Background: Recent clinical studies have not shown an overall benefit of high-frequency oscillatory ventilation (HFOV), possibly due to injurious or non-individualized HFOV settings. We compared conventional HFOV (HFOV) settings with HFOV settings based on mean transpulmonary pressures (P) in an animal model of experimental acute respiratory distress syndrome (ARDS).Methods: ARDS was induced in eight pigs by intrabronchial installation of hydrochloric acid (0. 1 N, pH 1.1; 2.5 ml/kg body weight). The animals were initially ventilated in volume-controlled mode with low tidal volumes (6 ml kg) at three positive end-expiratory pressure (PEEP) levels (5, 10, 20 cmHO) followed by HFOV and then HFOV P each at PEEP 10 and 20. The continuous distending pressure (CDP) during HFOV was set at mean airway pressure plus 5 cmHO. For HFOV P it was set at mean P plus 5 cmHO. Baseline measurements were obtained before and after induction of ARDS under volume controlled ventilation with PEEP 5. The same measurements and computer tomography of the thorax were then performed under all ventilatory regimens at PEEP 10 and 20.Results: Cardiac output, stroke volume, mean arterial pressure and intrathoracic blood volume index were significantly higher during HFOV P than during HFOV at PEEP 20. Lung density, total lung volume, and normally and poorly aerated lung areas were significantly greater during HFOV, while there was less over-aerated lung tissue in HFOV P. The groups did not differ in oxygenation or extravascular lung water index.Conclusion: HFOV P is associated with less hemodynamic compromise and less pulmonary overdistension than HFOV. Despite the increase in non-ventilated lung areas, oxygenation improved with both regimens. An individualized approach with HFOV settings based on transpulmonary pressure could be a useful ventilatory strategy in patients with ARDS. Providing alveolar stabilization with HFOV while avoiding harmful distending pressures and pulmonary overdistension might be a key in the context of ventilator-induced lung injury.