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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
SINGLE
Enrollment
40
Early and systematic use of NMBAs
Early and systematic use of prone positioning
Service Médecine Intensive et Réanimation
Marseille, France
RECRUITINGDifference between the plasma sRAGE value at the end of the first PP session and the baseline value before PP (∆ sRAGE).
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.
Time frame: Day 1
Plasma determination of IL1 before the first PP session
Inflammation, pulmonary epithelial and endothelial dysfunction
Time frame: Day 1
Plasma determination of IL1 1 hour after PP initiation at the first PP session
Inflammation, pulmonary epithelial and endothelial dysfunction
Time frame: Day 1
Plasma determination of IL1 at the end of the first PP session
Inflammation, pulmonary epithelial and endothelial dysfunction
Time frame: Day 1
Plasma determination of IL1 4 hours after return to supine after the first PP session
Inflammation, pulmonary epithelial and endothelial dysfunction
Time frame: Day 2
Plasma determination of TNFα before the first PP session
Inflammation, pulmonary epithelial and endothelial dysfunction
Time frame: Day 1
Plasma determination of TNFα 1 hour after PP initiation at the first PP session
Inflammation, pulmonary epithelial and endothelial dysfunction
Time frame: Day 1
Plasma determination of TNFα at the end of the first PP session
Inflammation, pulmonary epithelial and endothelial dysfunction
Time frame: Day 1
Plasma determination of TNFα 4 hours after return to supine after the first PP session
Inflammation, pulmonary epithelial and endothelial dysfunction
Time frame: Day 2
Plasma determination of sRAGE before the first PP session
Inflammation, pulmonary epithelial and endothelial dysfunction
Time frame: Day 1
Plasma determination of sRAGE 1 hour after PP initiation at the first PP session
Inflammation, pulmonary epithelial and endothelial dysfunction
Time frame: Day 1
Plasma determination of sRAGE at the end of the first PP session
Inflammation, pulmonary epithelial and endothelial dysfunction
Time frame: Day 1
Plasma determination of sRAGE 4 hours after return to supine after the first PP session
Inflammation, pulmonary epithelial and endothelial dysfunction
Time frame: Day 2
Plasma determination of angiopoietin 2 before the first PP session
Inflammation, pulmonary epithelial and endothelial dysfunction
Time frame: Day 1
Plasma determination of angiopoietin 2 1 hour after PP initiation at the first PP session
Inflammation, pulmonary epithelial and endothelial dysfunction
Time frame: Day 1
Plasma determination of angiopoietin 2 at the end of the first PP session
Inflammation, pulmonary epithelial and endothelial dysfunction
Time frame: Day 1
Plasma determination of angiopoietin 2 4 hours after return to supine after the first PP session
Inflammation, pulmonary epithelial and endothelial dysfunction
Time frame: Day 2
PaO2/FiO2 before each PP session
Hematosis
Time frame: Up to Day 28
PaO2/FiO2 1 hour after PP initiation at each PP session
Hematosis
Time frame: Up to Day 28
PaO2/FiO2 6 hours after PP initiation at each PP session
Hematosis
Time frame: Up to Day 28
PaO2/FiO2 at the end of each PP session
Hematosis
Time frame: Up to Day 28
PaO2/FiO2 4 hours after return to supine after each PP session
Hematosis
Time frame: Up to Day 28
PaO2/FiO2 48 hours after inclusion
Hematosis
Time frame: 48 hours after inclusion
PaO2/FiO2 72 hours after inclusion
Hematosis
Time frame: 72 hours after inclusion
PaO2/FiO2 7 days after inclusion
Hematosis
Time frame: 7 days after inclusion
pH before each PP session
Hematosis
Time frame: Up to Day 28
pH 1 hour after PP initiation at each PP session
Hematosis
Time frame: Up to Day 28
pH 6 hours after PP initiation at each PP session
Hematosis
Time frame: Up to Day 28
pH at the end of each PP session
Hematosis
Time frame: Up to Day 28
pH 4 hours after return to supine after each PP session
Hematosis
Time frame: Up to Day 28
pH 48 hours after inclusion
Hematosis
Time frame: 48 hours after inclusion
pH 72 hours after inclusion
Hematosis
Time frame: 72 hours after inclusion
pH 7 days after inclusion
Hematosis
Time frame: 7 days after inclusion
PaCO2 before each PP session
Hematosis
Time frame: Up to Day 28
PaCO2 1 hour after PP initiation at each PP session
Hematosis
Time frame: Up to Day 28
PaCO2 6 hours after PP initiation at each PP session
Hematosis
Time frame: Up to Day 28
PaCO2at the end of each PP session
Hematosis
Time frame: Up to Day 28
PaCO2 4 hours after return to supine after each PP session
Hematosis
Time frame: Up to Day 28
PaCO2 48 hours after inclusion
Hematosis
Time frame: 48 hours after inclusion
PaCO2 72 hours after inclusion
Hematosis
Time frame: 72 hours after inclusion
PaCO2 7 days after inclusion
Hematosis
Time frame: 7 days after inclusion
Plateau pressure (Pplat) before each PP session
Protective mechanical ventilation
Time frame: Up to Day 28
Plateau pressure (Pplat) 1 hour after PP initiation at each PP session
Protective mechanical ventilation
Time frame: Up to Day 28
Plateau pressure (Pplat) 6 hours after PP initiation at each PP session
Protective mechanical ventilation
Time frame: Up to Day 28
Plateau pressure (Pplat) at the end of each PP session
Protective mechanical ventilation
Time frame: Up to Day 28
Plateau pressure (Pplat) 4 hours after return to supine after each PP session
Protective mechanical ventilation
Time frame: Up to Day 28
Plateau pressure (Pplat) 48 hours after inclusion
Protective mechanical ventilation
Time frame: 48 hours after inclusion
Plateau pressure (Pplat) 72 hours after inclusion
Protective mechanical ventilation
Time frame: 72 hours after inclusion
Plateau pressure (Pplat) 7 days after inclusion
Protective mechanical ventilation
Time frame: 7 days after inclusion
Positive Expiratory Pressure (PEEP) before each PP session
Protective mechanical ventilation
Time frame: Up to Day 28
Positive Expiratory Pressure (PEEP) 1 hour after PP initiation at each PP session
Protective mechanical ventilation
Time frame: Up to Day 28
Positive Expiratory Pressure (PEEP) 6 hours after PP initiation at each PP session
Protective mechanical ventilation
Time frame: Up to Day 28
Positive Expiratory Pressure (PEEP) at the end of each PP session
Protective mechanical ventilation
Time frame: Up to Day 28
Positive Expiratory Pressure (PEEP) 4 hours after return to supine after each PP session
Protective mechanical ventilation
Time frame: Up to Day 28
Positive Expiratory Pressure (PEEP) 48 hours after inclusion
Protective mechanical ventilation
Time frame: 48 hours after inclusion
Positive Expiratory Pressure (PEEP) 72 hours after inclusion
Protective mechanical ventilation
Time frame: 72 hours after inclusion
Positive Expiratory Pressure (PEEP) 7 days after inclusion
Protective mechanical ventilation
Time frame: 7 days after inclusion
Driving Pressure (Δp) before each PP session
Protective mechanical ventilation
Time frame: Up to Day 28
Driving Pressure (Δp) 1 hour after PP initiation at each PP session
Protective mechanical ventilation
Time frame: Up to Day 28,
Driving Pressure (Δp) 6 hours after PP initiation at each PP session
Protective mechanical ventilation
Time frame: Up to Day 28
Driving Pressure (Δp) at the end of each PP session
Protective mechanical ventilation
Time frame: Up to Day 28
Driving Pressure (Δp) 4 hours after return to supine after each PP session
Protective mechanical ventilation
Time frame: Up to Day 28
Driving Pressure (Δp) 48 hours after inclusion
Protective mechanical ventilation
Time frame: 48 hours after inclusion
Driving Pressure (Δp) 72 hours after inclusion
Protective mechanical ventilation
Time frame: 72 hours after inclusion
Driving Pressure (Δp) 7 days after inclusion
Protective mechanical ventilation
Time frame: 7 days after inclusion
Tidal Volume (Vt) before each PP session
Protective mechanical ventilation
Time frame: Up to Day 28
Tidal Volume (Vt) 1 hour after PP initiation at each PP session
Protective mechanical ventilation
Time frame: Up to Day 28
Tidal Volume (Vt) 6 hours after PP initiation at each PP session
Protective mechanical ventilation
Time frame: Up to Day 28
Tidal Volume (Vt) at the end of each PP session
Protective mechanical ventilation
Time frame: Up to Day 28
Tidal Volume (Vt) 4 hours after return to supine after each PP session
Protective mechanical ventilation
Time frame: Up to Day 28
Tidal Volume (Vt) 48 hours after inclusion
Protective mechanical ventilation
Time frame: 48 hours after inclusion
Tidal Volume (Vt) 72 hours after inclusion
Protective mechanical ventilation
Time frame: 72 hours after inclusion
Tidal Volume (Vt) 7 days after inclusion
Protective mechanical ventilation
Time frame: 7 days after inclusion
Respiratory Rate (Fr) before each PP session
Protective mechanical ventilation
Time frame: Up to Day 28
Respiratory Rate (Fr) 1 hour after PP initiation at each PP session
Protective mechanical ventilation
Time frame: Up to Day 28
Respiratory Rate (Fr) 6 hours after PP initiation at each PP session
Protective mechanical ventilation
Time frame: Up to Day 28
Respiratory Rate (Fr) at the end of each PP session
Protective mechanical ventilation
Time frame: Up to Day 28
Respiratory Rate (Fr) 4 hours after return to supine after each PP session
Protective mechanical ventilation
Time frame: Up to Day 28
Respiratory Rate (Fr) 48 hours after inclusion
Protective mechanical ventilation
Time frame: 48 hours after inclusion
Respiratory Rate (Fr) 72 hours after inclusion
Protective mechanical ventilation
Time frame: 72 hours after inclusion
Respiratory Rate (Fr) 7 days after inclusion
Protective mechanical ventilation
Time frame: 7 days after inclusion
Esophageal pressure (for equipped sites) before each PP session
Alveolar recruitment
Time frame: Up to Day 28
Esophageal pressure (for equipped sites) 1 hour after PP initiation at each PP session
Alveolar recruitment
Time frame: Up to Day 28
Esophageal pressure (for equipped sites) at the end of each PP session
Alveolar recruitment
Time frame: Up to Day 28
Transpulmonary pressure (TPP) (for equipped sites) before each PP session
Alveolar recruitment
Time frame: Up to Day 28
Transpulmonary pressure (TPP) (for equipped sites) 1 hour after PP initiation at each PP session
Alveolar recruitment
Time frame: Up to Day 28
Transpulmonary pressure (TPP) (for equipped sites) at the end of each PP session
Alveolar recruitment
Time frame: Up to Day 28
Electrical Impedance Tomography data (for equipped sites) before each PP session
Alveolar recruitment
Time frame: Up to Day 28
Electrical Impedance Tomography data (for equipped sites) 1 hour after PP initiation at each PP session
Alveolar recruitment
Time frame: Up to Day 28
Electrical Impedance Tomography data (for equipped sites) at the end of each PP session
Alveolar recruitment
Time frame: Up to Day 28
Pneumothorax
Barotrauma
Time frame: Within the first 7 days
Pneumomediastinum
Barotrauma
Time frame: Within the first 7 days
Sub cutaneous emphysema
Barotrauma
Time frame: Within the first 7 days
Hospital mortality
Time frame: At Day 28
Hospital mortality
Time frame: At Day 90
Ventilator free days (VFD)
Time frame: At Day 28
Ventilator free days (VFD)
Time frame: At Day 90
Number of days alive without extra-respiratory organ failure
Time frame: At Day 28
Number of days alive without extra-respiratory organ failure
Time frame: At Day 90
Length of stay in intensive care unit
Time frame: Maximum 3 months after inclusion (follow-up duration)
Length of hospital stay
Time frame: Maximum 3 months after inclusion (follow-up duration)
Medical Research Council (MRC)
Time frame: At day 28 or discharge
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