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| ID | Type | Description | Link |
|---|---|---|---|
| ID-RCB | Other Identifier | 2023-A01797-38 |
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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Prone Positioning and NMBAs (PP-NMBAs) | Experimental | Early and systematic use of Prone positioning and NMBAs |
|
| Prone Positioning (PP) | Active Comparator | Early and systematic use of prone positioning with NMBAs indicated ONLY as rescue |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| NMBAs | Drug | Early and systematic use of NMBAs |
| |
| Measure | Description | Time Frame |
|---|---|---|
| Difference 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. | Day 1 |
| Measure | Description | Time Frame |
|---|---|---|
| Plasma determination of IL1 before the first PP session | Inflammation, pulmonary epithelial and endothelial dysfunction | Day 1 |
| Plasma determination of IL1 1 hour after PP initiation at the first PP session |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Sami Hraiech, MD | Contact | 0491964358 | +33 | sami.hraiech@ap-hm.fr |
| Name | Affiliation | Role |
|---|---|---|
| François Cremieux | AP-HM | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Service Médecine Intensive et Réanimation | Recruiting | Marseille | 13015 | France |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 31197492 | Background | Papazian L, Aubron C, Brochard L, Chiche JD, Combes A, Dreyfuss D, Forel JM, Guerin C, Jaber S, Mekontso-Dessap A, Mercat A, Richard JC, Roux D, Vieillard-Baron A, Faure H. Formal guidelines: management of acute respiratory distress syndrome. Ann Intensive Care. 2019 Jun 13;9(1):69. doi: 10.1186/s13613-019-0540-9. | |
| 31112383 | Background |
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| ID | Term |
|---|---|
| D016684 | Prone Position |
| ID | Term |
|---|---|
| D011187 | Posture |
| D009142 | Musculoskeletal Physiological Phenomena |
| D055687 | Musculoskeletal and Neural Physiological Phenomena |
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| Prone positioning |
| Other |
Early and systematic use of prone positioning |
|
Inflammation, pulmonary epithelial and endothelial dysfunction
| Day 1 |
| Plasma determination of IL1 at the end of the first PP session | Inflammation, pulmonary epithelial and endothelial dysfunction | Day 1 |
| Plasma determination of IL1 4 hours after return to supine after the first PP session | Inflammation, pulmonary epithelial and endothelial dysfunction | Day 2 |
| Plasma determination of TNFα before the first PP session | Inflammation, pulmonary epithelial and endothelial dysfunction | Day 1 |
| Plasma determination of TNFα 1 hour after PP initiation at the first PP session | Inflammation, pulmonary epithelial and endothelial dysfunction | Day 1 |
| Plasma determination of TNFα at the end of the first PP session | Inflammation, pulmonary epithelial and endothelial dysfunction | Day 1 |
| Plasma determination of TNFα 4 hours after return to supine after the first PP session | Inflammation, pulmonary epithelial and endothelial dysfunction | Day 2 |
| Plasma determination of sRAGE before the first PP session | Inflammation, pulmonary epithelial and endothelial dysfunction | Day 1 |
| Plasma determination of sRAGE 1 hour after PP initiation at the first PP session | Inflammation, pulmonary epithelial and endothelial dysfunction | Day 1 |
| Plasma determination of sRAGE at the end of the first PP session | Inflammation, pulmonary epithelial and endothelial dysfunction | Day 1 |
| Plasma determination of sRAGE 4 hours after return to supine after the first PP session | Inflammation, pulmonary epithelial and endothelial dysfunction | Day 2 |
| Plasma determination of angiopoietin 2 before the first PP session | Inflammation, pulmonary epithelial and endothelial dysfunction | Day 1 |
| Plasma determination of angiopoietin 2 1 hour after PP initiation at the first PP session | Inflammation, pulmonary epithelial and endothelial dysfunction | Day 1 |
| Plasma determination of angiopoietin 2 at the end of the first PP session | Inflammation, pulmonary epithelial and endothelial dysfunction | Day 1 |
| Plasma determination of angiopoietin 2 4 hours after return to supine after the first PP session | Inflammation, pulmonary epithelial and endothelial dysfunction | Day 2 |
| PaO2/FiO2 before each PP session | Hematosis | Up to Day 28 |
| PaO2/FiO2 1 hour after PP initiation at each PP session | Hematosis | Up to Day 28 |
| PaO2/FiO2 6 hours after PP initiation at each PP session | Hematosis | Up to Day 28 |
| PaO2/FiO2 at the end of each PP session | Hematosis | Up to Day 28 |
| PaO2/FiO2 4 hours after return to supine after each PP session | Hematosis | Up to Day 28 |
| PaO2/FiO2 48 hours after inclusion | Hematosis | 48 hours after inclusion |
| PaO2/FiO2 72 hours after inclusion | Hematosis | 72 hours after inclusion |
| PaO2/FiO2 7 days after inclusion | Hematosis | 7 days after inclusion |
| pH before each PP session | Hematosis | Up to Day 28 |
| pH 1 hour after PP initiation at each PP session | Hematosis | Up to Day 28 |
| pH 6 hours after PP initiation at each PP session | Hematosis | Up to Day 28 |
| pH at the end of each PP session | Hematosis | Up to Day 28 |
| pH 4 hours after return to supine after each PP session | Hematosis | Up to Day 28 |
| pH 48 hours after inclusion | Hematosis | 48 hours after inclusion |
| pH 72 hours after inclusion | Hematosis | 72 hours after inclusion |
| pH 7 days after inclusion | Hematosis | 7 days after inclusion |
| PaCO2 before each PP session | Hematosis | Up to Day 28 |
| PaCO2 1 hour after PP initiation at each PP session | Hematosis | Up to Day 28 |
| PaCO2 6 hours after PP initiation at each PP session | Hematosis | Up to Day 28 |
| PaCO2at the end of each PP session | Hematosis | Up to Day 28 |
| PaCO2 4 hours after return to supine after each PP session | Hematosis | Up to Day 28 |
| PaCO2 48 hours after inclusion | Hematosis | 48 hours after inclusion |
| PaCO2 72 hours after inclusion | Hematosis | 72 hours after inclusion |
| PaCO2 7 days after inclusion | Hematosis | 7 days after inclusion |
| Plateau pressure (Pplat) before each PP session | Protective mechanical ventilation | Up to Day 28 |
| Plateau pressure (Pplat) 1 hour after PP initiation at each PP session | Protective mechanical ventilation | Up to Day 28 |
| Plateau pressure (Pplat) 6 hours after PP initiation at each PP session | Protective mechanical ventilation | Up to Day 28 |
| Plateau pressure (Pplat) at the end of each PP session | Protective mechanical ventilation | Up to Day 28 |
| Plateau pressure (Pplat) 4 hours after return to supine after each PP session | Protective mechanical ventilation | Up to Day 28 |
| Plateau pressure (Pplat) 48 hours after inclusion | Protective mechanical ventilation | 48 hours after inclusion |
| Plateau pressure (Pplat) 72 hours after inclusion | Protective mechanical ventilation | 72 hours after inclusion |
| Plateau pressure (Pplat) 7 days after inclusion | Protective mechanical ventilation | 7 days after inclusion |
| Positive Expiratory Pressure (PEEP) before each PP session | Protective mechanical ventilation | Up to Day 28 |
| Positive Expiratory Pressure (PEEP) 1 hour after PP initiation at each PP session | Protective mechanical ventilation | Up to Day 28 |
| Positive Expiratory Pressure (PEEP) 6 hours after PP initiation at each PP session | Protective mechanical ventilation | Up to Day 28 |
| Positive Expiratory Pressure (PEEP) at the end of each PP session | Protective mechanical ventilation | Up to Day 28 |
| Positive Expiratory Pressure (PEEP) 4 hours after return to supine after each PP session | Protective mechanical ventilation | Up to Day 28 |
| Positive Expiratory Pressure (PEEP) 48 hours after inclusion | Protective mechanical ventilation | 48 hours after inclusion |
| Positive Expiratory Pressure (PEEP) 72 hours after inclusion | Protective mechanical ventilation | 72 hours after inclusion |
| Positive Expiratory Pressure (PEEP) 7 days after inclusion | Protective mechanical ventilation | 7 days after inclusion |
| Driving Pressure (Δp) before each PP session | Protective mechanical ventilation | Up to Day 28 |
| Driving Pressure (Δp) 1 hour after PP initiation at each PP session | Protective mechanical ventilation | Up to Day 28, |
| Driving Pressure (Δp) 6 hours after PP initiation at each PP session | Protective mechanical ventilation | Up to Day 28 |
| Driving Pressure (Δp) at the end of each PP session | Protective mechanical ventilation | Up to Day 28 |
| Driving Pressure (Δp) 4 hours after return to supine after each PP session | Protective mechanical ventilation | Up to Day 28 |
| Driving Pressure (Δp) 48 hours after inclusion | Protective mechanical ventilation | 48 hours after inclusion |
| Driving Pressure (Δp) 72 hours after inclusion | Protective mechanical ventilation | 72 hours after inclusion |
| Driving Pressure (Δp) 7 days after inclusion | Protective mechanical ventilation | 7 days after inclusion |
| Tidal Volume (Vt) before each PP session | Protective mechanical ventilation | Up to Day 28 |
| Tidal Volume (Vt) 1 hour after PP initiation at each PP session | Protective mechanical ventilation | Up to Day 28 |
| Tidal Volume (Vt) 6 hours after PP initiation at each PP session | Protective mechanical ventilation | Up to Day 28 |
| Tidal Volume (Vt) at the end of each PP session | Protective mechanical ventilation | Up to Day 28 |
| Tidal Volume (Vt) 4 hours after return to supine after each PP session | Protective mechanical ventilation | Up to Day 28 |
| Tidal Volume (Vt) 48 hours after inclusion | Protective mechanical ventilation | 48 hours after inclusion |
| Tidal Volume (Vt) 72 hours after inclusion | Protective mechanical ventilation | 72 hours after inclusion |
| Tidal Volume (Vt) 7 days after inclusion | Protective mechanical ventilation | 7 days after inclusion |
| Respiratory Rate (Fr) before each PP session | Protective mechanical ventilation | Up to Day 28 |
| Respiratory Rate (Fr) 1 hour after PP initiation at each PP session | Protective mechanical ventilation | Up to Day 28 |
| Respiratory Rate (Fr) 6 hours after PP initiation at each PP session | Protective mechanical ventilation | Up to Day 28 |
| Respiratory Rate (Fr) at the end of each PP session | Protective mechanical ventilation | Up to Day 28 |
| Respiratory Rate (Fr) 4 hours after return to supine after each PP session | Protective mechanical ventilation | Up to Day 28 |
| Respiratory Rate (Fr) 48 hours after inclusion | Protective mechanical ventilation | 48 hours after inclusion |
| Respiratory Rate (Fr) 72 hours after inclusion | Protective mechanical ventilation | 72 hours after inclusion |
| Respiratory Rate (Fr) 7 days after inclusion | Protective mechanical ventilation | 7 days after inclusion |
| Esophageal pressure (for equipped sites) before each PP session | Alveolar recruitment | Up to Day 28 |
| Esophageal pressure (for equipped sites) 1 hour after PP initiation at each PP session | Alveolar recruitment | Up to Day 28 |
| Esophageal pressure (for equipped sites) at the end of each PP session | Alveolar recruitment | Up to Day 28 |
| Transpulmonary pressure (TPP) (for equipped sites) before each PP session | Alveolar recruitment | Up to Day 28 |
| Transpulmonary pressure (TPP) (for equipped sites) 1 hour after PP initiation at each PP session | Alveolar recruitment | Up to Day 28 |
| Transpulmonary pressure (TPP) (for equipped sites) at the end of each PP session | Alveolar recruitment | Up to Day 28 |
| Electrical Impedance Tomography data (for equipped sites) before each PP session | Alveolar recruitment | Up to Day 28 |
| Electrical Impedance Tomography data (for equipped sites) 1 hour after PP initiation at each PP session | Alveolar recruitment | Up to Day 28 |
| Electrical Impedance Tomography data (for equipped sites) at the end of each PP session | Alveolar recruitment | Up to Day 28 |
| Pneumothorax | Barotrauma | Within the first 7 days |
| Pneumomediastinum | Barotrauma | Within the first 7 days |
| Sub cutaneous emphysema | Barotrauma | Within the first 7 days |
| Hospital mortality | At Day 28 |
| Hospital mortality | At Day 90 |
| Ventilator free days (VFD) | At Day 28 |
| Ventilator free days (VFD) | At Day 90 |
| Number of days alive without extra-respiratory organ failure | At Day 28 |
| Number of days alive without extra-respiratory organ failure | At Day 90 |
| 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 |
| National Heart, Lung, and Blood Institute PETAL Clinical Trials Network; Moss M, Huang DT, Brower RG, Ferguson ND, Ginde AA, Gong MN, Grissom CK, Gundel S, Hayden D, Hite RD, Hou PC, Hough CL, Iwashyna TJ, Khan A, Liu KD, Talmor D, Thompson BT, Ulysse CA, Yealy DM, Angus DC. Early Neuromuscular Blockade in the Acute Respiratory Distress Syndrome. N Engl J Med. 2019 May 23;380(21):1997-2008. doi: 10.1056/NEJMoa1901686. Epub 2019 May 19. |
| 20843245 | Background | Papazian L, Forel JM, Gacouin A, Penot-Ragon C, Perrin G, Loundou A, Jaber S, Arnal JM, Perez D, Seghboyan JM, Constantin JM, Courant P, Lefrant JY, Guerin C, Prat G, Morange S, Roch A; ACURASYS Study Investigators. Neuromuscular blockers in early acute respiratory distress syndrome. N Engl J Med. 2010 Sep 16;363(12):1107-16. doi: 10.1056/NEJMoa1005372. |
| 23688302 | Background | Guerin C, Reignier J, Richard JC, Beuret P, Gacouin A, Boulain T, Mercier E, Badet M, Mercat A, Baudin O, Clavel M, Chatellier D, Jaber S, Rosselli S, Mancebo J, Sirodot M, Hilbert G, Bengler C, Richecoeur J, Gainnier M, Bayle F, Bourdin G, Leray V, Girard R, Baboi L, Ayzac L; PROSEVA Study Group. Prone positioning in severe acute respiratory distress syndrome. N Engl J Med. 2013 Jun 6;368(23):2159-68. doi: 10.1056/NEJMoa1214103. Epub 2013 May 20. |
| 26903337 | Background | Bellani G, Laffey JG, Pham T, Fan E, Brochard L, Esteban A, Gattinoni L, van Haren F, Larsson A, McAuley DF, Ranieri M, Rubenfeld G, Thompson BT, Wrigge H, Slutsky AS, Pesenti A; LUNG SAFE Investigators; ESICM Trials Group. Epidemiology, Patterns of Care, and Mortality for Patients With Acute Respiratory Distress Syndrome in Intensive Care Units in 50 Countries. JAMA. 2016 Feb 23;315(8):788-800. doi: 10.1001/jama.2016.0291. |