The magnitude of inspiratory effort relief within the first 2 hours of non-invasive ventilation for hypoxic respiratory failure was shown in a recent exploratory clinical study to be an early and accurate predictor of outcome at 24 hours. We simulated the application of non-invasive ventilation to three patients whose physiological and clinical characteristics match the data in that study. Reductions in inspiratory effort corresponding to reductions of esophageal pressure swing greater than 10 cmH2O more than halved the values of total lung stress, driving pressure, power and transpulmonary pressure swing. In the absence of significant reductions in inspiratory pressure, multiple indicators of lung injury increased after application of non-invasive ventilation. Clinical Relevance- We show using computer simulation that reduced inspiratory pressure after application of noninvasive ventilation translates directly into large reductions in multiple well-established indicators of lung injury, providing a potential physiological explanation for recent clinical findings.