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J Thorac Cardiovasc Surg 2005;129:1421-1429
© 2005 The American Association for Thoracic Surgery
Cardiothoracic Transplantation |
a Division of Cardiothoracic Surgery, Department of Surgery, Washington University School of Medicine, St Louis, Mo
b Division of Pulmonary Medicine and Critical Care, Department of Internal Medicine; the Department of Pediatrics; Washington University School of Medicine, St Louis, Mo
c Jacqueline Maritz Lung Center at Barnes-Jewish Hospital, St Louis Children’s Hospital, St Louis, Mo.
Received for publication April 22, 2004; revisions received December 15, 2004; accepted for publication January 13, 2005. * Address for reprints: Bryan F. Meyers, MD, One Barnes-Jewish Plaza, 3108 Queeny Tower, St Louis, MO 63110. (Email: meyersb{at}wustl.edu).
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Abstract |
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METHODS: We performed a retrospective review from our databases, tracking outcomes after adult and pediatric lung transplantation. The 983 operations between July 1988 and September 2003 included 277 pediatric and 706 adult recipients. Bilateral (74%), unilateral (19%), and living lobar transplants (4%) comprised the bulk of this experience. Retransplantations accounted for 44 (4.5%) of the operations.
RESULTS: The groups differed by indication for transplantation. The adults included 57% with emphysema and 17% with cystic fibrosis, and the children included no patients with emphysema and 50% with cystic fibrosis. Hospital mortality was 96 (9.8%) of 983, including 46 (17%) of 277 of the children and 50 (7%) of 706 of the adults. The overall survival curves did not differ between adults and children (P = .56). Freedom from bronchiolitis obliterans syndrome at 5 and 10 years was 45% and 18% for adults and 48% and 30% for children, respectively (P = .53). The causes of death for adults included bronchiolitis obliterans syndrome (40%), respiratory failure (17%), and infection (14%), whereas the causes of death in children included bronchiolitis obliterans syndrome (35%), infection (28%), and respiratory failure (21%) (P < .01). Posttransplantation lymphoproliferative disease occurred in 12% of pediatric recipients and 6% of adults (P < .01). The frequency of treated airway complications did not differ between adults and children (9% vs 11%, P = .48). The frequency of primary graft dysfunction did not differ between children (22%) and adults (23%), despite disparity in the use of cardiopulmonary bypass.
CONCLUSION: These results highlight major complications after lung transplantation. Despite differences in underlying diagnoses and operative techniques, the 2 cohorts of patients experienced remarkably similar outcomes.
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Methods |
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Patient Population
The patients in this report include all patients undergoing lung transplantation or heart-lung transplantation at Barnes-Jewish Hospital or St Louis Children’s Hospital from July 1988 through September 2003. Table 1 describes the demographic data of these patients.
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Postoperative Management
Routine postoperative management has been discussed elsewhere.3,4 In general, the management has been consistent over time and between the 2 programs. Both programs have depended on 3-drug immunosuppression (typically prednisone, cyclosporine [INN: ciclosporin], and azathioprine), and both programs have routine scheduled surveillance bronchoscopy to guide the maintenance immunosuppression.
Statistical Analysis
Descriptive statistics were expressed as means ± standard deviation unless otherwise specified. Categoric data were expressed as counts and proportions. Comparisons were done with paired, 2-tailed t tests for means of normally distributed continuous variables and Wilcoxon rank sum tests for skewed data. Fisher exact or 
2 tests were used to analyze differences among the categorical data. Kaplan-Meier estimate was used to depict survival. All data analysis was performed with SPSS software (SPSS 11.0 for Windows; SPSS Inc, Chicago, Ill).
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Results |
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Another costly consequence of early lung dysfunction is the burden of acute retransplantation. This controversial therapy has been performed 11 times in our collective experience, 5 in pediatric recipients and 6 in adults. In these instances the resources consumed as a direct consequence of PGD are not limited to financial and hospital resources. They also include the very limited availability of lung allografts suitable for transplantation. In this manner the use of acute retransplantation as a response to severe PGD has survival implications even for patients on the waiting list because their likelihood of undergoing successful transplantation will decrease as the use of allografts for retransplantation increases.
In addition to the acute effects of PGD, there has been some evidence that this early difficulty increases the recipient’s likelihood for chronic graft dysfunction as well. We observed a small but statistically significant increase in the hazard for chronic rejection in the survivors of PGD versus those who did not have the condition. This tendency is shown by the reduction in the mean time to development of bronchiolitis obliterans syndrome (BOS), from 4.5 years (95% confidence interval [CI], 3.8–5.2) in those without PGD to 3.3 years (95% CI, 2.2–4.4) in those with PGD. A comparison of freedom from BOS in those with and without PGD revealed a statistically significant association by using the log-rank test (P = .044, Figure E2).
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Airway Anastomotic Complications
One of the sentinel complications in lung transplantation is the development of an airway anastomotic complication that requires therapy.6 In our overall cohort there was no association between the rate of airway complications and classification of adult versus pediatric transplantation. The adults experienced a rate of anastomotic complication of 66 (9.3%) of 706, whereas the pediatric airway complication rate was 30 (10.8%) of 277. In review of the entire experience over time, there was an association between the rate and quintile of experience (P = .016), with the highest rate occurring in the initial quintile of experience from 1988 through 1993 (Table 3). There was no association between patient diagnosis and the rate of anastomotic complications (P = .72). Analysis to determine the effect of acute graft dysfunction on the development of airway complications failed to show a statistically significant association between these outcomes. The odds ratio describing the association between PGD and subsequent airway complications is 1.2 (95% CI, 0.8–1.85).
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BOS and Posttransplantation Lymphoproliferative Disease
Although PGD is the dominant problem faced early after lung transplantation, the development of chronic rejection or BOS is the major driver of morbidity in the late posttransplantation period. Figure E3 shows that there is no difference between the adult and the pediatric experience with regard to freedom from BOS over time. The median time to the diagnosis of BOS is 4.5 years (95% CI, 2.8–6.2) for the pediatric group and 4.3 years (95% CI, 3.6–4.9) for the adult population.
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Long-term survival is also comparable between the groups. The 10-year survival curves are depicted in Figure 2. There is no significant difference between the survival curves (P = .56), and the median time to death is 5.9 years (95% CI, 4.4–7.4) for the pediatric cohort and 6.3 years (95% CI, 5.6–7.0) for the adults. The causes of death are listed in Figure 3, with BOS and graft failure together accounting for the majority of the deaths.
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Discussion |
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Lung transplantation is a therapy for which the costs and incremental cost-effectiveness ratio are coming under increasing scrutiny. Many analyses have concluded that it is an expensive but effective therapy. A study by the University of Pittsburgh in 1997 reported median costs of $94,000 per transplantation and average costs of $154,000 per transplantation, a disparity that was due to some higher cost outliers.7 A Dutch study in 1998 that assessed incremental cost-effectiveness of transplantation over medical therapy reported a baseline scenario in which the incremental cost per quality-adjusted life year gained was $116,000 for lung transplantation compared with medical therapy.8 The most recent and comprehensive of such analyses was the UK study that compared the cost-effectiveness of single, bilateral, and heart-lung transplantation with an estimated cost per quality-adjusted life year for these operations of $48,000, $33,000, and $29,000, respectively. Although the latter estimates are within the range of values that society is readily willing to pay for health care interventions, the other previous estimates are perhaps more representative of the situation in the United States.9
It is apparent from these data that PGD creates a substantial burden on the population of lung transplant recipients. On the basis of the attributable risks of death, hospital resource consumption, and allograft, a reduction of the rate of PGD by 50% (from 22% to 11%) in our population could have saved 50 lives, eliminated the need for 6 retransplantations, and reduced hospital resource consumption by more than 400 ICU-ventilator days, as well as more than 300 additional non-ICU days. Our review did not reveal any reliable clinical prediction rules that might identify high-risk recipients or donors, and our rate of PGD appears comparable with rates reported by others.10–13
The differences we report in the rates of PTLD in children and adults confirms earlier work by others who have reported rates of 5% or less in adults and rates as high as 16% in children.14–17 Risk factors for this neoplasm appear to be pretransplant seronegativity for Epstein-Barr virus and lower age. It is typical for reports to describe a 50% mortality, with the majority of the deaths occurring within a few months of the diagnosis of the PTLD.17–20
It is a bit concerning that the trend of any specific complication over time does not show a steady trend toward elimination of that complication. The incidence of PGD seemed to be trending downward, but a recent increase has erased the improvements seen in the midportion of the experience (Table 2). The rate of anastomotic complications decreased rapidly in the early experience and has seen little change in the last decade (Table 3). On the surface, one might hope that experience would bring increased skill and judgment sufficient to gradually eliminate all but the most unpredictable complications. It is of course more complicated than that. One must keep in mind the multiple subtle changes in many aspects of these patients’ care that have taken place over the period of observation. In the earliest era, stringent criteria were required before declaring potential donor lungs acceptable for transplantation. Gradually, experience accumulated that demonstrated the safety and effectiveness of using less-than-perfect donor lungs for most recipient indications. Other changes over the years have been subtle evolution of anastomotic techniques, multiple alterations of lung procurement and cold preservation, and intermittent changes to the cohort of surgeons performing the implantations. The growing list of waiting patients makes transplantation teams now willing to accept organs from distant cities with the full knowledge that the increased travel times will prolong the ischemic times and increase the risk for early and late graft dysfunction. In many instances the changes in decision making have been a conscious decision to accept the possibility of a less ideal outcome to increase the supply of donor organs and therefore increase the availability of lung transplantation in general.
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Discussion |
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Dr Meyers. For the adults, we use the PaO2/fraction of inspired oxygen ratio in the first 24 hours after transplantation, and the patients who had a ratio of less than 150 were characterized as having PGD. In the pediatric database, if they had radiographic characteristics consistent with reperfusion injury and mechanical ventilation for more than a week or acute retransplantation, they were characterized as having PGD.
Dr Keshavjee. Second, the use of ECMO in children in your experience was about 10%, whereas in adults it was 3%. Is this due to an increased incidence of PGD, or is it perhaps a lower threshold to institute this advanced therapy in a child rather than an adult?
Dr Meyers. Because this study lumps together disparate groups of patients, it is challenging to answer such a question.
As you saw, on the basis of the criteria we used to characterize the patients, the incidence of PGD was the same in adults and children, yet either the severity or the response was different between the pediatric surgeons and the adult surgeons. My sense is that the severity in the children was worse because both groups of surgeons are loathe to start an acute postoperative patient on ECMO, and therefore the profound nature of the hypoxemia in the children seemed to be worse and therefore merit ECMO more frequently.
Dr Keshavjee. Finally, if we are going to encourage the use of living donor transplantation, one of the reasons to do so might theoretically be that you get a better quality graft from a non-brain-dead donor or shorter ischemic time. Were there any advantages with respect to complications or disadvantages that you noted between your living donor experience and your deceased donor experience?
Dr Meyers. Dr Blackstone would characterize that as an apples and oranges comparison because the living donor recipients were only the pediatric recipients, and they generally all had cystic fibrosis. Our general philosophy has been to primarily use the living donor strategy in patients who would not likely survive to the time it would take to get a cadaveric donor. As a result, that group is negatively biased by worse comorbidities. Therefore I do not know whether such a comparison could be made.
Dr Larry R. Kaiser (Philadelphia, Pa). Bryan, I enjoyed the article very much. I noticed in your most recent time period there seemed to be a slight increase in the incidence of airway complications, as well as a slight increase in the incidence of PGD. Is this because of your efforts to use these worst sort of donors or the marginal sort of donors?
Dr Meyers. We touch on that in the article, and it is disconcerting. You would like to see a gradual shaving away of complications as experience is accumulated, but there certainly have been a lot of changes over the period of time in which these data were accumulated. Use of more marginal donors and donors from longer distance all might contribute to that uptick in the PGD rate and also perhaps the anastomotic complication rate.
We are also liberal in terms of integrating the thoracic surgical fellows and the transplantation fellows into the construction of the anastomosis, and it might be that although the cumulative experience has been gained over 15 years, you reset the clock with each new fellow every 6 months, and therefore there is a constant relearning of what needs to be done.
Dr Malcolm M. DeCamp (Cleveland, Ohio). Bryan, congratulations, that is a fabulous series, and we look forward to you mining these data for years to come to identify that low-hanging fruit.
Over the course of your experience, have you changed any of the procurement techniques, used different preservation solutions, and/or modified your approach to using double-lung grafts, perhaps for more marginal donors? Those things seem more likely to affect PGD rather than some of the other things, such as the use of induction immunosuppression or some of the longer-term determinants of survival. The most dramatic thing that you have shown is that all the factors that affect mortality occur acutely in the hospitalization, whereas the long-term outcomes seem quite similar. I wonder whether you could comment on what you have done differently over the course of time and how those changes might affect your reported outcomes.
Dr Meyers. As you can imagine, there have been a lot of evolutionary changes. We did make a transition from a modification of Euro-Collins to Perfadex a couple of years ago.
We have been very liberal for almost 10 years now using nitric oxide in recipients. We have lately used some inhaled Flolan either instead of or sometimes in addition to nitric oxide at the time of implantation. And the interaction between the quality of the donor and the recipient—there is certainly a real one there, but it is difficult to capture in a talk like this.
Where you would be very reluctant to accept a marginal graft for a single-lung transplant for pulmonary hypertension, you would certainly consider it for a patient with emphysema, and a patient with emphysema has very wide latitude with regard to the size of bilateral lungs that you might put in, whereas other recipients might be more constrained.
Therefore it is difficult to globalize over the experience, but yes, there are a lot of small evolutionary changes that have taken place.
Dr John Benfield (Los Angeles, Calif). I cannot help but recall coming to Toronto when Joel Cooper had done his first successful lung transplantation and the tribute that he paid at that time to Griff Pearson and to the environment that permitted the development of this field here in Toronto. Environment is so important, and even though this might not add much to the science of what was presented, at least it might add a touch of history.
Dr Thomas L. Spray (Philadelphia, Pa). I was quite struck by the fact that the incidence of BOS was the same in the pediatric and adult populations, and yet there have been several other studies from your center suggesting that BOS is less common in the very young patient.
In addition, because very young patients are hard to evaluate for BOS, I wonder whether you could comment on how you made the diagnosis of BOS, especially in the pediatric population, and compared that with the adult population because the diagnosis might be quite difficult to make in a very young patient who cannot do a pulmonary function test.
Dr Meyers. Thanks, Dr Spray, for that question. It is quite a challenge. My recollection of the description from the St Louis Children’s Hospital transplantation team about how they measure pulmonary function tests in infants essentially amounts to a forced exhalation measurement with a spirometer on a baby. The child is basically squeezed around the chest and abdomen, and certainly that is a very crude assessment of lung function.
But with regard to the reported freedom of BOS in the youngest children, those children make up a very small fraction of the overall pediatric experience, with a substantial fraction being composed of teenagers who experienced a rate of BOS similar to that observed in the adults. Therefore the classification certainly is not ideal, but this is the best we can go on based on the 2 databases that have been maintained throughout the experience.
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Footnotes |
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