Bruno François1, Alain Cariou1, Raphaël Clere-Jehl1, Pierre-François Dequin1, Françoise Renon-Carron1, Thomas Daix1, Christophe Guitton1, Nicolas Deye1, Stéphane Legriel1, Gaëtan Plantefève1, Jean-Pierre Quenot1, Arnaud Desachy1, Toufik Kamel1, Sandrine Bedon-Carte1, Jean-Luc Diehl1, Nicolas Chudeau1, Elias Karam1, Isabelle Durand-Zaleski1, Bruno Giraudeau1, Philippe Vignon1, Amélie Le Gouge1. 1. From Réanimation Polyvalente (B.F., T.D., P.V.), INSERM Centre d'Investigation Clinique (CIC) 1435 (B.F., T.D., P.V.), and Unité des Essais Cliniques, Pharmacie à Usage Intérieur (F.R.-C.), Centre Hospitalier Universitaire (CHU) Dupuytren, and INSERM Unité Mixte de Recherche (UMR) 1092, Faculté de Médecine, Université de Limoges (B.F., T.D., P.V.), Limoges, Médecine Intensive et Réanimation, Hôpitaux Universitaires Paris Centre (site Cochin), Assistance Publique-Hôpitaux de Paris (AP-HP) (A.C.), Université Paris Descartes (A.C.), Réanimation Médicale, CHU Lariboisière, AP-HP (N.D.), INSERM UMR S942, Université Paris Diderot (N.D.), Réanimation Médicale, Hôpital Européen Georges-Pompidou, AP-HP (J.-L.D.), INSERM UMR S1140, Université Paris Descartes (J.-L.D.), and AP-HP, Unité de Recherche Clinique en Économie de la Santé d'Ile de France and Hôpital Henri Mondor (I.D.-Z.), Paris, Université de Strasbourg, Faculté de Médecine, Hôpitaux Universitaires de Strasbourg, Service de Réanimation, Nouvel Hôpital Civil, Strasbourg (R.C.-J.), Médecine Intensive-Réanimation (P.-F.D.) and INSERM Unité 1100 (P.-F.D.), CHU Bretonneau, and INSERM CIC 1415, CHU de Tours (B.G., A.L.G.), Tours, Médecine Intensive et Réanimation, CHU de Nantes, and Centre de Recherche en Transplantation et Immunologie UMR 1064, INSERM, Université de Nantes, Nantes (C.G.), Réanimation Médico-chirurgicale, Centre Hospitalier du Mans, Le Mans (C.G., N.C.), Réanimation Médico-chirurgicale, Centre Hospitalier André Mignot, Versailles (S.L.), Réanimation Polyvalente, Centre Hospitalier Victor Dupouy, Argenteuil (G.P.), Médecine Intensive et Réanimation, CHU François Mitterrand, Lipness Team, Centre de Recherche INSERM Lipides, Nutrition, Cancer-UMR 1231, and INSERM CIC 1432, Epidémiologie Clinique, Université de Bourgogne, Dijon (J.-P.Q.), Réanimation Polyvalente, Centre Hospitalier d'Angoulême, Angoulême (A.D.), Médecine Intensive et Réanimation, Centre Hospitalier Régional d'Orléans, Orléans (T.K.), Réanimation Polyvalente, Centre Hospitalier de Périgueux, Périgueux (S.B.-C.), and Réanimation Polyvalente, Centre Hospitalier, Brive la Gaillarde (E.K.) - all in France.
Abstract
BACKGROUND:Patients who are treated with targeted temperature management after out-of-hospital cardiac arrest with shockable rhythm are at increased risk for ventilator-associated pneumonia. The benefit of preventive short-term antibiotic therapy has not been shown. METHODS: We conducted a multicenter, double-blind, randomized, placebo-controlled trial involving adult patients (>18 years of age) in intensive care units (ICUs) who were being mechanically ventilated after out-of-hospital cardiac arrest related to initial shockable rhythm and treated with targeted temperature management at 32 to 34°C. Patients with ongoing antibiotic therapy, chronic colonization with multidrug-resistant bacteria, or moribund status were excluded. Either intravenous amoxicillin-clavulanate (at doses of 1 g and 200 mg, respectively) or placebo was administered three times a day for 2 days, starting less than 6 hours after the cardiac arrest. The primary outcome was early ventilator-associated pneumonia (during the first 7 days of hospitalization). An independent adjudication committee determined diagnoses of ventilator-associated pneumonia. RESULTS: A total of 198 patients underwent randomization, and 194 were included in the analysis. After adjudication, 60 cases of ventilator-associated pneumonia were confirmed, including 51 of early ventilator-associated pneumonia. The incidence of early ventilator-associated pneumonia was lower with antibiotic prophylaxis than with placebo (19 patients [19%] vs. 32 [34%]; hazard ratio, 0.53; 95% confidence interval, 0.31 to 0.92; P = 0.03). No significant differences between the antibiotic group and the control group were observed with respect to the incidence of late ventilator-associated pneumonia (4% and 5%, respectively), the number of ventilator-free days (21 days and 19 days), ICU length of stay (5 days and 8 days if patients were discharged and 7 days and 7 days if patients had died), and mortality at day 28 (41% and 37%). At day 7, no increase in resistant bacteria was identified. Serious adverse events did not differ significantly between the two groups. CONCLUSIONS: A 2-day course of antibiotic therapy with amoxicillin-clavulanate in patients receiving a 32-to-34°C targeted temperature management strategy after out-of-hospital cardiac arrest with initial shockable rhythm resulted in a lower incidence of early ventilator-associated pneumonia than placebo. No significant between-group differences were observed for other key clinical variables, such as ventilator-free days and mortality at day 28. (Funded by the French Ministry of Health; ANTHARTIC ClinicalTrials.gov number, NCT02186951.).
RCT Entities:
BACKGROUND:Patients who are treated with targeted temperature management after out-of-hospital cardiac arrest with shockable rhythm are at increased risk for ventilator-associated pneumonia. The benefit of preventive short-term antibiotic therapy has not been shown. METHODS: We conducted a multicenter, double-blind, randomized, placebo-controlled trial involving adult patients (>18 years of age) in intensive care units (ICUs) who were being mechanically ventilated after out-of-hospital cardiac arrest related to initial shockable rhythm and treated with targeted temperature management at 32 to 34°C. Patients with ongoing antibiotic therapy, chronic colonization with multidrug-resistant bacteria, or moribund status were excluded. Either intravenous amoxicillin-clavulanate (at doses of 1 g and 200 mg, respectively) or placebo was administered three times a day for 2 days, starting less than 6 hours after the cardiac arrest. The primary outcome was early ventilator-associated pneumonia (during the first 7 days of hospitalization). An independent adjudication committee determined diagnoses of ventilator-associated pneumonia. RESULTS: A total of 198 patients underwent randomization, and 194 were included in the analysis. After adjudication, 60 cases of ventilator-associated pneumonia were confirmed, including 51 of early ventilator-associated pneumonia. The incidence of early ventilator-associated pneumonia was lower with antibiotic prophylaxis than with placebo (19 patients [19%] vs. 32 [34%]; hazard ratio, 0.53; 95% confidence interval, 0.31 to 0.92; P = 0.03). No significant differences between the antibiotic group and the control group were observed with respect to the incidence of late ventilator-associated pneumonia (4% and 5%, respectively), the number of ventilator-free days (21 days and 19 days), ICU length of stay (5 days and 8 days if patients were discharged and 7 days and 7 days if patients had died), and mortality at day 28 (41% and 37%). At day 7, no increase in resistant bacteria was identified. Serious adverse events did not differ significantly between the two groups. CONCLUSIONS: A 2-day course of antibiotic therapy with amoxicillin-clavulanate in patients receiving a 32-to-34°C targeted temperature management strategy after out-of-hospital cardiac arrest with initial shockable rhythm resulted in a lower incidence of early ventilator-associated pneumonia than placebo. No significant between-group differences were observed for other key clinical variables, such as ventilator-free days and mortality at day 28. (Funded by the French Ministry of Health; ANTHARTIC ClinicalTrials.gov number, NCT02186951.).
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