Moderate to Severe Acute Respiratory Distress Syndrome
Conditions
Brief summary
The improved survival of patients with acute respiratory distress syndrome (ARDS) over the last decades is related to the use of so-called protective mechanical ventilation. Two therapies have been shown to increase survival among the most hypoxemic patients (PaO2/FiO2 \< 150 mmHg): a continuous use of neuromuscular blocking agents (NMBAs) for 48 hours in the acute phase of ARDS and prone positioning (PP). NMBAs and PP are part of the latest guidelines from French ICU Society. However, North American guidelines recommend PP for patients with severe ARDS only but not NMBAs, given the results of the ROSE study which did not confirm the benefit on mortality demonstrated in the ACURASYS study. However, in the ROSE study, ventilatory strategy, use of NMBAs and PP were different from the ACURASYS study. Yet, NMBAs and PP are frequently associated in clinical practice, particularly with the COVID-19 pandemic, but also in randomized trials. In the PROSEVA study, almost all the patients (91%) received a continuous infusion of NMBAs during PP. Indeed, there is a common physiopathological rationale in both techniques: they favor the homogenization of transpulmonary pressures (TPP), reduce lung overdistension, Pendelluft effect and thus ventilator induced lung injury (VILI), in particular barotrauma and biotrauma. This reduction of biotrauma has been demonstrated for PP and NMBAs separately, but never by comparing the combined effect of the 2 techniques to each of them separately. This comparison requires reliable tools. In recent years, the soluble form of the receptor for advanced glycation end products (sRAGE), a new biomarker specific of pulmonary epithelial aggression and therefore of biotrauma, has been described and evaluated during ARDS and appears to be associated with the severity of pulmonary damage and prognosis. Overall, despite an interesting physiopathological rationale and a clinically widespread practice, there is currently no study evaluating the synergistic effect of PP and NMBAs in the treatment of ARDS, in particular on the prevention of VILI, and more precisely of biotrauma. This question seems crucial to better specify the respective place of each of these treatments in the management strategy of ARDS patients whose prevalence and mortality remain high. The objective of this study is therefore to evaluate, using a recent and reliable biomarker, the synergistic effect of a short-term NMBAs infusion using cisatracurium and PP on the reduction of biotrauma during moderate to severe ARDS. The investigators will compare this synergistic treatment to the use of PP alone. They will also evaluate, in secondary objectives, the effects of PP and NMBAs combination on clinical outcomes and on the patients' prognosis.
Interventions
DRUGNMBAs
Early and systematic use of NMBAs
OTHERProne positioning
Early and systematic use of prone positioning
Sponsors
Assistance Publique Hopitaux De Marseille
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Age \> 18 years * Written informed consent of proxy to the study participation * Invasive mechanical ventilation for ≤ 72 hours at inclusion * Criteria of moderate to severe ARDS according to the Berlin definition * Patients covered by or having the rights to social security
Exclusion criteria
* Pregnant or breast-feeding women, patients deprived of freedom or under legal authority * Patients having undergone previous PP sessions during the same stay * Patients who had already been curarized prior to inclusion * Patient currently receiving ECMO or any technique of extracorporeal CO2 removal at the time of inclusion * Patient with a contraindication to PP * Previous hypersensitivity or anaphylactic reaction to any NMBA * Chronic respiratory insufficiency with oxygen or long-term ventilation * SAPS II score at the time of enrollment \> 75 * Patients who are moribund or for whom limitations of active therapies have been decided.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Difference between the plasma sRAGE value at the end of the first PP session and the baseline value before PP (∆ sRAGE). | Day 1 | Our primary outcome will be the comparison of the differences in plasma sRAGE levels before and after the first PP session (∆ sRAGE), a kinetic being probably more relevant than a raw value, given the observed inter-individual variations of sRAGE at basal state. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Tidal Volume (Vt) 7 days after inclusion | 7 days after inclusion | Protective mechanical ventilation |
| Respiratory Rate (Fr) before each PP session | Up to Day 28 | Protective mechanical ventilation |
| pH before each PP session | Up to Day 28 | Hematosis |
| Plasma determination of IL1 before the first PP session | Day 1 | Inflammation, pulmonary epithelial and endothelial dysfunction |
| Plasma determination of IL1 1 hour after PP initiation at the first PP session | Day 1 | Inflammation, pulmonary epithelial and endothelial dysfunction |
| Plasma determination of IL1 at the end of the first PP session | Day 1 | Inflammation, pulmonary epithelial and endothelial dysfunction |
| Plasma determination of IL1 4 hours after return to supine after the first PP session | Day 2 | Inflammation, pulmonary epithelial and endothelial dysfunction |
| Plasma determination of TNFα before the first PP session | Day 1 | Inflammation, pulmonary epithelial and endothelial dysfunction |
| Plasma determination of TNFα 1 hour after PP initiation at the first PP session | Day 1 | Inflammation, pulmonary epithelial and endothelial dysfunction |
| Plasma determination of TNFα at the end of the first PP session | Day 1 | Inflammation, pulmonary epithelial and endothelial dysfunction |
| Plasma determination of TNFα 4 hours after return to supine after the first PP session | Day 2 | Inflammation, pulmonary epithelial and endothelial dysfunction |
| Plasma determination of sRAGE before the first PP session | Day 1 | Inflammation, pulmonary epithelial and endothelial dysfunction |
| Plasma determination of sRAGE 1 hour after PP initiation at the first PP session | Day 1 | Inflammation, pulmonary epithelial and endothelial dysfunction |
| Plasma determination of sRAGE at the end of the first PP session | Day 1 | Inflammation, pulmonary epithelial and endothelial dysfunction |
| Plasma determination of sRAGE 4 hours after return to supine after the first PP session | Day 2 | Inflammation, pulmonary epithelial and endothelial dysfunction |
| Plasma determination of angiopoietin 2 before the first PP session | Day 1 | Inflammation, pulmonary epithelial and endothelial dysfunction |
| Plasma determination of angiopoietin 2 1 hour after PP initiation at the first PP session | Day 1 | Inflammation, pulmonary epithelial and endothelial dysfunction |
| Plasma determination of angiopoietin 2 at the end of the first PP session | Day 1 | Inflammation, pulmonary epithelial and endothelial dysfunction |
| Plasma determination of angiopoietin 2 4 hours after return to supine after the first PP session | Day 2 | Inflammation, pulmonary epithelial and endothelial dysfunction |
| PaO2/FiO2 before each PP session | Up to Day 28 | Hematosis |
| PaO2/FiO2 1 hour after PP initiation at each PP session | Up to Day 28 | Hematosis |
| PaO2/FiO2 6 hours after PP initiation at each PP session | Up to Day 28 | Hematosis |
| PaO2/FiO2 at the end of each PP session | Up to Day 28 | Hematosis |
| PaO2/FiO2 4 hours after return to supine after each PP session | Up to Day 28 | Hematosis |
| PaO2/FiO2 48 hours after inclusion | 48 hours after inclusion | Hematosis |
| PaO2/FiO2 72 hours after inclusion | 72 hours after inclusion | Hematosis |
| PaO2/FiO2 7 days after inclusion | 7 days after inclusion | Hematosis |
| pH 1 hour after PP initiation at each PP session | Up to Day 28 | Hematosis |
| pH 6 hours after PP initiation at each PP session | Up to Day 28 | Hematosis |
| pH at the end of each PP session | Up to Day 28 | Hematosis |
| pH 4 hours after return to supine after each PP session | Up to Day 28 | Hematosis |
| pH 48 hours after inclusion | 48 hours after inclusion | Hematosis |
| pH 72 hours after inclusion | 72 hours after inclusion | Hematosis |
| pH 7 days after inclusion | 7 days after inclusion | Hematosis |
| PaCO2 before each PP session | Up to Day 28 | Hematosis |
| PaCO2 1 hour after PP initiation at each PP session | Up to Day 28 | Hematosis |
| PaCO2 6 hours after PP initiation at each PP session | Up to Day 28 | Hematosis |
| PaCO2at the end of each PP session | Up to Day 28 | Hematosis |
| PaCO2 4 hours after return to supine after each PP session | Up to Day 28 | Hematosis |
| PaCO2 48 hours after inclusion | 48 hours after inclusion | Hematosis |
| PaCO2 72 hours after inclusion | 72 hours after inclusion | Hematosis |
| PaCO2 7 days after inclusion | 7 days after inclusion | Hematosis |
| Plateau pressure (Pplat) before each PP session | Up to Day 28 | Protective mechanical ventilation |
| Plateau pressure (Pplat) 1 hour after PP initiation at each PP session | Up to Day 28 | Protective mechanical ventilation |
| Tidal Volume (Vt) 6 hours after PP initiation at each PP session | Up to Day 28 | Protective mechanical ventilation |
| Tidal Volume (Vt) at the end of each PP session | Up to Day 28 | Protective mechanical ventilation |
| Plateau pressure (Pplat) 6 hours after PP initiation at each PP session | Up to Day 28 | Protective mechanical ventilation |
| Plateau pressure (Pplat) at the end of each PP session | Up to Day 28 | Protective mechanical ventilation |
| Plateau pressure (Pplat) 4 hours after return to supine after each PP session | Up to Day 28 | Protective mechanical ventilation |
| Plateau pressure (Pplat) 48 hours after inclusion | 48 hours after inclusion | Protective mechanical ventilation |
| Tidal Volume (Vt) 4 hours after return to supine after each PP session | Up to Day 28 | Protective mechanical ventilation |
| Plateau pressure (Pplat) 72 hours after inclusion | 72 hours after inclusion | Protective mechanical ventilation |
| Plateau pressure (Pplat) 7 days after inclusion | 7 days after inclusion | Protective mechanical ventilation |
| Positive Expiratory Pressure (PEEP) before each PP session | Up to Day 28 | Protective mechanical ventilation |
| Positive Expiratory Pressure (PEEP) 1 hour after PP initiation at each PP session | Up to Day 28 | Protective mechanical ventilation |
| Positive Expiratory Pressure (PEEP) 6 hours after PP initiation at each PP session | Up to Day 28 | Protective mechanical ventilation |
| Positive Expiratory Pressure (PEEP) at the end of each PP session | Up to Day 28 | Protective mechanical ventilation |
| Tidal Volume (Vt) 48 hours after inclusion | 48 hours after inclusion | Protective mechanical ventilation |
| Positive Expiratory Pressure (PEEP) 4 hours after return to supine after each PP session | Up to Day 28 | Protective mechanical ventilation |
| Positive Expiratory Pressure (PEEP) 48 hours after inclusion | 48 hours after inclusion | Protective mechanical ventilation |
| Positive Expiratory Pressure (PEEP) 72 hours after inclusion | 72 hours after inclusion | Protective mechanical ventilation |
| Positive Expiratory Pressure (PEEP) 7 days after inclusion | 7 days after inclusion | Protective mechanical ventilation |
| Driving Pressure (Δp) before each PP session | Up to Day 28 | Protective mechanical ventilation |
| Driving Pressure (Δp) 1 hour after PP initiation at each PP session | Up to Day 28, | Protective mechanical ventilation |
| Driving Pressure (Δp) 6 hours after PP initiation at each PP session | Up to Day 28 | Protective mechanical ventilation |
| Driving Pressure (Δp) at the end of each PP session | Up to Day 28 | Protective mechanical ventilation |
| Driving Pressure (Δp) 4 hours after return to supine after each PP session | Up to Day 28 | Protective mechanical ventilation |
| Driving Pressure (Δp) 48 hours after inclusion | 48 hours after inclusion | Protective mechanical ventilation |
| Driving Pressure (Δp) 72 hours after inclusion | 72 hours after inclusion | Protective mechanical ventilation |
| Driving Pressure (Δp) 7 days after inclusion | 7 days after inclusion | Protective mechanical ventilation |
| Tidal Volume (Vt) before each PP session | Up to Day 28 | Protective mechanical ventilation |
| Tidal Volume (Vt) 1 hour after PP initiation at each PP session | Up to Day 28 | Protective mechanical ventilation |
| Respiratory Rate (Fr) 1 hour after PP initiation at each PP session | Up to Day 28 | Protective mechanical ventilation |
| Respiratory Rate (Fr) 6 hours after PP initiation at each PP session | Up to Day 28 | Protective mechanical ventilation |
| Respiratory Rate (Fr) at the end of each PP session | Up to Day 28 | Protective mechanical ventilation |
| Respiratory Rate (Fr) 4 hours after return to supine after each PP session | Up to Day 28 | Protective mechanical ventilation |
| Respiratory Rate (Fr) 48 hours after inclusion | 48 hours after inclusion | Protective mechanical ventilation |
| Respiratory Rate (Fr) 72 hours after inclusion | 72 hours after inclusion | Protective mechanical ventilation |
| Respiratory Rate (Fr) 7 days after inclusion | 7 days after inclusion | Protective mechanical ventilation |
| Esophageal pressure (for equipped sites) before each PP session | Up to Day 28 | Alveolar recruitment |
| Esophageal pressure (for equipped sites) 1 hour after PP initiation at each PP session | Up to Day 28 | Alveolar recruitment |
| Esophageal pressure (for equipped sites) at the end of each PP session | Up to Day 28 | Alveolar recruitment |
| Transpulmonary pressure (TPP) (for equipped sites) before each PP session | Up to Day 28 | Alveolar recruitment |
| Transpulmonary pressure (TPP) (for equipped sites) 1 hour after PP initiation at each PP session | Up to Day 28 | Alveolar recruitment |
| Transpulmonary pressure (TPP) (for equipped sites) at the end of each PP session | Up to Day 28 | Alveolar recruitment |
| Tidal Volume (Vt) 72 hours after inclusion | 72 hours after inclusion | Protective mechanical ventilation |
| Electrical Impedance Tomography data (for equipped sites) 1 hour after PP initiation at each PP session | Up to Day 28 | Alveolar recruitment |
| Electrical Impedance Tomography data (for equipped sites) at the end of each PP session | Up to Day 28 | Alveolar recruitment |
| Pneumothorax | Within the first 7 days | Barotrauma |
| Pneumomediastinum | Within the first 7 days | Barotrauma |
| Sub cutaneous emphysema | Within the first 7 days | Barotrauma |
| Hospital mortality | At Day 28 | — |
| Ventilator free days (VFD) | At Day 28 | — |
| Number of days alive without extra-respiratory organ failure | At Day 28 | — |
| Length of stay in intensive care unit | Maximum 3 months after inclusion (follow-up duration) | — |
| Length of hospital stay | Maximum 3 months after inclusion (follow-up duration) | — |
| Medical Research Council (MRC) | At day 28 or discharge | — |
| Electrical Impedance Tomography data (for equipped sites) before each PP session | Up to Day 28 | Alveolar recruitment |
Countries
France
Contacts
Primary ContactSami Hraiech, MD
Outcome results
None listed