RATIONALE Lung-protective ventilation using a lower respiratory rate (RR) is an appealing strategy to reduce ventilation intensity, which may require permissive hypercapnia. However, the feasibility and safety of this so-called 'permissive lung-protective ventilation' must be investigated, before conducting a large randomized clinical trial to evaluate its effectiveness on patient-centered outcomes.

OBJECTIVE To study the feasibility and safety of permissive lung-protective ventilation in adult critically ill patients receiving invasive ventilation for acute hypoxemic respiratory failure, and to inform the design of a future randomized clinical trial in this patient population.

HYPOTHESIS Permissive lung-protective ventilation is a feasible and safe ventilation strategy.

STUDY DESIGN Multicenter, randomized clinical pilot trial. STUDY POPULATION Critically ill patients, aged > 18 years, intubated for acute hypoxemic respiratory failure, and expected to receive ventilation for > 24 hours.

METHODS Patients are randomized to permissive lung-protective ventilation wherein RR is stepwise reduced, or to conventional lung-protective ventilation.

OUTCOME MEASURES The primary endpoint is feasibility, assessed by the difference in respiratory rate (RR) between the two groups, from the start of mechanical ventilation until first extubation. Secondary endpoints include protocol compliance and feasibility of collecting data, and safety, assessed by the occurrence of unacceptable hypercapnia and hypoxemia and the incidence of ventilator-associated complications SAMPLE SIZE To estimate the appropriate sample size for this pilot study, we considered the primary feasibility endpoint of detecting a difference in the respiratory rate (RR). Assuming an expected mean difference in RR of 7.5, based on previous studies [1, 2], with an SD of 10, a power of 90% and an alpha of 0.05, with a drop-out rate estimated at 10%, a two-tailed t-test was used. The required sample size is 84 patients (42 patients per group).

NATURE AND EXTENT OF THE BURDEN AND RISKS ASSOCIATED WITH PARTICIPATION, BENEFIT AND GROUP RELATEDNESS Ventilation with a lower RR may require permissive hypercapnia, which, when kept within safe limits, is safe. In current daily practice, there is no guidance in setting RR; consequently, RR varies widely across patients and is often set high. This pilot study compares two forms of lung-protective ventilation, both considered standard care in current ICU practice. The control group receives conventional ventilation with low tidal volumes and high RR to maintain normal PaCO₂ and pH. The intervention group, permissive ventilation, uses a lower RR to reduce mechanical power, accepting mild hypercapnia and acidosis. Permissive ventilation is most often reserved for patients with severe lung conditions, where ventilator settings are more complex and ventilation intensity is high. In these patients, permissive ventilation is considered safe, and may even be beneficial. We aim to evaluate this strategy more broadly in critically ill patients. The collection of demographic, ventilation and outcome data causes no harm to patients. Blood is drawn for arterial blood gas analysis, but this is also part of standard care.

Inclusion Criteria:

• admission to one of the participating ICUs;
• intubated and receiving invasive ventilation with an expected duration of ventilation of at least 24 hours.

Exclusion Criteria:

• age below 18 years;
• receiving invasive ventilation > 1 hour in the ICU, or receiving invasive ventilation > 6 hours directly preceding the current ICU admission (i.e., in the operating room or in the emergency department);
• receiving or planned to receive veno-venous, veno-arterial or arterio-venous extracorporeal membrane oxygenation (ECMO);
• having COPD GOLD III and IV;
• contra-indication for hypercapnia, such as ongoing cardiac ischemia (as defined in the guideline of the European Society of Cardiology), or having suspected or confirmed increased intracranial pressure due to brain injury, judged by the attending physician;
• any neurologic diagnosis that can prolong duration of mechanical ventilation, e.g., Guillain-Barré syndrome, high spinal cord lesion or amyotrophic lateral sclerosis, multiple sclerosis, or myasthenia gravis;
• suspected or confirmed pregnancy;
• participation in another interventional trial using similar endpoints;
• previously randomized in this study;
• no informed consent; or
• admitted for terminal care