Invasive ventilation is a frequently applied intervention in intensive care unit (ICU) patients and is recognized as a potentially harmful intervention. This thesis contains a series of investigations that focus on ventilator management, positive end–expiratory pressure (PEEP), and mechanical power (MP) in intensive care unit (ICU) patients without acute respiratory distress syndrome (ARDS). Despite the absence of evidence for benefit of ventilation with high PEEP in patients without ARDS, high PEEP is increasingly used in these patients worldwide. A multicenter randomized controlled clinical trial tested whether use of a lower PEEP strategy was noninferior to a strategy with higher PEEP with respect to the composite endpoint of duration of ventilation and mortality. There were no differences in this composite endpoint and the secondary endpoints. These findings support the use of lower PEEP in patients without ARDS. Further, a substudy showed that lower PEEP had no beneficial effects on cardiac function compared to higher PEEP. An international prospective observational study in ventilated ICU patients reported on ventilation practice and outcome in patients in low– and middle– income countries (LMICs). In LMICs tidal volume was lower and PEEP was higher in patients with ARDS compared to patients without ARDS, and pulmonary complications occurred often.. In another study, geo-economic differences in ventilation management and outcome between high income countries (HICs) and LMICs were identified. Ventilation management was similar in HICs and LMICs, patients in LMICs had a higher mortality. Finally, an individual data analysis of three randomized trials showed that mechanical power had associations with mortality in ventilated ICU patients without ARDS.