- Email: [email protected]
The first transplantation of the lung in a human revisited
OUR SURGICAL HERITAGE
The First Transplantation of the Lung in a Human Revisited David A. Blumenstock, MD, and Carol Lewis, ScD, MPH Department of Surgery and Research Institute, The Mary Imogene Bassett Hospital, Cooperstown, New York
The first homotransplantation of the lung in a human was performed in early 1963, thirty years ago. It is the purpose of this review to evaluate the significance of this event and to determine its effects on the further development of lung transplantation. (Ann Thorac Surg 1993;56:1423-5)
Lung Homotransplantation in Man Report of the Initial Case Jnmes D. H n r d c MD, W a t f s R . Wvbb. MD,Martin L. Dnlsun, lr., MD. nnd George R. Wnlker. lr., MD. Jnekron. Miss
T
he first transplantation of the lung in a human was performed by Dr James D. Hardy and his collaborators, Watts R. Webb, Martin L. Dalton, Jr, and George R. Walker, Jr, at the University of Mississippi on June 11, 1963, thirty years ago [l].This clinical attempt was preceded by extensive experimental studies of reimplantation and homotransplantation of the lung in more than 400 animals in Dr Hardy’s laboratory [2]. These studies had shown a lung could be surgically removed and successfully reimplanted in orthotopic position in the same animal; in addition, this lung could retain sufficient function to allow survival of the host when the contralateral pulmonary artery was ligated, effectively preventing gas exchange by the in situ contralateral lung. Based on these studies and the experience of investigators elsewhere, and after thoughtful evaluation, consideration was given to attempting unilateral lung transplantation in a human patient with severe pulmonary insufficiency when a suitable recipient was encountered. On April 15, 1963, a potential candidate for lung transplantation therapy was admitted to the University of Mississippi Medical Center. The patient, a 58-year-old male convict serving a life sentence, was admitted with a history of productive cough, purulent blood-streaked sputum, dyspnea on minimal exertion, and opacification of the left chest on radiologic study. Bronchoscopic biopsy confirmed the clinical diagnosis of squamous carcinoma of the left main bronchus. A scalene node biopsy was negative for tumor. In addition he had chronic renal disease and azotemia, and was treated for his renal disease. When the patient’s condition stabilized, a decision was made to recommend transplantation of the lung Address reprint requests to Dr Blumenstock, Department of Surgery, The Mary Imogene Bassett Hospital, One AtweU Rd, Cooperstown, NY 13326.
0 1993 by The Society of Thoracic Surgeons
when a suitable lung donor became available. On June 11, 1963, a patient with a massive myocardial infarction was seen in the emergency room and could not be resuscitated by closed cardiac massage and endotracheal ventilation. Permission for autopsy was obtained and preparations were made for harvest of a donor lung. Transplantation of the left lung was successfully performed. At thoracotomy, the recipient was found to have tumor implants visible between the aorta and esophagus. Although the tumor could not be completely resected, it was decided to proceed with pneumonectomy and transplantation. Splenectomy and thymectomy were considered at operation but were deemed inadvisable. The lung transplantation was successfully completed by separate anastomoses of the superior and inferior pulmonary veins, the pulmonary artery, and the bronchus; all four anastomoses functioned well. The lung transplantation resulted in significant improvement in the patient’s pulmonary status. Immunotherapy consisted of azathioprine, prednisolone, and cobalt 60 irradiation to the thymus. The patient died of renal failure 18 days after transplantation, with no evidence of rejection in the transplanted lung at postmortem examination. Replacement of diseased organs with healthy ones has been a dream of physicians for centuries. As poetically noted by Reemtsma (personal communication), the first transplantation could be considered to have occurred in Greek mythology when Daedalus, builder of the Labyrinth for King Midas of Crete, was forced to flee from Athens to Crete after killing one of his students in a jealous rage. He fashioned wings which he attached to himself and his son Icarus. Daedalus flew and escaped but, against his father’s warning, headstrong Icarus flew too close to the sun, lost (rejected) his wings, and perished. The current success of organ transplantation has been the result of research involving numerous investigators in surgical disciplines and scientists in many fields, particularly immunology and hematology. Transplantation of major organs first became theoretically possible in 1907 when Alexis Carrell, working at the Rockefeller Institute, reported the development of techniques for the anastomosis of blood vessels, which provided the technical basis of transplantation of major organs. He described an experiment in which the lung of a kitten was transplanted into the neck of an adult cat [3]. In 1944, Medewar [4] clarified the significance of the phenomenon of immunologic rejection, which was not fully understood by early investigators. No other lung transplantations were performed until 1947, when Demikhov [5] of the Soviet 0003-4975/93/$6.00
1424
Ann Thorac Surg 1993;561423-5
HERITAGE BLUMENSTOCK AND LEWIS FIRST LUNG TRANSPLANTATION
Union described orthotopic pulmonary lobe transplants in animals with 10-day maximum survival. Metras [6], in 1950, reported a major technical advance by describing the suturing of atrium to atrium rather than reconstructing individual veins for the pulmonary venous anastamosis. The full extent of Metras’ contribution to thoracic surgery and lung transplantation was not appreciated until much later [7]. Neptune and associates [8] independently reported a similar maneuver shortly thereafter. In 1951, Juvenelle [9] reported the first long-term reimplanted lung in the dog. The significance of Dr Hardy’s initial human lung transplant lies in the demonstration that the technical aspects of the surgical procedure in a human could allow survival and function of a human lung, and that the rejection of the transplant could be prevented for a period of time with then available immunotherapy. In the 7 years after Dr Hardy’s first human transplant, 23 additional human unilateral lung transplantations were performed, by 20 different surgeons [lo]. All but 1 patient died within 1 month of transplantation; the single survivor, Dr Derom’s patient, lived for 10 months [ll]. It is apparent that lack of success, particularly the inadequacy of therapy to prevent rejection and the sepsis that occurred in immunosuppressed recipients, caused a general reassessment of the situation. Transplantation of the lung has lagged behind that of other organs, such as the heart and kidney, due to a number of factors: the anatomic structure is complex, involving the pulmonary artery, the pulmonary veins, and the bronchus, with its delicate blood supply. In addition, suitable donor lungs were scarce, in part due to the high incidence of lung infection in potential donor organs, and lungs may be especially sensitive to anoxic damage during transplantation. Results of lung transplantation have been reviewed in detail [12, 131. Currently, techniques have been developed for single- and double-lung transplants, lobe transplants, and combined heart and lung transplants. In recent years, the Toronto Lung Transplant Group, headed by Dr Joel Cooper, has been one of the leaders in the further development of lung transplantation in humans [14-161. Results continue to improve [17]. By the end of 1991, the Registry of the International Society for Heart and Lung Transplantations reported almost 27,000 transplants including only 716 single-lung, 289 double-lung, 6
lobar, and 1,212 heart-lung transplantations [18]. Twoyear survival for heart-lung transplants is 40%; singlelung, 60%; and double-lung, 50%. Doctor Hardy’s initial human lung transplantation opened the way for exciting developments in human lung transplantation, and began a new era of therapy for lung disease in humans.
References 1. Hardy JD, Webb WR, Dalton ML Jr. Lung homotransplantation in man. Report of the initial case. JAMA 1963;186: 1065-74. 2. Hardy JD, Webb WR, Walker GR. Reimplantation and ho-
motransplantation of lung; laboratory studies and clinical potential. Ann Surg 1963;157707-13. 3. Carrel1 A. Surgery of blood vessels, etc. Bull Hopkins Hosp
1907;18:18-28. 4. Medewar PB. The behavior and fate of skin autografts and skin homografts in rabbits. J Anat 1944;78:176-9. 5. Demikov VP. Experimental transplantation of vital organs. New York: Consultants Bureau, 1962. 6. Metras H. Note preliminaire sur la greffe totale du poumon chez le chien. Fr Acad Sci 1950;231:1176-7. 7. Metras D. Henri Metras: a pioneer in lung transplantation. J Heart Lung Transplant 1992;11:1213-6. 8. Neptune WB, Weller R, Bailey CP. Experimental lung transplantation. J Thorac Surg 1953;26:27549. 9. Juvenelle AA. Pneumonectomy with reimplantation of the
lung in dog for physiologic study. J Thorac Cardiovasc Surg
1951;21:111-3. 10. Wildevuur CRH, Benfield JR. A review of 23 human lung transplantations by 20 surgeons. Ann Surg 1970;9:489-515. 11. Derom F, Barbier F, Ringnoir S, et al. Ten-month survival
after lung homotransplantation in man. J Thorac Cardiovasc Surg 1971;61:835-46. 12. Veith FJ. Lung transplantation. Surg Clin North Am 1978;58:
357-64. 13. Benfield JR. A perspective of lung transplantation. Chest 1980;78:548-9. 14. The Toronto Transplant Group. Experience with single-lung transplantation for pulmonary fibrosis. JAMA 1988;259: 2258-62. 15. Cooper JD. Lung transplantation. Ann Thorac Surg 1989;47 2 M . 16. Pasque MK, Cooper JD, Kaiser LR. Improved technique for bilateral lung transplantation. Ann Thorac Surg 1990;49: 785-91. 17. Starnes VA, Lewiston NL, Luikart H, Theodore J, Stinson B,
Shumway NE. Current trends in lung transplantation. Lobar transplantation and expanded use of single lungs. J Thorac Cardiovasc Surg 1992;104:1060-6. 18. The Registry of the International Society for Heart and Lung Transplantation: ninth official report-1992. J Heart and Lung Transplant 1992;11:599-606.
Editor’s Note We asked Dr Hardy for a response to Dr Blumenstock and Dr Lewis’ interesting article.
Dr Hardy’s Commentay It is a pleasure and indeed a privilege to provide additional comment regarding the first clinical lung transplantation so well described above, for Dr David A. Blumenstock was a true pioneer of experimental lung transplantation.
Continuing in the historical discussion, I will direct my remarks to 3 nontransplanted patients whose clinical courses brought our group to the conviction that, with several years of laboratory experience behind us, we
The First Transplantation of the Lung in a Human Revisited David A. Blumenstock, MD, and Carol Lewis, ScD, MPH Department of Surgery and Research Institute, The Mary Imogene Bassett Hospital, Cooperstown, New York
The first homotransplantation of the lung in a human was performed in early 1963, thirty years ago. It is the purpose of this review to evaluate the significance of this event and to determine its effects on the further development of lung transplantation. (Ann Thorac Surg 1993;56:1423-5)
Lung Homotransplantation in Man Report of the Initial Case Jnmes D. H n r d c MD, W a t f s R . Wvbb. MD,Martin L. Dnlsun, lr., MD. nnd George R. Wnlker. lr., MD. Jnekron. Miss
T
he first transplantation of the lung in a human was performed by Dr James D. Hardy and his collaborators, Watts R. Webb, Martin L. Dalton, Jr, and George R. Walker, Jr, at the University of Mississippi on June 11, 1963, thirty years ago [l].This clinical attempt was preceded by extensive experimental studies of reimplantation and homotransplantation of the lung in more than 400 animals in Dr Hardy’s laboratory [2]. These studies had shown a lung could be surgically removed and successfully reimplanted in orthotopic position in the same animal; in addition, this lung could retain sufficient function to allow survival of the host when the contralateral pulmonary artery was ligated, effectively preventing gas exchange by the in situ contralateral lung. Based on these studies and the experience of investigators elsewhere, and after thoughtful evaluation, consideration was given to attempting unilateral lung transplantation in a human patient with severe pulmonary insufficiency when a suitable recipient was encountered. On April 15, 1963, a potential candidate for lung transplantation therapy was admitted to the University of Mississippi Medical Center. The patient, a 58-year-old male convict serving a life sentence, was admitted with a history of productive cough, purulent blood-streaked sputum, dyspnea on minimal exertion, and opacification of the left chest on radiologic study. Bronchoscopic biopsy confirmed the clinical diagnosis of squamous carcinoma of the left main bronchus. A scalene node biopsy was negative for tumor. In addition he had chronic renal disease and azotemia, and was treated for his renal disease. When the patient’s condition stabilized, a decision was made to recommend transplantation of the lung Address reprint requests to Dr Blumenstock, Department of Surgery, The Mary Imogene Bassett Hospital, One AtweU Rd, Cooperstown, NY 13326.
0 1993 by The Society of Thoracic Surgeons
when a suitable lung donor became available. On June 11, 1963, a patient with a massive myocardial infarction was seen in the emergency room and could not be resuscitated by closed cardiac massage and endotracheal ventilation. Permission for autopsy was obtained and preparations were made for harvest of a donor lung. Transplantation of the left lung was successfully performed. At thoracotomy, the recipient was found to have tumor implants visible between the aorta and esophagus. Although the tumor could not be completely resected, it was decided to proceed with pneumonectomy and transplantation. Splenectomy and thymectomy were considered at operation but were deemed inadvisable. The lung transplantation was successfully completed by separate anastomoses of the superior and inferior pulmonary veins, the pulmonary artery, and the bronchus; all four anastomoses functioned well. The lung transplantation resulted in significant improvement in the patient’s pulmonary status. Immunotherapy consisted of azathioprine, prednisolone, and cobalt 60 irradiation to the thymus. The patient died of renal failure 18 days after transplantation, with no evidence of rejection in the transplanted lung at postmortem examination. Replacement of diseased organs with healthy ones has been a dream of physicians for centuries. As poetically noted by Reemtsma (personal communication), the first transplantation could be considered to have occurred in Greek mythology when Daedalus, builder of the Labyrinth for King Midas of Crete, was forced to flee from Athens to Crete after killing one of his students in a jealous rage. He fashioned wings which he attached to himself and his son Icarus. Daedalus flew and escaped but, against his father’s warning, headstrong Icarus flew too close to the sun, lost (rejected) his wings, and perished. The current success of organ transplantation has been the result of research involving numerous investigators in surgical disciplines and scientists in many fields, particularly immunology and hematology. Transplantation of major organs first became theoretically possible in 1907 when Alexis Carrell, working at the Rockefeller Institute, reported the development of techniques for the anastomosis of blood vessels, which provided the technical basis of transplantation of major organs. He described an experiment in which the lung of a kitten was transplanted into the neck of an adult cat [3]. In 1944, Medewar [4] clarified the significance of the phenomenon of immunologic rejection, which was not fully understood by early investigators. No other lung transplantations were performed until 1947, when Demikhov [5] of the Soviet 0003-4975/93/$6.00
1424
Ann Thorac Surg 1993;561423-5
HERITAGE BLUMENSTOCK AND LEWIS FIRST LUNG TRANSPLANTATION
Union described orthotopic pulmonary lobe transplants in animals with 10-day maximum survival. Metras [6], in 1950, reported a major technical advance by describing the suturing of atrium to atrium rather than reconstructing individual veins for the pulmonary venous anastamosis. The full extent of Metras’ contribution to thoracic surgery and lung transplantation was not appreciated until much later [7]. Neptune and associates [8] independently reported a similar maneuver shortly thereafter. In 1951, Juvenelle [9] reported the first long-term reimplanted lung in the dog. The significance of Dr Hardy’s initial human lung transplant lies in the demonstration that the technical aspects of the surgical procedure in a human could allow survival and function of a human lung, and that the rejection of the transplant could be prevented for a period of time with then available immunotherapy. In the 7 years after Dr Hardy’s first human transplant, 23 additional human unilateral lung transplantations were performed, by 20 different surgeons [lo]. All but 1 patient died within 1 month of transplantation; the single survivor, Dr Derom’s patient, lived for 10 months [ll]. It is apparent that lack of success, particularly the inadequacy of therapy to prevent rejection and the sepsis that occurred in immunosuppressed recipients, caused a general reassessment of the situation. Transplantation of the lung has lagged behind that of other organs, such as the heart and kidney, due to a number of factors: the anatomic structure is complex, involving the pulmonary artery, the pulmonary veins, and the bronchus, with its delicate blood supply. In addition, suitable donor lungs were scarce, in part due to the high incidence of lung infection in potential donor organs, and lungs may be especially sensitive to anoxic damage during transplantation. Results of lung transplantation have been reviewed in detail [12, 131. Currently, techniques have been developed for single- and double-lung transplants, lobe transplants, and combined heart and lung transplants. In recent years, the Toronto Lung Transplant Group, headed by Dr Joel Cooper, has been one of the leaders in the further development of lung transplantation in humans [14-161. Results continue to improve [17]. By the end of 1991, the Registry of the International Society for Heart and Lung Transplantations reported almost 27,000 transplants including only 716 single-lung, 289 double-lung, 6
lobar, and 1,212 heart-lung transplantations [18]. Twoyear survival for heart-lung transplants is 40%; singlelung, 60%; and double-lung, 50%. Doctor Hardy’s initial human lung transplantation opened the way for exciting developments in human lung transplantation, and began a new era of therapy for lung disease in humans.
References 1. Hardy JD, Webb WR, Dalton ML Jr. Lung homotransplantation in man. Report of the initial case. JAMA 1963;186: 1065-74. 2. Hardy JD, Webb WR, Walker GR. Reimplantation and ho-
motransplantation of lung; laboratory studies and clinical potential. Ann Surg 1963;157707-13. 3. Carrel1 A. Surgery of blood vessels, etc. Bull Hopkins Hosp
1907;18:18-28. 4. Medewar PB. The behavior and fate of skin autografts and skin homografts in rabbits. J Anat 1944;78:176-9. 5. Demikov VP. Experimental transplantation of vital organs. New York: Consultants Bureau, 1962. 6. Metras H. Note preliminaire sur la greffe totale du poumon chez le chien. Fr Acad Sci 1950;231:1176-7. 7. Metras D. Henri Metras: a pioneer in lung transplantation. J Heart Lung Transplant 1992;11:1213-6. 8. Neptune WB, Weller R, Bailey CP. Experimental lung transplantation. J Thorac Surg 1953;26:27549. 9. Juvenelle AA. Pneumonectomy with reimplantation of the
lung in dog for physiologic study. J Thorac Cardiovasc Surg
1951;21:111-3. 10. Wildevuur CRH, Benfield JR. A review of 23 human lung transplantations by 20 surgeons. Ann Surg 1970;9:489-515. 11. Derom F, Barbier F, Ringnoir S, et al. Ten-month survival
after lung homotransplantation in man. J Thorac Cardiovasc Surg 1971;61:835-46. 12. Veith FJ. Lung transplantation. Surg Clin North Am 1978;58:
357-64. 13. Benfield JR. A perspective of lung transplantation. Chest 1980;78:548-9. 14. The Toronto Transplant Group. Experience with single-lung transplantation for pulmonary fibrosis. JAMA 1988;259: 2258-62. 15. Cooper JD. Lung transplantation. Ann Thorac Surg 1989;47 2 M . 16. Pasque MK, Cooper JD, Kaiser LR. Improved technique for bilateral lung transplantation. Ann Thorac Surg 1990;49: 785-91. 17. Starnes VA, Lewiston NL, Luikart H, Theodore J, Stinson B,
Shumway NE. Current trends in lung transplantation. Lobar transplantation and expanded use of single lungs. J Thorac Cardiovasc Surg 1992;104:1060-6. 18. The Registry of the International Society for Heart and Lung Transplantation: ninth official report-1992. J Heart and Lung Transplant 1992;11:599-606.
Editor’s Note We asked Dr Hardy for a response to Dr Blumenstock and Dr Lewis’ interesting article.
Dr Hardy’s Commentay It is a pleasure and indeed a privilege to provide additional comment regarding the first clinical lung transplantation so well described above, for Dr David A. Blumenstock was a true pioneer of experimental lung transplantation.
Continuing in the historical discussion, I will direct my remarks to 3 nontransplanted patients whose clinical courses brought our group to the conviction that, with several years of laboratory experience behind us, we