ObjectiveWe report the evolution of severe ventilator-induced lung injury associated with lethal systemic capillary leak syndrome, when sheep were ventilated at a peak inspiratory pressure of 50 cm H2O, at a respiratory rate of 8 breaths·min−1, with an inspiratory time of 2.5 secs.DesignA prospective laboratory animal study.SettingExperimental animal research laboratory.SubjectsMixed breed sheep.InterventionsSheep were anesthetized, paralyzed, and mechanically ventilated.Measurements and Main ResultsThis sheep model was characterized by a rapidly evolving massive anasarca, hemoconcentration, cardiac dysfunction, multiple system organ failure, and severe ventilator-induced lung injury. Cardiovascular changes and profound hemoconcentration developed within 6 hrs from the start of mechanical ventilation, along with a major decline in pulmonary compliance and deterioration in arterial blood gases. When total static lung compliance decreased to 0.15 mL (cm H2O)−1·kg−1(7–30 hrs), the sheep were randomized to two groups. Group I received high (recruitive) positive end-expiratory pressure (9–20 cm H2O), adjusted as needed; group II received low (supportive) positive end-expiratory pressure (2–6 cm H2O). Sheep in both groups progressively deteriorated and died with cardiocirculatory failure and multiple system organ failure within 12–24 hrs from start of treatment.ConclusionsThis model of lethal systemic capillary leak syndrome with multiple system organ failure differs greatly from our previous sheep model of acute ventilator-induced lung injury in which sheep were ventilated with a peak inspiratory pressure of 50 cm H2O, a respiratory rate of 4 breaths·min−1, and an inspiratory time of 1.35 secs, without inducing capillary leak syndrome. The mere change of respiratory rate from 4 to 8 breaths·min−1, with a near doubling of the inspiratory time to 2.5 secs, although maintaining eucapnia, resulted in lethal systemic capillary leak syndrome and multiple system organ failure with both gross and microscopic pathology of lungs greatly different from our previous model of mechanical ventilation-induced acute respiratory distress syndrome.