A mechanical ventilator system configured to control positive end expiratory pressure (PEEP) in a subject, the mechanical ventilator system comprising: a pressure generator configured to generate a pressurized flow of breathable gas for delivery to an airway of the subject; one or more sensors configured to generate output signals conveying information related to breathing of the subject, wherein the information related to the breathing of the subject includes a flow rate of the pressurized flow of breathable gas Q and a pressure of breathable gas at a mouth of the subject P ao; and one or more hardware processors operatively coupled to the pressure generator and the one or more sensors configured by machine-readable instructions to: determine tidal volume and transpulmonary pressure of the subject based on the information in the output signals, wherein determining the transpulmonary pressure of the subject based on the information in the output signals comprises: modeling the lungs and chest wall as an elastic compartment served by a single resistive pathway; determining an airway resistance R and elasticity E based on Q and P ao; determining alveolar pressure P al and muscular pressure P mus in the subject based on R and E; and determining the transpulmonary pressure by subtracting P mus from P al; determine a target PEEP level based on lung volume and the transpulmonary pressure, the lung volume determined based on the tidal volume; and cause the pressure generator to adjust the pressurized flow of breathable gas to maintain the determined target PEEP level. a pressure generator configured to generate a pressurized flow of breathable gas for delivery to an airway of the subject; one or more sensors configured to generate output signals conveying information related to breathing of the subject, wherein the information related to the breathing of the subject includes a flow rate of the pressurized flow of breathable gas Q and a pressure of breathable gas at a mouth of the subject P ao; and one or more hardware processors operatively coupled to the pressure generator and the one or more sensors configured by machine-readable instructions to: determine tidal volume and transpulmonary pressure of the subject based on the information in the output signals, wherein determining the transpulmonary pressure of the subject based on the information in the output signals comprises: modeling the lungs and chest wall as an elastic compartment served by a single resistive pathway; determining an airway resistance R and elasticity E based on Q and P ao; determining alveolar pressure P al and muscular pressure P mus in the subject based on R and E; and determining the transpulmonary pressure by subtracting P mus from P al; determine a target PEEP level based on lung volume and the transpulmonary pressure, the lung volume determined based on the tidal volume; and cause the pressure generator to adjust the pressurized flow of breathable gas to maintain the determined target PEEP level. determine tidal volume and transpulmonary pressure of the subject based on the information in the output signals, wherein determining the transpulmonary pressure of the subject based on the information in the output signals comprises: modeling the lungs and chest wall as an elastic compartment served by a single resistive pathway; determining an airway resistance R and elasticity E based on Q and P ao; determining alveolar pressure P al and muscular pressure P mus in the subject based on R and E; and determining the transpulmonary pressure by subtracting P mus from P al; determine a target PEEP level based on lung volume and the transpulmonary pressure, the lung volume determined based on the tidal volume; and cause the pressure generator to adjust the pressurized flow of breathable gas to maintain the determined target PEEP level.