SEvoflurane for Sedation in ARds

Acute Respiratory Distress Syndrome Clinical Trial

— SESAR  

Official title:

Sevoflurane for Sedation in Acute Respiratory Distress Syndrome: A Multicenter Prospective Randomized Trial

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04235608
• Other study ID #: SESAR - RBHP 2018 JABAUDON
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: May 3, 2020
• Est. completion date: October 2, 2024

Study information

• Verified date: June 2024
• Source: University Hospital, Clermont-Ferrand
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 700
• Est. completion date: October 2, 2024
• Est. primary completion date: October 31, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Acute Lung Injury
• Acute Respiratory Distress Syndrome
• Respiratory Distress Syndrome
• Respiratory Distress Syndrome, Newborn
• Syndrome

Intervention

Drug:
• Inhaled sedation with sevoflurane
Inhaled sedation with sevoflurane using the Anesthesia Conserving Device (AnaConDa-S, Sedana Medical, Danderyd, Sweden).
• intravenous sedation with propofol
intravenous sedation with propofol, as already routinely used in participating ICUs.

Locations

Country	Name	City	State
France	University Hospital	Amiens
France	University Hospital	Angers
France	Hospital Belfort	Belfort
France	Hospital	Béthune
France	Cavale Blanche Hospital - University Hospital	Brest
France	Hospital	Cannes
France	Hospital Chartres	Chartres
France	University Hospital,	Clermont Ferrand
France	Jean Perrin Comprehensive Cancer Center	Clermont-Ferrand
France	University Hospital	Clermont-Ferrand
France	University Hospital	Dijon
France	Hospital	Dunkerque
France	Salengro Hospital - University Hospital	Lille
France	Timone Hospital - Assistance Publique-Hôpitaux	Marseille
France	Hospital Martigues	Martigues
France	Hospital	Melun
France	Lapeyronie Hospital - University Hospital	Montpellier
France	Saint-Eloi Hospital - University Hospital	Montpellier
France	Hotel Dieu Hospital - University Hospital	Nantes
France	Pasteur 2 Hospital - University Hospital	Nice
France	Carémeaux Hospital - University Hospita	Nîmes
France	Diaconesses - La Croix Simon Hospital	Paris
France	Pitié-Salpêtrière Hospital, - Assistance Publique-Hôpitaux	Paris
France	Saint-Antoine University Hospital - Assistance Publique-Hôpitaux	Paris
France	Saint-Louis University Hospital - Assistance Publique-Hôpitaux	Paris
France	University Hospital	Poitiers
France	University Hospital	Reims
France	University Hospital	Rennes
France	Hospital	Saint-Brieuc
France	Hospital Saint-Nazaire	Saint-Nazaire
France	Hospital	Saintes
France	Hautepierre Hospital, University Hospitals	Strasbourg
France	Hospital Valenciennes	Valenciennes

Sponsors (1)

Lead Sponsor	Collaborator
University Hospital, Clermont-Ferrand

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Ventilator-free days through day 14 (Exploratory outcome)	Number of days alive and off the ventilator at 14 days, thereby considering death as a competing event	Day 14
Other	Ventilator-free days through day 7 (Exploratory outcome)	Number of days alive and off the ventilator at 7 days, thereby considering death as a competing event	Day 7
Other	Organ failure-free days through day 7 (Exploratory outcome)	Organ failure is defined as present on any date 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 for development of organ failures to death, hospital discharge or study day 7, whichever comes first. Each day a patient is alive and free of a given organ failure will be scored as a failure-free day. Any day that a patient is alive and free of all organ failures will represent days alive and free of all organ failure.	Day 7
Other	ICU-free days through day 28 (Exploratory outcome)		Day 28
Other	Hospital-free days through day 28 (Exploratory outcome)		Day 28
Other	Changes in oxygenation index through day 7 (Exploratory outcome)		Day 7
Other	Changes in PaO2/FiO2 through day 7 (Exploratory outcome)		Day 7
Other	Changes in PaCO2 through day 7 (Exploratory outcome)		Day 7
Other	Changes in arterial pH through day 7 (Exploratory outcome)		Day 7
Other	Changes in PEEP through day 7 (Exploratory outcome)		Day 7
Other	Changes in inspiratory plateau pressure through day 7 (Exploratory outcome)		Day 7
Other	Changes in static compliance of the respiratory system through day 7 (Exploratory outcome)		Day 7
Other	Changes in ventilatory ratio through day 7 (Exploratory outcome)		Day 7
Other	Use of rescue procedures for refractory hypoxemia through day 28 (Exploratory outcome)	Rescue procedures will be chosen according to the practice at clinical sites: nitric oxide, epoprostenol sodium, high frequency ventilation, use of neuromuscular blockade after 48 h from randomization, and extracorporeal membrane oxygenation.	Day 28
Other	ICU-acquired delirium through day 7 (Exploratory outcome)	Confusion Assessment Method for the ICU (CAM-ICU) assessed daily from study entry to study day 7, death or ICU discharge, whichever comes first.	Day 7
Other	Disability at 3 months (Exploratory outcome)	Katz Activities of Daily Living (ADL)	Day 90
Other	Disability at 12 months (Exploratory outcome)	Katz Activities of Daily Living (ADL)	Day 365
Other	Health-Related Quality of Life at 3 months (Exploratory outcome)	Short Form-36 (SF-36)	Day 90
Other	Health-Related Quality of Life at 12 months (Exploratory outcome)	Short Form-36 (SF-36)	Day 365
Other	Self-rated health at 3 months (Exploratory outcome)	Health questionnaire (1 standard item)	Day 90
Other	Self-rated health at 12 months (Exploratory outcome)	Health questionnaire (1 standard item)	Day 365
Other	Pain-interference at 3 months (Exploratory outcome)	Pain-interference (1 standard item)	Day 90
Other	Pain-interference at 12 months (Exploratory outcome)	Pain-interference (1 standard item)	Day 365
Other	Post-Traumatic Stress Symptoms-14 at 3 months (Exploratory outcome)		Day 90
Other	Hospital Anxiety and Depression Scale at 3 months (Exploratory outcome)		Day 90
Other	Post-Traumatic Stress Symptoms-14 at 12 months (Exploratory outcome)		Day 365
Other	Hospital Anxiety and Depression Scale at 12 months (Exploratory outcome)		Day 365
Other	Cognitive function at 3 months (Exploratory outcome)	Alzheimer's Disease-8	Day 90
Other	Cognitive function at 12 months (Exploratory outcome)	Alzheimer's Disease-8	Day 365
Other	Subsequent return to work, hospital and emergency department use, and location of residence at 3 months (Exploratory outcome)		Day 90
Other	Subsequent return to work, hospital and emergency department use, and location of residence at 12 months (Exploratory outcome)		Day 365
Other	Healthcare-related costs during ICU stay (Exploratory outcome)		Through study completion, an average of 1 year
Other	Healthcare-related costs during hospital stay (Exploratory outcome)		Through study completion, an average of 1 year
Other	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)	Changes over time (as measured at study entry and on days 1, 2, 4, 6 and 14 or ICU discharge, whichever occurs first)	Day 14
Other	Change in urine biomarkers of TIMP-2 and IGFBP-7 (acute kidney injury) though day 14 (Exploratory biological outcome)	Changes over time (as measured at study entry and on days 1, 2, 4, 6 and 14 or ICU discharge, whichever occurs first)	Day 14
Other	Change in plasma total fluoride and hexafluoroisopropanol (sevoflurane metabolism) though day 14 (Exploratory biological outcome)	Changes over time (as measured at study entry and on days 1, 2, 4, 6 and 14 or ICU discharge, whichever occurs first)	Day 14
Other	Genetic analysis: DNA and RNA expressions through day 2 (Exploratory biological outcome)	Whole blood will be collected at baseline and at 48 h for RNA and DNA studies	Day 2
Other	Total protein level within undiluted pulmonary edema fluid (alveolar fluid clearance) through day 1 (Exploratory biological outcome)	Undiluted pulmonary edema fluid will be collected at baseline and 24 h from 50 patients from each group	Day 1
Other	Biomarker measurements in the fluid from heat moisture exchanger filters (control group) or AnaConDa-S devices (intervention group) through day 1 (Exploratory biological outcome)	Heat moisture exchanger filter or AnaConDa-S devices will be collected at 24 h in 30 patients randomized to the control group and 30 patients randomized to intervention group	Day 1
Other	Biomarker measurements in the broncho-alveolar lavage fluid through day 6 (Exploratory biological outcome)	Broncho-alveolar lavage fluid samples will be collected from a total of 25 patients within 48 h from study entry and between day 4 and day 6 after randomization	Day 6
Other	Hemodynamic measures (mean arterial pressure) through day 7 (Safety outcome)		Day 7
Other	Hemodynamic measures (dose of infused norepinephrine or other vasopressor) through day 7 (Safety outcome)		Day 7
Other	Hemodynamic measures (serum lactate level) through day 7 (Safety outcome)		Day 7
Other	Measures of renal function (KDIGO criteria for acute kidney injury) through day 7 (Safety outcome)		Day 7
Other	Supraventricular tachycardia or new onset atrial fibrillation through day 7 (Safety outcome)		Day 7
Other	Severe hypercapnic acidosis with arterial pH <7.15 through day 7 (Safety outcome)		Day 7
Other	Development of malignant hyperthermia through day 7 (Safety outcome)		Day 7
Other	Development of propofol-related infusion syndrome through day 7 (Safety outcome)		Day 7
Other	Development of pneumothorax or bronchopleural fistula persistent despite drainage through day 7 (Safety outcome)		Day 7
Primary	Ventilator-free days through day 28	Number of days alive and off the ventilator at 28 days, thereby considering death as a competing event	Day 28
Secondary	90-day survival (Key secondary outcome)		Day 90
Secondary	All-cause, all-location 28-day mortality (Secondary outcome)		Day 28
Secondary	All-cause hospital 28-day mortality (Secondary outcome)		Day 28
Secondary	All-cause, all-location 14-day mortality (Secondary outcome)		Day 14
Secondary	All-cause, all-location 7-day mortality (Secondary outcome)		Day 7