Medium-term outcome after lung transplantation is comparable between brain-dead and cardiac-dead donors

Transcription

1 FEATURED ARTICLES Medium-term outcome after lung transplantation is comparable between brain-dead and cardiac-dead donors Stéphanie I. De Vleeschauwer, DVM, a Shana Wauters, MSc, b Lieven J. Dupont, MD, PhD, a,c Stijn E. Verleden, MSc, a Anna Willems-Widyastuti, MSc, a Bart M. Vanaudenaerde, PhD, a Geert M. Verleden, MD, PhD, a,c and Dirk E.M. Van Raemdonck, MD, PhD b,d a From the Laboratories of Pneumology and b Experimental Thoracic Surgery, Katholieke Universiteit Leuven; and the Departments of c Pneumology and d Thoracic Surgery, University Hospitals Leuven, Leuven, Belgium. KEYWORDS: cardiac-dead donor; lung transplantation; BOS; survival BACKGROUND: Donation after cardiac death (DCD) to overcome the donor organ shortage is now moving into the clinical setting, but the medium-term outcome after DCD lung transplantation (LTx) remains largely unknown. METHODS: In this retrospective study, DCD LTx recipients (n 21) were compared with a cohort of donation-after-brain-death (DBD) LTx recipients (n 154) transplanted between February 2007 and July Immediate (post)operative outcome was evaluated by assessing need for peri-operative extracorporeal membrane oxygenation (ECMO), time to extubation, hospital discharge and primary graft dysfunction (PGD) within the first 48 hours. Survival, incidence of bronchiolitis obliterans syndrome (BOS), acute rejection (AR) and inflammatory markers in blood and in bronchoalveolar lavage (BAL) were assessed and compared over a median follow-up of 327 days for DCD and 531 days for DBD, showing no statistically significant difference (NS). RESULTS: There were no differences between groups with regard to patient characteristics except for a higher number of patients transplanted for obliterative bronchiolitis in the DCD group (4 of 21 vs 7 of 154; p 0.05). In the DCD group, 2 of 21 patients died, vs 23 of 154 patients in the DBD group (NS). Actuarial survival rates at 6 months, 1 year and 3 years are 95%, 95% and 71% for the DCD group and 96%, 91% and 75% for the DBD group (NS). Three patients (14%) in the DCD group developed BOS vs 15 patients (10%) in the DBD group (NS). Survival and freedom from BOS were not different between the groups. AR, inflammatory markers and immediate (post)operative outcome also did not differ. CONCLUSIONS: In our experience, both early- and medium-term outcome in DCD lung recipients is comparable to that of DBD lung recipients. Use of lungs recovered from controlled donors after cardiac death is a safe option for expansion of the donor pool. J Heart Lung Transplant 2011;30: International Society for Heart and Lung Transplantation. All rights reserved. The widespread application of lung transplantation (LTx) to all patients who may benefit is hampered by an organ shortage. One option for expansion of the donor pool is the use of organs from those who donate after cardiac death (DCD). Although the first LTx was performed with a Reprint requests: Dirk E.M. Van Raemdonck, MD, PhD, Department of Thoracic Surgery, University Hospital Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium. Telephone: Fax: address: dirk.vanraemdonck@uzleuven.be /$ -see front matter 2011 International Society for Heart and Lung Transplantation. All rights reserved. doi: /j.healun DCD lung, 1 it was long believed that warm ischemia after cardiac arrest would further jeopardize organ function. Animal studies, however, have shown that acceptable warm ischemia time to preserve graft function is limited to 60 to 90 minutes. 2 After a decade of extensive research, 3 LTx from DCDs has slowly moved into the clinic with the first reports presented by Love et al 4 and Steen et al. 5 Both studies described successful LTx from a controlled and uncontrolled DCD donor, respectively. 6 Since then, several groups have embarked on DCD LTx. So far, the LTx team

2 976 The Journal of Heart and Lung Transplantation, Vol 30, No 9, September 2011 in Madrid is the only group routinely using lungs recovered from uncontrolled, Category I DCD donors (dead on arrival). 7 They reported good results in 17 recipients, although the incidence rates of primary graft dysfunction (PGD) and bronchiolitis obliterans syndrome (BOS) were higher and 3-year survival was lower when compared with data from the International Society for Heart and Lung Transplantation (ISHLT). 8 More groups worldwide have reported, in abstract form, short-term outcome using controlled, Category III (awaiting cardiac arrest) donors Institutional reports on large numbers with longer follow-up, however, are scarce, comprising a total of nearly 100 recipients Our group has previously reported an initial experience with early outcomes in 5 DCD lung recipients. 19 In this study we review our experience over the last 4 years with a cohort of 21 patients and report on their immediate post-operative and medium-term ( 1 year) outcomes. Methods In this retrospective study, all DCD lung recipients (n 21), single or double, were assessed and compared with a cohort of DBD recipients (n 154) transplanted in the same period of February 2007 to July Heart lung transplant recipients (n 4) were excluded. Donor preparation and management was performed as previously described. 19 Briefly, donors were selected according standard ISHLT criteria 20 and the same criteria regarding age, gas exchange, chest X-ray appearance, bronchoscopy findings and smoking history were considered. This information was also available from these controlled DCDs (Maastricht Category III) in the hours prior to organ recovery. Extended criteria were applied for both types of donors. A member of our team was sent to the donor hospital to check the quality of the lungs during multi-organ retrieval. All lungs were retrieved by one of our transplant surgeons. Lungs from DCDs having an agonal phase exceeding 60 minutes between ventilatory switch-off and circulatory arrest were not accepted. After a no-touch period of 5 minutes, a quick sternotomy and laparotomy was performed. Pleural cavities were opened and lungs were inspected. Due to the short expected warm ischemia in these controlled DCDs, neither topical cooling nor lung inflation was considered necessary. In the study period, lungs were offered from 24 DCDs. Lungs from 3 such donors were finally not transplanted for following reasons: agonal phase 60 minutes (n 1); emphysematous lungs (n 1); or severe pleural adhesions after previous sternotomy for cardiopulmonary bypass (n 1). Lungs from all other DCDs (n 21) were included in this study. Outcome parameters For both groups, ischemic times, oxygenation, PGD, time to extubation, time to discharge from intensive care unit (ICU) and hospital, and forced expiratory volume in 1 second (FEV 1 ) before and best value after LTx were evaluated. For DCD donors, agonal time, defined as the period between ventilator switch-off and cardiac arrest, as well as warm ischemia time elapsed between circulatory arrest and start of cold pulmonary flush, were recorded. Cold ischemia in both DCD and DBD lungs was defined as the interval between cold flush and blood reperfusion of each lung in the recipient. To estimate inflammation on a systemic level, C-reactive protein (CRP) was measured at different time-points; bronchoalveolar lavage (BAL) samples were taken routinely at fixed time-points after LTx and neutrophil percentages were measured to assess airway inflammation. Acute rejection (AR) was assessed by taking transbronchial biopsies (TBBs) and BOS was evaluated based on pulmonary function testing, according to its definition. 21 Oxygenation and PGD grading Oxygenation, expressed as the ratio of partial pressure of oxygen/fraction of inspired oxygen (PaO 2 /FIO 2 ), was measured at time of ICU admission (0 hour), and 12, 24 and 48 hours later. PGD was classified according to the grading system proposed by the ISHLT working group on PGD. 22 Briefly, patients with a PaO 2 /FIO 2 ratio 200 were classified as PGD Grade 3, between 200 and 300 as PGD Grade 2 and 300 as PGD Grade 0 or 1, independent from infiltrates on chest X-ray at a particular time-point. CRP assessement Plasma CRP (not high-sensitivity) was measured at Days 1, 21, 90, 180, 360, 540 and 720 post-operatively (Tina-quant CRP [latex] assay; Roche Diagnostics, Mannheim, Germany), with a sensitivity threshold of 1 mg/liter. FEV 1 measurement FEV 1 was measured with a Masterscreen spirometer (Jaeger, Hoechberg, Germany). According to ATS criteria, the best of 3 attempts, with a variability of 10%, was retained for analysis and results expressed in liters. 23 The last FEV 1 measurement before LTx and best FEV 1 measurement after LTx of each patient were considered for analysis. BAL assessment BAL is performed routinely at fixed time-points after transplantation (Days 1, 21, 90, 180, 360, 540 and 720 postoperatively). Bronchoscopy was performed as previously described. 24 Briefly, two 50-ml aliquots of sterile saline were instilled in a sub-segmental branch of the right middle lobe or in the lingula. Both recovered fractions were pooled and used for culture and total and differential cell count. After centrifugation (300g, 10 minutes) of the BAL fluid, cell counts were performed. A cytospin was made with 10 5 cells/ml in a Shandon cytocentrifuge (Techgen, Zellik, Belgium) and stained with May Grünwald Giemsa. At least 300 cells were counted.

3 De Vleeschauwer et al. Medium-term Outcome After DCD LTx 977 Table 1 Patient and Donor Characteristics DBD (n 154) DCD (n 21) n %/IQR n %/IQR p-value Patient characteristics Age 54 (43 60) 55 (50 59) 0.8 Gender Female 76 49% 8 38% 0.33 Male 78 51% 13 62% Type of LTx BLTx % 20 95% 0.17 SLTx 25 16% 1 5% Follow-up (days) 531 ( ) 327 ( ) 0.18 Underlying disease Emphysema 75 49% 10 48% 0.93 Pulmonary fibrosis 31 20% 5 24% 0.7 CF 18 12% 2 10% 0.77 OB 7 5% 4 19% 0.01 a BOS 7 3 Post-BMT 1 1 -ATD 5 3% 0.4 Sarcoidosis 5 3% 0.4 PPH 4 3% 0.46 Bronchiectasis 4 3% 0.46 Others b 5 3% 0.46 Donor characteristics Age (years) 45 (36 53) 48 (42 53) 0.18 Gender Female 82 53% 8 38% 0.19 Male 72 47% 13 62% PO 2 (FIO 2 1) (mm Hg) 454 ( ) 452 ( ) 0.83 Time on ventilator (h) 52 (32 96) 68 (22 129) 0.95 Cause of brain injury Trauma 58 38% 6 29% 0.48 Vascular 82 53% 6 29% 0.04 a Others 14 9% 9 43% a Warm ischemia (min) NA 15 (12 18) Cold ischemia First lung ( ) a Second lung ( ) a Agonal phase (min) NA 14 (10 21) 1 -ATD, 1 -anti-trypsin deficiency; BLTx, bilateral lung transplantation; BMT, bone marrow transplantation; BOS, bronchiolitis obliterans syndrome; CF, cystic fibrosis; DBD, donation after brain death; DCD, donation after cardiac death; NA, not available; OB, obliterative bronchiolitis; PPH, primary pulmonary hypertension; SLTx, single-lung transplantation. a Statistically significant. b Includes 1 acute rejection, 1 histiocytosis X, 2 lymphangioleiomyomatosis, 1 epithelioid hemangioendothelioma. TBB study TBBs were routinely performed in each patient at time of discharge and 3 months after LTx, and thereafter if AR was suspected. AR was assessed by an independent pathologist according to criteria of the ISHLT Lung Rejection Study Group. 25 Statistical analysis Data analysis was performed with GraphPad Prism 4 (GraphPad, Inc., San Diego, CA). Results are presented as median (interquartile range [IQR]). Significance levels between groups were tested using unpaired t-tests and the chi-square test as appropriate. p 0.05 was considered significant. Results Donors The causes of brain injury in the DCD donors were trauma (n 6), vascular (n 6), asphyxia (n 5) or euthanasia

4 978 The Journal of Heart and Lung Transplantation, Vol 30, No 9, September 2011 (n 4) performed in accordance with Belgian legislation. The agonal phase in these donors was 14 (10 to 21) minutes. In the DBD donors, significantly more donors had brain death from vascular insults (n 82, p 0.038), with 58 donors dying after trauma and 14 from other reasons. Patient and donor characteristics are summarized in Table 1. Recipients Patients receiving DCD lungs had a median follow-up of 327 (185 to 675) days, and DBD recipients a median of 531 (233 to 873) days (p not statistically significant [NS]). No differences were found between groups with regard to age, gender and type of LTx. Underlying diseases were not different between the two groups apart from a higher number of patients transplanted for obliterative bronchiolitis (OB) in the DCD group (4 of 21 vs 7 of 154; p 0.01) (Table 1). Immunosuppressive therapy was also not different between groups (p NS for tacrolimus, cyclosporine, azathriopine and mycophenolate mofetil). Immediate (post)operative outcome Warm ischemia time in the DCDs was 15 (IQR: 12 to 18, range 10 to 25) minutes. Cold ischemia times in the DBD group were 246 (218 to 280) minutes for the first and 384 (339 to 439) minutes for the second lung. In the DCD group these times were significantly longer: 297 (266 to 332) minutes and 435 (399 to 517) minutes for first and second lung, respectively (p and p 0.002) (Table 1). In the DCD group, 2 patients (10%) required cardiopulmonary support with extracorporeal membrane oxygenation (ECMO) during surgery vs 38 (25%) patients in the DBD group (p NS) (Table 2). Patients were extubated after 3 (1 to 7) days in the DBD group vs 3.5 (1 to 11) days in the DCD group. Patients in the DBD group were discharged from the ICU after 7 (3.5 to 14.5) days and from the hospital after 30 (24 to 42) days. In the DCD group, discharge from the ICU took place after 7 (5 to 19) days and from the hospital after 29 (23 to 42) days (p NS) (Table 2). PGD grades at the different time-points are plotted in Figure 1. PGD grades were not significantly different between groups at any of the measured time-points (T0 to T48). Notably, none of the DCD lung recipients developed a serious bronchial complication. Survival No significant difference in survival was found between the groups (Figure 2A). Actuarial survival rates at 6 months, 1 year and 3 years are 95%, 95% and 71% for the DCD group and 96%, 91% and 75% for the DBD group. In the DCD group 2 patients have died (10%): 1 patient died after 90 days in the ICU due to multiple complications, and the other died after 1,005 days as a result of BOS after a second LTx for BOS. In the DBD group 23 patients (15%) have died after a median of 282 (129 to 469) days. Six of these Table 2 Patient Outcome patients died due to infections, 5 as a consequence of BOS, 2 from recurrent AR, 3 from tumors, 2 from pulmonary embolism and the others due to various reasons (1 each of acute respiratory distress syndrome, pulmonary bleeding, cerebrovascular accident, heart failure and colon perforation). In the DBD group, 88 patients completed 18 months of follow-up, 10 of whom died within this period; in the DCD group, 7 patients completed 18 months of follow-up, 1 of whom died. BOS and FEV 1 evolution DBD DCD (n 154) (n 21) p-value Immediate (post)operative outcome Use of bypass 38 (25%) 2 (10%) 0.11 Extubation (days) 3 (1 7) 4 (1 11) 0.27 ICU stay (days) 7 (4 15) 7 (5 19) 0.32 Hospital stay (days) 30 (24 42) 29 (23 42) 0.84 FEV 1 Before LTx % 26 (21 35) 26 (20 37) 0.92 Days before 101 (39 234) 89 (47 199) 0.56 Best after LTx % 93 (75 112) 94 (78 106) 0.42 Days after 240 (85 480) 121 (70 229) 0.16 Increase (%) 60 (39 86) 64 (38 85) 0.52 Acute rejection grade A1 37 (24%) 3 (14%) 0.32 A2 18 (12%) 1 (5%) 0.34 A3 2 (1%) B1 27 (18%) 3 (14%) 0.71 B2 18 (12%) 2 (10%) 0.78 B3 6 (4%) 1 (5%) 0.85 DBD, donation after brain death; DCD, donation after cardiac death; FEV 1, forced expiratory volume in 1 second; ICU, intensive care unit; LTx, lung transplantation. In the DCD group, 3 patients (14%) developed BOS after a median of 328 days (IQR could not be measured with 3 patients). In the DBD group, 15 patients (almost 10%) developed BOS after a median of 480 (257 to 652) days. These differences were not statistically significant (p 0.16) (Figure 2B). FEV 1 measurements before LTx were not different between the groups: 26% (21% to 35%) for the DBD and 26% (20% to 37%) for the DCD recipients. These were measured 101 (39 to 234) days and 89 (47 to 199) days before LTx, respectively (p NS). Best FEV 1 after LTx was not different either, with a median of 93% (75 to 112) for the DBD group and 94% (78 to 106) for the DCD group. Best measurements were recorded after 240 (85 to 480) days and 121 (70 to 229) days, respectively (p NS). FEV 1 increased by 60% (39% to 86%) in the DBD group and by 64% (38% to 85%) in the DCD group (p NS) (Table 2).

5 De Vleeschauwer et al. Medium-term Outcome After DCD LTx 979 Figure 1 Primary graft dysfunction. Proportions of the different PGD grades at 0, 12, 24 and 48 hours after transplantantion in DBD recipients (A) and DCD recipients (B). No significant differences were found. AR episodes In the DBD group, 37 patients had (at least) 1 episode of Grade A1 AR, 18 patients had Grade A2 AR, and 2 patients had Grade A3 AR. In the DCD group, 3 patients each had 1 episode of AR Grade A1 and 1 patient had an episode of Grade A2 AR. These differences were not significant (p 0.32, p 0.34 and p 0.60, respectively). In the DBD group, 27 patients had at least 1 episode of Grade B1, 18 had Grade B2 and 6 had Grade B3 rejection. In the DCD group the corresponding numbers included 3 patients with Grade B1, 2 with Grade B2 and 1 with Grade B3 rejection. Again, these differences were not significant (p 0.71, p 0.78 and p 0.85, respectively) (Table 2). Inflammatory parameters Percentages of neutrophils in BAL at the different timepoints did not differ between groups, although the percentage was high in the DCD group at 540 days (p NS). Also, CRP measurements in blood at these different time-points did not differ. Neutrophil percentages and CRP measurements are plotted in Figure 3. Discussion This retrospective study has demonstrated that outcomes of Category III DCD lung recipients are comparable to those of DBD recipients both in the early post-operative phase, with similar PGD grades, post-operative discharge, and FEV 1 increase, and in the medium term, with no differences in AR, BOS and survival between groups. These results confirm the initial findings reported by our and other centers. DCD lungs can therefore be used safely to expand the donor pool. The number of reports on early outcome in DCD LTx recipients increased considerably with more and more centers reporting their initial experiences More recently, the number of full reports has augmented. Mason et al reported their initial experience in 4 patients with a follow-up between 4 and 34 months. 16 The Melbourne group reported donor characteristics and outcome in 8 patients. 15 In Canada, 10 LTxs from 9 DCD donors were performed, resulting in 90% survival after a median of 270 days. 18 In none of these reports, however, was outcome compared with that of DBD LTx recipients. Only 3 groups have so far compared cohorts of DCD and DBD lung recipients. The St. Louis group transplanted lungs from 11 DCD donors over a period of 5 years. 12 Only donors that met standard criteria were used and lungs were implanted in patients with low peri-operative risk only. During the 18-month follow-up there was higher peri-operative mortality compared with recipients of conventional donors. BOS stages were described for the DCD recipients, but BOS prevalence was not compared with that for DBD recipients. The Groningen group reported on 35 DCD LTxs over a period of 4 years. 14 Initially, only conventional donors were selected, but later extended criteria donors were also used. After a median Figure 2 Survival (A) and freedom from BOS (B) in both donor groups. Data under the figures represent the number of patients evaluated at each time-point. No significant differences were found.

6 980 The Journal of Heart and Lung Transplantation, Vol 30, No 9, September 2011 Figure 3 Inflammatory markers. Percentage of neutrophils in BAL (A) and levels of CRP (B) at different post-operative days (POD) in DBD and DCD recipients. Data under the figures represent the number of samples available at each time-point. No significant differences were found. follow-up of 15 months in their initial study of 21 patients no differences were found between groups with regard to survival and BOS. However, in the more recent study including 35 patients, a lower incidence of BOS was seen in the DCD recipients and no differences in survival were found. The Wisconsin group assigned DCD lungs only to patients who would not survive otherwise while waiting for a conventional donor. Eighteen LTxs were performed from DCDs over a period of 16 years with a median follow-up of 1,380 days, 13 No differences in survival and BOS incidence were found. Our results confirm the equally good outcome of DCD LTx recipients. Nevertheless, some remarkable differences could be seen between our findings and those of other centers. Rates of DCD/DBD differ considerably between centers. At our center, 21 of 175 (12%) of LTx were performed with lungs from DCDs. In The Netherlands this figure was 24%, yet in the other centers it was considerably lower (St. Louis 3.8%, Wisconsin 4.3%, Canada 4.3%, Cleveland 2%). Another difference from other centers was the length of warm ischemia. At our center, warm ischemia, defined as the time between complete cardiac arrest and cold flush, was only 15 minutes, whereas this was about 30 to 60 minutes at other centers. This disparity may be explained by a different definition of warm ischemia being used. 26 The cold ischemia time in our cohort was significantly longer for DCD donors. This can be explained in part by the allocation rules in Eurotransplant where DCD lungs are not offered until 4 hours before the planned donor procedure. This sometimes created logistical problems with operating rooms not available to start anesthesia on the recipient in a timely fashion. Moreover, DBD lungs are usually evaluated/accepted about 30 minutes before cold flush, whereas in DCD donors the decision to accept lungs is usually made after cold flush and thorough inspection of the lungs and therefore at a later stage, resulting in delayed onset of anesthesia in the recipient. Despite warm ischemia and longer cold ischemia, PGD and immediate post-operative outcome were not worse than in the DBD recipients. This should not be surprising because brain death itself may cause lung injury by changes in systemic blood pressure, due to a sympathetic storm and changes in the vasomotor tone, and the release of pro-inflammatory cytokines, finally leading to neurogenic pulmonary edema. 27 To our knowledge, we are the first group to compare inflammatory parameters, both locally in BAL and systemically in serum, between DBD and DCD groups. BAL neutrophilia has always been associated with BOS, 28 but recently it has been shown that BAL neutrophilia is not present in all BOS patients, leading to a distinction between two BOS phenotypes depending on BAL neutrophilia and reversibility on azithromycin therapy. 29 BOS patients have also been found to have elevated CRP levels that predicted graft failure. 30 In this study we found that evolution of inflammatory parameters, on the systemic and local level, was the same in both groups. Although BAL neutrophilia was high at 540 days in the DCD group, this could be attributed to one of the patients having developed neutrophilic reversible allograft dysfunction. This was treated with azithromycin leading to complete resolution of BAL neutrophilia. 29 In our previous case control study of the first 5 DCD recipients at our center, 19 we reported that DCD recipients were extubated earlier, had fewer infections, and had a greater increase in FEV 1, with values higher during the first 6 months, although statistically not different. Patients in the DCD group were discharged sooner from the ICU and from the hospital, and CRP values after LTx returned to normal more rapidly than in DBD recipients. More DCD recipients had Grade 3 PGD, especially in the first hours after LTx, but with fast recovery in the course of 48 hours. 19 These differences were no longer seen in the present study including larger numbers. We are not the first to report outcomes in DCD lung recipients; however, because this approach is still considered innovative, reporting single-center series may contribute to the worldwide experience. Our study has some limitations. Although the data were collected prospectively, the study is retrospective. Some data, especially PO 2 and/or FIO 2, were missing in some patients at some time-points and were excluded from the analyses. There were no differences between groups in demographics, except for OB, with more patients transplanted for OB in the DCD group. We do not believe that this difference between groups

7 De Vleeschauwer et al. Medium-term Outcome After DCD LTx 981 influenced our results. Another limitation is the short follow-up period, especially in DCD recipients. Although no differences were identified in actuarial survival, longer follow-up until death is needed to compare actual survival between groups. Our results confirm that DCD LTx recipients have a comparable short- and medium-term outcome when compared with DBD LTx recipients. DCDs can therefore be used safely to expand the lung donor pool. Disclosure statement This study was presented in part at the 31st annual meeting and scientific sessions of the International Society for Heart and Lung Transplantation, April 2011, San Diego, California. The authors thank the other staff members of the Department of Thoracic Surgery (Dr Coosemans, Dr Decaluwe, Dr De Leyn, Dr Nafteux) and Dr Neyrinck from the Department of Anesthesiology, for their important contributions to this work. D.v.R. was supported by grants from the Research Foundation (FWO) of Flanders (G.3C04.99). G.M.V. was supported by grants from the KUL (OT/050/10) and the FWO of Flanders (G and G ). None of the authors have any conflicts of interest to disclose. References 1. Hardy JD, Webb WR, Dalton ML Jr, et al. Lung homotransplantation in man. JAMA 1963;186: Van Raemdonck DE, Jannis NC, De Leyn PR, et al. Warm ischemic tolerance in collapsed pulmonary grafts is limited to 1 hour. Ann Surg 1998;228: Van Raemdonck DE, Rega FR, Neyrinck AP, et al. Non-heart-beating donors. Semin Thorac Cardiovasc Surg 2004;16: Love RB, Stringham JC, Chomiak PN, et al. Successful lung transplantation using a non-heart-beating donor. J Heart Lung Transplant 1995;14:S Steen S, Sjoberg T, Pierre L, et al. Transplantation of lungs from a non-heart-beating donor. Lancet 2001;357: Kootstra G, Daemen JH, Oomen AP. Categories of non-heart-beating donors. Transplant Proc 1995;27: de Antonio DG, Marcos R, Laporta R, et al. Results of clinical lung transplant from uncontrolled non heart-beating donors. J Heart Lung Transplant 2007;26: Christie JD, Edwards LB, Kucheryavaya AY, et al. The registry of the International Society for Heart and Lung Transplantation: twentyseventh official adult lung and heart lung transplant report J Heart Lung Transplant 2010;29: Butt T, Aitchison J, Corris P, et al. Lung transplantation from deceased donors without pretreatment. J Heart Lung Transplant 2007;26(suppl): S Ahmed IM, Yap M, Hamilton A, et al. Preliminary outcomes after lung transplantation from donors with cardiac death. J Heart Lung Transplant 2009;28(suppl):S Haj-Yahia S, Bahrami T, Khaghani A, et al. Lung transplantation from non heart beating donors: the Harefield Experience. J Heart Lung Transplant 2009;28(suppl):S Puri V, Scavuzzo M, Guthrie T, et al. Lung transplantation and donation after cardiac death: a single center experience. Ann Thorac Surg 2009;88: De Oliveira NC, Osaki S, Maloney JD, et al. Lung transplantation with donation after cardiac death donors: long-term follow-up in a single center. J Thorac Cardiovasc Surg 2010;139: Van De Wauwer C, Verschuuren EA, van der Bij W, et al. The use of non-heart-beating lung donors category III can increase the donor pool. Eur J Cardiothorac Surg 2011;39: Snell GI, Levvey BJ, Oto T, et al. Early lung transplantation success utilizing controlled donation after cardiac death donors. Am J Transplant 2008;8: Mason DP, Murthy SC, Gonzalez-Stawinski GV, et al. Early experience with lung transplantation using donors after cardiac death. J Heart Lung Transplant 2008;27: Mason DP, Thuita L, Alster JM, et al. Should lung transplantation be performed using donation after cardiac death? The United States experience. J Thorac Cardiovasc Surg 2008;136: Cypel M, Sato M, Yildirim E, et al. Initial experience with lung donation after cardiocirculatory death in Canada. J Heart Lung Transplant 2009;28: De Vleeschauwer S, Van Raemdonck D, Vanaudenaerde B, et al. Early outcome after lung transplantation from non-heart-beating donors is comparable to heart-beating donors. J Heart Lung Transplant 2009; 28: Orens JB, Boehler A, de Perrot M, et al. A review of lung transplant donor acceptability criteria. J Heart Lung Transplant 2003;22: Estenne M, Maurer JR, Boehler A, et al. Bronchiolitis obliterans syndrome 2001: an update of the diagnostic criteria. J Heart Lung Transplant 2002;21: Christie JD, Carby M, Bag R, et al. Report of the ISHLT working group on Primary Lung Graft Dysfunction part II: definition. A consensus statement of the International Society for Heart and Lung Transplantation. J Heart Lung Transplant 2005;24: Standardization of spirometry 1987 update. Statement of the American Thoracic Society. Am Rev Respir Dis 1987;136: Vanaudenaerde BM, Wuyts WA, Geudens N, et al. Broncho-alveolar lavage fluid recovery correlates with airway neutrophilia in lung transplant patients. Respir Med 2008;102: Yousem SA, Berry GJ, Cagle PT, et al. Revision of the 1990 working formulation for the classification of pulmonary allograft rejection. J Heart Lung Transplant 1996;15: Levvey BJ, Westall GP, Kotsimbos T, et al. Definitions of warm ischemic time when using controlled donation after cardiac death lung donors. Transplantation 2008;86: Avlonitis VS, Fisher AJ, Kirby JA, et al. Pulmonary transplantation: the role of brain death in donor lung injury. Transplantation 2003;75: DiGiovine B, Lynch JP III, Martinez FJ, et al. Bronchoalveolar lavage neutrophilia is associated with obliterative bronchiolitis after lung transplantation: role of IL-8. J Immunol 1996;157: Vanaudenaerde BM, Meyts I, Vos R, et al. A dichotomy in bronchiolitis obliterans syndrome after lung transplantation revealed by azithromycin therapy. Eur Respir J 2008;32: Vos R, Vanaudenaerde BM, De Vleeschauwer SI, et al. Circulating and intrapulmonary C-reactive protein: a predictor of bronchiolitis obliterans syndrome and pulmonary allograft outcome. J Heart Lung Transplant 2009;28: