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Background: Ultra-protective lung ventilation in acute respiratory distress syndrome or early weaning and/or avoidance of mechanical ventilation in decompensated chronic obstructive pulmonary disease may be facilitated by the use of extracorporeal CO2 removal (ECCO2R). We tested the CO2 removal performance of a new ECCO2R (CO2RESET) device in an experimental animal model. Methods: Three healthy pigs were mechanically ventilated and connected to the CO2RESET device (surface area = 1.8 m2, EUROSETS S.r.l., Medolla, Italy). Respiratory settings were adjusted to induce respiratory acidosis with the adjunct of an external source of pure CO2 (target pre membrane lung venous PCO2 (PpreCO2): 80–120 mmHg). The amount of CO2 removed (VCO2, mL/min) by the membrane lung was assessed directly by the ECCO2R device. Results: Before the initiation of ECCO2R, the median PpreCO2 was 102.50 (95.30–118.20) mmHg. Using fixed incremental steps of the sweep gas flow and maintaining a fixed blood flow of 600 mL/min, VCO2 progressively increased from 0 mL/min (gas flow of 0 mL/min) to 170.00 (160.00–200.00) mL/min at a gas flow of 10 L/min. In particular, a high increase of VCO2 was observed increasing the gas flow from 0 to 2 L/min, then, VCO2 tended to progressively achieve a steady-state for higher gas flows. No animal or pump complications were observed. Conclusions: Medium-flow ECCO2R devices with a blood flow of 600 mL/min and a high surface membrane lung (1.8 m2) provided a high VCO2 using moderate sweep gas flows (i.e., >2 L/min) in an experimental swine models with healthy lungs. [ABSTRACT FROM AUTHOR]