Table 1 Eligibility criteria for INSPiRE-ICU2

Inclusion Criteria

1. Adults ≥ 18 years of age

2. Patients who are anticipated to require > 12 h of invasive mechanical ventilation and continuous sedation in the ICU

3. Receipt of continuous sedation due to clinical need for sedation to RASS < 0

Exclusion Criteria

1. Need for RASS − 5

2. Sedation for invasive mechanical ventilation immediately prior to Baseline for > 72 h (patients who have been extubated for at least 24 h and subsequently re-intubated will have sedation for invasive mechanical ventilation starting from when they were re-intubated)

3. Severe neurological condition that causes the patient to lack ability to participate in the study (i.e., unable to be assessed for RASS and Critical Care Pain Observation Tool), including, but not restricted to, patients with acute stroke, severe head trauma, meningitis, suspected of having elevated intracranial pressure (ICP), or the need for ICP monitoring

4. Ventilator tidal volume < 200 or > 1000 mL at baseline

5. Need for extracorporeal membrane oxygenation (ECMO), extracorporeal CO₂ removal (ECCO2R), high frequency oscillation ventilation (HFOV), or high-frequency percussive ventilation (HFPV) at screening

6. Comfort care only (end of life care)

7. Contraindication to propofol or isoflurane, including:

a. Known or suspected personal or family history of malignant hyperthermia (MH) or high risk for MH or acute drug-induced muscle injury (e.g., muscular dystrophies);

b. Severe hemodynamic compromise, defined as the need for norepinephrine

 ≥ 0.3 mcg/kg/min (or equivalent vasopressor dose) to maintain blood pressure

within acceptable range, assumed to be mean arterial pressure ≥ 65 mmHg unless

prescribed clinically; or

c. Allergy to isoflurane or propofol, or have propofol infusion syndrome

8. History of ventricular tachycardia/long QT syndrome

9. Requirement of IV benzodiazepine or barbiturate administration for seizures or dependencies, including alcohol withdrawal

10. Neuromuscular disease that impairs spontaneous ventilation (e.g., C5 or higher spinal cord injury, amyotrophic lateral sclerosis)

11. Concurrent enrollment in another study that, in the Investigator’s opinion, would impact the patient’s safety or assessments of this study

12. Participation in other study involving investigational drug(s) or devices(s) within 30 days prior to randomization

13. Previous randomization or receipt of treatment in this study or in INSPiRE-ICU1;

14. Anticipated requirement of treatment with continuous infusion of a neuromuscular blocking agent for > 4 h

15. Female patients who are pregnant or breast-feeding

16. Imperative need for continuous active humidification through ventilator circuit

17. Attending physician’s refusal to include the patient

18. Inability to obtain informed consent