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Introduction The objective was to study the effects of a novel lung volume optimization procedure (LVOP) using highfrequency oscillatory ventilation (HFOV) upon gas exchange, the transpulmonary pressure (TPP), and hemodynamics in a porcine model of surfactant depletion. Methods With institutional review board approval, the hemodynamics, blood gas analysis, TPP, and pulmonary shunt fraction were obtained in six anesthetized pigs before and after saline lung lavage. Measurements were acquired during pressure-controlled ventilation (PCV) prior to and after lung damage, and during a LVOP with HFOV. The LVOP comprised a recruitment maneuver with a continuous distending pressure (CDP) of 45 mbar for 2.5 minutes, and a stepwise decrease of the CDP (5 mbar every 5 minute) from 45 to 20 mbar. The TPP level was identified during the decrease in CDP, which assured a change of the PaO2/FIO2 ratio < 25% compared with maximum lung recruitment at CDP of 45 mbar (CDP45). Data are presented as the median (25th–75th percentile); differences between measurements are determined by Friedman repeated-measures analysis on ranks and multiple comparisons (Tukey's test). The level of significance was set at P < 0.05. Results The PaO2/FiO2 ratio increased from 99.1 (56.2–128) Torr at PCV post-lavage to 621 (619.4–660.3) Torr at CDP45 (CDP45) (P < 0.031). The pulmonary shunt fraction decreased from 51.8% (49–55%) at PCV post-lavage to 1.03% (0.4–3%) at CDP45 (P < 0.05). The cardiac output and stroke volume decreased at CDP45 (P < 0.05) compared with PCV, whereas the heart rate, mean arterial pressure, and intrathoracic blood volume remained unchanged. A TPP of 25.5 (17–32) mbar was required to preserve a difference in PaO2/FIO2 ratio < 25% related to CDP45; this TPP was achieved at a CDP of 35 (25– 40) mbar. Conclusion This HFOV protocol is easy to perform, and allows a fast determination of an adequate TPP level that preserves oxygenation. Systemic hemodynamics, as a measure of safety, showed no relevant deterioration throughout the procedure.