Inhaled sedation versus propofol in respiratory failure in the ICU (INSPiRE-ICU2): study protocol for a multicenter randomized controlled trial

Abstract

Background: Patients undergoing invasive mechanical ventilation often require pharmacologic sedation to facilitate tolerance of this life-sustaining intervention, but sedatives currently used in routine care have substantial limitations. Isoflurane is an inhaled volatile anesthetic with pharmacologic properties potentially suitable to sedation of ventilator-dependent critically ill patients, but need for specialized drug administration equipment has limited its use historically to general anesthesia in the operating theatre. This trial will evaluate isoflurane, administered using a novel drug delivery system, for sedation of ventilator-dependent adult intensive care unit (ICU) patients in the United States (US).

Methods: The Inhaled Sedation versus Propofol in Respiratory Failure in the ICU (INSPiRE-ICU2) is a phase 3, multicenter, randomized, controlled, assessor-blinded non-inferiority trial that will evaluate efficacy and safety of inhaled isoflurane delivered via the Sedaconda ACD-S, compared to intravenous propofol, for sedation of mechanically ventilated adult ICU patients. At 16 US hospitals, 235 enrolled patients requiring continuous sedation during invasive mechanical ventilation will be randomized in 1.5:1 ratio to inhaled isoflurane or intravenous propofol for sedation. Treatment duration is expected to be at least 12 h and may last up to 48 (± 6) h or until no longer needing continuous sedation, whichever occurs first. The primary endpoint is the percentage of time sedation depth is maintained within the targeted range (Richmond Agitation Sedation Scale - 1 to - 4), in the absence of rescue sedation, during the treatment period. Secondary superiority outcomes include opioid exposure, wake-up time, cognitive recovery after end-of-treatment, and preservation of spontaneous breathing effort.

Discussion: The INSPiRE-ICU2 trial will help determine the potential role of isoflurane for sedation of ventilator-dependent adult patients in the ICU. Key trial design features, including adoption of the estimand framework and blinded assessments of sedation depth, pain, and cognitive recovery, will ensure a rigorous evaluation of isoflurane for ICU sedation. TRIAL REGISTRATION: ClinicalTrials.gov, NCT05327296. First registered on April 5, 2022.

Keywords: Clinical trial protocol; Deep sedation; Inhalation anesthetic; Isoflurane; Moderate sedation; Propofol; Randomized controlled trial; Respiratory failure.

Fig. 1

Sedaconda ACD schematic and ventilator circuit adaptations. A Cross-sectional internal schematic view of the Sedaconda ACD, which can be thought of as a heat-moisture exchanger (HME) modified to facilitate efficient administration of volatile anesthetics. Two key adaptations to facilitate drug delivery are the infusion line/evaporator rod through which drug enters the ventilator circuit, and the anesthetic gas reflector that adsorbs 90% of exhaled anesthetic, which is then re-breathed with the following inspiratory cycle. B Configuration of the ventilator circuit for administration of volatile anesthetic via the Sedaconda ACD. Though the gas analyzer can be used to monitor end-tidal concentration of isoflurane, the drug is titrated not to any particular concentration but rather to clinically ascertained sedation depth using Richmond Agitation Sedation Scale (RASS)

Fig. 2

Blinding set-up. Blinding study drug entails unique considerations because propofol is a white intravenous infusion while isoflurane is a clear colorless volatile liquid that is administered via a specialized inhalational delivery device, the Sedaconda ACD. Plastic wraps are used to cover the propofol bottle and infusion line (or their dummy equivalent), as well as the Sedaconda ACD (or heat-moisture exchanger) placed inline with the ventilator circuit. A volatile anesthetic scavenger is placed on the ventilator exhaust and gas sampling monitor connected to the ACD or heat-moisture exchanger in both arms (not shown). The gas sampling monitor displays only end-tidal carbon dioxide by default to preserve blinding, though the study team can access additional data views as needed for periodic recording of end-tidal isoflurane concentration in patients assigned to the intervention arm

Fig. 3

Study scheme. Key events during the screening, post-randomization, treatment, and follow-up periods are depicted. Abbreviations: CPOT = Critical Care Pain Observation Tool; D = day(s); EOT = end of treatment; h = hour(s); IV = intravenous; LAR = legally authorized representative; M = month; RASS = Richmond Agitation Sedation Scale; Sedaconda ACD-S = Sedaconda Anaesthetic Conserving Device - S; SOC = standard of care; W = week(s)