Time to generate ventilator-induced lung injury among mammals with healthy lungs: A unifying hypothesis

Purpose: To investigate ventilator-induced lung injury (VILI), several experimental models were designed including different mammalian species and ventilator settings, leading to a large variability in the observed time-course and injury severity. We hypothesized that the time-course of VILI may be fully explained from a single perspective when considering the insult actually applied, i.e. lung stress and strain. Methods: Studies in which healthy animals were aggressively ventilated until preterminal VILI were selected via a Medline search. Data on morphometry, ventilator settings, respiratory function and duration of ventilation were derived. For each animal group, lung stress (transpulmonary pressure) and strain (end-inspiratory lung inflation/lung resting volume ratio) were estimated. Results: From the Medline search 20 studies including five mammalian species (sheep, pigs, rabbits, rats, mice) were selected. Time to achieve preterminal VILI varied widely (18-2,784 min), did not correlate with either tidal volume (expressed in relation to body weight) or airway pressure applied, but was weakly associated with lung stress (r ² = 0.25, p = 0.008). In contrast, the duration of mechanical ventilation was closely correlated with both lung strain (r ² = 0.85, p <0.0001) and lung strain weighted for the actual time of application during each breath (r ² = 0.83, p <0.0001), according to exponential decay functions. When it was normalized for the lung strain applied, larger species showed a greater resistance to VILI than smaller species (medians, 25th-75th percentiles: 690, 460-2,001 min vs. 16, 4-59 min, respectively; p <0.001). Conclusion: Lung strain may play a critical role as a unifying rule describing the development of VILI among mammals with healthy lungs.