Effects of SEvoflurane on Gas Exchange and Inflammation in Patients With ARDS (SEGA Study)

Study Overview
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Brief Summary
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Numerous trials support the efficacy and safety of volatile anesthetic agents, namely inhalation of sevoflurane through dedicated devices, for the sedation of ICU patients. Several preclinical studies have shown that sevoflurane inhalation improves gas exchange and decreases pulmonary and systemic inflammation in experimental models of acute respiratory distress syndrome (ARDS). The purpose of our prospective monocentric, randomized, controlled trial is to evaluate the effects of an early 48-hour sevoflurane inhalation on gas exchange and inflammation in patients with ARDS.

Detailed Description
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BACKGROUND: Acute respiratory distress syndrome (ARDS) is characterized by hypoxemic respiratory failure that can be lethal in 30 to 60% of patients. Its pathophysiological landmark, diffuse alveolar damage, is associated with alveolar inflammation, epithelial injury and alveolar fluid clairance impairment. Several preclinical studies have shown that early sevoflurane inhalation improves gas exchange, reduces alveolar edema and attenuates pulmonary and systemic inflammation in experimental models of ARDS. To date, no clinical trial has assessed the effects of early sevoflurane inhalation in ARDS patients. DESIGN NARRATIVE: The purpose of this prospective, randomized, controlled study is to evaluate the effects of a 48-hour sevoflurane inhalation strategy on gas exchange and both systemic and pulmonary inflammation in the early phase of ARDS. After inclusion, ICU patients with moderate to severe ARDS (according to the Berlin definition of ARDS criteria; JAMA 2010) will be randomized into two groups : a conventional group, in which intravenous sedation with midazolam will be administered a sevoflurane group, in which patients will inhale sevoflurane during a 48 hour-period, through dedicated devices Arterial blood gases will be analyze before randomization and at 24, 48, 72, 96, and 120 hours. Bronchoalveolar lavages (BAL) and blood samples will be assessed before randomization and at 48 hours, in order to measure tumor necrosis factor-alpha (TNFα), interleukin (IL)-1β, IL-6, IL-8 and sRAGE levels. Duplicate assays will be performed with Multiplex (TNFα/interleukins) or ELISA (sRAGE). During the 48-hour treatment period, bispectral index (BIS®) values ranging from 40 to 50 will be targeted and neuromuscular blocking agents (cisatracurium) will be administered in both groups. Protective ventilation strategies will be applied, as well as other guidelines or recommendations on the management of ICU patients with ARDS.

Official Title
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Effect of Early 48-hour Sevoflurane Inhalation on Gas Exchange and Inflammation in Patients Presenting With Acute Respiratory Distress Syndrome (ARDS) : a Monocentric, Prospective, Randomized Study.

Conditions
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Acute Respiratory Distress Syndrome

Intervention / Treatment
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* Drug: sevoflurane
* Drug: midazolam


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with criteria for moderate to severe ARDS since less than 24 hours ( Informed consent Exclusion Criteria: Suspected or proven intracranial hypertension Midazolam, sevoflurane or cisatracurium allergy Medical history of malignant hyperthermia Severe liver failure Chemotherapy treatment in the last month Severe neutropenia (< 0.5 G/l)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: conventional group<br>a conventional group, in which intravenous sedation with midazolam will be administered | Drug: midazolam<br>* Sedation with intravenous midazolam<br>|
| Experimental: sevoflurane group<br>a sevoflurane group, in which patients will inhale sevoflurane during a 48 hour-period, through dedicated devices | Drug: sevoflurane<br>* Sedation with inhaled sevoflurane<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PaO2/FiO2 ratio |  | at 48 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| - Plasma and alveolar levels of proinflammatory cytokines : tumor necrosis factor alpha (TNFα, interleukin (IL)-1β, IL-6, IL-8 |  | at 48 hours | 
| Plasma and alveolar levels of sRAGE |  | at 48 hours | 
| PaO2/FiO2 ratio |  | at day 1, day 3, day 5 | 
| Lowest PaO2/FiO2 during the first 5 days of the study |  | at 5 days | 
| Mean PaO2/FiO2 ratio during the first 5 days of the study |  | at 5 days | 
| Pulmonary static compliance, resistance and elastance |  | at day 1, day 2 | 
| Duration of controlled mechanical ventilation |  | at day 30 | 
| Total duration of mechanical ventilation (controlled/assisted) |  | at day 30 | 
| Number of ventilatory-free days |  | at day 30 | 
| Number of organ failure-free days |  | at day 30 | 
| Vasopressor requirements |  | at 48 hours | 
| Mortality |  | at day 30 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Acute respiratory distress syndrome (ARDS), Sevoflurane, Mechanical ventilation, Intensive Care Unit (ICU), Prospective study, Lung injury, Gas exchange, Inflammation, Receptor for advanced glycation end-produts (RAGE), sRAGE