Evaluation of Isoflurane Inhalation Versus Intravenous Propofol and Sufentanil for Delirium Prevention in Mechanically Ventilated ICU Patients

The primary objective of this study is to determine the impact of an early inhaled sedation strategy using **Isoflurane** on the frequency of **delirium** occurrence in patients undergoing invasive mechanical ventilation. This is compared to a conventional intravenous sedation strategy. The clinical relevance of this objective lies in potentially reducing the incidence of delirium, a common and serious complication in intensive care units (ICUs), which can lead to prolonged hospital stays and increased morbidity.

Secondary objectives include:

• Determining ICU morbidity and mortality.
• Assessing the length of stay in the ICU and the number of days without intensive care at day 28.
• Evaluating the number of days without mechanical ventilation.
• Investigating the incidence of delirium after weaning from sedation.
• Assessing the quality of sedation, specifically compliance with target-based prescribing.
• Evaluating the safety of use, including hemodynamic, hepatic, and renal parameters.
• Systematically collating dosages of vasopressor amines, vascular filling, and the need for renal replacement.
• Determining the incidence of agitation requiring additional prescription medication.
• Assessing the rate of physical restraint, excluding hand restraint if per service protocol.
• Evaluating the rate of self-extubation and catheter or probe removal.
• Determining the rate of self- or hetero-aggressions.
• Assessing long-term cognitive, psychological, and quality-of-life consequences.
• Evaluating the efficacy of sedation in a specific subgroup of patients who are difficult to sedate, such as those with excessive alcohol consumption, long-term psychotropic treatment, or unweaned drug addiction.
• Determining the economic value of the Isoflurane inhalation sedation strategy.

The clinical trial focuses on patients diagnosed with **delirium** and aims to evaluate the impact of an early inhaled sedation strategy using Isoflurane compared to a conventional intravenous sedation strategy. The study population includes both male and female participants aged 18 and over, who require mechanical ventilation for at least 24 hours and immediate continuous sedation for comfort, safety, and to facilitate life-sustaining measures. Consent must be obtained from the patient or a relative. The trial does not specifically target a vulnerable population. The sponsor has not provided information regarding the total number of participants or specific lifestyle considerations such as diet or physical activity.

The clinical trial is designed to evaluate the impact of an early inhaled sedation strategy using **isoflurane** compared to a conventional intravenous sedation strategy in patients requiring invasive mechanical ventilation in an intensive care setting. This is a randomized, double-blind, controlled trial with an estimated duration from August 30, 2024, to August 6, 2025. The primary objective is to assess the occurrence of **delirium** in the intensive care unit, with secondary endpoints including ICU mortality, length of stay, and cognitive consequences assessed at 3 and 12 months.

Participants will be randomly assigned to receive either the inhaled sedation strategy with **isoflurane** or the intravenous sedation strategy with **propofol** and **sufentanil**. The trial will include an initial screening visit to confirm eligibility based on criteria such as age (18 years and over), requirement for mechanical ventilation for at least 24 hours, and the need for continuous sedation. Informed consent will be obtained from the patient or a relative.

Study visits will be scheduled to monitor the participants' progress and collect data on the primary and secondary endpoints. Follow-up visits will occur at regular intervals to assess sedation quality, the need for additional medication or physical restraint, and any adverse events. The end-of-study visit will evaluate the overall outcomes and gather final data on the participants' health status.

The expected length of participant involvement is up to 28 days, corresponding to the maximum treatment period for the sedation strategies. Conditions that may lead to early termination from the study include withdrawal of consent, significant protocol deviations, or adverse events that compromise the participant's safety. The trial aims to provide valuable insights into the effectiveness and safety of inhaled versus intravenous sedation strategies in critically ill patients.

The clinical trial involves the administration of **Propofol**, marketed as Propofol Baxter 10 mg/mL Emulsion for Injection/Infusion. This medication is provided in the form of an emulsion suitable for both injection and infusion. The active substance, propofol, is of chemical origin. The administration route is **intravenous**, with a maximum daily dose of 12,000 mg and a total maximum dose of 336,000 mg over a treatment period of up to 28 days. The medication is used in its commercial form without any modifications, adhering to the Summary of Product Characteristics (SmPC).

**Sufentanil** is utilized as an auxiliary treatment in the study. It is administered as an injection, with the active substance also being of chemical origin. The dosing is calculated based on body weight, with a maximum daily dose of 720 µg/kg and a total maximum dose of 17,280 µg over the course of 28 days. Sufentanil is used according to its commercial form, following the SmPC guidelines.

The experimental treatment in this trial is **Isoflurane**, marketed as Isoflurane Belamont, a liquid for inhalation via vapor. The active substance, isoflurane, is chemically derived and administered through inhalation gas. The maximum daily dose is 360 mL, with a total maximum dose of 10,080 mL over a 28-day period. Isoflurane is used in its commercial form, consistent with the SmPC.

Participant compliance with the dosing schedules is monitored throughout the trial to ensure adherence to the prescribed treatment regimens. The trial aims to compare the effects of an inhaled sedation strategy using isoflurane with a conventional intravenous sedation strategy in patients undergoing invasive mechanical ventilation.

Efficacy in the clinical trial titled "Comparison of an inhaled sedation strategy with an intravenous sedation strategy in intensive care patients treated with invasive mechanical ventilation: INASED study" will be assessed using both primary and secondary endpoints. The primary endpoint is the occurrence of **delirium** in the intensive care unit, measured as a binary outcome (yes/no). Secondary endpoints include ICU mortality, D28 mortality, length of stay in intensive care, and the number of days living without mechanical ventilation in intensive care at D28. Additional secondary measures involve the CAM-ICU scale assessed every 8 hours, compliance with the sedation target, and the need for additional medication or physical restraint to manage agitation.

Further secondary endpoints include the number of accidental removals of medical tubes and devices by the patient, the number of self- or hetero-aggressive acts, average hospital costs per patient, and the daily and cumulative dose of sedatives. Cognitive consequences will be evaluated through the calculation of CDR and IQCODE scores, with cognitive, psychological, and quality of life assessments conducted at 3 and 12 months. These efficacy parameters will be collected and analyzed according to the trial's predefined schedule and methodologies, ensuring a comprehensive evaluation of the sedation strategies' impact on patient outcomes.