Clinical trial NCT04235608: SEvoflurane for Sedation in ARds
Official title: Sevoflurane for Sedation in Acute Respiratory Distress Syndrome: a Multicenter Prospective Randomized Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Acute Respiratory Distress Syndrome
Keywords: ARDS
Sedation
Inhaled sevoflurane
Lead sponsor: University Hospital, Clermont-Ferrand
Sponsor class: OTHER
First posted: 2020-01-22
Enrollment: 700
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Investigator-initiated, multicenter, prospective, randomized, stratified, parallel-group clinical trial with blinded outcome assessment and concealed allocation of patients with moderate-to-severe ARDS to a strategy of inhaled sedation with sevoflurane or to a strategy of current intravenous sedation practice using propofol.
Primary purpose: TREATMENT

Brief summary: This study evaluates whether a sedation with inhaled sevoflurane will decrease mortality and increase time off the ventilator at 28 days in patients with acute respiratory distress syndrome (ARDS).

Half of the patients will receive inhaled sedation with sevoflurane and the other half will receive intravenous sedation with propofol.

Detailed description: PRIMARY OBJECTIVE:

To assess the efficacy of a sedation with inhaled sevoflurane in improving in reducing mortality and morbidity in patients with moderate-severe ARDS in comparison to a control group receiving intravenous sedation with propofol.

PRIMARY HYPOTHESIS:

Inhaled sedation with sevoflurane will improve a composite outcome of mortality and time off the ventilator at 28 days, in patients with moderate-severe ARDS.

The trial will accrue a maximum of 700 patients. Patients will be recruited from participating intensive care units and randomized to the active (inhaled sevoflurane) or control (intravenous propofol).

The overall strategy is to screen and enroll early, every newly intubated, acutely ill or postoperative, patient at each site, using clinically obtained pulse oximetry and blood gases.

By providing superior awakening and extubation times, as well as lung-protective effects from anti-inflammatory and protective effects from epithelial injury, inhaled sevoflurane may hasten recovery from lung injury and improve outcomes.

Eligibility criteria: Inclusion Criteria:

* Age ≥18 years
* Presence for ≤24 hours of all of the following conditions, within one week of a clinical insult or new or worsening respiratory symptoms:

  * PaO2/FiO2 \<150 mmHg with positive end-expiratory pressure (PEEP) ≥8 cmH2O (or, if arterial blood gas not available, SpO2/FiO2 that is equivalent to a PaO2/FiO2 \<150 mmHg with PEEP ≥8 cmH2O and a confirmatory SpO2/FiO2 between 1-6 hours after the initial SpO2/FiO2 determination)
  * Bilateral opacities not fully explained by effusions, lobar/lung collapse, or nodules
  * Respiratory failure not fully explained by cardiac failure or fluid overload; need objective assessment (e.g., echocardiography) to exclude hydrostatic edema if no risk factor present

Exclusion Criteria:

* Absence of affiliation to the French Sociale security
* Patient under a tutelage measure or placed under judicial protection
* Continuous sedation with inhaled sevoflurane at enrollment
* Known pregnancy
* Currently receiving ECMO therapy
* Chronic respiratory failure defined as PaCO2 \>60 mmHg in the outpatient setting
* Home mechanical ventilation (non-invasive ventilation or via tracheotomy) except for CPAP/BIPAP used solely for sleep-disordered breathing
* Body mass index \>40 kg/m2
* Chronic liver disease defined as a Child-Pugh score of 12-15
* Expected duration of mechanical ventilation \<48 hours
* Moribund patient, i.e. not expected to survive 24 hours despite intensive care
* Burns \>70% total body surface
* Previous hypersensitivity or anaphylactic reaction to sevoflurane or cisatracurium
* 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)
* Known hypersensitivity to propofol or any of its components
* Known allergy to eggs, egg products, soybeans, and soy products
* Suspected or proven intracranial hypertension
* Tidal volume of 6 mL/kg predicted body weight (PBW) below 200 mL (as recommended by the manufacturer for the use of the AnaConDa-S (Sedana Medical, Danderyd, Sweden)
* Enrollment in another interventional ARDS trial with direct impact on sedation and mechanical ventilation
* Endotracheal ventilation for greater than 120 hours (5 days)
* Persistent bronchopleural fistula despite chest tube drainage
* PaO2/FiO2 (if available) \>200 mmHg after meeting inclusion criteria and before randomization

Primary outcomes:
measure: Ventilator-free days through day 28
timeFrame: Day 28
Secondary outcomes:
measure: 90-day survival (Key secondary outcome)
timeFrame: Day 90
measure: All-cause, all-location 28-day mortality (Secondary outcome)
timeFrame: Day 28
measure: All-cause hospital 28-day mortality (Secondary outcome)
timeFrame: Day 28
measure: All-cause, all-location 14-day mortality (Secondary outcome)
timeFrame: Day 14
measure: All-cause, all-location 7-day mortality (Secondary outcome)
timeFrame: Day 7
Other outcomes:
measure: Ventilator-free days through day 14 (Exploratory outcome)
timeFrame: Day 14
measure: Ventilator-free days through day 7 (Exploratory outcome)
timeFrame: Day 7
measure: Organ failure-free days through day 7 (Exploratory outcome)
timeFrame: Day 7
measure: ICU-free days through day 28 (Exploratory outcome)
timeFrame: Day 28
measure: Hospital-free days through day 28 (Exploratory outcome)
timeFrame: Day 28
measure: Changes in oxygenation index through day 7 (Exploratory outcome)
timeFrame: Day 7
measure: Changes in PaO2/FiO2 through day 7 (Exploratory outcome)
timeFrame: Day 7
measure: Changes in PaCO2 through day 7 (Exploratory outcome)
timeFrame: Day 7
measure: Changes in arterial pH through day 7 (Exploratory outcome)
timeFrame: Day 7
measure: Changes in PEEP through day 7 (Exploratory outcome)
timeFrame: Day 7
measure: Changes in inspiratory plateau pressure through day 7 (Exploratory outcome)
timeFrame: Day 7
measure: Changes in static compliance of the respiratory system through day 7 (Exploratory outcome)
timeFrame: Day 7
measure: Changes in ventilatory ratio through day 7 (Exploratory outcome)
timeFrame: Day 7
measure: Use of rescue procedures for refractory hypoxemia through day 28 (Exploratory outcome)
timeFrame: Day 28
measure: ICU-acquired delirium through day 7 (Exploratory outcome)
timeFrame: Day 7
measure: Disability at 3 months (Exploratory outcome)
timeFrame: Day 90
measure: Disability at 12 months (Exploratory outcome)
timeFrame: Day 365
measure: Health-Related Quality of Life at 3 months (Exploratory outcome)
timeFrame: Day 90
measure: Health-Related Quality of Life at 12 months (Exploratory outcome)
timeFrame: Day 365
measure: Self-rated health at 3 months (Exploratory outcome)
timeFrame: Day 90
measure: Self-rated health at 12 months (Exploratory outcome)
timeFrame: Day 365
measure: Pain-interference at 3 months (Exploratory outcome)
timeFrame: Day 90
measure: Pain-interference at 12 months (Exploratory outcome)
timeFrame: Day 365
measure: Post-Traumatic Stress Symptoms-14 at 3 months (Exploratory outcome)
timeFrame: Day 90
measure: Hospital Anxiety and Depression Scale at 3 months (Exploratory outcome)
timeFrame: Day 90
measure: Post-Traumatic Stress Symptoms-14 at 12 months (Exploratory outcome)
timeFrame: Day 365
measure: Hospital Anxiety and Depression Scale at 12 months (Exploratory outcome)
timeFrame: Day 365
measure: Cognitive function at 3 months (Exploratory outcome)
timeFrame: Day 90
measure: Cognitive function at 12 months (Exploratory outcome)
timeFrame: Day 365
measure: Subsequent return to work, hospital and emergency department use, and location of residence at 3 months (Exploratory outcome)
timeFrame: Day 90
measure: Subsequent return to work, hospital and emergency department use, and location of residence at 12 months (Exploratory outcome)
timeFrame: Day 365
measure: Healthcare-related costs during ICU stay (Exploratory outcome)
timeFrame: Through study completion, an average of 1 year
measure: Healthcare-related costs during hospital stay (Exploratory outcome)
timeFrame: Through study completion, an average of 1 year
measure: Plasma biomarker levels of IL-8, sTNFr1, bicarbonates (hyperinflammatory ARDS phenotype), IL-6 (VILI), ANG-2 (endothelial activation), and sRAGE (alveolar epithelial injury) though day 14 (Exploratory biological outcome)
timeFrame: Day 14
measure: Change in urine biomarkers of TIMP-2 and IGFBP-7 (acute kidney injury) though day 14 (Exploratory biological outcome)
timeFrame: Day 14
measure: Change in plasma total fluoride and hexafluoroisopropanol (sevoflurane metabolism) though day 14 (Exploratory biological outcome)
timeFrame: Day 14
measure: Genetic analysis: DNA and RNA expressions through day 2 (Exploratory biological outcome)
timeFrame: Day 2
measure: Total protein level within undiluted pulmonary edema fluid (alveolar fluid clearance) through day 1 (Exploratory biological outcome)
timeFrame: Day 1
measure: Biomarker measurements in the fluid from heat moisture exchanger filters (control group) or AnaConDa-S devices (intervention group) through day 1 (Exploratory biological outcome)
timeFrame: Day 1
measure: Biomarker measurements in the broncho-alveolar lavage fluid through day 6 (Exploratory biological outcome)
timeFrame: Day 6
measure: Hemodynamic measures (mean arterial pressure) through day 7 (Safety outcome)
timeFrame: Day 7
measure: Hemodynamic measures (dose of infused norepinephrine or other vasopressor) through day 7 (Safety outcome)
timeFrame: Day 7
measure: Hemodynamic measures (serum lactate level) through day 7 (Safety outcome)
timeFrame: Day 7
measure: Measures of renal function (KDIGO criteria for acute kidney injury) through day 7 (Safety outcome)
timeFrame: Day 7
measure: Supraventricular tachycardia or new onset atrial fibrillation through day 7 (Safety outcome)
timeFrame: Day 7
measure: Severe hypercapnic acidosis with arterial pH <7.15 through day 7 (Safety outcome)
timeFrame: Day 7
measure: Development of malignant hyperthermia through day 7 (Safety outcome)
timeFrame: Day 7
measure: Development of propofol-related infusion syndrome through day 7 (Safety outcome)
timeFrame: Day 7
measure: Development of pneumothorax or bronchopleural fistula persistent despite drainage through day 7 (Safety outcome)
timeFrame: Day 7
Locations:
city: Amiens
country: France
facility: University Hospital
city: Angers
country: France
facility: University Hospital
city: Belfort
country: France
facility: Hospital Belfort
city: Brest
country: France
facility: Cavale Blanche Hospital - University Hospital
city: Béthune
country: France
facility: Hospital
city: Cannes
country: France
facility: Hospital
city: Chartres
country: France
facility: Hospital Chartres
city: Clermont Ferrand
country: France
facility: University Hospital,
city: Clermont-Ferrand
country: France
facility: Jean Perrin Comprehensive Cancer Center
city: Clermont-Ferrand
country: France
facility: University Hospital
city: Dijon
country: France
facility: University Hospital
city: Dunkerque
country: France
facility: Hospital
city: Lille
country: France
facility: Salengro Hospital - University Hospital
city: Marseille
country: France
facility: Timone Hospital - Assistance Publique-Hôpitaux
city: Martigues
country: France
facility: Hospital Martigues
city: Melun
country: France
facility: Hospital
city: Montpellier
country: France
facility: Lapeyronie Hospital - University Hospital
city: Montpellier
country: France
facility: Saint-Eloi Hospital - University Hospital
city: Nantes
country: France
facility: Hotel Dieu Hospital - University Hospital
city: Nice
country: France
facility: Pasteur 2 Hospital - University Hospital
city: Nîmes
country: France
facility: Carémeaux Hospital - University Hospita
city: Paris
country: France
facility: Diaconesses - La Croix Simon Hospital
city: Paris
country: France
facility: Pitié-Salpêtrière Hospital, - Assistance Publique-Hôpitaux
city: Paris
country: France
facility: Saint-Antoine University Hospital - Assistance Publique-Hôpitaux
city: Paris
country: France
facility: Saint-Louis University Hospital - Assistance Publique-Hôpitaux
city: Poitiers
country: France
facility: University Hospital
city: Reims
country: France
facility: University Hospital
city: Rennes
country: France
facility: University Hospital
city: Saint-Brieuc
country: France
facility: Hospital
city: Saint-Nazaire
country: France
facility: Hospital Saint-Nazaire
city: Saintes
country: France
facility: Hospital
city: Strasbourg
country: France
facility: Hautepierre Hospital, University Hospitals
city: Valenciennes
country: France
facility: Hospital Valenciennes
Study officials:
affiliation: University Hospital, Clermont-Ferrand
name: Matthieu Jabaudon
role: STUDY_CHAIR
affiliation: University Hospital, Clermont-Ferrand
name: Raïko Blondonnet
role: PRINCIPAL_INVESTIGATOR
affiliation: APHP - La Pitié Salpêtrière
name: Jean-Michel Constantin
role: PRINCIPAL_INVESTIGATOR
affiliation: Nantes University Hospital
name: Antoine Roquilly
role: PRINCIPAL_INVESTIGATOR
affiliation: CHU Montpellier - Saint-Eloi
name: Samir Jaber
role: PRINCIPAL_INVESTIGATOR
affiliation: APHP - Saint-Louis
name: Virginie Lemiale
role: PRINCIPAL_INVESTIGATOR
affiliation: CHU NICE
name: Carole Ichai
role: PRINCIPAL_INVESTIGATOR
affiliation: APHM - La Timone
name: Lionel Velly
role: PRINCIPAL_INVESTIGATOR
affiliation: CHU Nîmes
name: Stéphanie Bulyez
role: PRINCIPAL_INVESTIGATOR
affiliation: University Hospital, Angers
name: Sigismond Lasocki
role: PRINCIPAL_INVESTIGATOR
affiliation: CHU Dijon
name: Jean-Pierre Quenot
role: PRINCIPAL_INVESTIGATOR
affiliation: CHU Rennes
name: Thomas Lebouvier
role: PRINCIPAL_INVESTIGATOR
affiliation: CH Brieuc
name: François Legay
role: PRINCIPAL_INVESTIGATOR
affiliation: CHU Poitiers
name: Arnaud W. Thille
role: PRINCIPAL_INVESTIGATOR
affiliation: Centre Jean-Perrin Clermont-Ferrand
name: Alexandre Lautrette
role: PRINCIPAL_INVESTIGATOR
affiliation: CHU Strasbourg
name: Julien Pottecher
role: PRINCIPAL_INVESTIGATOR
affiliation: APHP - Saint-Antoine
name: Franck Verdonk
role: PRINCIPAL_INVESTIGATOR
affiliation: CH Béthune
name: Christophe Vinsonneau
role: PRINCIPAL_INVESTIGATOR
affiliation: CH Cannes
name: Pierre-Marie Bertrand
role: PRINCIPAL_INVESTIGATOR
affiliation: CH Melun-Sénart
name: Mehran Monchi
role: PRINCIPAL_INVESTIGATOR
affiliation: CHU REIMS
name: Joël Cousson
role: PRINCIPAL_INVESTIGATOR
affiliation: CHU Amiens
name: Julien Maizel
role: PRINCIPAL_INVESTIGATOR
affiliation: CHU Brest
name: Erwan L'Her
role: PRINCIPAL_INVESTIGATOR
affiliation: CHU Dijon
name: Belaïd Bouhemad
role: PRINCIPAL_INVESTIGATOR
affiliation: CHU Montpellier - Lapeyronie
name: Boris Jung
role: PRINCIPAL_INVESTIGATOR
affiliation: CHU Poitiers
name: Claire Dahyot-Fizelier
role: PRINCIPAL_INVESTIGATOR
affiliation: Hopital Diaconesses - La Croix Simon
name: Claire Lhommet
role: PRINCIPAL_INVESTIGATOR
affiliation: CH Dunkerque
name: Caroline Varillon
role: PRINCIPAL_INVESTIGATOR
affiliation: CHU Lille
name: Arthur Durand
role: PRINCIPAL_INVESTIGATOR
affiliation: APHM - La Timone
name: Marc Gainnier
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital Valenciennes
name: Fabien Lambiotte
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital, Saint Nazaire
name: Julien Lorber
role: PRINCIPAL_INVESTIGATOR
affiliation: HOSPITAL, SAINTES
name: Delphine Brégeaud
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital Martigues
name: Aziz Berrouba
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital Belfort
name: Julio Badie
role: PRINCIPAL_INVESTIGATOR
affiliation: HOSPITAL, CHARTRES
name: Alexandre Conia
role: PRINCIPAL_INVESTIGATOR
affiliation: University Hospital, Clermont-Ferrand
name: François Thouy
role: PRINCIPAL_INVESTIGATOR
References: