Evaluation of Inhaled Sevoflurane Versus Intravenous Sedation in ICU Patients at High Risk for Acute Respiratory Distress Syndrome

The primary objective of this randomized clinical trial is to assess the **efficacy** of inhaled **sevoflurane** compared to current intravenous sedation practices in improving the PaO2/FiO2 ratio in ICU patients at high risk for Acute Respiratory Distress Syndrome (ARDS). This is clinically relevant as enhancing oxygenation in critically ill patients can potentially reduce the progression to ARDS, a severe condition with high morbidity and mortality.

Secondary objectives include evaluating:

• Progression to ARDS as defined by the Berlin criteria.
• Safety, focusing on clinical adverse events, of the two sedation strategies.
• Effects on the rate of pneumonia.
• Effects on respiratory mechanics.
• Effects on gas exchange and physiological measures.
• Effects on ICU-acquired delirium.
• Effects on hemodynamic measures and renal function using KDIGO criteria for acute kidney injury.
• Effects on organ dysfunction.
• Effects on the duration of mechanical ventilation.
• Effects on 28-day mortality.
• Effects on the number of days off the ventilator at 28 days, considering death as a competing event.
• Biological collection of plasma samples for future mechanistic and endotyping studies of the biological effects of sevoflurane.
• Presence of subphenotypes among patients at risk of developing ARDS.

The clinical trial involves **patients in ICU** with risks of Acute Respiratory Distress Syndrome (ARDS). The study population includes both male and female participants aged 18 years and older. Participants are admitted to participating ICUs with at least one known risk factor for ARDS and a Lung Injury Prediction Score (LIPS) equal to or greater than 4. They are under invasive mechanical ventilation with an expected duration of sedation of four hours or more. All participants are affiliated with the French Sécurité Sociale. The sponsor has not provided information regarding the total number of participants. The trial population was selected based on these criteria, ensuring a focus on individuals at high risk for ARDS. No specific lifestyle considerations such as diet or physical activity are highlighted, and the population does not include vulnerable groups.

The clinical trial is designed to evaluate the efficacy of **sevoflurane** inhalation compared to standard intravenous sedation in critically ill patients at risk of developing Acute Respiratory Distress Syndrome (ARDS). This is a randomized, double-blind, controlled trial with an estimated duration from July 2023 to July 2025. Participants will be randomly assigned to receive either inhaled sevoflurane or one of the comparator intravenous sedatives, including **dexmedetomidine**, **cisatracurium besilate**, **midazolam**, or **propofol**. The primary endpoint is the longitudinal evolution in the PaO2/FiO2 ratio, while secondary endpoints include progression to ARDS, rate of pneumonia, ventilator-free days, organ failure-free days, mortality, length of ICU stay, physiological measures, ICU-acquired delirium, and biomarker measurements.

Study visits will follow a structured sequence, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age ≥ 18 years, admission to ICU with risk factors for ARDS, and expected sedation duration of at least 4 hours. Follow-up visits will be conducted to monitor the primary and secondary endpoints, with the end-of-study visit marking the conclusion of the participant's involvement. The expected length of participant involvement is up to 5 days, corresponding to the maximum treatment period for the investigational and comparator products. Conditions that may lead to early termination from the study include adverse events, withdrawal of consent, or any situation where continued participation is deemed unsafe by the investigator.

The clinical trial involves the use of several treatments, including the experimental medication **Sevoflurane**. Sevoflurane is administered as a liquid for inhalation via vapor, under the trade name SEVOFLURANE BAXTER 1 ml/ml. The pharmaceutical form is an inhalation vapor, liquid, and it is delivered through inhalation use. The maximum daily dose is 250 ml, with a total maximum dose of 1250 ml over a treatment period of up to 5 days. The administration is facilitated by the Système Anaconda device, which has a CE mark, ensuring compliance with European safety standards.

**Dexmedetomidine** is used as a comparator treatment in the trial. It is provided as a concentrate for solution for infusion, with the trade name Dexmedetomidine 100 micrograms/ml. The pharmaceutical form is a solution for infusion, administered intravenously. The maximum daily dose is 24 µg/Kg, with a total maximum dose of 120 µg/Kg over a 5-day treatment period.

Another comparator treatment is **Cisatracurium Besilate**, marketed as NIMBEX 5 mg/ml. This medication is available as a solution for injection/infusion and is administered intravenously. The maximum daily dose is 12960 µg/Kg, with a total maximum dose of 25920 µg/Kg, and the treatment period is limited to 2 days. It is used for neuromuscular blockade.

**Midazolam**, under the trade name HYPNOVEL 1 mg/ml, is also used as a comparator. It is provided as a solution for injection/infusion and administered intravenously. The maximum daily dose is 5 mg, with a total maximum dose of 25 mg over a 5-day treatment period. Midazolam serves as a hypnotic agent in the trial.

Lastly, **Propofol** is included as an auxiliary treatment, marketed as DIPRIVAN 20 mg/ml. It is an emulsion for injection, delivered intravenously. The maximum daily dose is 1.5 mg/Kg, with a total maximum dose of 7.5 mg/Kg over a 5-day treatment period. Propofol is used as a hypnotic in the study.

The efficacy of inhaled **sevoflurane** in critically ill patients at risk of developing Acute Respiratory Distress Syndrome (ARDS) will be assessed through a randomized clinical trial. The primary endpoint for evaluating efficacy is the longitudinal evolution in the PaO2/FiO2 ratio, which is a measure of lung function and oxygenation efficiency. Secondary endpoints include progression to ARDS assessed according to the Berlin criteria, rate of pneumonia, ventilator-free days, organ failure-free days, mortality, length of ICU stay, physiological measures, ICU-acquired delirium, and biomarker measurements.

Data collection will involve regular monitoring of the PaO2/FiO2 ratio and other secondary endpoints throughout the treatment period. The trial will compare the efficacy of inhaled sevoflurane against current intravenous sedation practices. The schedule for measuring these parameters will be aligned with the treatment duration, which is set to a maximum of 5 days. The analysis will focus on determining the improvement in oxygenation and other clinical outcomes in patients receiving sevoflurane compared to those under standard sedation protocols.