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Atelectasis develops in critically ill obese patients when undergoing mechanical ventilation due to increased pleural pressure. The current study aimed to determine the relationship between transpulmonary pressure, lung mechanics, and lung morphology and to quantify the benefits of a decremental positive end-expiratory pressure trial preceded by a recruitment maneuver.Prospective, crossover, nonrandomized interventional study.Medical and Surgical Intensive Care Units at Massachusetts General Hospital (Boston, MA) and University Animal Research Laboratory (São Paulo, Brazil).Critically ill obese patients with acute respiratory failure and anesthetized swine.Clinical data from 16 mechanically ventilated critically ill obese patients were analyzed. An animal model of obesity with reversible atelectasis was developed by placing fluid filled bags on the abdomen to describe changes of lung mechanics, lung morphology, and pulmonary hemodynamics in 10 swine.In obese patients (body mass index, 48 ± 11 kg/m2), 21.7 ± 3.7 cm H2O of positive end-expiratory pressure resulted in the lowest elastance of the respiratory system (18.6 ± 6.1 cm H2O/L) after a recruitment maneuver and decremental positive end-expiratory pressure and corresponded to a positive (2.1 ± 2.2 cm H2O) end-expiratory transpulmonary pressure. Ventilation at lowest elastance positive end-expiratory pressure preceded by a recruitment maneuver restored end-expiratory lung volume (30.4 ± 9.1 mL/kg ideal body weight) and oxygenation (273.4 ± 72.1 mm Hg). In the swine model, lung collapse and intratidal recruitment/derecruitment occurred when the positive end-expiratory transpulmonary pressure decreased below 2–4 cm H2O. After the development of atelectasis, a decremental positive end-expiratory pressure trial preceded by lung recruitment identified the positive end-expiratory pressure level (17.4 ± 2.1 cm H2O) needed to restore poorly and nonaerated lung tissue, reestablishing lung elastance and oxygenation while avoiding increased pulmonary vascular resistance.In obesity, low-to-negative values of transpulmonary pressure predict lung collapse and intratidal recruitment/derecruitment. A decremental positive end-expiratory pressure trial preceded by a recruitment maneuver reverses atelectasis, improves lung mechanics, distribution of ventilation and oxygenation, and does not increase pulmonary vascular resistance.