Antibiotherapy During Therapeutic Hypothermia to Prevent Infectious Complications (ANTHARTIC)

Prevention of Early Ventilator-associated Pneumonia With Antibiotic Therapy in Patients Treated With Mild Therapeutic Hypothermia After Cardiac Arrest.

Mild therapeutic hypothermia is currently recommended in management of cardiac arrests with shockable rhythm. In mechanically ventilated patients who were resuscitated after out-of-hospital cardiac arrests, mild therapeutic hypothermia side effects are conductive for infectious complications and especially for ventilator-associated pneumonia (VAP).

Despite high incidence of VAP and other infectious complications, it is not currently recommended to use antibiotic prophylaxis on the responsible germs. Yet VAP incidence could be decreased if an antibiotic therapy was systematically given to patient treated with mild therapeutic hypothermia after a cardiac arrest. Several retrospective studies showed less infectious complications but also decreased morbidity and mortality related to these complications when antibiotic therapy was given early to patients treated with therapeutic hypothermia after cardiac arrest.

Study Overview

• Status: Completed
• Conditions: Ventilator-associated Pneumonia; Cardiac Arrests With Shockable Rhythm; Mild Therapeutic Hypothermia; Preventive Antibiotics
• Intervention / Treatment: Drug: Amoxicillin - clavulanic acid; Drug: Placebo

Detailed Description

Multicenter add-on randomized controlled double-blind trial assessing the efficacy of preventive antibiotics amoxicillin-clavulanic acid vs placebo to prevent occurrence of early VAP after out-of-hospital cardiac arrest receiving mild therapeutic hypothermia, in addition to usual VAP prevention measures.

• Study Type: Interventional
• Enrollment (Actual): 197
• Phase: Phase 3

Contacts and Locations

Study Locations

• France
  • Argenteuil, France, 95107
    • CH Argenteuil - Service de Réanimation
  • Brive La Gaillarde, France, 19100
    • CH Brive La Gaillarde - Service de Réanimation
  • Dijon, France, 21079
    • CHU Dijon - Serve de Réanimation
  • Garches, France, 92380
    • AP-HP - Hôpital pointcaré - Service de Réanimation
  • Le Mans, France, 72000
    • CH du Mans
  • Limoges, France, 87042
    • CHU de Limoges - Service de réanimation polyvalente
  • Nantes, France
    • CHU Nantes - Service de réanimation
  • Orleans, France, 47067
    • CHU Orléans - service de Réanimation
  • Paris, France, 75010
    • AP-HP - Hôpital Lariboisière - Service de Réanimation
  • Paris, France, 75014
    • AP-HP - Hôpital Cochin - Service de Réanimation
  • Paris, France, 75015
    • AP-HP - Hôpital Européen Georges Pompidou - Service de Réanimation
  • Perigueux, France, 24019
    • CH Périgueux
  • Strasbourg, France, 67000
    • CHU Strasbourg - service de Réanimation
  • Tours, France, 37044
    • CHU Tours - Service de Réanimation
  • Versailles, France, 78000
    • CH Versailles - service de Réanimation
  • Saint Michel
    • Angoulême, Saint Michel, France, 16470
      • CH Angouleme - Service de Réanimation

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Older than 18 years-old, intubated and mechanically ventilated after out-of-hospital resuscitated cardiac arrest secondary to shockable rhythm
• Hospitalized in an ICU
• Mild therapeutic hypothermia procedure (32° to 35°C) scheduled (24 to 36 hours)
• Delay from ROSC to randomisation < 6 hours
• Consent from family members or emergency consent

Exclusion Criteria:

• Pregnancy
• Out-of-hospital cardiac arrest secondary to non shockable rhythm and In-hospital cardiac arrest
• Need for cardiac support by cardiopulmonary bypass
• Ongoing antibiotic therapy or during the week before
• Ongoing or concomitant pneumonia
• Known chronic colonization with MRB
• Hypersensitivity to the active substances, to any of the penicillins or to any of the excipients.
• History of a severe immediate hypersensitivity reaction (e.g. anaphylaxis) to another beta-lactam agent (e.g. a cephalosporin, carbapenem or monobactam).
• History of jaundice/hepatic impairment due to amoxicillin/clavulanic acid, according to the latest version of the SmPC.
• Previous lung disease
• Predictable decision of early care limitation
• Patient under guardianship or curatorship
• Moribund patient
• Participation to another trial within 30 days

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: DOUBLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Amoxicillin clavulanic acid; Amoxicillin-clavulanic acid 1g, three times a day during 2 days, started within one hour after randomization and before the beginning of hypothermia.	Drug: Amoxicillin - clavulanic acid; Amoxicillin-clavulanic acid 1g, three times a day during 2 days, started within one hour after randomization and before the beginning of hypothermia.
PLACEBO_COMPARATOR: Placebo; Placebo 1g, three times a day during 2 days, started within one hour after randomization and before the beginning of hypothermia.	Drug: Placebo; Placebo 1g, three times a day during 2 days, started within one hour after randomization and before the beginning of hypothermia.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence reduction of early VAP	Incidence reduction of early VAP with short term amoxicillin-clavulanic acid in patients treated with hypothermia after out-of-hospital cardiac arrest	7 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mortality	Mortality	28 days
Early nosocomial infectious complications		28 days

Collaborators and Investigators

• Sponsor: University Hospital, Limoges
• Investigators: Principal Investigator: Bruno FRANCOIS, MD, Limoges UH

Publications and helpful links

General Publications

• Francois B, Cariou A, Clere-Jehl R, Dequin PF, Renon-Carron F, Daix T, Guitton C, Deye N, Legriel S, Plantefeve G, Quenot JP, Desachy A, Kamel T, Bedon-Carte S, Diehl JL, Chudeau N, Karam E, Durand-Zaleski I, Giraudeau B, Vignon P, Le Gouge A; CRICS-TRIGGERSEP Network and the ANTHARTIC Study Group. Prevention of Early Ventilator-Associated Pneumonia after Cardiac Arrest. N Engl J Med. 2019 Nov 7;381(19):1831-1842. doi: 10.1056/NEJMoa1812379.

Study record dates

Study Major Dates

• Study Start (ACTUAL): August 18, 2014
• Primary Completion (ACTUAL): October 27, 2016
• Study Completion (ACTUAL): September 14, 2017

Study Registration Dates

• First Submitted: July 8, 2014
• First Submitted That Met QC Criteria: July 9, 2014
• First Posted (ESTIMATE): July 10, 2014

Study Record Updates

• Last Update Posted (ACTUAL): March 18, 2020
• Last Update Submitted That Met QC Criteria: March 16, 2020
• Last Verified: March 1, 2020

More Information

Terms related to this study

• Keywords: ventilator-associated pneumonia; cardiac arrests with shockable rhythm; Mild therapeutic hypothermia; preventive antibiotics
• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Lung Diseases; Disease Attributes; Cross Infection; Iatrogenic Disease; Body Temperature Changes; Healthcare-Associated Pneumonia; Pneumonia; Heart Arrest; Hypothermia; Pneumonia, Ventilator-Associated; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Anti-Bacterial Agents; beta-Lactamase Inhibitors; Amoxicillin; Clavulanic Acid; Clavulanic Acids
• Other Study ID Numbers: I13018 ANTHARTIC