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Ann Thorac Surg 2002;74:1663-1670
© 2002 The Society of Thoracic Surgeons
a Division of Cardiothoracic Surgery, Washington University Medical Center, St. Louis, Missouri, USA
b Division of Pulmonary Medicine, Washington University Medical Center, St. Louis, Missouri, USA
* Address reprint requests to Dr Patterson, Division of Cardiothoracic Surgery, Washington University Medical Center, Queeny Tower, Suite 3108, One Barnes-Jewish Hospital Plaza, St. Louis, MO, 63110-1013 USA
e-mail: pattersona{at}msnotes.wustl.edu
Presented at the Forty-eighth Annual Meeting of the Southern Thoracic Surgical Association, San Antonio, TX, Nov 8–10, 2001.
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Abstract |
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METHODS: A retrospective analysis was undertaken of the 306 consecutive lung transplants for emphysema performed at our institution between 1988 and 2000 (220 COPD, 86 AAD). Follow-up was complete and averaged 3.7 years.
RESULTS: The mean age of AAD recipients (49 ± 6 years) was less than those with COPD (55 ± 6 years; p < 0.001). Hospital mortality was 6.2%, with no difference between COPD and AAD, or between single-lung transplants and bilateral-lung transplants. Hospital mortality during the most recent 6 years was significantly lower (3.9% vs 9.5%, p = 0.044). Five-year survival was 58.6% ± 3.5%, with no difference between COPD (56.8% ± 4.4%) and AAD (60.5% ± 5.8%). Five-year survival was better with bilateral-lung transplants (66.7% ± 4.0%) than with single-lung transplants (44.9% ± 6.0%, p < 0.005). Independent predictors of mortality by Cox analysis were single lung transplantation (relative hazard = 1.98, p < 0.001), and need for cardiopulmonary bypass during the transplant (relative hazard = 1.84, p = 0.038).
CONCLUSIONS: AAD recipients, despite a younger age, do not achieve significantly superior survival results than those with COPD. Bilateral lung transplantation for emphysema results in better long-term survival. Accumulated experience and modifications in perioperative care over our 13-year series may explain recently improved early and long-term survival.
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Introduction |
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We evaluated our series of lung transplants for emphysema from 1988 to 2000 (N = 306) at Washington University in order to determine factors predicting morbidity and mortality, and to identify differences in outcome between recipients with COPD and AAD.
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Material and methods |
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Operative method
The donor procurement technique used by our institution has been previously described [3]. All donors received intravenous, broad-spectrum antibiotics within a few hours before retrieval. Donors were pretreated with intravenous heparin (4 mg/kg) and a bolus dose of prostaglandin E1 (500 µg) administered directly into the pulmonary artery immediately before aortic cross-clamp. Lungs were flushed with cold antegrade, modified Euro-Collins solution (60 to 80 mL/kg). In the last 4 years, retrograde pneumoplegia, using the same solution (5 mL/kg), has been administered into each pulmonary vein [4]. In the last 3 years, nitroprusside (10 mg/L) has been added to the flush solution. Lungs are harvested en bloc and preserved by immersion in cold saline solution for transportation to our institution. The operative technique employed at our institution for recipient implantation has also been previously described [5, 6].
Recipient criteria
Our standard recipient selection criteria have been previously reported [7]. Recipients are listed for transplantation when they have developed disabling lung disease with a limited prognosis and no other systemic illness that would complicate or be complicated by lung transplantation and immunosuppression. All patients listed for lung transplantation were enrolled in an active pulmonary rehabilitation program.
Postoperative care
In our institution, the early postoperative care is relatively standardized. Mechanical ventilation is discontinued when gas exchange and weaning parameters permit. Routine empiric perioperative antibiotics with broad-spectrum gram-negative and gram-positive coverage are administered. Subsequent antibiotic selection is based on the results of donor and recipient bronchial cultures. Prophylaxis against Pneumocystis carinii consists of trimethoprim-sulfamethoxazole given once daily until discharge, at which time the regimen is changed to administration three times per week. Cytomegalovirus (CMV) mismatches (donor CMV seropositive and recipient seronegative) with a high risk for infection receive intravenous ganciclovir prophylaxis for 12 weeks. All patients were monitored for viremia with weekly blood cultures.
A standard immunosuppressive protocol consisting of cyclosporine, corticosteroids, and azathioprine is employed. Other agents, including tacrolimus, mycophenolate mofetil, and sirolimus, have been used depending upon clinical course. Immunosuppression induction typically includes antithymocyte globulin. We perform routine surveillance flexible bronchoscopy, bronchoalveolar lavage, and transbronchial biopsies at 2, 3, and 6 weeks and at 12 months, as well as on an as-needed basis thereafter.
For the purpose of our study, a diagnosis of acute rejection required pathologic confirmation from a transbronchial biopsy specimen obtained during the first year after transplantation. Rejection was graded according to the grading system of the International Society for Heart and Lung Transplantation (ISHLT) [8]. Severe acute rejection was deemed to be present if any transbronchial biopsy was graded A3 or higher. Increased frequency of rejection was ascribed to those patients with rejection scored A2 or worse on three or more biopsies in the first year [9]. BOS was diagnosed and classified according to the grading system devised by the ISHLT [10].
Data collection and statistical analysis
We collected preoperative and postoperative data from recipient medical charts and our lung transplantation database. Recipient follow-up was complete in all patients transplanted through December 2000.
Normally distributed continuous data are expressed as means ± standard deviation. Medians with interquartile ranges are used when continuous data are skewed. Categorical data are expressed as counts and proportions. Unrelated two-group comparisons employ unpaired, two-tailed t tests for means of normally distributed continuous variables and the Wilcoxon’s rank-sum tests for nonparametric data. 
2 or Fisher’s exact tests are used to analyze differences among the categorical data. Kaplan-Meier estimates are used to depict survival and freedom from BOS. Survival and BOS-free survival comparison between groups of patients was completed using the Mantel-Haenszel log-rank test. Cox multivariate proportional hazards regression method was used to identify risk factors for survival after transplantation. The time to death was selected as the principal outcome. The regression model was constructed using dependent variables known or suspected to be independent predictors of the outcome based on previous published results and the univariate differences observed between our two groups (COPD and AAD).
The following categorical variables were considered: marginal versus ideal donor, recipient gender, recipient diagnosis (COPD vs AAD vs other), single versus bilateral transplant, recipient ventilator dependent or not at time of transplant, use of CPB, requirement for extracorporeal membrane oxygenator (ECMO), primary graft dysfunction as defined by the pulmonary arterial oxygen tension (PaO2) divided by the fraction of inspired oxygen (FiO2) being less than 150 mm Hg, CMV cytomegalovirus mismatch, presence of A3 rejection in recipient, three or more versus less than three distinct bouts of A2 rejection, and date of transplant (1988 to 1994 vs 1995 to 2000). The following continuous variables were considered: recipient age in years and ischemic time in minutes.All data analysis was performed using Systat (Systat 7.0 for Windows SPSS Inc., Chicago, IL). All p values < 0.05 were considered to be statistically significant.
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Results |
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Operative parameters
Intraoperative parameters are shown in Table 2.
AAD patients received, as a group, a significantly higher proportion of BLT than the COPD group (84.9% vs 66.8%; p = 0.002). The mean age of BLT recipients from both AAD and COPD groups (48 and 54 years) was lower than SLT recipients from these respective groups (53 and 57 years, p < 0.02).
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Survival
Overall hospital mortality was 6.2%, with no difference between COPD recipients (5.5%) and AAD recipients (8.1%, p = 0.43). There was no difference in hospital mortality between single (7.0%) and bilateral (5.9%) transplant recipients (p = 0.79). Hospital mortality was lower in our most recent experience (1995 to 2000, n = 180), with 3.9% versus 9.5% from our early series (1988 to 1994, n = 126; p = 0.044).
Overall 5-year survival was 58.6% ± 3.5%. AAD recipients had a 5-year survival of 60.5% ± 5.8%, whereas COPD recipients had a 56.8% ± 4.4% rate (p = 0.53; Fig 2). Five-year survival for all other diagnoses receiving lung transplantation (n = 248) was 54.4% ± 3.5%. Emphysema patients receiving BLT had a significantly higher 5-year survival at 66.7% ± 4.0%, as compared with SLT recipients at 44.9% ± 6.0% (p < 0.001; Fig 3). This improved survival for BLT recipients was also observed within the groups of AAD and COPD patients. Whereas the 5-year survival for BLT recipients with AAD and COPD was 69.7% and 64.1%, respectively; for SLT recipients it was 23.1% and 50.3% (p < 0.001). Figure 4 shows the overall Kaplan-Meier survival curves for the initial experience (1988 to 1994) and recent experience (1995 to 2000). The latter group demonstrated a trend toward a higher 5-year survival (70.4% ± 4.6%) than the earlier group (53.7% ± 4.5%, p = 0.06). Mean follow-up was 5.4 ± 3.3 years and 2.5 ± 1.6 years, respectively.
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Posttransplantation functional results
Table 3
details the forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), 6-minute walk test (6MW), and arterial carbon dioxide tension (PaCO2) from the preoperative time of evaluation to the 5-year time point posttransplantation. Whereas there are no differences between AAD and COPD groups at each time point, both groups show statistically significant improvement in all the above measures when comparing the preoperative baseline with the function at the 1-year time point
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Comment |
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TopAbstractIntroductionMaterial and methodsResultsCommentDiscussionReferences |
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At our institution, 55.2% of lung transplants are performed for emphysema (COPD and AAD). This is a higher proportion than the worldwide experience (45.9%) as reported by the ISHLT in their most recent annual report [1]. In our series, AAD cases accounted for 28% of lung transplants for emphysema, a larger percentage than is reported in the ISHLT registry (22.8%). Our lung transplant program may have a proclivity for emphysema patients as a byproduct of our institution’s early and continued interest in lung volume reduction surgery (LVRS). Increased referrals of end-stage emphysema patients for LVRS evaluation may yield an increased number of potential transplant candidates with this diagnosis. We have previously reported on the impact of LVRS on subsequent lung transplantation [13].
Emphysema patients have 77% less risk of dying on the lung transplant waiting list than patients with all other diagnoses [14, 15]. The current recipient waiting list algorithm used in the United States is based solely on the individual waiting time of each listed patient rather than on disease severity. Only in the case of a local donor or a rare UNOS-approved variance may a program allocate donor lungs on the basis of other criteria. Particular to our lung transplant program is the fact that approximately 75% of our donor lungs originate from outside our region, and are offered only to the patient with the longest waiting time regardless of diagnosis. The increased waiting list longevity of patients with emphysema, therefore, favors them in terms of obtaining a transplant.
AAD recipients, when compared with their COPD counterparts, demonstrated relatively similar outcomes. No statistical significance was found in the 5-year survival of the two groups, despite the significantly younger age of the AAD group and the generally held perception that AAD recipients, though similarly disabled from a pulmonary standpoint, have less comorbidity than their COPD counterparts [16].
Improved long-term survival of BLT over SLT in emphysema has been previously reported [17, 18] and remains a favorable prognostic factor in the ISHLT registry [1]. Our results show a similar survival advantage for BLT over SLT. Our institutional preference of BLT for emphysema patients is evident in our series. Whereas the ISHLT registry reports 27.9% of emphysema patients receive BLT worldwide, our series posts a proportion of 71.9%.
We favor the BLT procedure in emphysema patients due to its record of superior survival, and our finding that postoperative ventilator management is much easier in the emphysema patients with BLT. The BLT procedure also allows us to use marginal donor lungs without significantly affecting our results, offsetting considerations of maximal donor organ use that would otherwise favor SLT. We also feel that BLT, although a longer procedure, is not any more complex an operation.
A number of factors have been raised to explain the superiority in terms of survival of BLT over SLT. Of particular importance is selection bias, which may occur if BLT is being chosen preferentially for younger or healthier recipients. We found in our study that BLT recipients were, in fact, younger than those receiving SLT. This was true in both the AAD group and the COPD group. However, a selection bias favoring BLT was not universally the case, as all 6 ventilator-dependent patients in our series underwent bilateral transplantation.
Another form of selection bias is "operative tolerability," where it is decided to forego implanting the second lung when the procedure to implant the first lung has been difficult. This factor would select BLT only for patients able to tolerate a bilateral procedure. This bias may be of particular significance in a program such as ours where BLT is used preferentially and the preoperative intention to treat with SLT is relatively infrequent.
The corollary to the above hypothesis is the bias to persist with a BLT in a younger patient despite difficulties during implantation of the first lung, to the extent of instituting CPB. The similar situation in an older, COPD patient may have resulted in aborting the second side of a previously planned BLT, even before the use of CPB. This may have been a factor in AAD patients receiving more BLT with more CPB usage. Whereas 9.5% of BLT procedures were performed with the assistance of CPB, only 3.5% of SLT procedures employed CPB.
BLT recipients may be favored as well by having two grafts, and thus more reserve. This may be especially important if chronic rejection (BOS) develops. As well, operative complications such as phrenic nerve injury or bronchial anastomotic complications are uncommon but of much greater significance in SLT recipients.
In our series, CPB was used in only 7.8% of all cases. There is a conscious effort at our institution to employ CPB only as necessary, because we believe that its routine use is unwarranted and possibly deleterious [19, 20]. The fact that, by regression analysis, CPB was one of two factors found to be associated with a statistically higher risk of mortality is not unexpected. Our strategy of CPB use only when needed selects out cases of particular difficulty and therefore increased risk.
The evolution of our lung transplant program has not only seen an increase in volume of cases but has clearly benefited from the continuing growth of experience. Evolution and improvements in preoperative patient selection, operative technique, and perioperative management have seen a reduction in hospital mortality in the last 6 years (3.9%) as compared with the initial 7-year cohort (9.5%). The long-term survival results from our most recent experience are improved over those of our initial years. Though promising, results such as these should always be viewed in the context of the differing follow-up periods. Inevitably, the earlier cohort has a longer follow-up and is more fully representative of the long-term results. All survivors from the early group have reached the 5-year time point, whereas this is not the case in the later group. The earlier cohort has, therefore, had more opportunity to develop complications such as BOS, which most certainly affect survival results.
This review of our single-institution experience in lung transplantation for emphysema confirms the very satisfactory results obtainable for both COPD and AAD recipients. Although AAD recipients are generally younger than their COPD counterparts, they have similar long-term survival after lung transplantation. Our series further underlines the survival advantage of bilateral- over single-lung transplantation for emphysema. Moreover, our results demonstrate the infrequent need for cardiopulmonary bypass and argue against its routine use in lung transplantation for emphysema.
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Discussion |
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DR CASSIVI: In our program, we obviously have a certain proclivity for emphysema patients due to our institutional interest in lung volume reduction and transplantation. We have transplanted patients who have had previous lung volume reduction, and they have not had any worse results in terms of short- and long-term outcomes. The operation is somewhat different in that the pneumonectomy is sometimes more challenging. However, in terms of the outcomes, these patients do just as well.
With regard to lung volume reduction surgery as a bridge to transplantation, it is certainly a topic that has been previously discussed. As a generality, age is a major factor a person who is younger may benefit from lung volume reduction first and thus allow them to then be bridged over to a transplant at a later date. Extent and distribution of disease is another important factor in our evaluation of emphysema patients. Some patients being evaluated for lung volume reduction surgery have homogenous disease and are therefore more appropriate candidates for transplantation. At evaluation, we do try to categorize the patients as candidates for one or the other operation if appropriate.
DR ROBERT D. DAVIS, JR (Durham, NC): Dr Cassivi, that was an excellent presentation and, again, compliments on the excellent results that your group has continued to have with these patients. We recently analyzed combined data from Duke and Toronto lung transplant programs. We found the same survival benefit and lower rates of bronchiolitis in patients receiving bilateral-lung transplants versus single-lung transplants. My question is, what is the role of single-lung transplant for patients with emphysema? Obviously there is a donor shortage, but are we just doing a poor palliative operation by offering single-lung transplants for this disease?
When you compare results, I think that your data suggest that the outcomes doing a bilateral-lung transplant for emphysema essentially becomes equivalent to what we would expect with the best recipient cohort, the cystic fibrosis population, and that a 70% 5-year survival is achievable with a double-lung transplant, where everyone is finding 35% to 45% 5-year survival in the patients getting single-lung transplants for emphysema.
It is a difficult question, to essentially take more patients out of the mix by doing bilateral lung transplants, but is it really fair to those patients by performing single-lung transplants?
DR CASSIVI: Thank you for your question. We have a similar attitude in St. Louis in terms of our preference for the bilateral sequential lung transplantation procedure. We believe it has better long-term results. We also believe that it does not add significantly to the complexity of the operation. A bilateral-lung transplant is just a bit longer. As well, at Washington University in St. Louis, we often use marginal donors for the bilateral procedures in emphysema. We do not use marginal donors for the other diseases. With better long-term outcomes and expansion of the donor pool by using marginal organs that would otherwise be wasted, we propose that these strategies go a long way in overcoming any ethical questions of donor organ allocation. Therefore, we would prefer, when the possibility avails itself, to perform bilateral transplants for our patients.
The role of single-lung transplantation is therefore in question. I believe there are certain cases where, in an older patient, after the first lung has been gone into and it has been somewhat difficult, we have tended to "cut our losses" and proceed only with the single lung. That scenario has happened only on very rare occasions.
Without any specific cases to demonstrate this point, I believe there is a corollary to the scenario that I have just presented. It is in the younger patients, the alpha-1’s particularly, where instead of stopping at one lung, we may proceed along on cardiopulmonary bypass to put in that second lung. In general, our institutional preference a priori is for bilateral-lung transplantation for the reasons that I have mentioned here and in my presentation.
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