Laurent Argaud1, Martin Cour1, Pierre-Yves Dubien2, François Giraud3, Claire Jossan4, Benjamin Riche5, Romain Hernu6, Michael Darmon7, Yves Poncelin8, Xavier Tchénio9, Jean-Pierre Quenot10, Marc Freysz11, Cyrille Kamga12, Pascal Beuret13, Pascal Usseglio14, Michel Badet15, Bastien Anette16, Kevin Chaulier17, Emel Alasan18, Sonia Sadoune19, Xavier Bobbia20, Fabrice Zéni21, Pierre-Yves Gueugniaud22, Dominique Robert23, Pascal Roy5, Michel Ovize24. 1. Hospices Civils de Lyon, Hôpital Edouard Herriot, Service de Réanimation Médicale, Lyon, France2Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche 1060, Carmen, Equipe Cardioprotection, Lyon, France3Université de Lyon, Uni. 2. Hospices Civils de Lyon, Service d'Aide Médicale Urgente 69, Lyon, France. 3. Centre Hospitalier Universitaire de Saint-Etienne, Service d'Aide Médicale Urgente 42A, Saint-Etienne, France. 4. Hospices Civils de Lyon, Hôpital Louis Pradel, Explorations Fonctionnelles Cardiovasculaires et Centre d'Investigation Clinique de Lyon, Lyon, France. 5. Université de Lyon, Université Claude Bernard Lyon 1, Lyon, France7Hospices Civils de Lyon, Centre Hospitalier Lyon-Sud, Service de Biostatistique, Lyon, France8Centre National de la Recherche Scientifique Unité Mixte de Recherche 5558, Laboratoire de Bio. 6. Hospices Civils de Lyon, Hôpital Edouard Herriot, Service de Réanimation Médicale, Lyon, France. 7. Centre Hospitalier Universitaire de Saint-Etienne, Hôpital Nord, Service de Réanimation Polyvalente, Saint-Etienne, France. 8. Centre Hospitalier de Bourg-en-Bresse, Hôpital Fleyriat, Service d'Aide Médicale Urgente 01, Bourg-en-Bresse, France. 9. Centre Hospitalier de Bourg-en-Bresse, Hôpital Fleyriat, Service de Réanimation Polyvalente, Bourg-en-Bresse, France. 10. Centre Hospitalier Universitaire de Dijon, Hôpital François Mitterand, Service de Réanimation Médicale, Dijon, France. 11. Centre Hospitalier Universitaire de Dijon, Service d'Aide Médicale Urgente 21, Dijon, France. 12. Centre Hospitalier de Roanne, Service d'Aide Médicale Urgente 42B, Roanne, France. 13. Centre Hospitalier de Roanne, Service de Réanimation et Soins Continus, Roanne, France. 14. Centre Hospitalier Métropole Savoie, Service d'Aide Médicale Urgente 73, Chambéry, France. 15. Centre Hospitalier Métropole Savoie, Service de Réanimation Polyvalente, Chambéry, France. 16. Centre Hospitalier de Villefranche-sur-Saône, Service Mobile d'Urgence et de Réanimation de Villefranche-sur-Saône, Villefranche-sur-Saône, France. 17. Centre Hospitalier de Villefranche-sur-Saône, Service de Réanimation, Villefranche-sur-Saône, France. 18. Centre Hospitalier d'Ardèche Nord, Service Mobile d'Urgence et de Réanimation d'Annonay, Annonay, France. 19. Centre Hospitalier Régional Universitare, Service d'Aide Médicale Urgente 54, Nancy, France. 20. Centre Hospitalier Universitaire de Nîmes, Pôle Anesthésie Réanimation Douleur Urgences, Nîmes, France. 21. Centre Hospitalier Universitaire de Saint-Etienne, Service d'Aide Médicale Urgente 42A, Saint-Etienne, France9Centre Hospitalier Universitaire de Saint-Etienne, Hôpital Nord, Service de Réanimation Polyvalente, Saint-Etienne, France. 22. Université de Lyon, Université Claude Bernard Lyon 1, Lyon, France4Hospices Civils de Lyon, Service d'Aide Médicale Urgente 69, Lyon, France. 23. Hospices Civils de Lyon, Hôpital Edouard Herriot, Service de Réanimation Médicale, Lyon, France3Université de Lyon, Université Claude Bernard Lyon 1, Lyon, France. 24. Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche 1060, Carmen, Equipe Cardioprotection, Lyon, France3Université de Lyon, Université Claude Bernard Lyon 1, Lyon, France6Hospices Civils de Lyon, Hôpital Louis Pradel, Explo.
Abstract
IMPORTANCE: Experimental evidence suggests that cyclosporine prevents postcardiac arrest syndrome by attenuating the systemic ischemia reperfusion response. OBJECTIVE: To determine whether early administration of cyclosporine at the time of resuscitation in patients with out-of-hospital cardiac arrest (OHCA) would prevent multiple organ failure. DESIGN, SETTING, AND PARTICIPANTS: A multicenter, single-blind, randomized clinical trial was conducted from June 22, 2010, to March 13, 2013 (Cyclosporine A in Out-of-Hospital Cardiac Arrest Resuscitation [CYRUS]). Sixteen intensive care units in 7 university-affiliated hospitals and 9 general hospitals in France participated. A total of 6758 patients who experienced nonshockable OHCA (ie, asystole or pulseless electrical activity) were assessed for eligibility. Analyses were performed according to the intention-to-treat analysis. INTERVENTIONS: Patients received an intravenous bolus injection of cyclosporine, 2.5 mg/kg, at the onset of advanced cardiovascular life support (cyclosporine group) or no additional intervention (control group). MAIN OUTCOMES AND MEASURES: The primary end point was the Sequential Organ Failure Assessment (SOFA) score, assessed 24 hours after hospital admission, which ranges from 0 to 24 (with higher scores indicating more severe organ failure). Secondary end points included survival at 24 hours, hospital discharge, and favorable neurologic outcome at discharge. RESULTS: Of the 6758 patients screened, 794 were included in intention-to-treat analysis (cyclosporine, 400; control, 394). The median (interquartile range [IQR]) ages were 63.0 (54.0-71.8) years for the cyclosporine group and 66.0 (57.0-74.0) years for the control group. The cohorts included 293 men (73.3%) in the treatment group and 288 men (73.1%) in the control group. At 24 hours after hospital admission, the SOFA score was not significantly different between the cyclosporine (median, 10.0; IQR, 7.0-13.0) and the control (median, 11.0; IQR, 7.0-15.0) groups. Survival was not significantly different between the 98 (24.5%) cyclosporine vs 101 (25.6%) control patients at hospital admission (adjusted odds ratio [aOR], 0.94; 95% CI, 0.66-1.34), at 24 hours for 67 (16.8%) vs 62 (15.7%) patients (aOR, 1.08; 95% CI, 0.71-1.63), and at hospital discharge for 10 (2.5%) vs 5 (1.3%) patients (aOR, 2.00; 95% CI, 0.61-6.52). Favorable neurologic outcome at discharge was comparable between the cyclosporine and control groups: 7 (1.8%) vs 5 (1.3%) patients (aOR, 1.39; 95% CI, 0.39-4.91). CONCLUSION AND RELEVANCE: In patients presenting with nonshockable cardiac rhythm after OHCA, cyclosporine does not prevent early multiple organ failure. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01595958; EudraCT Identifier: 2009-015725-37.
RCT Entities:
IMPORTANCE: Experimental evidence suggests that cyclosporine prevents postcardiac arrest syndrome by attenuating the systemic ischemia reperfusion response. OBJECTIVE: To determine whether early administration of cyclosporine at the time of resuscitation in patients with out-of-hospital cardiac arrest (OHCA) would prevent multiple organ failure. DESIGN, SETTING, AND PARTICIPANTS: A multicenter, single-blind, randomized clinical trial was conducted from June 22, 2010, to March 13, 2013 (Cyclosporine A in Out-of-Hospital Cardiac Arrest Resuscitation [CYRUS]). Sixteen intensive care units in 7 university-affiliated hospitals and 9 general hospitals in France participated. A total of 6758 patients who experienced nonshockable OHCA (ie, asystole or pulseless electrical activity) were assessed for eligibility. Analyses were performed according to the intention-to-treat analysis. INTERVENTIONS:Patients received an intravenous bolus injection of cyclosporine, 2.5 mg/kg, at the onset of advanced cardiovascular life support (cyclosporine group) or no additional intervention (control group). MAIN OUTCOMES AND MEASURES: The primary end point was the Sequential Organ Failure Assessment (SOFA) score, assessed 24 hours after hospital admission, which ranges from 0 to 24 (with higher scores indicating more severe organ failure). Secondary end points included survival at 24 hours, hospital discharge, and favorable neurologic outcome at discharge. RESULTS: Of the 6758 patients screened, 794 were included in intention-to-treat analysis (cyclosporine, 400; control, 394). The median (interquartile range [IQR]) ages were 63.0 (54.0-71.8) years for the cyclosporine group and 66.0 (57.0-74.0) years for the control group. The cohorts included 293 men (73.3%) in the treatment group and 288 men (73.1%) in the control group. At 24 hours after hospital admission, the SOFA score was not significantly different between the cyclosporine (median, 10.0; IQR, 7.0-13.0) and the control (median, 11.0; IQR, 7.0-15.0) groups. Survival was not significantly different between the 98 (24.5%) cyclosporine vs 101 (25.6%) control patients at hospital admission (adjusted odds ratio [aOR], 0.94; 95% CI, 0.66-1.34), at 24 hours for 67 (16.8%) vs 62 (15.7%) patients (aOR, 1.08; 95% CI, 0.71-1.63), and at hospital discharge for 10 (2.5%) vs 5 (1.3%) patients (aOR, 2.00; 95% CI, 0.61-6.52). Favorable neurologic outcome at discharge was comparable between the cyclosporine and control groups: 7 (1.8%) vs 5 (1.3%) patients (aOR, 1.39; 95% CI, 0.39-4.91). CONCLUSION AND RELEVANCE: In patients presenting with nonshockable cardiac rhythm after OHCA, cyclosporine does not prevent early multiple organ failure. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01595958; EudraCT Identifier: 2009-015725-37.
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