Inhaled Sevoflurane for ARDS Prevention (IPA)

Randomized Clinical Trial of Inhaled Sedation With Sevoflurane in Critically Ill Patients at Risk of Developing the Acute Respiratory Distress Syndrome

This study focuses on patients who are at risk of developing a serious, life-threatening respiratory disease called Acute Respiratory Distress Syndrome (ARDS), which severely disrupts the function of their lungs.

Preclinical studies have shown that the use of a volatile anesthetic agent such as Sevoflurane could be beneficial in the treatment and prevention of this respiratory condition. By improving gas exchange and attenuating pulmonary inflammation in particular, this agent would make it possible to prevent deterioration or to restore pulmonary function more rapidly.

Half of the patients will receive inhaled sedation with sevoflurane and the other half will receive intravenous sedation already routinely used in participating ICUs (typically propofol, dexmedetomidine or a benzodiazepine, i.e. drugs approved for sedation).

The aim of this study is to assess whether the use of Sevoflurane could be beneficial in the prevention of ARDS.

Study Overview

• Status: Recruiting
• Conditions: Acute Respiratory Distress Syndrome
• Intervention / Treatment: Drug: Inhaled sedation with sevoflurane; Drug: Intravenous sedation (current practice)

Detailed Description

MAIN OBJECTIVE To assess the efficacy of inhaled sevoflurane, compared to current intravenous sedation practice, for improving PaO2/FiO2 in ICU patients at high risk for ARDS.

HYPOTHESIS The investigators hypothesized that a strategy of inhaled sedation with sevoflurane could be more effective than current intravenous sedation practice at improving pulmonary function during the early days of ICU admission, in patients at risk of ARDS.

• Study Type: Interventional
• Enrollment (Estimated): 80
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Lise Laclautre; Phone Number: +33473754963; Email: llaclautre_perrier@chu-clermontferrand.fr

Study Locations

• France
  • Not Required For This Country
    • Clermont-ferrand, Not Required For This Country, France, 63000
      • Recruiting
      • Chu Clermont-Ferrand
      • Contact: Dominique Morand; Phone Number: +33684894678; Email: dmorand@chu-clermontferrand.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Age ≥ 18 years
2. Admitted to participating ICUs with at least one known risk factor for ARDS and a LIPS equals to, or greater than, 4 (Appendix D)105
3. Patient under invasive mechanical ventilation
4. With expected duration of sedation superior or equal to 4 hours
5. Affiliation to the French Sécurité Sociale

Exclusion Criteria:

• Patient under judicial protection, guardianship or supervision, as defined by art L1121-8 of the Public Health Code
• Patient under psychiatric care as defined by art. L1121-6 of the Public Health Code
• Patient deprived of their freedom by judiciary or administrative order
• Known pregnancy
• Presence of ARDS prior to randomization
• Endotracheal ventilation for greater than 24 hours prior to randomization
• Home mechanical ventilation (non-invasive ventilation or via tracheotomy) except for CPAP/BIPAP used solely for sleep-disordered breathing
• Tidal volume of 6 mL/kg predicted body weight (PBW) below 200 mL (i.e. height inferior to 134cm for a man and 139cm for a woman)
• Moribund patient, i.e. not expected to survive 24 hours despite intensive care
• Previous hypersensitivity or anaphylactic reaction to sevoflurane or to the intravenous sedation agent routinely used in the participating ICU (such as midazolam, propofol, or dexmedetomidine)
• Absolute contra-indications to the intravenous sedation agent routinely used in the participating ICU (such as midazolam, propofol, or dexmedetomidine)
• Medical history of malignant hyperthermia
• Long QT syndrome at risk of arrhythmic events
• Medical history of liver disease attributed to previous exposure to a halogenated agent (including sevoflurane)
• Suspected or proven intracranial hypertension
• Enrollment in another interventional trial with direct impact on oxygenation

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Inhaled sedation with sevoflurane; Sevoflurane as vaporized via the Anesthesia Conserving Device (Sedaconda-ACD-S, Sedana Medical, Danderyd, Sweden).	Drug: Inhaled sedation with sevoflurane; In both arms, the management of sedation will be conducted in the broader picture of ICU patient care, as per current standard practice in participating ICUs, and following the current guidelines for Pain, Agitation, Delirium, Immobility, and Sleep Disruption (PADIS) published in 2018 by the Society of Critical Care Medicine. Among many recommendations, this will include the monitoring and titration of both sedation and analgesia using validated scores such as the Richmond Agitation-Sedation Scale (RASS) for sedation. As a result of the current recommendations, the level, dose, and duration of sedation will vary among patients and will be decided by the treating clinicians. The choice of the analgesic drug(s) will be as per the treating clinicians. Other aspects of critical care will adhere to standard care, including the use of the "Checklist for Lung Injury Prevention" (CLIP).; Other Names: Experimental
Active Comparator: Intravenous sedation; The investigators will not mandate the sedative type, but rather encourage the use of sedatives that are already routinely used in participating ICUs (typically a benzodiazepine, propofol, or dexmedetomidine, i.e. drugs approved for sedation).	Drug: Intravenous sedation (current practice); In both arms, the management of sedation will be conducted in the broader picture of ICU patient care, as per current standard practice in participating ICUs, and following the current guidelines for Pain, Agitation, Delirium, Immobility, and Sleep Disruption (PADIS) published in 2018 by the Society of Critical Care Medicine. Among many recommendations, this will include the monitoring and titration of both sedation and analgesia using validated scores such as the Richmond Agitation-Sedation Scale (RASS) for sedation. As a result of the current recommendations, the level, dose, and duration of sedation will vary among patients and will be decided by the treating clinicians. The choice of the analgesic drug(s) will be as per the treating clinicians. Other aspects of critical care will adhere to standard care, including the use of the "Checklist for Lung Injury Prevention" (CLIP).; Other Names: Control

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
PaO2/FiO2 ratio	longitudinal evolution in the PaO2/FiO2 ratio	within 5 days from randomization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression to ARDS	Progression to ARDS will be assessed according to the Berlin criteria, including chest radiographs	within 5 days from randomization
Rate of pneumonia	Pneumonia will be defined according to the 3 following criteria: Two chest radiographs showing signs of pneumonia, or one in absence of cardiomyopathy or underlying pulmonary condition.; One item among: body temperature ≥38.3°C without evident cause, leukocytes <4000/mm3 or ≥12000/mm3; Two items among: purulent secretions, cough or dyspnea, increased need for oxygen supplementation or ventilatory assistance.	Presence of pneumonia will be assessed daily until Day 5, and at Day 28 or ICU discharge, whichever comes first.
Ventilator-free days to day 28	Ventilator free days to day 28 are defined as the number of days from the time of initiating unassisted breathing to day 28 after randomization, assuming survival for at least two consecutive calendar days after initiating unassisted breathing and continued unassisted breathing to day 28. If a patient returns to assisted breathing and subsequently achieves unassisted breathing to day 28, VFDs will be counted from the end of the last period of assisted breathing to day 28. A period of assisted breathing lasting less than 24 hours and for the purpose of a surgical procedure will not count against the VFD calculation. If a patient was receiving assisted breathing at day 27 or dies prior to day 28, VFDs will be zero.	28 days after randomization
Organ failure to day 5	Organ failure is defined as present when the most abnormal vital signs or clinically available lab value meets the definition of clinically significant organ failure according to SOFA scores. Patients will be followed daily from randomization to day 5 for development of organ failures.	5 days after randomization
Mortality at day 28	The occurrence of death in the ICU will be recorded until day 28.	28 days after randomization
Length of ICU-stay up to 28 days	The total number of days from admission to ICU discharge will be recorded until day 28	28 days after randomization
Physiological measures: Oxygenation	- Oxygenation Index on study days 1-5	28 days after randomization
Physiological measures: PaCO2	- PaCO2 on study days 1-5	28 days after randomization
Physiological measures: pH	- Arterial pH on study days 1-5	28 days after randomization
Physiological measures: PEEP	- Level of PEEP (and static auto-PEEP in patients under controlled ventilation) on study days 1-5	28 days after randomization
Physiological measures: Plateau pressure	- Plateau pressure, static compliance of the respiratory system on study day 1-5	28 days after randomization
Physiological measures: Pneumothorax	- Development of pneumothorax through day 28	28 days after randomization
Physiological measures: Switch from controlled to pressure-support ventilation	- Time to switching from controlled to pressure-support ventilation through day 5	28 days after randomization
Physiological measures: Airway occlusion pressure	- Airway occlusion pressure at 0.1 s (P0.1), an index of respiratory drive, on the day the patient is switched to pressure-support ventilation if within 5 days since randomization	28 days after randomization
Hemodynamic measures	- Hemodynamic measures (mean arterial pressure, dose of infused norepinephrine or other vasopressor, serum lactate level) on study days 1-5	28 days after randomization
Physiological measures: Acute kidney injury	- KDIGO criteria for acute kidney injury 24 through day 5	28 days after randomization
Physiological measures: Supraventricular tachycardia	- Supraventricular tachycardia (SVT) or new onset atrial fibrillation through day 5	28 days after randomization
ICU-acquired delirium	The Confusion Assessment Method for the ICU (CAM-ICU, Appendix C )97 will be assessed daily from study entry to study day 28, death or ICU discharge, whichever comes first.	28 days after randomization
Biomarker measurements	Plasma samples will be collected from indwelling catheters (when available) at study entry and on days 1, 2, 3, 4, 5 in order to assemble a biological collection aimed at further investigating the effects of inhaled sedation with sevoflurane in patients with ARDS. The investigators will also collect whole blood samples at study entry and on day 2 for future studies of macrophage activation profiles and RNA and DNA studies.	from inclusion to 5 days

Collaborators and Investigators

• Sponsor: University Hospital, Clermont-Ferrand
• Investigators: Principal Investigator: Matthieu JABAUDON, University Hospital, Clermont-Ferrand

Study record dates

Study Major Dates

• Study Start (Actual): July 24, 2023
• Primary Completion (Estimated): May 31, 2025
• Study Completion (Estimated): July 31, 2025

Study Registration Dates

• First Submitted: April 27, 2023
• First Submitted That Met QC Criteria: May 5, 2023
• First Posted (Actual): May 9, 2023

Study Record Updates

• Last Update Posted (Estimated): December 11, 2023
• Last Update Submitted That Met QC Criteria: December 4, 2023
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Keywords: ARDS; Sedation; Inhaled sevoflurane
• Additional Relevant MeSH Terms: Pathologic Processes; Respiratory Tract Diseases; Respiration Disorders; Lung Diseases; Disease; Infant, Newborn, Diseases; Lung Injury; Infant, Premature, Diseases; Syndrome; Respiratory Distress Syndrome; Respiratory Distress Syndrome, Newborn; Acute Lung Injury; Physiological Effects of Drugs; Central Nervous System Depressants; Anesthetics, General; Anesthetics; Platelet Aggregation Inhibitors; Anesthetics, Inhalation; Sevoflurane
• Other Study ID Numbers: IPA trial (AOI 2019 JABAUDON)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No