One-hit Models of Ventilator-induced Lung Injury

Background One important explanation for the detrimental effects of conventional mechanical ventilation is the biotrauma hypothesis that ventilation may trigger proinflammatory responses that subsequently cause lung injury. This hypothesis has frequently been studied in so-called one-hit models (overventilation of healthy lungs) that so far have failed to establish an unequivocal link between inflammation and hypoxemic lung failure. This study was designed to develop a one-hit biotrauma model. Methods Mice (six per group) were ventilated for up to 7 h (positive end-expiratory pressure 2 cm H2O) and received 300 μl/h fluid support. Series_1: initial plateau pressures of 10, 24, 27, or 30 cm H2O. Series_2: ventilation with pressure release at 34 cm H2O and initial plateau pressure of 10, 24, 27, or 30 cm H2O. To study the significance of inflammation, the latter groups were also pretreated with the steroid dexamethasone. Results Within 7 h, 20 of 24 mice ventilated with plateau pressure of 27 cm H2O or more died of a catastrophic lung failure characterized by strongly increased proinflammatory markers and a precipitous decrease in pulmonary compliance, blood pressure, and oxygenation. Pretreatment with dexamethasone reduced inflammation, but prolonged median survival time by 30 min. Conclusions Our findings demonstrate a sharp distinction between ventilation with 24 cm H2O that was well tolerated and ventilation with 27 cm H2O that was lethal for most animals due to catastrophic lung failure. In the former case, inflammation was benign and in the latter, a by-product that only accelerated lung failure. The authors suggest that biotrauma—when defined as a ventilation-induced and inflammation-dependent hypoxemia—is difficult to study in murine one-hit models of ventilation, at least not within 7 h. (Anesthesiology 2017; 126:909-22)