Functional outcomes and quality of life after normothermic ex vivo lung perfusion lung transplantation

Functional outcomes and quality of life after normothermic ex vivo lung perfusion lung transplantation

Author's Accepted Manuscript Functional Outcomes and Quality of Life After Normothermic Ex Vivo Lung Perfusion Lung Transplantation J.M. Tikkanen, M...

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Author's Accepted Manuscript

Functional Outcomes and Quality of Life After Normothermic Ex Vivo Lung Perfusion Lung Transplantation J.M. Tikkanen, M. Cypel, T.N. Machuca, S. Azad, M. Binnie, C.W. Chow, C. Chaparro, M. Hutcheon, K. Yasufuku, M. de Perrot, A.F. Pierre, T.K. Waddell, S. Keshavjee, L.G. Singer http://www.jhltonline.org

PII: DOI: Reference:

S1053-2498(14)01416-8 http://dx.doi.org/10.1016/j.healun.2014.09.044 HEALUN5886

To appear in:

J Heart Lung Transplant

Cite this article as: J.M. Tikkanen, M. Cypel, T.N. Machuca, S. Azad, M. Binnie, C.W. Chow, C. Chaparro, M. Hutcheon, K. Yasufuku, M. de Perrot, A.F. Pierre, T.K. Waddell, S. Keshavjee, L.G. Singer, Functional Outcomes and Quality of Life After Normothermic Ex Vivo Lung Perfusion Lung Transplantation, J Heart Lung Transplant, http://dx.doi.org/10.1016/j.healun.2014.09.044 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Functional Outcomes and Quality of Life After Normothermic Ex Vivo Lung Perfusion Lung Transplantation Tikkanen JM, Cypel M, Machuca TN, Azad S, Binnie M, Chow CW, Chaparro C, Hutcheon M, Yasufuku K, de Perrot M, Pierre AF, Waddell TK, Keshavjee S, Singer LG. Toronto Lung Transplant Program, University Health Network, University of Toronto, ON, Canada.

Corresponding author: Lianne Singer, Medical Director, Toronto Lung Transplant Program, Toronto General Hospital, 585 University Avenue, 11 PMB 134, Toronto, ON Canada M5G 2N2. Email: [email protected]

Abstract Background Ex vivo lung perfusion (EVLP) is an effective method to assess and improve function of otherwise unacceptable lungs, alleviating the shortage of donor lungs. The early results with EVLP have been encouraging, but longer term results, including functional and patient-reported outcomes, are not well characterized. Methods This retrospective single-center study included all lung transplants performed between September 2008 and December 2012. We investigated whether recipients of EVLPtreated lungs had differences in survival or rate of chronic lung allograft dysfunction (CLAD) compared to contemporaneous recipients of conventional donor lungs. We also studied functional (highest FEV1 predicted, change in 6MWD, number of acute rejection episodes) and quality of life outcomes. Results Altogether 403 lung transplants were performed. 63 (15.6%) underwent EVLP. Allograft survival for EVLP- and conventional donor lung recipients was 79% vs. 85%, 71% vs. 73% and 58% vs. 57% at 1-, 3-, and 5-years post-transplant, respectively (log-rank P=NS). Freedom from CLAD was also similar (log-rank P=0.53). There were no significant differences in functional outcomes such as highest FEV1 predicted (76.5±23.8% vs. 75.8±22.8%, P=0.85), change in 6MWD (194m±108m vs. 183m±126m, P=0.57), or the number of acute rejection episodes (1.5±1.4 vs. 1.3±1.3, P=0.36). Both EVLP- and conventional donor group reported a significantly improved quality of life after transplantation but there was no intergroup difference.

Conclusion EVLP is a safe and effective method of assessing and utilizing high risk donor lungs prior to transplantation leading to acceptable long-term survival, graft function and improvements of quality of life which are comparable to conventionally selected donor lungs.

Introduction Although the number of lung transplants performed world-wide has steadily increased (1), the number of patients on the waiting list still exceeds the number of available donor lungs and many patients unfortunately die while waiting for lung transplantation (2). One of the major factors limiting the use of potential donor lungs is that only around 15% of lungs from multi-organ donors are used for transplantation (3, 4). The majority of potential donor lungs are considered unsuitable due to lung injury occurring after brain death and to complications associated with treatment in the intensive care unit such as barotrauma, infection, and pulmonary edema. To address this issue, our program developed and implemented a strategy of ex vivo lung perfusion (EVLP) to better assess and treat those donor lungs that do not meet optimal donor lung criteria (5). The high-risk lungs from brain death and cardiac death donors were placed on the EVLP-circuit for 4-6 hours and the oxygenation, pulmonary vascular resistance, dynamic compliance, and peak inspiratory pressure were evaluated hourly. Our criteria for transplantation included stability or improvement of lung function during EVLP period. Using this strategy, we were able to demonstrate that the recipients of EVLP-treated lung allografts had similar rates of primary graft dysfunction and 30-day mortality compared to recipients of conventional donor lungs (5, 6). The early encouraging results have led to increasing use of EVLP world-wide (7, 8). Although we have shown comparable results with EVLP in the short term, the impact of EVLP-treatment on long term effects in lung transplant recipients is unknown. We hypothesized that long-term outcomes of EVLP-treated lung allograft recipients are at least similar to recipients of conventional donor lungs. In addition to survival and chronic lung allograft dysfunction, we assessed functional and quality-of-life outcomes of EVLPtreated lung allograft recipients. Methods Study design This is a single-center retrospective study. Outcomes of consecutive recipients undergoing transplantation after normothermic EVLP of high-risk donor lungs were compared with those of contemporaneous conventional donor lung recipients. The UHN REB approved this retrospective study of longer term outcomes. We assessed all lung transplants performed between September 2008 and December 2012. Recipients for any available donor lungs, whether conventional or EVLP, were selected

on the basis of blood type, size of the organ (total lung capacity), and waiting-list status, in keeping with our usual practice. After the lungs were transplanted, standard care was provided in both groups, including fluid management, antimicrobial prophylaxis, immunosuppression, and surveillance bronchoscopy according to the current Toronto Lung Transplant Program protocol (9).

Inclusion and exclusion criteria Donors High-risk donor lungs eligible for EVLP were defined as those meeting any one of the following criteria (5, 6): best ratio of the partial pressure of arterial oxygen (PaO2) to FiO2 of less than 300 mm Hg; pulmonary edema, defined as bilateral interstitial infiltrates without evidence of infection, detected on the last chest radiograph by the lungtransplant physician assessing the donor; poor lung deflation or inflation during direct intraoperative visual examination at the donor site and other concerning donor risk factors such as blood transfusions exceeding 10 units. In the early part of our study (2008-2010) we routinely placed donation after cardiac death (DCD) donor lungs on EVLP. From 2011 onwards with accumulating experience and international data supporting safety of using DCD donors, we placed DCD donors on EVLP only if they were extended criteria or if interval from withdrawal of life support therapies and cardiac arrest was higher than 60min. DCD-donors were defined by Maastricht category III or category IV (10). Donor lungs with established pneumonia, severe mechanical lung injury (i.e., contusions in more than one lobe), or gross gastric aspiration were excluded. Normothermic EVLP The methodology of normothermic EVLP has been published in detail (5). In brief, lungs are initially flush preserved with a cold Perfadex flush. After transportation to our Organ Repair Laboratory at Toronto General Hospital, the lungs were transferred to the EVLP chamber (XVIVO Perfusion Inc., Colorado, USA). The pulmonary artery and left atrium were cannulated and connected to the circuit and anterograde flow was started at 150 mL/min with the perfusate at room temperature. The temperature of the perfusate was then gradually increased to 37°C. When 32°C was reached, ventilation was initiated and the perfusate flow rate was gradually increased to a target maintenance flow of 40% of the calculated donor cardiac output. The flow of gas used to deoxygenate and provide carbon dioxide to the inflow perfusate via a gas exchange membrane was then initiated at 1 L/min. Mean pulmonary artery pressures were maintained between 7 and 15 mm Hg. A positive left atrial pressure was maintained between 3 and 5 mm Hg. A protective mode of mechanical ventilation was applied using a tidal volume of 7 mL/kg (based on donor ideal body weight) at 7 breaths/min, positive end expiratory pressure of 5 cmH2O, and FiO2 of 21%. The lungs were recruited with inspiratory holds to a peak airway pressure of 20 cmH2O every hour. For the evaluation of lung function, FiO2 was increased to 100%, tidal volumes were increased to 10 mL/kg, and respiratory rate was increased to 10 breaths/min for 5 minutes. The pH, pCO2, electrolytes, and glucose were maintained at physiologic levels in the perfusate. At the end of EVLP, the lung was cooled down in

the circuit to 10°C for a 10-15 minute period. Thereafter, perfusion and ventilation were stopped (FiO2 was increased to 50% for lung storage), and the trachea was clamped to maintain the lungs in an inflated state. The lungs were then statically preserved at 4°C in Perfadex until transplantation. Recipients All patients who underwent single or bilateral lung transplantation (including retransplant) between September 2008 and December 2012 were included. Patients who underwent combined heart–lung transplantation were excluded. We included all patients bridged for transplantation with invasive mechanical ventilation or extracorporeal life support (ECLS). Study end points The primary end points of this study were allograft survival (freedom from retransplantation and death from all causes) and development of chronic allograft dysfunction (freedom from CLAD). CLAD was defined according to the ISHLT criteria for diagnosis of bronchiolitis obliterans syndrome (BOS1 or higher) on the basis of forced expiratory volume in one second (FEV1) and each patient that met this criteria for BOS was screened by two independent authors (JMT, LGS) to confirm the diagnosis. The secondary end points were highest FEV1% of predicted, number of biopsy-proven acute rejection episodes in the first post-operative year and change in the 6 minute walk distance (6MWD) after transplantation. For the quality of life studies, we included data for a subset of patients who had also participated in a prospective cohort study of health-related quality of life (HRQL) in advanced lung disease and lung transplantation, and for whom we had both pre- and posttransplant data available. For patients with multiple HRQL assessments, we used the pretransplant HRQL assessment closest to the transplant date, and the first post-transplant health-related quality of life (HRQL) assessment, done at 3-12 months post-transplant. HRQL was studied using an interactive, internet-based questionnaire (11). Initial HRQL assessments were self-completed in clinic, whereas subsequent assessments were either done in clinic or from home. Assessments were not performed during hospital admission. The questionnaire included a disease-specific health index, the St. George’s Respiratory Questionnaire (SGRQ) (12) and a generic health index, Medical Outcomes Study 36Item Short Form Health Survey (SF-36) (13).The SGRQ has three domains: symptoms, activity, and impacts, as well as a total score. Scores range from 0 to 100, with higher scores indicating worse HRQL. For SF-36, a higher score signifies better HRQL. The SF36 includes 8 domains as well as physical and mental component summary scores (PCS, MCS), and a global rating of change. The PCS and MCS are normalized to a mean score of 50.

Statistics All statistical analyses were performed by using SPSS 21 (IBM, NY, USA) with results expressed as means +/- standard deviations. Numerical data was compared using Student’s T Test and Fisher’s exact test was used to compare categorical data. Survival and freedom from CLAD analyses were performed using log rank. P<0.05 was considered as statistically significant. Results From September 2008 to December 2012, a total of 403 lung transplants were performed. Of these, 63 (15.6%) were treated with EVLP and the 340 remaining patients formed the conventional donor lung arm. The study layout is presented in Figure 1. Donor demographics The donor demographics are presented in Table 1. There were no statistically significant differences in donor gender, age, chest x-ray abnormalities, smoking history, or bronchoscopic culture findings, but as expected, the peak PaO2/FiO2-ratio of the EVLPdonor lungs was significantly worse than in the conventional donor group. There were significantly more DCD donors in the EVLP-group. Table 2 shows detailed donor characteristics of our EVLP-cohort. Recipient demographics The recipient demographics are shown in Table 3. The recipient sex, age, preoperative diagnosis, and preoperative bridging to transplant were similar between EVLP and conventional donor groups. However, there were significantly more single-lung transplants in the EVLP-group (23.8% vs. 13.2%, P=0.028). Recipient outcomes The survival of recipients receiving EVLP-donor lungs was comparable to that of recipients of conventional donor lungs (Figure 2A). As there was a difference in the number of single-lung transplants between the groups, we also investigated the survival of single lung transplants (SLT) and bilateral lung transplant (BLT) patients separately. (Figure 2B,C). There was also a significant difference in the use of DCD donors between the EVLP group and conventional donor group as most DCD donor lungs undergo EVLP in our program. Again, no significant differences in survival were noted between the EVLP group and conventional donor group when we compared survival in recipients of donation after neurologic determination of death (NDD) or DCD lungs (Figure 2D,E). Our second end-point was development of chronic lung allograft dysfunction (CLAD). The rate of CLAD was similar between the EVLP group and the conventional donor group (Figure 3A). When we evaluated SLT and BLT recipients separately, CLAD-free survival remained similar between EVLP and conventional donor groups (Figure 3B,C).

CLAD-free survival was significantly better in the EVLP group compared to conventional donor group in patients receiving NDD lungs (P=0.03) with only one out of the 37 patients developing CLAD. There was no significant difference in CLAD rates of DCD donor recipients (Figure 3D,E). The number of acute rejection episodes in the first postoperative year, the maximum change in the 6MWD between pre- and post-transplant, and the highest FEV1/predicted FEV1 achieved after lung transplant were similar between EVLP- and conventional donor groups (Table 4). Quality of life Both EVLP- and conventional donor lung recipients showed a clear and significant improvement in both mental and physical aspects in their quality of life after transplantation compared to pre-transplant levels. There were no differences in quality of life improvement between EVLP and conventional lung groups (Figure 4).

Discussion We have previously shown that EVLP allows an advanced objective assessment and improvement of high-risk donor lungs without negatively impacting short-term recipient outcomes. Currently, 15-20% of our donor lungs come through EVLP, making it an integral part of our transplant program. The use of EVLP has also allowed our program to expand our donor pool and our annual number of lung transplants has steadily increased. This study expands on our prior reports of short-term outcomes, representing the longest follow-up and largest sample size so far in this patient group. We show here that in addition to survival, the rate of CLAD as well as functional and quality-of-life outcomes of recipients of EVLP-donor lungs are comparable to those attained by recipients of conventional donor lungs. The donor lungs in the EVLP-group had either impaired gas exchange or other concerning features that prevented the transplant team from using the lungs directly. Most of the NDD donors belonging to the EVLP group would have been rejected if not for the availability of EVLP at our center. Additionally, in the early part of our experience, all DCD-donor lungs were placed on EVLP as we felt that DCD-donor lungs were less predictable than conventional donor lungs. With increasing experience with DCD donors and the accumulating literature showing equal outcomes using DCD and NDD donors (14), we did not routinely place all DCD donor lungs on EVLP after 2011. However we still have a lower threshold to re-evaluate those organs prior to transplant. In accordance with our short-term follow up studies (5, 6, 15), we did not observe any difference in long-term outcomes when the DCD and NDD donor groups were separately compared between the conventional donor and EVLP-groups.

One interesting difference between the EVLP and conventional donor groups was that there were significantly more SLT-patients in the EVLP-group compared to conventional donor group (24% vs. 13%). This reflects the fact that EVLP treatment allowed us to salvage at least one lung from an otherwise unacceptable donor in many cases. The outcomes were not affected by the increased rate of SLT in the EVLP group in any way. In this report we have included all consecutive transplants performed – including the nearly 10% of recognized higher risk patients bridged to transplant with either invasive ventilation and/or ECLS in this study. As the EVLP-group tended to have more bridged patients than the conventional donor group, it was by no means a privileged group (Table 2). Although the early outcomes including rate of primary graft dysfunction, early hospital and ICU stay, bronchial complications, and mortality have been reported to be similar between EVLP and conventional donor groups (5,6), there is uncertainty whether using high-risk donor lungs undergoing EVLP might lead to inferior long term outcomes. In this study, we show that the rate of acute rejection, peak pulmonary function after transplantation, and change in 6MWD are all similar between EVLP and conventional donor groups. Also, freedom from CLAD and allograft failure were very similar. Remarkably, only one 1/37 patients receiving EVLP-treated NDD donor lungs developed CLAD during the follow-up and there was a significant difference in CLAD-free survival between the conventional NDD donor and EVLP-treated NDD donor groups (Figure 3D). The true significance of this finding is still unclear and may be due to a type 1 error. Further studies and follow-up are required to assess the effect of EVLP on BOS development in the setting of NDD donor lungs. . The subset of patients who answered the health-related quality of life questionnaires showed a marked improvement of their quality of life in both groups after lung transplantation without intergroup differences. Because HRQL assessment was not initially planned in the evaluation of EVLP, we only have HRQL data for a limited number of patients. As HRQL was only studied in stable outpatients, we acknowledge that the HRQL benefits may be somewhat overestimated, but are nonetheless dramatic. We have previously shown very large HRQL benefits of lung transplantation even after assignment of the worst possible HRQL scores to patients with missing HRQL data (16). This study provides additional evidence that EVLP is a safe and effective method to evaluate potential donor lungs and improve donor lung utilization for successful transplantation. Our program is aggressive in using donor lungs and we currently accept lungs from 40% of the multiorgan donors offered. This is a significantly higher rate than the approximately 15% reported in the lung transplant literature (3,4). Although there is an international trend to use more marginal donors, it is often difficult to predict the outcome of transplantation of a marginal donor. EVLP allows the surgeons to further test and improve function of questionable lungs and to follow the trajectory of the performance of these lungs prior to making the decision to transplant. The number of lung transplants in our center has risen from 82 in 2008 to 133 in 2013 without any substantial increase in the number of multiorgan donors in our province, and we believe that EVLP has played an integral part in our increased acceptance rates.

In addition to being a tool to evaluate potential donor lungs, EVLP has potential to be much more than a diagnostic tool alone. EVLP allows direct manipulation of the lung allograft in a very controlled environment. One can administer targeted therapies either intra-bronchially or intravascularly to the lungs without systemic side effects. For instance, intra-tracheal gene delivery via viral vectors has been shown to be feasible in experimental models of lung transplantation (17-20) but also to have less associated systemic inflammation if administered during EVLP compared to a conventional in vivo setting (21). Therefore, it is possible that in the near future in addition to increasing the donor pool, we will be able to actively recondition and/or treat donor lungs during EVLP and thereby improve post-transplant outcomes. In conclusion, normothermic EVLP assessment and treatment of donor lungs is associated with survival, functional and HRQL benefits which are equivalent to the outcomes achieved with conventional donor lungs. . Conflicts of interest: S Keshavjee, M Cypel and T Waddell Disclosures: Founding members of Perfusix Canada Inc, Perfusix USA Inc, and XOR Labs Toronto Inc.

Acknowledgements: The primary author (JM Tikkanen) received personal grants from the Biomedicum Foundation, Helsinki, Finland and Jane and Aatos Erkko Foundation, Helsinki, Finland to support research work abroad. Both foundations are non-profit organizations without any commercial interest in EVLP or lung transplantation. The health-related quality of life substudy was funded by grants from the Canadian Institutes for Health Research, the Physicians’ Services Inc. Foundation and the Canadian Lung Transplant Study Group.

References 1. Yusen RD, Christie JD, Edwards LB, et al.: The Registry of the International Society for Heart and Lung Transplantation: thirtieth adult lung and heart-lung transplant report--2013; focus theme: age. J Heart Lung Transplant 2013;32:965-78. 2. Valapour M, Paulson K, Smith JM, et al.: OPTN/SRTR 2011 Annual Data Report: lung. Am J Transplant 2013;13 Suppl 1:149-77. 3. Klein AS, Messersmith EE, Ratner LE, Kochik R, Baliga PK, Ojo AO: Organ donation and utilization in the United States, 1999-2008. Am J Transplant 2010;10:97386.

4. Israni AK, Zaun D, Rosendale JD, Snyder JJ, Kasiske BL: OPTN/SRTR 2012 Annual Data Report: deceased organ donation. Am J Transplant 2014;14 Suppl 1:167-83. 5. Cypel M, Yeung JC, Liu M, et al.: Normothermic ex vivo lung perfusion in clinical lung transplantation. N Engl J Med 2011;364:1431-40. 6. Cypel M, Yeung JC, Machuca T, et al.: Experience with the first 50 ex vivo lung perfusions in clinical transplantation. J Thorac Cardiovasc Surg 2012;144:1200-6. 7. Aigner C, Slama A, Hotzenecker K, et al.: Clinical ex vivo lung perfusion-pushing the limits. Am J Transplant 2012;12:1839-47. 8. Wallinder A, Ricksten SE, Silverborn M, et al.: Early results in transplantation of initially rejected donor lungs after ex vivo lung perfusion: a case-control study. Eur J Cardiothorac Surg 2013. 9. de Perrot M, Chaparro C, McRae K, et al.: Twenty-year experience of lung transplantation at a single center: Influence of recipient diagnosis on long-term survival. J Thorac Cardiovasc Surg 2004;127:1493-501. 10. 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;139:1306-15. 11. Bhinder S, Chowdhury N, Granton J, et al.: Feasibility of internet-based healthrelated quality of life data collection in a large patient cohort. J Med Internet Res 2010;12:e35. 12. Jones PW, Quirk FH, Baveystock CM, Littlejohns P: A self-complete measure of health status for chronic airflow limitation. The St. George's Respiratory Questionnaire. Am Rev Respir Dis 1992;145:1321-7. 13. Ware JE, Jr., Gandek B: Overview of the SF-36 Health Survey and the International Quality of Life Assessment (IQOLA) Project. J Clin Epidemiol 1998;51:903-12. 14. Levvey BJ, Harkess M, Hopkins P, et al. Excellent clinical outcomes from a national donation-after-determination-of-cardiac-death lung transplant collaborative. Am J Transplant. 2012;12(9):2406-13. 15. Cypel M, Sato M, Yildirim E, et al.: Initial experience with lung donation after cardiocirculatory death in Canada. J Heart Lung Transplant 2009;28:753-8. 16. Eskander A, Waddell TK, Faughnan ME, Chowdhury N, Singer LG: BODE index and quality of life in advanced chronic obstructive pulmonary disease before and after lung transplantation. J Heart Lung Transplant 2011;30:1334-41. 17. Fischer S, Liu M, MacLean AA, et al.: In vivo transtracheal adenovirus-mediated transfer of human interleukin-10 gene to donor lungs ameliorates ischemia-reperfusion injury and improves early posttransplant graft function in the rat. Hum Gene Ther 2001;12:1513-26. 18. Krebs R, Tikkanen JM, Nykanen AI, et al.: Dual role of vascular endothelial growth factor in experimental obliterative bronchiolitis. Am J Respir Crit Care Med 2005;171:1421-9. 19. Martins S, de Perrot M, Imai Y, et al.: Transbronchial administration of adenoviral-mediated interleukin-10 gene to the donor improves function in a pig lung transplant model. Gene Ther 2004;11:1786-96. 20. Cypel M, Liu M, Rubacha M, et al.: Functional repair of human donor lungs by IL-10 gene therapy. Sci Transl Med 2009;1:4ra9.

21. Yeung JC, Wagnetz D, Cypel M, et al.: Ex vivo adenoviral vector gene delivery results in decreased vector-associated inflammation pre- and post-lung transplantation in the pig. Mol Ther 2012;20:1204-11. Legends to Figures Figure 1. Study layout Altogether 413 donor lungs were accepted after initial assessment by our surgical team for either direct transplantation (conventional donor group, n=340) or for EVLP (n=73). After EVLP, ten (14%) donor lungs were rejected and 63 (86%) went on to be transplanted. The groups were further categorized according to whether the lungs came from donors after cardiac death (DCD) or after neurological determination of death (NDD). Figure 2. The effect of EVLP-treatment on freedom from death or retransplantation Figure 2A: Kaplan-Meier curves depicting the freedom from death or retransplantation of patients receiving EVLP-treated lungs compared to recipients of conventional donor lungs in the whole study cohort. The Y-axis depicts the proportion of patients free from death or retransplant and the X-axis shows days post-transplant. The number of patients at risk is shown below the X-axis at yearly time points. Log-rank analyses were used to determine statistical significance. Figure 2B: Analysis with single-lung transplanted patients only. Figure 2C: Analysis in bilateral transplant recipients. Figure 2D: Freedom from death or retransplantation in recipients of lungs from donors after neurological determination of death (NDD) Figure 2E: Freedom from death or retransplantation in recipients of donors after cardiac death (DCD)

Figure 3. The effect of EVLP-treatment on freedom from chronic lung allograft dysfunction (CLAD) Figure 3A: Kaplan-Meier curves depicting the freedom from CLAD in patients receiving EVLP-treated lungs compared to recipients of conventional donor lungs in the whole study cohort. The Y-axis depicts the proportion of patients free from CLAD and the Xaxis shows days post-transplant. The number of patients at risk is shown below the Xaxis at yearly time points. Figure 3B: Freedom from CLAD in single-lung transplant recipients only.

Figure 3C: Freedom from CLAD in bilateral transplant recipients. Figure 3D: Freedom from CLAD in recipients of lungs from donors after neurological determination of death (NDD). Figure 3E: Freedom from CLAD in recipients of lungs from donors after cardiac death (DCD). Log-rank analyses were used to determine statistical significance. Figure 4. The effect of EVLP-treatment on change in quality of life after lung transplantation Medical Outcomes Study 36- Item Short Form Health Survey (SF-36) and the St. George’s Respiratory Questionnaire (SGRQ) were used to compare the change of lung transplant recipients` quality of life after transplantation. The mean changes between the pre- and post-transplant quality of life measurements are shown. For SF-36, a higher score signifies better QOL. The SF-36 includes 8 domains as well as physical and mental component summary scores (PCS, MCS), and a global rating of change. The PCS and MCS are normalized to a mean score of 50. The SGRQ has three domains: symptoms, activity, and impacts, as well as a total score. Scores range from 0 to 100, with higher scores indicating worse HRQL. Black bars show 95% confidence interval. N=66 in control group, n=17 in EVLP group.

Table 1. Donor demographics Donor

EVLP (n=63)

EVLP

EVLP

All

NDD (n=36)

DCD (n=27)

Conventional Conv. Conv. PDonors donors Donors value (n=340) All NDD DCD (n=322) (n=18)

Gender (female/male) Age (years) (mean ± SD) Best PaO2:FiO2 while in donor (mean ± SD) Abnormal chest radiograph (n,%) Positive smoking history (n,%)

31/32

18/18

13/14

180/160

34 (54%) 17 (52%) 14 (58%) 163 (48%)

147 7 (39%) 0.22 (48%)

Positive BAL culture (n,%)

46 (73%) 24 (67%) 22 (81%) 197 (58%)

185 12 (57%) (67%)

0.08

DCD donor (n,%)

27 (43%) N/A

N/A

<0.001

171/151 9/9

0.34

43.1±14.9 42.4±15.344.0±14.5 45.8±17.6

46.1±1740.5±19 0.25

384±102 368±99

456±77 451±66 <0.001

406±105 456±76

39 (62%) 23 (69%) 9 (50%)

N/A

170 (50%)

18 (5%)

148 10 (50%) (56%)

N/A

0.09

Abbreviations: BAL, bronchoalveloar lavage; DCD, donor after cardiac death. Numerical data was compared using Student’s T Test and Fisher’s exact test was used to compare categorical data between EVLP and conventional donor groups.

Table 3. Recipient demographics Recipient

EVLP (n=63)

Conventional donors (n=340)

P-value

Gender (female/male)

32/31

141/199

0.11

Age (years, mean ± SD)

50.3±14.6

52.3±14.2

0.29

Pulmonary fibrosis

22 (35%)

121 (36%)

0.65

COPD/emphysema

20 (32%)

90 (26%)

Cystic fibrosis

14 (22%)

67 (20%)

Pulmonary arterial Hypertension

3 (5%)

14 (4%)

Retransplantation

1 (2%)

14 (4%)

Other

3 (5%)

34 (10%)

Total

63 (100%)

340 (100%)

Mechanical ventilation

6 (10%)

19 (6%)

0.18

ECLS

4 (6%)

13 (4%)

0.27

Bilateral lung

48 (76.1%)

295 (86.7%)

0.028

Single lung

15 (23.8%)

45 (13.2%)

Diagnosis (n,%)

Bridge to transplant (n,%)

Transplantation (n,%)

Abbreviations: ECLS, extracorporeal life support. Numerical data was compared using Student’s T Test and Fisher’s exact test was used to compare categorical data.

Table 4. Recipient outcomes

NO. acute rejections in first postoperative year (A1+)

Conventional n donors

EVLP

n

1.5±1.4

49 1.3±1.3

Maximum change in 6MWD (metres, pre vs post194m±108m 48 183m±126m transplant) Highest predicted FEV1 (only DBLTx)

76.5±23.8%

51 75.8±22.8%

Significance

277 P=0.36

284 P=0.57

291 P=0.85

Abbreviations: 6MWD, 6-minute walking distance; FEV1, forced expiratory volume in one second; DBLTx, double lung transplantation. Acute rejection episodes were defined as biopsy-confirmed grade A1 or higher rejection. The change in 6MWD was determined using the last available distance pretransplant and comparing it with the highest recorded distance post-transplant. Single-lung transplant recipients were excluded from the highest predicted FEV1 as there was a significant difference in the proportion of single-lung transplant recipients between the conventional donor and EVLP-groups.

Table 2. Detailed demographics for EVLP-donors Dono r Age

Donor Gende r

36 56 57 20 69 20 22 48 45 68

Dono r type

Donor Smoke r

Type of Tx

P/F ratio upon arriva l

Last P/F ratio prior to explan t

Abnorma l CXR

Femal e

NDD

Yes

BLT

473

374

No

Yes

Male

DCD

Yes

BLT

505

No

Yes

NDD

No

BLT

439

430

No

No

NDD

No

BLT

106

322

Yes

Yes

NDD

No

BLT

233

304

Yes

Yes

DCD

Yes

BLT

355

286

Yes

Yes

DCD

No

RSL T

385

380

No

Yes

DCD prior to 2011

NDD

No

BLT

300

460

No

Yes

Severe erythema, purulent secretions in BAL

DCD

Yes

BLT

492

No

No

DCD prior to 2011

DCD

No

BLT

334

No

No

DCD prior to 2011

NDD

No

LSL T

NDD

No

DCD

Yes

RSL T BLT

Femal e Femal e Male Femal e Femal e Femal e Femal e Femal e

523

Positiv e BAL Culture

Comments

Worsening gases, pilot DCD prior to 2011, pilot Pilot Atelectasis on the right, pilot Perihilar edema Worsening gases, contusion

40

Femal e Male

23

Male

NDD

No

BLT

160

533

Yes

Yes

27

Femal e

NDD

Yes

RSL T

282

159

Yes

Yes

38

Male

NDD

No

BLT

469

450

No

No

49

Male

NDD

No

BLT

507

498

Yes

Yes

59 16

DCD DCD

Yes Yes

BLT BLT

506 549

462 532

No No

No Yes

DCD

No

BLT

Yes

DCD prior to 2011

42

Male Male Femal e Male

Diffuse infiltrates on the right, impaired gas exchange Worsening gases, bilateral contusions DCD prior to 2011 Lower lobe atelectasis, diffuse edema Worsening gases, left side contusion Bilateral pulmonary emboli and cardiac arrest prior to death Diffuse edema on the left DCD prior to 2011 DCD prior to 2011

DCD

Yes

BLT

59

195

Yes

54

Male

NDD

Yes

RSL T

100

100

DCD prior to 2011 Diffuse edema bilaterally, impaired gas exchange

21

17

20

Femal e

252

275

Yes

Yes

540

254

Yes

Yes

No

Yes

479

Yes

Yes

59 33 49

Male Femal e Femal e

NDD

Yes

BLT

117

268

Yes

No

DCD

Unkn

BLT

458

328

No

Yes

DCD

Unkn

BLT

355

450

No

Yes

21

Male

NDD

No

BLT

226

199

Yes

No

48

Femal e

NDD

Yes

RSL T

419

291

Yes

No

32

Femal e

NDD

Yes

BLT

175

323

Yes

No

57

Femal e

DCD

No

LSL T

143

Yes

Yes

54

Male

DCD

No

BLT

340

315

Yes

Yes

44

Femal e

NDD

No

BLT

325

318

Yes

Yes

31

Male

DCD

Yes

BLT

351

249

Yes

Yes

63

Male

NDD

Yes

BLT

351

335

Yes

Yes

54

Femal e

NDD

Yes

BLT

408

270

No

No

49

Male

NDD

Yes

BLT

314

465

Yes

No

25

Femal e

NDD

Yes

BLT

395

Yes

Yes

41

Femal e

DCD

Yes

BLT

49

Male

DCD

Yes

RSL T

40

Femal e

NDD

Yes

BLT

490

320

No

Yes

Yes

Yes

No

RML atelectasis, impaired gas exchange Worsening gases, DCD Bilateral purulent secretions Worsening gases, diffuse infiltrates on CXR bilaterally, purulent secretions Purulent secretions, worsening gas exchange LLL atelectasis and purulent secretions on the left RLL atelectasis, impaired gas exchange Worsening gases, LLL atelectasis Diffuse bilateral infiltrates on CXR Worsening gases, Right-side infiltrate in CXR LLL atelectasis and purulent secretions on the left Worsening gases Diffuse edema and purulent secretions in BAL RLL infiltrate and purulent secretions Bile contents during bronchoscopy, heavy lower lobes, arterial blood gases on PEEP 8 Prolonged ischemia time (West coast), CXR infiltrates Multiple rib fractures, RLL contusion/laceratio n

61 64 19

Femal e Male Femal e

DCD

No

BLT

472

371

No

NDD

Yes

341

No

Yes

NDD

No

BLT RSL T

506

No

Yes

Yes

No

53

Femal e

NDD

Yes

RSL T

269

321

59

Male

NDD

No

BLT

311

350

38

Male

NDD

Yes

BLT

379

279

46

Male

DCD

No

BLT

188

418

Yes

45

Male

DCD

No

449

477

Yes

45

Male

DCD

No

449

477

Yes

56

Male

DCD

No

BLT

314

57

Femal e

NDD

Yes

BLT

346

37

Femal e

DCD

Yes

BLT

338

59

Femal e

DCD

Yes

BLT

397

30

Male

NDD

Yes

BLT

297

48

Male

NDD

No

BLT

60

Femal e

DCD

Yes

BLT

16

Femal e

NDD

No

LSL T

53

Femal e

DCD

Yes

LSL T

131

23

Male

DCD

Yes

BLT

373

52

Male

NDD

Unkn

BLT

129

44

Male

NDD

No

BLT

49

Male

NDD

Yes

63

Male

NDD

No

BLT RSL T

LSL T RSL T

No

Yes

Yes

Yes

Yes

Yes

301

Yes

No

305

Yes

Yes

340

Yes

No

252

Yes

Yes

280

314

Bilateral purulent secretions LLL atelectasis and purulent secretions on the left

Yes

Yes

527

Worsening gases

Yes

Worsening gases, purulent secretions Unwitnessed arrest?15 min CPR WLST to flush = 100 min WLST to flush = 100 min Diffuse erythema, purulent secretions Bilateral CXR infiltrates, bronchial erythema, purulent secretions Diffuse R infiltrates in CXR, purulent secretions Worsening gases Diffuse L infiltrates in CXR, purulent secretions Bilateral edema, CXR infiltrates RLL atelectasis, impaired gas exchange Prolonged ischemia time (West coast), low P/F ratio, RL extensive contusions

Yes

No

LLL atelectasis

Yes

Yes

LLL infiltrate on CXR

349

No

Yes

120

280

No

Yes

266

378

Yes

Yes

314

204

Yes

Yes

Impaired gas exchange, purulent secretions Left atelectasis RLL atelectasis, worsening gas

42

Femal e

NDD

Yes

BLT

307

239

No

No

exchange Worsening gas exchange, signs of aspiration, purulent secretions

Donor age is expressed in years. Donor smoking history was obtained from local medical personnel and family members. The P/F ratio was measured on FiO2 1.0 and the results shown are the first obtained value after our team arrived as well as the last value obtained prior to explant. A BAL culture was deemed positive if there was significant growth of a pathogenic species, samples growing only commensal flora or a non-pathogen are marked as negative. The first for donor lungs were part of our pilot EVLP-group and the three first patients had a shorter duration of EVLP than the others in this cohort. Prior to 2011, our group routinely put DCD lungs on EVLP but thereafter only when other clinical concerns were present. The clinical concerns from donor team notes are shown in the comments column. Abbreviations: NDD, neurological determination of death; DCD, donor after cardiac death; Tx, transplantation; BLT, bilateral transplantation; LSLT/RSLT, left or right single lung transplantation; CXR, chest X-ray; LLL,RLL, left/right lower lobe; WLST, withdrawal of life-sustaining therapy.

Figure 1.

Potentialdonorlungs n=413

Conventional donorgroup n=340(82%)

DCDdonors n=18(5%)

NDDdonors n=322(95%)

EVLPtreatment n=73(18%)

EVLPgroup n=63(86%)

DCDdonors n=27(43%)

Discarded Lungsn=10(14%)

NDDdonors n=36(57%)

Figure 2. A

B

C

D

E

Figure 3. A

B

C

D

E

Figure e 4.

SF36PCS

SF36M MCS

SGRQ