Lung (1990) Suppl:1165-1168
New York Inc. 1990
History of Heart-Lung Transplantation John H. Dark Cardio-Pulmonary Transplantation Unit, Freeman Hospital, Newcastleupon Tyne, England
Abstract. Over the next few years we will see expanded application of the single lung transplant. At the moment domino procedure, with its advantage of very reliable tracheal healing, has the advantage over the double lung operation. We would expect routine use of the heart from those heart-lung recipients with anything more than moderately impaired cardiac function.
Key words: Single lung transplant--Domino procedure--Double lung operation. Heart-lung transplantation has moved from the experimental era to the threshold of becoming an accepted form of treatment. It is useful at this stage to trace the development and to see if there are lessons from the past which can be applied to todays problems. In the West the history of experimental lung transplantation begins with Metras in 1950 and Juvenelle in 1951. When it was established that the lung would function without a bronchial blood supply or innervation, Metras introduced the concept of the atrial cuff. Prior to this, the Russian surgeon Demikov had already embarked on a long series of experiments which culminated in successful heart and lung transplantation without the use of cardiopulmonary bypass. He produced a number of ingenious preparations including a heterotopic heart-lung transplant into the abdomen. These results remained unpublished outside of Russia until 1962. Demikov's experiments were paralleled by a series of similar ones initially without cardio-pulmonary bypass and subsequently with the use of the pump oxygenator. These procedures were predominantly done in dogs, and it became apparent that only occasionally would an animal breath normally after cornOffprint requests to: J. H. Dark, Cardio-PulmonaryTransplantation Unit, Freeman Hospital, Freeman Road, High Heaton, GB-NewcastleUpon Tyne NE7 7DN, UK.
1166
J . H . Dark
plete pulmonary deinnervation. Most series had no survivors, some had one or two animals which lived for a few days. In particular, Lower and Schumway in 1961 had several medium-term survivors. Although it appeared that bilateral deinnervation was almost incompatible with life, other groups had consistent survival with bilateral reimplantation of the lungs. The physiology of the innervated lung was more exhaustively addressed by a group working in Groningen. It became apparent that the fatal combination was the major surgical trauma of heart and lung transplant and the deinnervation. Although a note of optimism runs through these early papers, there is no doubt that investigators felt that neural control of breathing might be a major problem in the clinical application of heart-lung transplantation. The next major breakthrough was made by Nakae and colleagues who performed this operation in a series of different animals, including primates, and demonstrated quite different breathing patterns. Primates, in this case baboons, breathed almost normally after deinnervation though the number of survivors was small. This work was built upon by Castaneda and colleagues, who by 1972 were obtaining consistent survival in a baboon model. Good surgical technique and meticulous hemostasis in particular was vital to the survival of the animal. At the same time as the development of heart and lung transplantation there was a great deal of work done with experimental single lung transplants. Again, in the dog model it was shown that animals could survive, at least in the medium-term, on one reimplanted or transplanted lung with ligation of the contralateral pulmonary artery. After these experiments there followed what might be termed the "heroic era" of pulmonary transplantation. Running in parallel with the explosion in interest in cardiac transplantation at the end of the 1960s were a number of sporadic attempts at the lung transplant procedure. They were beautifully reviewed by Wildevuur and Benfield in 1970 and again by Blumenstock in 1977. By that time the problems of the single lung transplant were apparent. Many patients were poorly selected being moribund or even ventilated at the time of transplant. In many cases contralateral disease was deleterious to the new lung, either because of disturbed ventilation and perfusion relations or cross infection. In long-term survivors bronchial dehiscence was a major cause of death. The identification of suitable patients, initially at least with restrictive lung disease, and the various approaches to ensuring integrity of the bronchial anastomosis are not part of this story but have subsequently developed in parallel with the heart and lung transplant. This story also has its heroic era. The first procedure was that of Cooley performed in 1968. The patient was a two-month-old child with complete atrioventricular canal defect and pulmonary hypertension. The child was weaned from bypass but died at 14 hours from the effects of mediastinal haemorrhage and also pulmonary edema. Lillehei performed the second clinical heart-lung transplant in 1970 in emphysema and cor pulmonale. Death was at 8 days from pseudomonas infection, probably acquired from the donor lung. Finally, Barnard performed a heart-lung transplant in 1971, again with chronic obstructive airways disease. There were separate bronchial anastomoses. The one to
1167
Heart-Lung Transplantation
Heartandlungdonor
,"
~
"'''".
Heartrecipient
Fig. 1. The double lung transplant.
the right lung dehisced at 12 days; this was managed by right pneumonectomy, but the patient died after a further 11 days from infection in the transplanted lung. These experimental operations proved that as in the subhuman primate, man would breath after pulmonary deinnervation and implantation and indeed the respiratory pattern in the two patients who were extubated were almost normal. The causes of death were similar to those that afflicted lung transplantation, i.e., poor recipient selection, doubtful organ preservation and the problems of controlling both infection and rejection with the immunosuppressive therapy available. Interest in pulmonary transplantation virtually ceased for most of the rest of the 1970s. The next and indeed most important advance was made by Reitz with the Stanford Group. They combined their vast clinical experience with heart transplantation with the use of the new drug Cyclosporin A, establishing expertise in the primate model to build upon the previous experiments of Castaneda. They rapidly produced long-term animal survivors and moved on to report the first long-term human survivors. Transplantation of heart and lungs obviated problems of persisting disease in the remaining native lung and almost guaranteed consistent tracheal healing. Monitoring of rejection was initially thought to be possible by the endomyocardial biopsy. This is known to be a misleading assumption. It led to under immunosuppression of many patients and may have contributed to a high incidence of chronic rejection manifested as obliterative bronchiolitis in many of the early series. The widespread adoption of transbronchial biopsy has resulted in more scientific control of early rejection and may subsequently have a positive impact on late chronic rejection. The extension, initially by the Pittsburg Group, of the heart-lung transplant to patients with parenchymal pulmonary disease emphasized the importance of
J. H. Dark
1168
Heartandrungdonor
Heartandlungrecipient Heartdonor/ / / , /
Heartrecipient
Fig. 2. "Domino" heart and lung transplant.
patient selection. The limiting problem of donor supply has led to the development of "economical procedures." The double lung transplant has been championed by the Toronto Group, although tracheal healing has been a major problem (Fig. 1). The culmination of this history of heart and lung transplantation is the domino procedure as described by Yacoub (Fig. 2). Future developments in pulmonary transplantation will be successful if the lessons of the past can be applied. Patient selection for any new procedure must be scrupulous but has to be reconciled with the bold clinical approach which, as has been shown in this history, was necessary for almost every advance.
References 1. Cooper DKC (1969) Transplantation of the heart and both lungs; one historical review. Thorax 24:383 2. Wildevuur CRH, Benfield JR (1972) A review of 23 human lung transplantations by 20 surgeons. Ann Thorac Surg 9:489-515 3. Reitz BA, Wallwork JL, Hunt SA, Pennock JL, Billingham NE, Oyer PE, Stinson EB, Shumway NE (1982) Heart-lung transplantation; successful therapy for patients with pulmonary vascular disease. N Engl J Meal 306:557-563 4. Patterson GA, Cooper JD, Dark JH, et al (1988) Experimental and clinical double lung transplantation. J Thorac Cardiovasc Surg 85:70-75 5. Penketh A, Higgenbottan T, Hakim M, WaUwork J (1987) Heart and lung transplantation in patients with end stage lung disease. Brit Meal J 295:311-314 6. Griffiths BP, Hardesty RL, Trento A, et al (1987) Heart-lung transplantation: lessons learned and future hopes. Ann Thorac Surg 43:6-16
New York Inc. 1990
History of Heart-Lung Transplantation John H. Dark Cardio-Pulmonary Transplantation Unit, Freeman Hospital, Newcastleupon Tyne, England
Abstract. Over the next few years we will see expanded application of the single lung transplant. At the moment domino procedure, with its advantage of very reliable tracheal healing, has the advantage over the double lung operation. We would expect routine use of the heart from those heart-lung recipients with anything more than moderately impaired cardiac function.
Key words: Single lung transplant--Domino procedure--Double lung operation. Heart-lung transplantation has moved from the experimental era to the threshold of becoming an accepted form of treatment. It is useful at this stage to trace the development and to see if there are lessons from the past which can be applied to todays problems. In the West the history of experimental lung transplantation begins with Metras in 1950 and Juvenelle in 1951. When it was established that the lung would function without a bronchial blood supply or innervation, Metras introduced the concept of the atrial cuff. Prior to this, the Russian surgeon Demikov had already embarked on a long series of experiments which culminated in successful heart and lung transplantation without the use of cardiopulmonary bypass. He produced a number of ingenious preparations including a heterotopic heart-lung transplant into the abdomen. These results remained unpublished outside of Russia until 1962. Demikov's experiments were paralleled by a series of similar ones initially without cardio-pulmonary bypass and subsequently with the use of the pump oxygenator. These procedures were predominantly done in dogs, and it became apparent that only occasionally would an animal breath normally after cornOffprint requests to: J. H. Dark, Cardio-PulmonaryTransplantation Unit, Freeman Hospital, Freeman Road, High Heaton, GB-NewcastleUpon Tyne NE7 7DN, UK.
1166
J . H . Dark
plete pulmonary deinnervation. Most series had no survivors, some had one or two animals which lived for a few days. In particular, Lower and Schumway in 1961 had several medium-term survivors. Although it appeared that bilateral deinnervation was almost incompatible with life, other groups had consistent survival with bilateral reimplantation of the lungs. The physiology of the innervated lung was more exhaustively addressed by a group working in Groningen. It became apparent that the fatal combination was the major surgical trauma of heart and lung transplant and the deinnervation. Although a note of optimism runs through these early papers, there is no doubt that investigators felt that neural control of breathing might be a major problem in the clinical application of heart-lung transplantation. The next major breakthrough was made by Nakae and colleagues who performed this operation in a series of different animals, including primates, and demonstrated quite different breathing patterns. Primates, in this case baboons, breathed almost normally after deinnervation though the number of survivors was small. This work was built upon by Castaneda and colleagues, who by 1972 were obtaining consistent survival in a baboon model. Good surgical technique and meticulous hemostasis in particular was vital to the survival of the animal. At the same time as the development of heart and lung transplantation there was a great deal of work done with experimental single lung transplants. Again, in the dog model it was shown that animals could survive, at least in the medium-term, on one reimplanted or transplanted lung with ligation of the contralateral pulmonary artery. After these experiments there followed what might be termed the "heroic era" of pulmonary transplantation. Running in parallel with the explosion in interest in cardiac transplantation at the end of the 1960s were a number of sporadic attempts at the lung transplant procedure. They were beautifully reviewed by Wildevuur and Benfield in 1970 and again by Blumenstock in 1977. By that time the problems of the single lung transplant were apparent. Many patients were poorly selected being moribund or even ventilated at the time of transplant. In many cases contralateral disease was deleterious to the new lung, either because of disturbed ventilation and perfusion relations or cross infection. In long-term survivors bronchial dehiscence was a major cause of death. The identification of suitable patients, initially at least with restrictive lung disease, and the various approaches to ensuring integrity of the bronchial anastomosis are not part of this story but have subsequently developed in parallel with the heart and lung transplant. This story also has its heroic era. The first procedure was that of Cooley performed in 1968. The patient was a two-month-old child with complete atrioventricular canal defect and pulmonary hypertension. The child was weaned from bypass but died at 14 hours from the effects of mediastinal haemorrhage and also pulmonary edema. Lillehei performed the second clinical heart-lung transplant in 1970 in emphysema and cor pulmonale. Death was at 8 days from pseudomonas infection, probably acquired from the donor lung. Finally, Barnard performed a heart-lung transplant in 1971, again with chronic obstructive airways disease. There were separate bronchial anastomoses. The one to
1167
Heart-Lung Transplantation
Heartandlungdonor
,"
~
"'''".
Heartrecipient
Fig. 1. The double lung transplant.
the right lung dehisced at 12 days; this was managed by right pneumonectomy, but the patient died after a further 11 days from infection in the transplanted lung. These experimental operations proved that as in the subhuman primate, man would breath after pulmonary deinnervation and implantation and indeed the respiratory pattern in the two patients who were extubated were almost normal. The causes of death were similar to those that afflicted lung transplantation, i.e., poor recipient selection, doubtful organ preservation and the problems of controlling both infection and rejection with the immunosuppressive therapy available. Interest in pulmonary transplantation virtually ceased for most of the rest of the 1970s. The next and indeed most important advance was made by Reitz with the Stanford Group. They combined their vast clinical experience with heart transplantation with the use of the new drug Cyclosporin A, establishing expertise in the primate model to build upon the previous experiments of Castaneda. They rapidly produced long-term animal survivors and moved on to report the first long-term human survivors. Transplantation of heart and lungs obviated problems of persisting disease in the remaining native lung and almost guaranteed consistent tracheal healing. Monitoring of rejection was initially thought to be possible by the endomyocardial biopsy. This is known to be a misleading assumption. It led to under immunosuppression of many patients and may have contributed to a high incidence of chronic rejection manifested as obliterative bronchiolitis in many of the early series. The widespread adoption of transbronchial biopsy has resulted in more scientific control of early rejection and may subsequently have a positive impact on late chronic rejection. The extension, initially by the Pittsburg Group, of the heart-lung transplant to patients with parenchymal pulmonary disease emphasized the importance of
J. H. Dark
1168
Heartandrungdonor
Heartandlungrecipient Heartdonor/ / / , /
Heartrecipient
Fig. 2. "Domino" heart and lung transplant.
patient selection. The limiting problem of donor supply has led to the development of "economical procedures." The double lung transplant has been championed by the Toronto Group, although tracheal healing has been a major problem (Fig. 1). The culmination of this history of heart and lung transplantation is the domino procedure as described by Yacoub (Fig. 2). Future developments in pulmonary transplantation will be successful if the lessons of the past can be applied. Patient selection for any new procedure must be scrupulous but has to be reconciled with the bold clinical approach which, as has been shown in this history, was necessary for almost every advance.
References 1. Cooper DKC (1969) Transplantation of the heart and both lungs; one historical review. Thorax 24:383 2. Wildevuur CRH, Benfield JR (1972) A review of 23 human lung transplantations by 20 surgeons. Ann Thorac Surg 9:489-515 3. Reitz BA, Wallwork JL, Hunt SA, Pennock JL, Billingham NE, Oyer PE, Stinson EB, Shumway NE (1982) Heart-lung transplantation; successful therapy for patients with pulmonary vascular disease. N Engl J Meal 306:557-563 4. Patterson GA, Cooper JD, Dark JH, et al (1988) Experimental and clinical double lung transplantation. J Thorac Cardiovasc Surg 85:70-75 5. Penketh A, Higgenbottan T, Hakim M, WaUwork J (1987) Heart and lung transplantation in patients with end stage lung disease. Brit Meal J 295:311-314 6. Griffiths BP, Hardesty RL, Trento A, et al (1987) Heart-lung transplantation: lessons learned and future hopes. Ann Thorac Surg 43:6-16
