Intrathoracic pressures at various levels of positive end-expiratory pressure (PEEP). P_Plat = plateau pressure, P_Pl = pleural pressure which is the esophageal pressure (P_eso), ΔP_A = transalveolar pressure. (A, B) PEEP = 15 cm H₂O. At end-exhalation (A), the PEEP of 15 cm H₂O is insufficient to counterbalance the pleural pressure of 22 cm H₂O leading to a transalveolar pressure of −7 cm H₂O which exerts a collapsing force on the lung and results in atelectasis. During an inspiratory hold (B), the plateau pressure of 25 cm H₂O offsets the pleural pressure of 24 cm H₂O and results in a transalveolar pressure of 1 cm H₂O just overcoming the collapsing force of the high pleural pressure during tidal breathing. At this level of PEEP, the low transalveolar pressure does not significantly change the pleural pressure, which remains stable during the tidal breath and therefore does not significantly alter venous return or cardiac output. (C, D) PEEP = 22 cm H₂O. At end-exhalation (C), the PEEP of 22 cm H₂O matches the pleural pressure of 22 cm H₂O, a transalveolar pressure of 0 cm H₂O prevents alveolar collapse. During an inspiratory hold (D), although the plateau pressure appears high at 35 cm H₂O, when counterbalanced by the pleural pressure of 24 cm H₂O, the transalveolar pressure is only 11 cm H₂O. This distending pressure on the lung does not create risk for volutrauma, and it does not affect the patient’s hemodynamics. (E, F) PEEP = 30 cm H₂O and increases pleural pressure. In this hypothetical scenario, at PEEP that exceeds pleural pressure, alveolar distention increases pleural pressure. At end-exhalation (E), the PEEP of 30 cm H₂O increases the pleural pressure to 26 cm H₂O. During an inspiratory hold (F), the plateau pressure of 50 cm H₂O increases pleural pressure to 30 cm H₂O. This increased pleural pressure impairs venous return, cardiac output, and cerebral perfusion pressure during the entire respiratory cycle.