Ann Thorac Surg 1999;67:305-312
© 1999 The Society of Thoracic Surgeons
a Division of Thoracic and Cardiovascular Surgery, Hannover Medical School, Hannover, Germany
Address reprint requests to Dr Haverich, Klinik für Thorax-, Herz- und Gefäßchirurgie, Medizinische Hochschule Hannover, D 30623 Hannover, Germany
Presented at the Forty-fifth Annual Meeting of the Southern Thoracic Surgical Association, Orlando, FL, Nov 1214, 1998.
Background. On the basis of a 5-year experience with heart transplantation and long-term animal experimentation, a lung transplantation program was instituted in 1987. After 10 years of experience, the entire patient population was reviewed.
Methods. Hospital records were reviewed to evaluate the underlying diagnosis, year of transplantation, type of procedure, and long-term follow-up. The changing scope of indications, procedures performed, and donor criteria, as well as survival data for various subgroups of high-risk candidates, were also examined.
Results. A total of 283 heartlung (n = 46), single-lung (n = 94), and bilateral lung transplantation procedures (n = 143) were performed, with 22 patients undergoing 24 retransplantation procedures. The overall 5-year survival rate was 63%, with no difference between types of operations. Patients with cystic fibrosis, emphysema, pulmonary fibrosis, and secondary pulmonary hypertension showed similar survival rates; primary pulmonary hypertension was associated with a lower long-term survival. In all groups, the bronchiolitis obliterans syndrome occurred at a rate of approximately 15%/year.
Conclusions. Acceptable long-term results can be obtained with lung transplantation. Because of expanded indications, no survival benefit was gained in the overall population over a 10-year period. The major obstacle to true long-term survival remains the bronchiolitis obliterans syndrome.
In 1982 my respected teacher and academic father Hans Georg Borst allowed me to apply for a research fellowship at Stanford University Medical Center. On July 1, 1983, I started working in Bruce Reitzs experimental research laboratory, the same unique room where much of the landmark studies on experimental heart transplantation had been performed. We used a primate model of orthotopic heart transplantation with surface cooling and deep hypothermic arrest without extracorporeal circulation. Also, combined heart and lung transplantation procedures were performed in the same species, again aiming at improving immunosuppression based on cyclosporine A. At that time no distant organ procurement was deemed possible for heart and lung transplantation . In fact, only 14 of such procedures had been done at Stanford, the only unit performing this operation at that time clinically. To achieve long-term preservation of the lung, allowing for distant organ procurement, a dog model was instituted. The design included single left-sided lung transplantation, aiming at 24-hour preservation. With the use of Euro-Collins solution, we devised a randomized protocol comparing low-flowlow-pressure preservation, as used in the clinical setting, with high-flowhigh-pressure flush perfusion using the same perfusate . These experiments resulted in a breakthrough in lung preservation; today, most clinical lung transplantations performed worldwide still use this method .
On the basis of clinical observations, we also studied the differential rejection between the heart and the lung in combined cardiopulmonary transplantation . Both in acute and in chronic experiments in primates we could clearly show that rejection in heart and lung transplant recipients would not occur simultaneously [5, 6].
Toward the end of my stay, a donor became available for a patient who had undergone heartlung transplantation 2 years earlier with obliterative bronchiolitis and end-stage pulmonary failure. I was allowed to participate in harvesting the donor organs for this operationthe first clinical heartlung retransplantation worldwide. After 9 hours of operation, it turned out to be successful.
Material and methods
Toward clinical lung transplantation program in hannover
Before 1987, our unit performed between 50 and 70 heart transplantations per year. At that time we compiled a waiting list for combined heart and lung transplantation. The previous year, I joined the first lung transplantation seminar in Toronto. The early results of that group were very convincing, and therefore we also accepted candidates for an isolated lung transplantation program. The first patient undergoing transplantation was a 3-year-old boy with pulmonary fibrosis of unknown origin who underwent combined heart and lung transplantation. In 1988, the first single- and double-lung transplantations were done. During the next 5 years, the number of heart transplantations decreased significantly because of our lung transplantation activities and limited space in the intensive care unit (Fig 1). At the same time, much energy was spent on lung growth  and improved pulmonary preservation, using different animal preparations in the experimental setting . Clinically, the program was characterized by steadily increasing numbers of lung transplantations , and some important observations were made in individual patients.
In 1992, we could report on a successful sequence of extracorporeal membrane oxygenation (ECMO) and subsequent lung transplantation in a 19-year-old man with severe pulmonary contusion after a car accident . The ECMO had to be started on day 6 after the injury, and repeated and severe intrapulmonary hemorrhage led us to place him on the "special urgency request" waiting list with Eurotransplant, our international organ allocation organization. Successful bilateral lung transplantation was later done in this patient, who never had gained consciousness after the accident, after permission was obtained from his parents. Since then, eight such procedures were done by our group , and a treatment algorithm (Fig 2) was developed for candidates on the waiting list with acute respiratory failure or patients with adult respiratory distress syndrome .
Interestingly, the proportion of recipients with negative cytolomegalovirus (CMV) serology declined from 48.8% to 36.3% from the first to the second 5-year period. From the beginning of our program, the CMV status of lung donors and recipients was determined only in retrospect, and no prospective matching was done, as in other units . Looking at long-term data on survival, there is no significant difference between CMV-positive and CMV-negative recipients (Fig 3D), with most CMV-negative patients converting postoperatively. At no time could we establish a correlation between CMV serology and the later occurrence of obliterative bronchiolitis.
Very strict criteria on donor selection were applied at the start of our lung transplantation program. As in many other institutions, the requirements for donor lungs were repeatedly modified during the past 10 years, as shown in Figure 4. These less restrictive criteria have clearly resulted in more available donor organs; however, the risk of early graft failure and increased rates of infection may be higher . A significant influence of any of the variables quoted, however, could not be demonstrated in our clinical series.
The previous description of the evolution of the program, including its donor and recipient characteristics, was necessary for the subsequent discussion of the results. Looking at the entire series of 259 patients, the in-hospital mortality rate (30 days or never left the hospital) was 8.2%. One-, 3-, and 5-year survival rates for all recipients were 77%, 70%, and 63%, respectively (Fig 7A). There was no significant difference in actuarial 1-year survival rates between the different procedures (heartlung transplantation, 78%; bilateral lung transplantation, 78%; single-lung transplantation, 77%) (Fig 7B). Significantly better survival rates were achieved in patients with cystic fibrosis (89%, p < 0.01), pulmonary fibrosis (81%, p < 0.05), obstructive lung disease (75%, p < 0.05), and Eisenmengers syndrome (83%, p < 0.01) than in patients with primary pulmonary hypertension (55%) (Fig 7C). Survival rates remained unchanged during the 10-year period of clinical experience (Fig 7D) despite expanding indications during the last years, as mentioned earlier. The cause of death in 91 recipients (heartlung transplantation, n = 19; bilateral lung transplantation, n = 37; single-lung transplantation, n = 35) included sepsis (n = 43), obliterative bronchiolitis (n = 28), cardiac failure (n = 5), early graft dysfunction (n = 2), cerebral hemorrhage (n = 2), and other (n = 13). Freedom from bronchiolitis obliterans syndrome was 80% at 1 year and 45% at 5 years.
Tolerance versus rejection
The data presented in the present report would clearly suggest that excellent short- and long-term results can be obtained, at least for certain indications in an individual lung transplantation center. These results would not have been possible without an extensive exchange of both people and ideas. Therefore, my first comment regarding "experience with lung transplantation" would be to again acknowledge the generosity of US thoracic surgeons in accepting younger colleagues from abroad for training and education. Many positive developments in our specialty would not have become a reality in Germany without the tremendous help that we received from this side of the ocean after the second world war.
My early experience at Stanford was of the utmost importance in influencing the thinking of a surgeon embarking on a new clinical program. The pioneering spirit, with an open-minded attitude toward new developments combined with an entire absence of xenophobia, was an important experience for me as a young German fellow. The synthesis of this pioneering spiritthe transition from idea to suitable experimental design using large animal preparations, followed by cautious trials in the surroundings of an excellent and dedicated clinical servicewas the keystone of the success of thoracic surgery in North America as I viewed it back in 1983.
Experience in lung transplantation does not differ from experience gained in other new fields of medicine, both on a personal and an institutional level. To quote Norman E. Shumway one could say, "Good judgment comes from experience and experience comes from bad experience." In looking back at the development of our lung transplantation program and that of others, many "old frontiers" were overcome with time, and "bad experience" was an important teacher for everybody.
How does the transplant surgeon learn?
In transplantation medicine much has been learned from individual cases, often operated on in emergency situations. As such, most of the so-called extended donor criteria were gradually implemented into clinical practice. Older age, smoking, nonoptimal lung function, and other characteristics shown in Figure 4 were allowed to be acceptable criteria on the basis of observations in individual cases. The same is true for some indications for transplantationbetter to say contraindications.
Unilateral lung transplantation for pulmonary hypertension and intracardiac repair of congenital heart defect represents one of these entities. Here, our first clinical success in 1989 was based on technical error. This early "good experience" turned into "bad experience" during the next 3 cases. Only then did "good judgment" allow us to relinquish this concept. Like most other lung transplantation programs , today we would prefer bilateral transplantation in these patients.
There are two other "old frontiers"retransplantation and ECMO as a bridge to lung transplantationwhere our unit was able to contribute substantially to the knowledge in the field of indications. Both situations have one criterion in commonthe lack of an alternative for the patient and no transplantationsui generis, meaning early death. With this outlook, the operation can hardly result in a bad experience for the patient. The transplant group, by contrast, may very well consider a poor outcome as a failure, especially if a new concept can only be validated or disapproved after a series of failures. Luckily, both retransplantation and ECMO as a bridge to lung transplantation turned out to be concepts that can be successfully applied in the clinical setting of lung transplantation. In terms of ECMO as a bridge to (re)transplantation, our group also has a large experience in international terms [17, 19, 26]. Careful selection of candidates both for application of ECMO and the subsequent decision of whether to perform or not to perform transplantation remain of utmost importance. In a doubtful situation, we would still decide in favor of the operation because it is also a decision in favor of the patient.
A similar situation is observed in retransplantation. Here, by contrast, the problem of scarcity of available donor organs becomes even more prominent. With a 1-year mortality rate on the waiting list for elective lung transplantation of approximately 20%, do we have the right to give donor organs to one individual twice? Bearing in mind the inference of this ethical dilemma, it remains my attitude that we not only have the right but the obligation to do the second operation if the results are not dramatically inferior to those obtained with the first transplantation . In this sense, we greatly appreciate the rules of the Eurotransplant Foundation, our European counterpart to UNOS (United Network of Organ Sharing) in the United States, for further allowing both acute and chronic lung retransplantation .
Expanding donor criteria and expanding indications for transplantation are based on the spirit of surgeons who are exploring the limits of the procedure, often in emergency situations. This attitude will be of importance in the future, when new avenues in lung transplantation are entered, such as the development of bioengineered grafts or xenotransplantation.
What will improve long-term results?
Today, the early results of lung transplantation do not differ substantially from heart transplantation data . Given the invasiveness of the procedure, and in view of its interference with the human organism, it appears unlikely that the operative mortality can be lowered significantly in the future. Therefore, I do not believe that improvement in surgical techniques will have an important impact on long-term results.
However, allocation of an individual candidate to a specific type of lung transplantation, in our experience, has an important effect. As mentioned earlier, we recommend the routine listing of patients with pulmonary hypertension and emphysema for bilateral transplantation. In our view, this approach has a significant effect on early and long-term results.
Among other items with potential influence on overall results, one could mention further improvement in lung preservation , more specific (locally applied?) immunosuppression , optimized control of infection, or timing and methodology of patient follow-up. There is no doubt that further improvements in the entire concept of lung transplantation will result in slightly increased long-term survival. However, in quantitative terms, their input will remain minimal.
The major obstacle to true long-term survival in lung transplantation is chronic allograft rejection, as in many other fields of solid-organ transplantation. The extremely high incidence of bronchiolitis obliterans syndrome places an ever-increasing number of patients with successfull transplantation into a situation with no alternative other than retransplantation or death. Given the magnitude of the problem, the entire concept of lung transplantation may well be disputed by health authorities in the future on the basis of costbenefit ratio analyses .
Although we as surgeons cannot contribute significantly to the research on chronic allograft rejection, we should encourage our basic scientists in transplant immunology to concentrate specifically on this problem and on the lung . Too many studies on lung rejection still focus on acute rejection episodes, but we need to enlarge our knowledge on chronic failure. Concepts of gene therapy  and tolerance induction  are urgently needed because xenotransplantation and bioengineered organs will not replace clinical lung allografts in the near future.
This discussion on experience with lung transplantation would not be complete if I failed to mention the tremendous benefits in terms of quality of life, that most recipients can enjoy after their operation for a long period. It therefore remains my most important experience to see young people active and mobile who otherwise would experience a miserable life and premature death from end-stage pulmonary failure.
This article has been cited by other articles:
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