1. Ex Vivo Lung Perfusion with Adenosine A2A Receptor Agonist Decreases Ischemia-Reperfusion Injury in Donation after Cardiac Death CE Wagner, NH Pope, EJ Charles, ME Huerter, MD Salmon, BT Carter, AK Sharma, MH Stoler, CL Lau, VE Laubach, IL Kron

2. The authors have no disclosures.

3. Background Number of patients on the lung transplant waiting list exceeds number of patients who undergo lung transplant Ex vivo lung perfusion (EVLP) has potential to expand donor lung pool – functional assessment of marginal donor lungs – isolated drug delivery without systemic effects Adenosine A2A receptor (A2AR) agonists have been shown to reduce ischemia-reperfusion (IR) injury after lung transplant

4. Current Study Purpose: determine outcomes after transplant of marginal donor lungs treated with an A2AR agonist during EVLP and reperfusion – Donation after cardiac death (DCD) donor lungs – Prolonged 12-hour cold preservation Porcine model Hypothesis: – A2AR agonist treatment during EVLP reduces IR injury – Continued A2AR agonist treatment during reperfusion further attenuates IR injury

5. Study Design Donor lungs… – procured from DCD donors after 15 min warm ischemia – preserved at 4°C for 12 hr – normothermic EVLP for 4 hr Left lungs transplanted and reperfused for 4 hr Animals randomized to 3 groups based on treatment with the A2AR agonist ATL-1223 (n=4/group) – DMSO: vehicle infusion during EVLP and reperfusion – ATL-E: ATL-1223 infusion during EVLP and vehicle infusion during reperfusion – ATL-E/R: ATL-1223 infusion during EVLP and reperfusion

6. Initial PaO2/FiO2 Ratios were Similar No difference in donor animal PaO2/FiO2 ratios – DMSO: 383.4 ± 83.7 mmHg – ATL-E: 492.1 ± 31.3 mmHg – ATL-E/R: 402.2 ± 32.9 mmHg

7. EVLP After each hour of EVLP, the following parameters were measured: – Peak airway pressure – Dynamic compliance – Pulmonary vascular resistance – PO2 gradient Clinical exclusion criteria after 4 hours of EVLP – >15% deterioration in airway pressure, compliance, and PVR – PO2 < 350 mmHg

8. Peak Airway Pressure during EVLP often Increased Peak airway pressure remained stable or worsened during EVLP in all donor lungs Percent change in peak airway pressure was often above the 15% threshold considered acceptable for clinical lung transplantation

9. Dynamic Compliance during EVLP often Decreased Dynamic compliance remained stable or worsened during EVLP in all donor lungs Percent change in dynamic compliance was often above the 15% threshold considered acceptable for clinical lung transplantation

10. Pulmonary Vascular Resistance during EVLP Increased Pulmonary vascular resistance worsened during EVLP in all donor lungs Percent change in pulmonary vascular resistance was often above the 15% threshold considered acceptable for clinical lung transplantation

11. PO2 Gradients during EVLP were Variable PO2 during EVLP was often below the 350 mmHg threshold considered acceptable for clinical lung transplantation – Every donor lung in this study would have been excluded clinically Peak airway pressure, dynamic compliance, pulmonary vascular resistance, and PO2 during EVLP were not predictive of final PaO2/FiO2 ratios

12. Final PaO2/FiO2 Ratios were Significantly Different Treated groups had significantly higher final PaO2/FiO2 ratios compared with the control group – DMSO: 84.8 ± 17.7 mmHg – ATL-E: 413.6 ± 18.8 mmHg – ATL-E/R: 430.1 ± 26.4 mmHg No difference in final PaO2/FiO2 ratios between treated groups

13. Conclusions IR injury is attenuated after transplant of DCD donor lungs preserved at 4°C for 12 hrs by treatment with an A2AR agonist during EVLP – Mechanism: inactivation of immune cells in the donor lung during EVLP – Clinical implications: Grade 3 PGD to Grade 1 PGD Lung function during EVLP does not predict lung function in the recipient Findings have potential to significantly expand the donor lung pool PGD GradePaO2/FiO2 RatioPulmonary Edema 0> 300 mmHgNo 1> 300 mmHgYes 2200-300 mmHgYes 3< 200 mmHgYes

14. Acknowledgements Mentors Irving Kron, MD Victor Laubach, PhD Christine Lau, MD, MBA Benjamin Kozower, MD, MPH Curtis Tribble, MD Technical Support Sheila Hammond Tony Herring Cindy Dodson Funding T32 HL007849 R01 HL130053