needed to reliably differentiate rejection from pneumonia which can present in almost identical fashion. In the laboratory, in this regard, transthoracic needle biopsy has proved helpful whereas trans bronchial biopsy has not. 9 In addition, we are presently evaluating cytological examination of alveolar lavage fluid as a method to provide safely more reliable differentiation between pneumonia and rejection. 1 4. Can lung allograft rejection be reversed? In the majority of instances when it occurs, lung allograft rejection can be effectively reversed by the administration of large intravenous bolus doses of methylprednisolone. 20 This has been shown to be true with both clinical and experimental lung allografts. In the latter instance, the occurrence and reversal of rejection have been documented both radiographically and histologically. 5. Can lung allograft rejection be prevented? The answer to this most important question is, "Yes, but." Several patients, including the one who survived six months, had minimal evidence of any serious pathology in their graft. 19·2 1. This indicates that permanent changes secondary to rejection can, on occasion, be prevented with present immunosuppression. However, it cannot be prevented in all or even the majority of instances, either clinically or experimentally.18· 23 Furthermore, present nonspecific immunosuppression exacts a vicious toll in lung transplant recipients as it does in recipients of other organs. Clearly, therefore, there is a pressing need for more effective, safer immunosuppression if widespread successful clinical lung transplantation is to become a reality.
RELATIONSHIP BETWEEN LUNG TRANSPLANTATION AND LONG-TERM EXTRACORPOREAL MEMBRANE OXYGENATOR SUPPORT Recently, membrane oxygenators have been used successfully to provide supplementary oxygenation for patients with acute respiratory insufficiency for periods up to two weeks. The relationship of lung transplantation to such systems of subacute extracorporeal artificial oxygenation remains to be precisely defined. Almost certainly the two modalities of treatment will be complementary. Partial bypasses employing membrance oxygenators may be useful to support lung transplant recipients through critical periods of transplant functional insufficiency. Similarly, patients who cannot survive withdrawal of extracorporeal support after several weeks may be candidates for lung transplantation.
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REFERENCES 1. Achterrath, U., Bliimcke, S., Veith, F. J., eta!.: Alveolar lavage cytology in transplanted lungs. I. Staining methods and findings in dogs with auto grafts and allografts without immunosuppression. J. Thorac. Cardiovasc. Surg., 69:510, 1975. 2. Alican, F., I sin, E., Cockrell, J. V., eta!.: One-stage allotransplantation of both lungs in the dog. Ann. Surg., 177:193, 1973. 3. Anderson, W. R., Conlon, T. F., Kiesel, T. M., eta!.: Morphologic characteristics of rejection of the baboon lung allograft. Primates Med., 7:81, 1972. 4. Blumenstock, D. A.: Transplantation of the lung. Transplantation, 5:917, 1967. 5. Byers, J. M., Sabanayagam, P., Baker, R. R., eta!.: Pathologic changes in baboon lung allografts. Ann. Surg., 178:757, 1973. 6. Derom, F., Barbier, F., Ringoir, S., eta!.: Ten-month survival after lung homotransplantation in man. J. Thorac. Cardiovasc. Surg., 61:835, 1971. 7. Haglin, J. J., Ruiz, E., Baker, R. C., eta!.: Histologic studies of human transplantation. In Wildevuur, C. (ed.): Morphology in Lung Transplantation. Basel, Switzerland, S. Karger, 1973, pp. 13-22. 8. Huggins, C. E.: Reimplantation of lobes of the lung: An experimental technique. Lancet, 2:1059, 1959. 9. Koerner, S. K., Hagstrom, J. W. C., and Veith, F. J.: Trans bronchial biopsy for the diagnosis of lung transplant rejection: Comparison with needle and open lung biopsy techniques in canine lung allografts. Am. Rev. Res. Dis., 114:575, 1976. 10. Koerner, S. K., Pinsker, K., Torres, M., eta!.: Lobar bronchial anastomoses to improve bronchial healing in lung transplantation. Surg. Forum, 27:195, 1976. 11. Kondo, Y., Cockrell, J. V., Kuwaharo, 0., eta!.: Histopathology of one-stage bilateral lung allografts. Ann. Surg., 180:753, 1974. 12. Kreuzer, W., Salem, G., Keiler, A., eta!.: Hemodynamic of rejection in canine pulmonary transplantation. Bull. Soc. Int. Chir., 34:27, 1975. 13. Mills, N. L., Boyd, A. D., and Gheranpong, C.: The significance of bronchial circulation in lung transplantation. J. Thorac. Cardiovasc. Surg., 60:866, 1970. 14. Stevens, P.M., Johnson, P. C., Bell, R. L., eta!.: Regional ventilation and perfusion after lung transplantation in patients with emphysema. New Engl. J. Med., 282:245, 1970. 15. Thomas, A., Blaisdell, F. W., Veith, F. j., eta!.: Manuscript in preparation. 16. Trummer, M. J., and Berg, P.: Lung Transplantation. Springfield, Ill., Charles C Thomas Publisher, 1968. 17. Veith, F. j., Crane, R., Torres, M., eta!.: Effective preservation and transportation of lung transplants. J. Thorac. Cardiovasc. Surg., 72:97, 1976. 18. Veith, F. J., Hagstrom, J. W. C., Anderson, W. R., eta!.: Alveolar manifestations of rejection: An important cause of the poor results with human lung transplantation. Ann. Surg., 175:336, 1972. 19. Veith, F. J., and Koerner, S. K.: The present status of lung transplantation. Arch. Surg., 109:734, 1974. 20. Veith, F. J., Koerner, S. K., Siegelman, S. S., eta!.: Diagnosis and reversal of rejection in experimental and clinical lung allografts. Ann. Thorac. Surg., 16:172, 1973. 21. Veith, F. J., Koerner, S. K., Siegelman, S. S., eta!.: Single lung transplantation in experimental and human emphysema. Ann. Surg., 178:463, 1973. 22. Veith, F. J., and Richards, K.: Improved technique for canine lung transplantation. Ann. Surg., 171:553, 1970. 23. Veith, F. J., Sinha, S. B. P., Dougherty, J. C., eta!.: Nature and evolution of lung allograft rejection with and without immunosuppression. J. Thorac. Cardiovasc. Surg., 63:509, 1972. 24. Wildevuur, C. R. H., and Benfield, J. R.: A review of 23 human lung transplantations by 20 surgeons. Ann. Thorac. Surg., 9:489, 1970. 25. Zapol, W.: Personal communication. Montefiore Hospital 111 East 210th Street New York, New York 10467