Jean-Michel Constantin1, Matthieu Jabaudon2, Jean-Yves Lefrant3, Samir Jaber4, Jean-Pierre Quenot5, Olivier Langeron6, Martine Ferrandière7, Fabien Grelon8, Philippe Seguin9, Carole Ichai10, Benoit Veber11, Bertrand Souweine12, Thomas Uberti13, Sigismond Lasocki14, François Legay15, Marc Leone16, Nathanael Eisenmann17, Claire Dahyot-Fizelier18, Hervé Dupont19, Karim Asehnoune20, Achille Sossou21, Gérald Chanques4, Laurent Muller3, Jean-Etienne Bazin2, Antoine Monsel6, Lucile Borao22, Jean-Marc Garcier23, Jean-Jacques Rouby6, Bruno Pereira22, Emmanuel Futier2. 1. Department of Perioperative Medicine, University Hospital of Clermont-Ferrand, Clermont-Ferrand, France; Laboratoire Génétique, Reproduction, et Développement, Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), Université Clermont Auvergne, Clermont-Ferrand, France; Multidisciplinary Intensive Care Unit, Department of Anaesthesiology and Critical Care, Pitié-Salpêtrière Hospital, Assistance Publique Hôpitaux de Paris, Paris, France. Electronic address: jmconstantin@chu-clermontferrand.fr. 2. Department of Perioperative Medicine, University Hospital of Clermont-Ferrand, Clermont-Ferrand, France; Laboratoire Génétique, Reproduction, et Développement, Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), Université Clermont Auvergne, Clermont-Ferrand, France. 3. Service des Réanimations, Pôle Anesthésie Douleur Urgences Réanimation, Centre Hospitalier Universitaire de Nîmes, Nîmes, France. 4. Montpellier University Hospital, Saint Eloi Intensive Care Unit and PhyMedExp, University of Montpellier, INSERM, CNRS, Montpellier, France. 5. Department of Intensive Care, François Mitterrand University Hospital, Dijon, France; Lipness Team, INSERM Research Centre, and LabExLipSTIC, University of Burgundy, Dijon, France; INSERM Centres d'Investigation Clinique, Department of Clinical Epidemiology, University of Burgundy, Dijon, France. 6. Multidisciplinary Intensive Care Unit, Department of Anaesthesiology and Critical Care, Pitié-Salpêtrière Hospital, Assistance Publique Hôpitaux de Paris, Paris, France. 7. Department of Anaesthesia and Intensive Care Medicine, Regional University Centre of Tours, Tours, France. 8. Service de Réanimation, General Hospital Le Mans, Le Mans, France. 9. Department of Intensive Care Medicine, University Hospital of Rennes, University of Rennes 1 and Unité Mixte de Recherche NuMeCan, Rennes, France. 10. Intensive Care Unit, University Hospital of Nice, Université Côte d'Azur, Nice, France. 11. Pôle Anesthésie-Réanimation-SAMU, Rouen University Hospital, Rouen, France. 12. Service de Médicine Intensive et Réanimation, University Hospital of Clermont-Ferrand, Clermont-Ferrand, France. 13. Department of Anaesthesiology and Intensive Care Medicine, Edouard Herriot Hospital, Hospices Civils de Lyon, Lyon, France. 14. Department of Anaesthesiology and Reanimation, University Hospital Angers, Angers, France. 15. Service de Réanimation, Hospital General Saint-Brieuc, Saint-Brieuc, France. 16. Service d'Anesthésie-Réanimation, Assistance Publique-Hôpitaux de Marseille, Hôpital Nord, Aix-Marseille Université, Marseille, France. 17. Department of Anaesthesiology and Critical Care, Centre Régional de Lutte Contre le Cancer Jean Perrin, Clermont-Ferrand, France. 18. Department of Anaesthesia-Intensive Care and Perioperative Medicine, University Hospital of Poitiers, University of Poitiers, INSERM, Poitiers, France. 19. Unité de Recherche Clinique Simplification des Soins chez les Patients Complexes, Université Jules Verne de Picardie, Service d'Anesthésie-Réanimation, Centre Hospitalier Universitaire d'Amiens Picardie, Amiens, France. 20. Service d'Anesthésie Réanimation Chirurgicale, Centre Hospitalier Universitaire de Nantes, Hôtel Dieu-HME Hospital, Nantes, France. 21. Service de Réanimation, Centre Hospitalier Général du Puy-en-Velay, Puy-en-Velay, France. 22. Biostatistical Unit, Department of Clinical Research and Innovation, University Hospital of Clermont-Ferrand, Clermont-Ferrand, France. 23. Department of Radiology, Estaing Hospital, University Hospital of Clermont-Ferrand, Clermont-Ferrand, France.
Abstract
BACKGROUND: The effect of personalised mechanical ventilation on clinical outcomes in patients with acute respiratory distress syndrome (ARDS) remains uncertain and needs to be evaluated. We aimed to test whether a mechanical ventilation strategy that was personalised to individual patients' lung morphology would improve the survival of patients with ARDS when compared with standard of care. METHODS: We designed a multicentre, single-blind, stratified, parallel-group, randomised controlled trial enrolling patients with moderate-to-severe ARDS in 20 university or non-university intensive care units in France. Patients older than 18 years with early ARDS for less than 12 h were randomly assigned (1:1) to either the control group or the personalised group using a minimisation algorithm and stratified according to the study site, lung morphology, and duration of mechanical ventilation. Only the patients were masked to allocation. In the control group, patients received a tidal volume of 6 mL/kg per predicted bodyweight and positive end-expiratory pressure (PEEP) was selected according to a low PEEP and fraction of inspired oxygen table, and early prone position was encouraged. In the personalised group, the treatment approach was based on lung morphology; patients with focal ARDS received a tidal volume of 8 mL/kg, low PEEP, and prone position. Patients with non-focal ARDS received a tidal volume of 6 mL/kg, along with recruitment manoeuvres and high PEEP. The primary outcome was 90-day mortality as established by intention-to-treat analysis. This study is registered online with ClinicalTrials.gov, NCT02149589. FINDINGS:From June 12, 2014, to Feb 2, 2017, 420 patients were randomly assigned to treatment. 11 patients were excluded in the personalised group and nine patients were excluded in the control group; 196 patients in the personalised group and 204 in the control group were included in the analysis. In a multivariate analysis, there was no difference in 90-day mortality between the group treated with personalised ventilation and the control group in the intention-to-treat analysis (hazard ratio [HR] 1·01; 95% CI 0·61-1·66; p=0·98). However, misclassification of patients as having focal or non-focal ARDS by the investigators was observed in 85 (21%) of 400 patients. We found a significant interaction between misclassification and randomised group allocation with respect to the primary outcome (p<0·001). In the subgroup analysis, the 90-day mortality of the misclassified patients was higher in the personalised group (26 [65%] of 40 patients) than in the control group (18 [32%] of 57 patients; HR 2·8; 95% CI 1·5-5·1; p=0·012. INTERPRETATION: Personalisation of mechanical ventilation did not decrease mortality in patients with ARDS, possibly because of the misclassification of 21% of patients. A ventilator strategy misaligned with lung morphology substantially increases mortality. Whether improvement in ARDS phenotyping can decrease mortality should be assessed in a future clinical trial. FUNDING: French Ministry of Health (Programme Hospitalier de Recherche Clinique InterRégional 2013).
RCT Entities:
BACKGROUND: The effect of personalised mechanical ventilation on clinical outcomes in patients with acute respiratory distress syndrome (ARDS) remains uncertain and needs to be evaluated. We aimed to test whether a mechanical ventilation strategy that was personalised to individual patients' lung morphology would improve the survival of patients with ARDS when compared with standard of care. METHODS: We designed a multicentre, single-blind, stratified, parallel-group, randomised controlled trial enrolling patients with moderate-to-severe ARDS in 20 university or non-university intensive care units in France. Patients older than 18 years with early ARDS for less than 12 h were randomly assigned (1:1) to either the control group or the personalised group using a minimisation algorithm and stratified according to the study site, lung morphology, and duration of mechanical ventilation. Only the patients were masked to allocation. In the control group, patients received a tidal volume of 6 mL/kg per predicted bodyweight and positive end-expiratory pressure (PEEP) was selected according to a low PEEP and fraction of inspired oxygen table, and early prone position was encouraged. In the personalised group, the treatment approach was based on lung morphology; patients with focal ARDS received a tidal volume of 8 mL/kg, low PEEP, and prone position. Patients with non-focal ARDS received a tidal volume of 6 mL/kg, along with recruitment manoeuvres and high PEEP. The primary outcome was 90-day mortality as established by intention-to-treat analysis. This study is registered online with ClinicalTrials.gov, NCT02149589. FINDINGS: From June 12, 2014, to Feb 2, 2017, 420 patients were randomly assigned to treatment. 11 patients were excluded in the personalised group and nine patients were excluded in the control group; 196 patients in the personalised group and 204 in the control group were included in the analysis. In a multivariate analysis, there was no difference in 90-day mortality between the group treated with personalised ventilation and the control group in the intention-to-treat analysis (hazard ratio [HR] 1·01; 95% CI 0·61-1·66; p=0·98). However, misclassification of patients as having focal or non-focal ARDS by the investigators was observed in 85 (21%) of 400 patients. We found a significant interaction between misclassification and randomised group allocation with respect to the primary outcome (p<0·001). In the subgroup analysis, the 90-day mortality of the misclassified patients was higher in the personalised group (26 [65%] of 40 patients) than in the control group (18 [32%] of 57 patients; HR 2·8; 95% CI 1·5-5·1; p=0·012. INTERPRETATION: Personalisation of mechanical ventilation did not decrease mortality in patients with ARDS, possibly because of the misclassification of 21% of patients. A ventilator strategy misaligned with lung morphology substantially increases mortality. Whether improvement in ARDS phenotyping can decrease mortality should be assessed in a future clinical trial. FUNDING: French Ministry of Health (Programme Hospitalier de Recherche Clinique InterRégional 2013).
Authors: Jack Gallifant; Joe Zhang; Maria Del Pilar Arias Lopez; Tingting Zhu; Luigi Camporota; Leo A Celi; Federico Formenti Journal: Br J Anaesth Date: 2021-11-09 Impact factor: 9.166
Authors: Lieuwe D J Bos; Antonio Artigas; Jean-Michel Constantin; Laura A Hagens; Nanon Heijnen; John G Laffey; Nuala Meyer; Laurent Papazian; Lara Pisani; Marcus J Schultz; Manu Shankar-Hari; Marry R Smit; Charlotte Summers; Lorraine B Ware; Raffaele Scala; Carolyn S Calfee Journal: Eur Respir Rev Date: 2021-02-02