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J Thorac Cardiovasc Surg 2002;123:421-428
© 2002 The American Association for Thoracic Surgery
Cardiothoracic Transplantation (TX) |
From the Toronto Lung Transplant Program, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada.
Received for publication May 14, 2001; revisions requested July 11, 2001; revisions received Sept 7, 2001. Accepted for publication Sept 14, 2001. Address for reprints: Shaf H. Keshavjee, MD, Director, Toronto Lung Transplant Program, Division of Thoracic Surgery, Toronto General Hospital, 200 Elizabeth St, EN 10-224, Toronto, Ontario M5G 2C4, Canada (E-mail: shaf.keshavjee{at}uhn.on.ca).
| Abstract |
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| Introduction |
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A number of options are available to improve donor availability and to reduce mortality on the waiting list. Epoprostenol (prostacyclin) infusion may prolong survival in patients with primary pulmonary hypertension. Lung volume reduction may provide an alternative or bridge to lung transplantation for select patients with emphysema. A priority system for allocating organs will help the neediest recipients receive transplants before more stable patients on the waiting list. Such a priority system may improve overall survival on the waiting list for the entire group of patients. Live donors and nonheart-beating lung donors are other options. Social awareness and political or legislative changes have the potential to significantly improve the donor pool. Unfortunately, many of these and other options simply have not alleviated the current donor shortage.
To overcome this donor shortage, some programs have initiated the use of marginal or extended donors after reports suggesting equivalent outcomes with respect to early morbidity and mortality.
3-5 Others have demonstrated equivalent 1-year pulmonary function and survival with extended donor lungs.
6 As our own program's use of extended donor lungs increased and our recipient selection criteria expanded, we believed it was appropriate to evaluate our outcomes with these organs compared with outcomes with standard or ideal donor lungs and to compare guideline and nonguideline recipients.
| Methods |
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Donor arterial PO2 was based on the final donor PO2 measurement before flushing the lungs. Although some donors had initial PO2 values of less than 300 mm Hg, after donor resuscitation and management, there were no final PO2 values of less than 300 mm Hg. Four donors had initial PO2 values of less than 300 mm Hg. Mucoid secretions on bronchoscopy that could be suctioned clear were considered normal, and those donors were placed into the standard donor group. Only donors with truly purulent secretions were placed into the extended donor group.
The multiorgan donor was managed to maintain euvolemia and to avoid excessive fluid administration. We routinely give 2 g of intravenous methylprednisolone (Solu-Medrol; Upjohn, Don Mills, Ontario, Canada) after initial contact with the donor hospital. The lung procurement follows standard procedures, with an antegrade flush through the main pulmonary artery; however, we use a low potassium dextran solution (Perfadex; Vitrolife, Uppsala, Sweden).
7
Guideline or nonguideline recipients were defined retrospectively by using the "International Guidelines for the Selection of Lung Transplant Candidates."
8 A subgroup analysis was finally performed, looking at combinations of (1) standard donor plus guideline recipient, (2) standard donor plus nonguideline recipient, (3) extended donor plus guideline recipient, and (4) extended donor plus nonguideline recipient.
The primary end point was 30-day mortality. Secondary end points included 90-day mortality, the ratio of PO2 to fraction of inspired oxygen (FIO2) on arrival in the intensive care unit (ICU), and ICU length of stay.
Statistical analysis was performed with the SigmaStat software package (Jandel Scientific, San Rafael, Calif). Comparison between groups was done with the unpaired t test for continuous variables or the 
2 test for categorical variables. Multiple table comparisons were performed with the Mantel-Haentzel test. Data are reported as means ± SD.
| Results |
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The only recipient factor that was significantly different between the 2 groups was the sex distribution. There were more male patients (63%) in the standard donor group and more female patients (63%) in the extended donor group (P = .005). Recipient age and diagnosis was not different between groups.
Table 4
shows the number of nonguideline recipients. Twenty-nine percent were nonguideline recipients, mostly because of older age or colonization with Burkholderia cepacia.
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The cause of death in the 6 extended donor lung recipients whose death was believed to be possibly related to the quality of the donor lungs are as follows(Table 8
). Patient 8 had an intraoperative cardiac arrest preceded by hemodynamic instability after the left lung graft had been implanted. Emergency cardiopulmonary bypass was instituted, but a combination of cardiac and pulmonary problems ultimately resulted in death on postoperative day 10. Patient 10 had a right single lung transplant for idiopathic pulmonary fibrosis. The donor had an infiltrate-contusion in the left upper lobe related to a motor vehicle accident, and we elected to transplant just the right lung. There was hemodynamic instability while the native right lung was being mobilized; cardiopulmonary bypass was instituted, and the case was completed. The patient had severe reperfusion injury and died on postoperative day 7. Patient 11 had sudden cardiac arrest intraoperatively shortly after reperfusion of the first implanted lung. Open cardiac massage and cardiopulmonary bypass were instituted, but the patient ultimately had profound neurologic injury and died on postoperative day 11. Patient 13 underwent transplantation with the aid of cardiopulmonary bypass. Gas exchange was impaired after weaning from bypass; the patient had ventricular fibrillation and was placed back on bypass. He was weaned a second time, and the chest was closed when hypotension and ventricular fibrillation again developed. Once again, he was placed back on bypass. Ultimately, he was weaned with the aid of an intra-aortic balloon pump. He died on postoperative day 9 of cardiogenic shock and acute lung injury. Patient 14 had severe reperfusion injury immediately and died on postoperative day 1. Patient 15's donor had a motor vehicle accident and had received a massive blood transfusion for a retroperitoneal hematoma. The recipient had severe reperfusion injury and died on postoperative day 2.
There were 3 deaths among 9 patients with cystic fibrosis and positive results for B cepacia in the extended donor group and no deaths in 5 patients with B cepacia in the standard group. Because B cepacia is an independent risk factor for posttransplant mortality, we compared the proportion of patients with B cepacia in each group to confirm that they were evenly distributed and found that to be the case. There were 5 of 65 patients with B cepacia in the standard group and 9 of 63 in the extended group (P = .346).
| Discussion |
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Kron and colleagues
3 reported the first series of lung transplants using marginal or extended donor lungs in 1993. They evaluated 11 extended donors and used 10, which amounted to 35% of the total lungs transplanted. One of their 10 extended donor transplant recipients died, for an early mortality rate of 10% in that group. All of their extended donors had been on a ventilator for less than 2 days, and all secretions on bronchoscopy could be easily cleared by suctioning. The mean duration of ventilation in our extended donor group was 60 hours, and 17% of those donors were ventilated for greater than 4 days before retrieval. This prolonged period in the ICU puts the donor at greater risk of nosocomial pneumonia and fluid overload and may partly contribute to the increased early mortality in the extended donor group in our study.
The 1995 report from the Washington University group
9 is the largest and most detailed series looking at the use of extended donor lungs. They had a total of 133 transplants, 33% of which were performed with extended donors. The majority of their extended donors were defined as such because of the presence of chest radiographic infiltrates. The 30-day mortality was 3.4% in the standard donor group and 0% in the extended donor group, and postoperative ventilation and gas exchange were not significantly different either. They concluded that successful outcomes can be achieved with the use of extended donor lungs. Unfortunately, they did not report the distribution of recipient diagnosis in their article but do suggest that extended donor lungs should be used primarily in recipients with emphysema.
In this study we have applied the same criteria to identify marginal donor lungs as were used by the Washington University group. Obviously, it is difficult or impossible to quantify chest radiographic infiltrates or purulent secretions. That is unfortunate because we believe that these 2 criteria are very important in determining whether a marginal donor will provide a good graft. It is our impression that the most difficult judgment decisions pertain to the chest radiograph, the bronchoscopic findings, and the intraoperative assessment of the donor lung by means of direct inspection and palpation. The experience of the retrieval surgeon is critical to a good outcome when using extended donor lungs. During the span of this study period, we began to use lungs with bilateral interstitial edema on radiographs and localized areas of purulent secretions. On one occasion, a left lower lobe pneumonia was excised by means of lobectomy, and only the left upper lobe was transplanted on that side into the recipient, who subsequently did well. On the contrary, patient 15, who died, received lungs from a donor with bilateral infiltrates, purulent secretions, and a significant blood transfusion caused by trauma. This situation clearly represents an extension beyond the limits of extended.
Bhorade and colleagues
6 from Loyola University Medical Center reported their experience with extended donor lungs in 2000. Their criteria for extended donors were slightly different from ours and were as follows: age greater than 55 years, smoking greater than 20 pack-years, presence of chest radiographic infiltrate, donor ventilator time of greater than 5 days, or donor use of inhaled drugs (cocaine or marijuana). There were no purulent bronchoscopic secretions, and all donors had PO2 values of greater than 350 mm Hg. Most of their extended donors were defined as such because of a smoking history or the use of cocaine or marijuana. Only 7 donors were ventilated for more than 5 days, and only 5 donors had radiographic infiltrates, most of which were believed to be atelectasis. They reported on a total of 113 lung transplants, 52 of which were from extended donors, for an extended donor rate of 46%. The hospital mortality for standard donors was 20%, and that for extended donors was 12%, which was not significantly different. They concluded that liberalization of donor criteria does not affect outcome after lung transplantation. In their study the factor that seems to have the greatest effect on mortality is a donor ventilation time of greater than 5 days, but only 13% of their extended donors were in this subgroup.
Since our program began in 1983, we have performed more than 400 lung transplants, with an overall 30-day mortality of 9%, and 12% of those patients were over the age of 60 years. As our program evolved, we began extending the indications for lung transplantation and accepting patients that did not meet the guidelines proposed by the International Society for Heart and Lung Transplantation (ISHLT) in 1998.
8 Our 30-day mortality compares favorably with that of other large and experienced lung transplant programs. Harringer and colleagues
10 from Hannover, Germany, reported their 10-year experience, with a 90-day mortality of 14%, and Meyers and coworkers
9 reported the St Louis 10-year experience, with an early hospital mortality of 8%. In fact, in their 10-year overall review, the St Louis extended donor use rate dropped to 26% compared with 33% in their study cohort from 1995.
From the cohort (n = 128) included in this study, 29% are nonguideline recipients, as defined by the ISHLT
8; that is, they are older (n = 19 [15%]) than the guidelines would recommend or are colonized with B cepacia (n = 14 [11%]). Our other nonguideline recipients had transplants that required concurrent aorta-coronary bypass, combined liver-lung transplant, or single lung transplantation for bronchoalveolar carcinoma after previous pneumonectomy and wedge resections. One case involved a retransplant for chronic rejection in a patient with cystic fibrosis. Early mortality with these nonguideline recipients did not seem to be increased, at least when standard donors were used(Table 6
). There seems to be room to further extend recipient selection criteria, but care needs to be taken not to place organs from truly extended donors into high-risk recipients. Late outcomes with nonguideline recipients need to be evaluated in the future as our experience with this group increases.
Currently, our program performs primarily bilateral lung transplantations. Eighty-four percent of the transplants in the study cohort were bilateral lung transplants, and the conclusions should probably be restricted to this group of recipients. Moreover, only 1 patient with a single lung transplant died early, and there were only 3 heart-lung transplants, all of which were in the standard donor group.
In this study we found that the use of extended donor lungs at a rate of 51% was associated with a significant increase in early mortality at both 30 and 90 days after lung transplant. Most of the deaths occurred within 30 days. Early 30-day mortality was 6.2% in the standard donor group and increased to 17.5% in the extended donor group. We do believe that extending the criteria for lung donation is justified and safe; however, the limits are difficult to define, particularly with respect to subjective indexes such as the chest radiographic and the bronchoscopic findings. It may be that a marginal donor rate of 51% is too high, especially with certain higher risk recipients.
Theoretically, an aggressive policy of donor assessment and use should result in a decrease in waiting time on the list and decreased deaths on the waiting list. It may also allow for expansion of recipient criteria. However, it does not seem ethically justified to use an extended donor if the waiting list is short or if the patients are not rapidly deteriorating on the list. If a transplant program has a fairly large donor pool, then this may be the case; however, for most programs, the waiting list is long and the donor pool is small, limited, or both. In this situation it seems justified to use an extended donor lung in certain circumstances.
What defines extended is a weakness of the currently accepted criteria. Most extended donor lungs will function well. Unilateral infiltrates, basal or dependent atelectasis, and mucoid secretions suctioned out completely almost always result in good graft function. Identification of these particular situations depends on the clinical experience of the retrieval surgeon and hands-on inspection in the donor operating room. Donor age by itself has also not been a problem in our experience and, in our opinion, is a less important criterion.
Most worrisome are the bilateral infiltrates or truly purulent secretions. Although the majority of extended donor lungs will function adequately, it is this subgroup that seems to have the highest risk of death(Table 8
). We examined the number of deaths with an extended criteria per extended criteria to get some numeric sense of the risk contained in each criteria(Table 9
). Admittedly, a multivariate regression with each donor criteria as an independent variable would be the most powerful analysis. Unfortunately, because of the small number of deaths, which is more important than the total number of patients, we were unable to examine this rigorously. However, purulent secretions on bronchoscopy and an abnormal chest radiograph seem to predict mortality.
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Our recipients seem relatively evenly matched in the 2 groups with respect to age and underlying diagnosis; however, there were significantly more female subjects in the extended donor group. It is unclear why this is the case. Perhaps because of smaller absolute lung size in female subjects, we were more likely to use an extended donor for fear that another donor of appropriate size would not come along soon enough, especially in rapidly deteriorating patients. Ultimately, the balance of male to female subjects is even when looking at the mortality in each group(Table 7
and8
).
In summary, many extended donor lungs will result in a good outcome after transplantation; however, extended donor use can result in increased early mortality compared with that with standard or ideal donors. Extended donors should be assessed by an experienced lung transplant surgeon, particularly if plans exist to use that lung in a higher risk recipient. Donors with bilateral infiltrates not related to atelectasis, frankly purulent secretions, or both, should be used with extreme caution. Extended donor age and smoking history do not seem to affect early outcome but may play a role in late functional results. Further work is needed to define the limits for extended donors, and these limits may change as lung preservation techniques are improved.
| Appendix: Discussion |
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I have several questions. First, as you stated, several reports have suggested equivalent outcomes when standard and marginal donors are used. As background for the audience, these series include the 1993 University of Virginia report (although their definition of marginal was more conservative, with a PO2 of up to 350 mm Hg and ventilator time of less than 2 days), the 1995 Washington University report (perhaps the largest series, which was later commented on by Dr Patterson at the 1999 meeting of the American Surgical Association), the 1999 Australian series (which used the same criteria as you did but also included patients who had yeast on their Gram stain), and finally, the 2000 Loyola series, which defined a marginal PO2 as less than 350 mm Hg.
Obviously, differences in chest radiographic and bronchoscopic findings are difficult to standardize among series. Lessons learned from one series cannot necessarily be applied to another. Furthermore, no consistent use of marginal donors in recipients with a particular diagnosis could be defined, but most avoided marginal donors for single lung transplants in primary pulmonary hypertension and strongly recommended the use of these donors in emphysematous recipients. Do you think your use in recipients with primary pulmonary hypertension, patients with cystic fibrosis with B Cepacia colonization, and even in reduced lung transplants explained your increased mortality in the extended or marginal group?
Second, given that reperfusion injury and acute dysfunction increase major histocompatibility complex II antigen expression and thereby possibly increase susceptibility to acute rejection and obliterative bronchiolitis, do you think that 30-day or even 1-year follow-up is adequate?
Third, in your series only one lung recipient died. Your policy favors double lung transplants. Some argue that with one marginal lung, a double lung is preferred. Others believe that with a single transplant, at least one lung is not vulnerable to reperfusion injury. Can you comment on the use of marginal donors with specific regard to single and double lung transplants?
Finally, in your report and in the series from Barnes Hospital, donor treatment with high-dose methylprednisolone (Solu-Medrol) is recommended. Are you aware of any data that demonstrate a beneficial effect of this practice?
Dr Bryan F. Meyers (St Louis, Mo). We have just recently reviewed 550 transplants at Washington University in St Louis and cannot demonstrate that using a marginal donor is an increased risk factor on the basis of survival or the development of acute rejection or bronchiolitis obliterans. I know that the University of Toronto has prior experience with marginal donors that was favorable, and I wonder if you looked at the possibility that this is just a bad run and a statistical aberration in a small number of patients. I noticed that you had an increased number of female donors. Female recipients and certain underlying recipient diagnoses are independent risk factors for early mortality on the basis of the ISHLT database. Do you think it might just be a fluke?
Dr Pierre. I will first address the issue about the female recipients. Female recipients in the ISHLT database are protective. They have a lower 1-year mortality than male recipients. Why we have more female recipients in our extended recipient group and why that group should have a higher mortality is hard to explain. I tried to address that somewhat, but I do not have a good explanation.
Dr Mulligan, you outlined a number of the previous studies that looked at marginal donor lungs, and I think an explanation as to how our donors and recipients differ would take some time, but your specific questions about the use of extended or marginal donor lungs in higher risk recipients is, I think, very important. My own belief is that I do not think we should be using these lungs in patients with B cepacia. I do not know that I can prove that getting the patients extubated and out of the ICU earlier will reduce the incidence of B cepacia infection or mortality from B cepacia, but patients with B cepacia do seem to represent a fair number of the deaths in this series. Therefore, I do think that patients with pulmonary hypertension, redo patients, and other difficult or complicated cases in which high risk might be expected in the perioperative period should probably also receive standard donor lungs or donor lungs that do not have marginal or extended criteria, such as bilateral infiltrates, or any question about the bronchoscopy.
In terms of long-term follow-up, I agree that this is a short-term study looking at 30-day or 90-day mortality. Long-term data will be very important to look at the outcome with respect to extended or marginal donor lungs, particularly when it comes to the other extended criteria, such as advanced donor age or smoking history, and the risk of malignancy will also become an issue.
As far as single lungs go, we do favor using marginal donor lungs in bilateral lung transplantation and avoid them in the use of single lungs. The one patient who died did receive a marginal donor lung for a single lung transplant; the donor lung was marginal because of an infiltrate and a contusion on the left side, and it was the right side that was transplanted. However, that patient obviously did not do well.
Regarding the use of methoprednisolone, there are not a lot of data supporting that. There is one report from Sacramento looking at the retrieval of organs after the administration of methoprednisolone, suggesting that the overall yield in retrieval was increased by the use of preoperative methoprednisolone to the donor.
| Footnotes |
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M. de Perrot, M. Liu, T. K. Waddell, and S. Keshavjee Ischemia-Reperfusion-induced Lung Injury Am. J. Respir. Crit. Care Med., February 15, 2003; 167(4): 490 - 511. [Abstract] [Full Text] [PDF] |
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