Study objectiveMultifactorial comparison of flow-controlled ventilation (FCV) to standard of pressure-controlled ventilation (PCV) in terms of oxygenation in cardiac surgery patients after chest closure. DesignProspective, non-blinded, randomized, controlled trial. SettingOperating theatre at an university hospital, Austria. PatientsPatients scheduled for elective, open, on-pump, cardiac surgery. InterventionsParticipants were randomized to either individualized FCV (compliance guided end-expiratory and peak pressure setting) or control of PCV (compliance guided end-expiratory pressure setting and tidal volume of 6–8 ml/kg) for the duration of surgery. MeasurementsThe primary outcome measure was oxygenation (PaO2/FiO2) 15 min after intraoperative chest closure. Secondary endpoints included CO2-removal assessed as required minute volume to achieve normocapnia and lung tissue aeration assessed by Hounsfield unit distribution in postoperative computed tomography scans. Main resultsBetween April 2020 and April 2021 56 patients were enrolled and 50 included in the primary analysis (mean age 70 years, 38 (76%) men). Oxygenation, assessed by PaO2/FiO2, was significantly higher in the FCV group (n = 24) compared to the control group (PCV, n = 26) (356 vs. 309, median difference (MD) 46 (95% CI 3 to 90) mmHg; p = 0.038). Additionally, the minute volume required to obtain normocapnia was significantly lower in the FCV group (4.0 vs. 6.1, MD -2.0 (95% CI -2.5 to ‐1.5) l/min; p < 0.001) and correlated with a significantly lower exposure to mechanical power (5.1 vs. 9.8, MD -5.1 (95% CI -6.2 to ‐4.0) J/min; p < 0.001). Evaluation of lung tissue aeration revealed a significantly reduced amount of non-aerated lung tissue in FCV compared to PCV (5 vs. 7, MD -3 (95% CI -4 to ‐1) %; p < 0.001). ConclusionsIn patients undergoing on-pump, cardiac surgery individualized FCV significantly improved oxygenation and lung tissue aeration compared to PCV. In addition, carbon dioxide removal was accomplished at a lower minute volume leading to reduced applied mechanical power.