SESAR: SEvoflurane for Sedation in ARds
Study Details
Study Description
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 3 |
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.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: inhaled sedation with sevoflurane Inhaled sedation with sevoflurane, as vaporized via the Anesthesia Conserving Device (AnaConDa-S, Sedana Medical, Danderyd, Sweden) |
Drug: Inhaled sedation with sevoflurane
Inhaled sedation with sevoflurane using the Anesthesia Conserving Device (AnaConDa-S, Sedana Medical, Danderyd, Sweden).
|
| Active Comparator: intravenous sedation with propofol intravenous sedation with propofol, as already routinely used in participating ICUs |
Drug: intravenous sedation with propofol
intravenous sedation with propofol, as already routinely used in participating ICUs.
|
Outcome Measures
Primary Outcome Measures
- Ventilator-free days through day 28 [Day 28]
Number of days alive and off the ventilator at 28 days, thereby considering death as a competing event
Secondary Outcome Measures
- 90-day survival (Key secondary outcome) [Day 90]
- All-cause, all-location 28-day mortality (Secondary outcome) [Day 28]
- All-cause hospital 28-day mortality (Secondary outcome) [Day 28]
- All-cause, all-location 14-day mortality (Secondary outcome) [Day 14]
- All-cause, all-location 7-day mortality (Secondary outcome) [Day 7]
Other Outcome Measures
- Ventilator-free days through day 14 (Exploratory outcome) [Day 14]
Number of days alive and off the ventilator at 14 days, thereby considering death as a competing event
- Ventilator-free days through day 7 (Exploratory outcome) [Day 7]
Number of days alive and off the ventilator at 7 days, thereby considering death as a competing event
- Organ failure-free days through day 7 (Exploratory outcome) [Day 7]
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.
- ICU-free days through day 28 (Exploratory outcome) [Day 28]
- Hospital-free days through day 28 (Exploratory outcome) [Day 28]
- Changes in oxygenation index through day 7 (Exploratory outcome) [Day 7]
- Changes in PaO2/FiO2 through day 7 (Exploratory outcome) [Day 7]
- Changes in PaCO2 through day 7 (Exploratory outcome) [Day 7]
- Changes in arterial pH through day 7 (Exploratory outcome) [Day 7]
- Changes in PEEP through day 7 (Exploratory outcome) [Day 7]
- Changes in inspiratory plateau pressure through day 7 (Exploratory outcome) [Day 7]
- Changes in static compliance of the respiratory system through day 7 (Exploratory outcome) [Day 7]
- Changes in ventilatory ratio through day 7 (Exploratory outcome) [Day 7]
- Use of rescue procedures for refractory hypoxemia through day 28 (Exploratory outcome) [Day 28]
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.
- ICU-acquired delirium through day 7 (Exploratory outcome) [Day 7]
Confusion Assessment Method for the ICU (CAM-ICU) assessed daily from study entry to study day 7, death or ICU discharge, whichever comes first.
- Disability at 3 months (Exploratory outcome) [Day 90]
Katz Activities of Daily Living (ADL)
- Disability at 12 months (Exploratory outcome) [Day 365]
Katz Activities of Daily Living (ADL)
- Health-Related Quality of Life at 3 months (Exploratory outcome) [Day 90]
Short Form-36 (SF-36)
- Health-Related Quality of Life at 12 months (Exploratory outcome) [Day 365]
Short Form-36 (SF-36)
- Self-rated health at 3 months (Exploratory outcome) [Day 90]
Health questionnaire (1 standard item)
- Self-rated health at 12 months (Exploratory outcome) [Day 365]
Health questionnaire (1 standard item)
- Pain-interference at 3 months (Exploratory outcome) [Day 90]
Pain-interference (1 standard item)
- Pain-interference at 12 months (Exploratory outcome) [Day 365]
Pain-interference (1 standard item)
- Post-Traumatic Stress Symptoms-14 at 3 months (Exploratory outcome) [Day 90]
- Hospital Anxiety and Depression Scale at 3 months (Exploratory outcome) [Day 90]
- Post-Traumatic Stress Symptoms-14 at 12 months (Exploratory outcome) [Day 365]
- Hospital Anxiety and Depression Scale at 12 months (Exploratory outcome) [Day 365]
- Cognitive function at 3 months (Exploratory outcome) [Day 90]
Alzheimer's Disease-8
- Cognitive function at 12 months (Exploratory outcome) [Day 365]
Alzheimer's Disease-8
- Subsequent return to work, hospital and emergency department use, and location of residence at 3 months (Exploratory outcome) [Day 90]
- Subsequent return to work, hospital and emergency department use, and location of residence at 12 months (Exploratory outcome) [Day 365]
- Healthcare-related costs during ICU stay (Exploratory outcome) [Through study completion, an average of 1 year]
- Healthcare-related costs during hospital stay (Exploratory outcome) [Through study completion, an average of 1 year]
- 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) [Day 14]
Changes over time (as measured at study entry and on days 1, 2, 4, 6 and 14 or ICU discharge, whichever occurs first)
- Change in urine biomarkers of TIMP-2 and IGFBP-7 (acute kidney injury) though day 14 (Exploratory biological outcome) [Day 14]
Changes over time (as measured at study entry and on days 1, 2, 4, 6 and 14 or ICU discharge, whichever occurs first)
- Change in plasma total fluoride and hexafluoroisopropanol (sevoflurane metabolism) though day 14 (Exploratory biological outcome) [Day 14]
Changes over time (as measured at study entry and on days 1, 2, 4, 6 and 14 or ICU discharge, whichever occurs first)
- Genetic analysis: DNA and RNA expressions through day 2 (Exploratory biological outcome) [Day 2]
Whole blood will be collected at baseline and at 48 h for RNA and DNA studies
- Total protein level within undiluted pulmonary edema fluid (alveolar fluid clearance) through day 1 (Exploratory biological outcome) [Day 1]
Undiluted pulmonary edema fluid will be collected at baseline and 24 h from 50 patients from each group
- Biomarker measurements in the fluid from heat moisture exchanger filters (control group) or AnaConDa-S devices (intervention group) through day 1 (Exploratory biological outcome) [Day 1]
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
- Biomarker measurements in the broncho-alveolar lavage fluid through day 6 (Exploratory biological outcome) [Day 6]
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
- Hemodynamic measures (mean arterial pressure) through day 7 (Safety outcome) [Day 7]
- Hemodynamic measures (dose of infused norepinephrine or other vasopressor) through day 7 (Safety outcome) [Day 7]
- Hemodynamic measures (serum lactate level) through day 7 (Safety outcome) [Day 7]
- Measures of renal function (KDIGO criteria for acute kidney injury) through day 7 (Safety outcome) [Day 7]
- Supraventricular tachycardia or new onset atrial fibrillation through day 7 (Safety outcome) [Day 7]
- Severe hypercapnic acidosis with arterial pH <7.15 through day 7 (Safety outcome) [Day 7]
- Development of malignant hyperthermia through day 7 (Safety outcome) [Day 7]
- Development of propofol-related infusion syndrome through day 7 (Safety outcome) [Day 7]
- Development of pneumothorax or bronchopleural fistula persistent despite drainage through day 7 (Safety outcome) [Day 7]
Eligibility Criteria
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
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | University Hospital | Amiens | France | ||
| 2 | University Hospital | Angers | France | ||
| 3 | Hospital Belfort | Belfort | France | ||
| 4 | Cavale Blanche Hospital - University Hospital | Brest | France | ||
| 5 | Hospital | Béthune | France | ||
| 6 | Hospital | Cannes | France | ||
| 7 | Hospital Chartres | Chartres | France | ||
| 8 | University Hospital, | Clermont Ferrand | France | 63011 | |
| 9 | Jean Perrin Comprehensive Cancer Center | Clermont-Ferrand | France | ||
| 10 | University Hospital | Clermont-Ferrand | France | ||
| 11 | University Hospital | Dijon | France | ||
| 12 | University Hospital | Dijon | France | ||
| 13 | Hospital | Dunkerque | France | ||
| 14 | Salengro Hospital - University Hospital | Lille | France | ||
| 15 | Timone Hospital - Assistance Publique-Hôpitaux | Marseille | France | ||
| 16 | Timone Hospital - Assistance Publique-Hôpitaux | Marseille | France | ||
| 17 | Hospital Martigues | Martigues | France | ||
| 18 | Hospital | Melun | France | 77000 | |
| 19 | Lapeyronie Hospital - University Hospital | Montpellier | France | ||
| 20 | Saint-Eloi Hospital - University Hospital | Montpellier | France | ||
| 21 | Hotel Dieu Hospital - University Hospital | Nantes | France | ||
| 22 | Pasteur 2 Hospital - University Hospital | Nice | France | ||
| 23 | Carémeaux Hospital - University Hospita | Nîmes | France | ||
| 24 | Diaconesses - La Croix Simon Hospital | Paris | France | ||
| 25 | Pitié-Salpêtrière Hospital, - Assistance Publique-Hôpitaux | Paris | France | ||
| 26 | Saint-Antoine University Hospital - Assistance Publique-Hôpitaux | Paris | France | ||
| 27 | Saint-Louis University Hospital - Assistance Publique-Hôpitaux | Paris | France | ||
| 28 | University Hospital | Poitiers | France | ||
| 29 | University Hospital | Poitiers | France | ||
| 30 | University Hospital | Reims | France | ||
| 31 | University Hospital | Rennes | France | ||
| 32 | Hospital | Saint-Brieuc | France | ||
| 33 | Hospital Saint-Nazaire | Saint-Nazaire | France | ||
| 34 | Hospital | Saintes | France | ||
| 35 | Hautepierre Hospital, University Hospitals | Strasbourg | France | ||
| 36 | University Hospital Tours | Tours | France | ||
| 37 | Hospital Valenciennes | Valenciennes | France |
Sponsors and Collaborators
- University Hospital, Clermont-Ferrand
Investigators
- Study Chair: Matthieu Jabaudon, University Hospital, Clermont-Ferrand
- Principal Investigator: Raïko Blondonnet, University Hospital, Clermont-Ferrand
- Principal Investigator: Jean-Michel Constantin, APHP - La Pitié Salpêtrière
- Principal Investigator: Antoine Roquilly, CHU Nantes
- Principal Investigator: Samir Jaber, CHU Montpellier - Saint-Eloi
- Principal Investigator: Virginie Lemiale, APHP - Saint-Louis
- Principal Investigator: Carole Ichai, CHU Nice
- Principal Investigator: Lionel Velly, APHM - La Timone
- Principal Investigator: Stéphanie Bulyez, CHU Nîmes
- Principal Investigator: Sigismond Lasocki, University Hospital, Angers
- Principal Investigator: Jean-Pierre Quenot, CHU Dijon
- Principal Investigator: Thomas Lebouvier, CHU Rennes
- Principal Investigator: François Legay, CH Brieuc
- Principal Investigator: Arnaud W. Thille, CHU Poitiers
- Principal Investigator: Alexandre Lautrette, Centre Jean-Perrin Clermont-Ferrand
- Principal Investigator: Julien Pottecher, CHU Strasbourg
- Principal Investigator: Marc Garnier, APHP - Saint-Antoine
- Principal Investigator: Christophe Vinsonneau, CH Béthune
- Principal Investigator: Pierre-Marie Bertrand, CH Cannes
- Principal Investigator: Mehran Monchi, CH Melun-Sénart
- Principal Investigator: Joël Cousson, CHU Reims
- Principal Investigator: Julien Maizel, CHU Amiens
- Principal Investigator: Erwan L'Her, CHU Brest
- Principal Investigator: Belaïd Bouhemad, CHU Dijon
- Principal Investigator: Boris Jung, CHU Montpellier - Lapeyronie
- Principal Investigator: Claire Dahyot-Fizelier, CHU Poitiers
- Principal Investigator: Claire Lhommet, Hopital Diaconesses - La Croix Simon
- Principal Investigator: Caroline Varillon, CH Dunkerque
- Principal Investigator: Arthur Durand, CHU Lille
- Principal Investigator: Marc Gainnier, APHM - La Timone
- Principal Investigator: Fabien Lambiotte, Hospital Valenciennes
- Principal Investigator: Julien Lorber, Hospital, Saint Nazaire
- Principal Investigator: Delphine Brégeaud, HOSPITAL, SAINTES
- Principal Investigator: Aziz Berrouba, Hospital Martigues
- Principal Investigator: Julio Badie, Hospital Belfort
- Principal Investigator: Alexandre Conia, HOSPITAL, CHARTRES
- Principal Investigator: Martine Ferrandière, Hospital Tours
- Principal Investigator: François Thouy, University Hospital, Clermont-Ferrand
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- SESAR - RBHP 2018 JABAUDON