ex vivo lung perfusion with adenosine a2a receptor agonist decreases ischemia-reperfusion injury in...

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

The authors have no disclosures.

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

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

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

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

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

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

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

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

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

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

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 Grade PaO2/FiO2 Ratio Pulmonary Edema

0 > 300 mmHg No

1 > 300 mmHg Yes

2 200-300 mmHg Yes

3 < 200 mmHg Yes

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