The proposal of this study is to compare inhaled sedation with isoflurane administered via the Sedaconda ACD-S system with intravenous sedation with propofol. Patients will be randomized 1:1 to receive either inhaled sedation with isoflurane administered via the Sedaconda ACD device (Sedana Medical, Uppsala, Sweden) or intravenous propofol. The primary endpoint is the number of ventilator-free days at 28 days after randomization.

Justification: Isoflurane has recently emerged as an attractive alternative for intensive care unit (ICU) sedation. Due to their favorable pharmaco-kinetic and dynamic profile, this agent has been progressively introduced into clinical practice. Isoflurane has proven to be non-inferior to propofol in terms of efficacy and safety and it has been suggested that it may facilitate ventilator weaning. However, no differences in length of mechanical ventilation were found. These studies have focused on short sedation durations. In fact, long-term effects and outcomes associated with isoflurane for ICU sedation are not yet fully understood.

Hypothesis: Inhaled sedation with isoflurane administered via the Sedaconda ACD-S system in critically ill patients leads to a shorter duration of mechanical ventilation at 28 days and a reduced length of ICU stay compared to intravenous sedation with propofol.

Main objective: To compare the number of ventilator-free days at day 28 post-randomization between critically ill patients receiving sedation with isoflurane versus those receiving intravenous sedation with propofol in critically ill patients expected to require more than 48 hours of invasive mechanical ventilation. Key secondary objective: To compare the number of ICU-free days at day 28 post-randomization in both treatment arms. Secondary objectives: To compare time to extubation after sedation withdrawal, efficacy in maintaining a target level of sedation, compare the percentage of patients requiring one or more additional hypnotics, compare the incidence and duration of delirium at day 28, assess mental, cognitive, and quality of life status at 90 days post-hospital discharge between both treatment groups.

Methodology: Phase IV, low-intervention, open-label, multicenter, randomized controlled trial with intention-to-treat analysis including mechanically ventilated patients expected to require a minimum of 48 hours of mechanical ventilation with a RASS score between -3 and -5. Patients will be randomized 1:1 to receive inhaled sedation with isoflurane administered via the Sedaconda ACD device (Sedana Medical, Uppsala, Sweden) or intravenous sedation with propofol. A total of 620 patients will be included from a pool of 22 participating centers.

Inclusion Criteria:

- Adult patients receiving mechanical ventilation, with an anticipated duration >48 hours after randomization, and requiring deep sedation (target RASS between -3 and -5).

Exclusion Criteria:

• Contraindication to isoflurane or propofol
• Patients with maternal ancestry from Venezuela, due to the potential presence of an mt-ND4 gene mutation associated with neurological injury after exposure to certain volatile anaesthetic agents
• Significant air leak, defined as a leak exceeding 30% of the delivered minute ventilation
• Allergy to isoflurane or propofol
• Cardiopulmonary arrest
• History of ventricular tachycardia or long QT syndrome
• Tidal volume < 300 mL or PaCO₂ > 50 mmHg at the time of randomization.
• Invasive mechanical ventilation for more than 48 hours at the time of randomization.
• Pregnancy
• Breast feeding
• Acute neurological condition
• Patients expected to require repeated surgical interventions during their ICU stay.
• ECMO
• ECCO2R
• Active humidification strictly required
• Neuromuscular disease or high spinal cord injury likely to prevent discontinuation of mechanical ventilation due to baseline condition
• Requirement for benzodiazepine use for a specific indication
• Burns
• Life expectancy less than 48 hours, or patients with such a level of severity that death during the ICU stay is considered highly likely.
• Any condition (e.g., blindness, deafness, dementia) or language barrier that prevents the administration of delirium or cognitive assessment scales.
• Lack of informed consent