ObjectivesTo investigate the settings necessary to achieve maximum gas exchange and pulmonary function while minimizing effects on cardiovascular hemodynamics during total liquid ventilation with a pressure-limited, time-cycled ventilator in a rat model.DesignProspective, randomized controlled animal study.SettingA university research laboratory.SubjectsMale Sprague-Dawley rats (n = 48).InterventionsAll animals had a tracheostomy tube designed for total liquid ventilation placed under anesthesia. The carotid artery was cannulated for blood pressure monitoring and for assessing blood gas data.Measurements and Main ResultsForty 492 ± 33 g rats were assigned to one of four inspiratory/expiratory ratio groups (inspiratory/expiratory ratio of 1:2, 1:2.5, 1:3, and 1:4). Total liquid ventilation was performed with a pressure-limited, time-cycled total liquid ventilator. Outcome measures were evaluated as a function of respiratory rate and included tidal volume, maximal alveolar ventilation, inspiratory and expiratory mean arterial pressures, the difference of mean arterial pressure between the inspiratory and expiratory phase, static end-inspiratory/expiratory pressures, Paco2, Pao2, tidal volume + approximate expiratory reserve volume, and lung volume-induced suppression of mean arterial pressure. Maximal alveolar ventilation increased and decreased in parabolic fashion as a function of respiratory rate and was maximal at rates of 4.3–6.8 breaths/min and high inspiratory/expiratory ratios that corroborated with optimal levels of Pao2and Paco2. Lung overdistention occurred at high respiratory rates and high inspiratory/expiratory ratios. Deleterious effects were observed on the difference of mean arterial pressure between the inspiratory and expiratory phase during total liquid ventilation at low respiratory rates, apparently due to increased tidal volume, and on suppression of mean arterial pressure at high inspiratory/expiratory ratios and high respiratory rate apparently due to “auto-positive end-expiratory pressure.” These effects were minimized in this model at respiratory rates ≥5.7 and ≤6.8 breaths/min and inspiratory/expiratory ratios ≤1:2.5. These settings were successfully tested in eight additional animals.ConclusionThese data demonstrate the feasibility of performing total liquid ventilation in rodents. A balance must be identified where gas exchange is optimal yet hemodynamics are least affected. In the specific system studied, an inspiratory/expiratory ratio of 1:2.5 and respiratory rate of 6.8 breaths/min appeared to provide optimal gas exchange while minimizing the effects on hemodynamics.