Mild Permissive Alkalosis Improves Outcomes in Porcine Negative Pressure Ventilation Ex-Situ Lung Perfusion

•Refinement of ESLP methodology is essential to optimize the clinical and research applications of this technology: Mild permissive alkalosis porcine NPV-ESLP demonstrated more reliable preservation with reduced inflammation compared to a physiologic pH strategy.•Here we demonstrate that manipulation of key variables in ex-situ organ perfusion to intentionally deviate from physiologic targets may in select instances improve organ function and preservation beyond a steadfast replication of normal physiology, which is the standard approach in ESLP.•The increased stability of ESLP lung function with the strategic application of mild permissive alkalosis during preservation has allowed our lab to achieve reliable, continuous ESLP of 36-hours. This is essential for the prolong dwell-time required for advanced therapeutics to improve marginal quality donor lungs and increase the donor pool of useable organs for transplant. Ex-Situ Lung Perfusion (ESLP) employs a membrane deoxygenator and mixed (N2/O2/CO2) or pure sweep gas (CO2) to target venous blood gas composition with physiologic pCO2 and pH. Clinically, mild permissive alkalosis counteracts elevated pulmonary vascular resistance (PVR) to improve perfusion. Increased PVR and pulmonary artery pressure (PAP) during ESLP mirrors rising pro-inflammatory cytokines. Increased hydrostatic pressure worsens edema and lung function. We report improved ESLP outcomes using mild permissive alkalosis. Twelve juvenile pig lungs underwent 12-hour Negative Pressure Ventilation (NPV)-ESLP with a physiologic pH (Control: pH 7.35-7.45, n=6) or mild permissive alkalosis (pH+: pH 7.45-7.55, n=6) by varying sweep CO2 delivery. Three left lungs per group were transplanted and assessed over 4-hours. Five Control lungs failed on ESLP due to high PAPs, low compliance, and poor oxygenation. Repeat Controls (n=6) were performed to attain 12-hours of ESLP. There were no failures in the pH+ group. Results are pH+ vs Control. Oxygenation (PaO2/FiO2 454.2 vs 438.2; P = .37) and dynamic compliance (21.38 vs 22.22 mL/cmH2O; P = .41) were stable over 12-hour NPV-ESLP. Mean evaluation pH/pCO2/HCO3- was 7.50/15.6/14.5 vs 7.41/38.7/24.7. Control lungs required repeat THAM and milrinone boluses on ESLP to prevent acidosis and treat elevated PVR; this was not necessary in the pH+ group. Weight-gain/hour was similar (1.23% vs 1.38%; P = .37). Mean left lung PF ratios 4-hours post-transplantation were 301 mmHg vs 196 mmHg (P = .11). Control TNF-⍺ and