Clinical trial NCT04023305: Sevoflurane PharmacokInetics in ARDS
Official title: Sevoflurane pharmacokInetics During Inhaled Sedation Relies on the Morphotype of ARDS in ICU Patients
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: NA
Conditions: Acute Respiratory Distress Syndrome
Keywords: Nonfocal Acute respiratory distress syndrome
Focal Acute respiratory distress syndrome
Sevoflurane
Pharmacokinetics
Mechanical ventilation
Lead sponsor: University Hospital, Clermont-Ferrand
Sponsor class: OTHER
First posted: 2019-07-17
Enrollment: 37
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Inhaled sedation with sevoflurane, will be vaporized via the miniaturized Anesthesia Conserving Device (AnaConDa-S®, Sedana Medical, Uppsala, Sweden).

Sevoflurane infusion rate will be adapted from manufacturer's instructions in order to reach a target of expired sevoflurane fraction (FEsevo) of 0.8-1.1.

Mechanical ventilation will be protocolized in both arms, based on recent results of a RCT from our group, in which 90-day survival was improved in patients with nonfocal ARDS when an individualized ventilation strategy was applied, compared to the ARDSNet strategy (PEEP set according to FiO2). We will recommend sites wait at least 12 hours before proning, as in the PROSEVA study.

In both groups, patients will receive cisatracurium besylate for neuromuscular blockade, and deep sedation will be protocolized to Richmond Agitation-Sedation Scale (RASS) of -4 to -5 (Ramsay of 5-6, or Riker of 1-2) before starting, and during, the cisatracurium besylate infusion.
Primary purpose: TREATMENT

Brief summary: The main objective of this study is to compare the pharmacokinetic models of sevoflurane-induced sedation during ARDS depending on the lung imaging phenotype (focal vs nonfocal phenotypes) The authors hypothesized that sevoflurane used for inhaled sedation could have distinct pharmacokinetic profiles depending on lung imaging phenotypes (focal vs nonfocal) during ARDS in ICU patients.

Detailed description: Adult patients admitted to the ICU within 12 hours of moderate-severe ARDS onset and under sedation with sevoflurane will be enrolled in the study with inclusion criteria. They will be enrolled, depending on their morphotype (focal or nonfocal), as routinely assessed in participating centers using CT-scan, chest x-ray and/or lung ultrasound.

These patients will receive inhaled sevoflurane as a standard practice of sedation that is routinely used in participating ICUs. After inclusion, the mechanical ventilation protocol must be initiated within two hours (if not already being used). In both groups, deep sedation followed by neuromuscular blockade must be initiated within four hours of inclusion.

Adult patients admitted to the ICU within 12 hours of moderate-severe ARDS onset and under sedation with sevoflurane will be enrolled in the study with inclusion criteria. They will be enrolled, depending on their morphotype (focal or nonfocal), as routinely assessed in participating centers using CT-scan, chest x-ray and/or lung ultrasound.

These patients will receive inhaled sevoflurane as a standard practice of sedation that is routinely used in participating ICUs. After inclusion, the mechanical ventilation protocol must be initiated within two hours (if not already being used). In both groups, deep sedation followed by neuromuscular blockade must be initiated within four hours of inclusion.

Blood sample will be collected at different times after the onset of sevoflurane administration and after its cessation.

Eligibility criteria: Inclusion Criteria:

* Age ≥18 years
* Presence for ≤ 12 hours of all of the following conditions, within one week of a clinical insult or new or worsening respiratory symptoms :

a PaO2/FiO2 \< 200 mmHg with positive end-expiratory pressure (PEEP) ≥ 8 cmH2O (or, if arterial blood gas not available : SpO2/FiO2 ratio that is equivalent to a PaO2/FiO2 \< 200 mmHg with PEEP ≥8 cmH2O, and a confirmatory SpO2/FiO2 ratio between 1-6 hours after the initial SpO2/FiO2 ratio determination) b Bilateral opacities not fully explained by effusions, lobar/lung collapse, or nodules c 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:

* Lack of informed consent
* Continuous sedation with inhaled sevoflurane at enrollment
* 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
* Tidal volume of 6 mL/kg predicted body weight (PBW) below 200 mL
* Decision to withhold life-sustaining treatment; except in those patients committed to full support except cardiopulmonary resuscitation
* 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
* Medical history of malignant hyperthermia
* Suspected or proven intracranial hypertension
* Know pregnancy - Pregnancy testing will be systematically performed to rule out pregnancy in female patients of reproductive age
* Enrollment in another interventional ARDS trial with direct impact on sedation and PEEP
* Endotracheal ventilation for greater than 120 hours (5 days)
* PaO2/FiO2 (if available) \> 200 mmHg after meeting inclusion criteria and before start of the study

Primary outcomes:
measure: Plasma concentrations of sevoflurane
timeFrame: 5 minutes after the detection by the monitor of sevoflurane (0.1%) in the breathing circuit
measure: Plasma concentrations of sevoflurane
timeFrame: 30 minutes after the detection by the monitor of sevoflurane (0.1%) in the breathing circuit
measure: Plasma concentrations of sevoflurane
timeFrame: 1 hour after the detection by the monitor of sevoflurane (0.1%) in the breathing circuit
measure: Plasma concentrations of sevoflurane
timeFrame: 6 hours after the detection by the monitor of sevoflurane (0.1%) in the breathing circuit
measure: Plasma concentrations of sevoflurane
timeFrame: 24 hours after the detection by the monitor of sevoflurane (0.1%) in the breathing circuit
measure: Plasma concentrations of sevoflurane
timeFrame: 48 hours after the detection by the monitor of sevoflurane (0.1%) in the breathing circuit
measure: Plasma concentrations of sevoflurane
timeFrame: 5 minutes after the cessation of sevoflurane administration
measure: Plasma concentrations of sevoflurane
timeFrame: 30 minutes after the cessation of sevoflurane administration
measure: Plasma concentrations of sevoflurane
timeFrame: 1 hour after the cessation of sevoflurane administration
measure: Plasma concentrations of sevoflurane
timeFrame: 4 hours after the cessation of sevoflurane administration
measure: Plasma concentrations of sevoflurane
timeFrame: 6 hours after the cessation of sevoflurane administration
Secondary outcomes:
measure: Plasma concentration of hexafluoroisopropanolol
timeFrame: Until sedation can be definitely interrupted or until day 7
measure: Fraction of inspired sevoflurane
timeFrame: Until sedation can be definitely interrupted or until day 7
measure: Fraction of expired sevoflurane
timeFrame: Until sedation can be definitely interrupted or until day 7
measure: Dose of sevoflurane
timeFrame: Until sedation can be definitely interrupted or until day 7
measure: Infusion duration of sevoflurane
timeFrame: Until sedation can be definitely interrupted or until day 7
measure: Infusion rate of remifentanil
timeFrame: Until sedation can be definitely interrupted or until day 7
measure: Values of a bispectral index
timeFrame: Until sedation can be definitely interrupted or until day 7
Other outcomes:
Locations:
city: Clermont-Ferrand
country: France
facility: Centre Jean Perrin
city: Clermont-Ferrand
country: France
facility: CHU
city: Paris
country: France
facility: APHP - University hospital of Saint-Louis
Study officials:
affiliation: University Hospital, Clermont-Ferrand
name: Raiko Blondonnet, MD, MSc
role: PRINCIPAL_INVESTIGATOR
References: