PERMISSive Lung-protective Ventilation RCT

RATIONALE Injury caused by mechanical ventilation is associated with its intensity, of which the respiratory rate (RR) is a substantial contributor. A permissive ventilation strategy that reduces RR and allows mild hypercapnia, may lower the intensity of ventilation and improve patient-centered outcomes. In this approach, RR is stepwise decreased to the lowest level compatible with predefined safety limits.

OBJECTIVE To compare permissive lung-protective ventilation with a lower RR, to conventional lung-protective ventilation, in adult critically ill patients receiving invasive ventilation.

HYPOTHESIS Permissive lung-protective ventilation, defined as a strategy that reduces ventilatory intensity by stepwise lowering RR to the lowest level permitted by predefined safety limits, is superior to conventional lung-protective ventilation, with respect to the number of days free from ventilation and alive at day 28 (VFD-28) in adult critically ill patients receiving invasive ventilation.

STUDY DESIGN International, multicenter, investigator-initiated, randomized, clinical, superiority trial.

STUDY POPULATION Critically ill patients, aged ≥ 18 years, intubated and expected to receive invasive ventilation for > 24 hours.

INTERVENTION AND COMPARISON Patients are randomized in a 1:1 ratio to permissive lung-protective ventilation with lower RR, or to conventional lung-protective ventilation.

STUDY ENDPOINTS The primary outcome is the number of VFD-28, a composite endpoint of duration of ventilation and death until day 28. The secondary outcomes include the individual components of this composite endpoint, namely duration of ventilation (analyzed separately in survivors and non-survivors) and 28-day mortality. Additional secondary outcomes are intensive care unit (ICU) and hospital length of stay, and ICU-, hospital, and 90-day mortality.

SAMPLE SIZE AND DATA ANALYSIS Based on previous literature, we assumed that the intervention would determine an increase in the number of VFD-28 of 2.4 days, with a standard deviation of 10. The required sample size with a t-test and allowing for a 15% inflation to account for rank-based testing, a power of 90%, an alpha of 0.05 and a drop-out rate of 10% is 926 patients (463 patients per group). Primary analysis will follow the intention-to-treat principle, with additional per-protocol analysis.

NATURE AND EXTENT OF THE BURDEN AND RISKS ASSOCIATED WITH PARTICIPATION, BENEFIT AND GROUP RELATEDNESS Ventilation with lower RR may result in higher PaCO2 and lower arterial pH. When kept within safe limits, evidence suggests that hypercapnia and mild acidosis are safe and do not lead to worse outcomes or severe adverse events. Both ventilation strategies are forms of lung-protective ventilation and are currently variably used as part of standard care. No other interventions are performed. 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. The collection of demographics, 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 intensive care units (ICUs);
• intubated and receiving invasive ventilation; and
• expected duration of ventilation of at least 24 hours (based on ICU admission diagnosis and clinical judgment).

Exclusion criteria

• age below 18 years;
• invasive ventilation before randomization > 2 hours in the ICU or invasive ventilation > 6 hours in the operating room or emergency department directly preceding the current ICU admission;
• receiving or planned to receive veno-venous, veno-arterial or arterio-venous extracorporeal membrane oxygenation (ECMO);
• contraindications 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 (traumatic) brain injury, judged by the attending physician;
• having severe Chronic Obstructive Pulmonary Disease (COPD); GOLD classification III or IV or classified in group B or E of the GOLD ABE assessment tool);
• after cardiac arrest;
• suspected or confirmed pregnancy;
• having 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;
• participation in another interventional trial using similar endpoints;
• previous randomization in this study;
• no informed consent or;
• admitted for palliative and terminal care.