Background: Invasive ventilation saves lives but carries major risks, including ventilation-associated lung damage and long-term functional impairment. Data from recent studies compel reassessment of the evidence for every step of the clinical treatment pathway.

Methods: This updated clinical practice guideline is based on pertinent publications retrieved by a systematic search in Medline, Embase, and the Cochrane Library up to April 2023, supplemented by further high-quality studies published up to June 2024. The recommendations were developed in evidence-to-decision–frameworks (EtDF) according to GRADE, with the participation of intensive-care nurses and early career clinician-scientists.

Results: For patients in acute respiratory failure, it is suggested that noninvasive respiratory support techniques should be used so that intubation can be avoided. It is further suggested that spontaneous breathing should be enabled early on during invasive ventilation. For the first time, the use of various techniques for titrating the positive end-expiratory pressure (PEEP) is suggested for patients with moderate to severe acute respiratory distress syndrome (ARDS). In such patients, techniques aiming at a higher PEEP can lower mortality by 9% in absolute terms (95% confidence interval [1; 16]) compared to lower-PEEP strategies. Strong recommendations are given against the routine use of muscle relaxation or corticosteroid therapy in moderate to severe ARDS. For patients with ARDS with a persistent, severe gas exchange disturbance after conservative options have been exhausted, veno-venous extracorporeal membrane oxygenation should be considered. VvECMO for patients with severe ARDS should be carried out at centers that are experienced in treating patients with severe ARDS and that fulfill specific structural requirements.

Conclusion: The goals of ventilator therapy should be to enable spontaneous breathing as soon as possible, keep respiratory parameters in the protective range, and adjust PEEP individually. Muscle relaxation or corticosteroids should not be part of the routine treatment of moderate to severe ARDS.