Acute Respiratory Distress Syndrome
Conditions
Keywords
ARDS, Sedation, Inhaled sevoflurane
Brief summary
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.
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.
Interventions
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).
DRUGIntravenous 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).
Sponsors
University Hospital, Clermont-Ferrand
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Masking description
Patients will be followed up for primary and secondary endpoints by members of the research staff who will be unaware of the trial group allocation. Information on whether the primary and secondary outcomes occur will be collected and entered into the electronic web-based case report form (eCRF) by trial or clinical trained personal (clinical research associate), blinded to the allocation group, under the supervision of the local principal investigator (PI) or designee who will also be unaware of the trial group allocation. Finally, the independent trial statistician and the members of the data monitoring and safety committee (DMSC) will also remain blinded for the allocation during analysis. However, the observation of differences in serious adverse events between the two groups will allow, for safety reasons may the DMSC deem necessary, to unblind allocation groups.
Intervention model description
Investigator-initiated, single-center, prospective, randomized, stratified, parallel-group clinical trial with blinded outcome assessment and concealed allocation of patients at risk of developing the ARDS to a strategy of inhaled sedation with sevoflurane or to a strategy of current intravenous sedation practice.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| PaO2/FiO2 ratio | within 5 days from randomization | longitudinal evolution in the PaO2/FiO2 ratio |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Rate of pneumonia | Presence of pneumonia will be assessed daily until Day 5, and at Day 28 or ICU discharge, whichever comes first. | 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. |
| Ventilator-free days to day 28 | 28 days after randomization | 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. |
| Organ failure to day 5 | 5 days after randomization | 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. |
| Mortality at day 28 | 28 days after randomization | The occurrence of death in the ICU will be recorded until day 28. |
| Length of ICU-stay up to 28 days | 28 days after randomization | The total number of days from admission to ICU discharge will be recorded until day 28 |
| Physiological measures: Oxygenation | 28 days after randomization | \- Oxygenation Index on study days 1-5 |
| Physiological measures: PaCO2 | 28 days after randomization | \- PaCO2 on study days 1-5 |
| Physiological measures: pH | 28 days after randomization | \- Arterial pH on study days 1-5 |
| Physiological measures: PEEP | 28 days after randomization | \- Level of PEEP (and static auto-PEEP in patients under controlled ventilation) on study days 1-5 |
| Progression to ARDS | within 5 days from randomization | Progression to ARDS will be assessed according to the Berlin criteria, including chest radiographs |
| Physiological measures: Pneumothorax | 28 days after randomization | \- Development of pneumothorax through day 28 |
| Physiological measures: Switch from controlled to pressure-support ventilation | 28 days after randomization | \- Time to switching from controlled to pressure-support ventilation through day 5 |
| Physiological measures: Airway occlusion pressure | 28 days after randomization | \- 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 |
| Hemodynamic measures | 28 days after randomization | \- Hemodynamic measures (mean arterial pressure, dose of infused norepinephrine or other vasopressor, serum lactate level) on study days 1-5 |
| Physiological measures: Acute kidney injury | 28 days after randomization | \- KDIGO criteria for acute kidney injury 24 through day 5 |
| Physiological measures: Supraventricular tachycardia | 28 days after randomization | \- Supraventricular tachycardia (SVT) or new onset atrial fibrillation through day 5 |
| ICU-acquired delirium | 28 days after randomization | 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. |
| Biomarker measurements | from inclusion to 5 days | 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. |
| Physiological measures: Plateau pressure | 28 days after randomization | \- Plateau pressure, static compliance of the respiratory system on study day 1-5 |
Countries
France
Contacts
Primary ContactLise Laclautre
Outcome results
None listed