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The selection of mechanical ventilator settings that ensure adequate oxygenation and carbon dioxide clearance while minimizing the risk of ventilator-associated lung injury (VALI) is a significant challenge for intensive-care clinicians. Current guidelines are largely based on previous experience combined with recommendations from a limited number of in vivo studies whose data are typically more applicable to populations than to individuals suffering from particular diseases of the lung. By combining validated computational models of pulmonary pathophysiology with global optimization algorithms, we generate in silico experiments to examine current practice and uncover optimal combinations of ventilator settings for individual patient and disease states. Formulating the problem as a multiobjective, multivariable constrained optimization problem, we compute settings of tidal volume, ventilation rate, inspiratory/expiratory ratio, positive end-expiratory pressure and inspired fraction of oxygen that optimally manage the tradeoffs between ensuring adequate oxygenation and carbon dioxide clearance and minimizing the risk of VALI for different pulmonary disease scenarios.