Prophylactic Antibiotics in Comatose Survivors of Out-of-hospital Cardiac Arrest

Prophylactic Versus Clinically-driven Antibiotics in Comatose Survivors of Out-of-hospital Cardiac Arrest

The purpose of this study is to determine whether there is potential benefits of prophylactic antibiotic treatment in comatose survivors of out-of-hospital cardiac arrest (OHCA) treated in intensive care unit with therapeutic hypothermia.

Study Overview

• Status: Completed
• Conditions: Out-of-hospital Cardiac Arrest
• Intervention / Treatment: Drug: Amoxicillin-Clavulanic acid

Detailed Description

Postresuscitation management of comatose survivors of out-of-hospital cardiac arrest (OHCA) significantly improved and "bundle of care" including therapeutic hypothermia, immediate coronary angiography, percutaneous coronary intervention (PCI) and contemporary intensive care nowadays leads to survival with good neurological recovery. Benefit of prophylactic antibiotics, which may suppress development of postresuscitation infection and especially early onset pneumonia and thereby decrease the severity of postresuscitation systemic inflammatory response, is controversial. Because of these uncertainties, the investigators performed a single-center randomized clinical trial comparing prophylactic versus clinically-driven administration of antibiotics in comatose survivors of OHCA. The investigators hypothesized that prophylactic antibiotics may decrease the severity of postresuscitation systemic inflammatory response by reducing the incidence of postresuscitation infection and especially pneumonia which was further addressed by repeat microbiological sampling.

• Study Type: Interventional
• Enrollment (Actual): 60
• Phase: Phase 4

Contacts and Locations

Study Locations

• Slovenia
  • Ljubljana, Slovenia, 1000
    • University Medical Centre Ljubljana

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:

• Female and male over 18 years old
• Comatose survivors of out-of-hospital cardiac arrest treated in intensive care unit with therapeutic hypothermia

Exclusion Criteria:

• Suspected or confirmed pregnancy
• Allergy to amoxicillin-clavulanic acid
• Tracheobronchial aspiration
• Antibiotic therapy before cardiac arrest
• Need of antibiotics due to other causes
• Candidates for immediate veno-arterial extracorporeal membrane oxygenation (VA ECMO)
• Patients in whom no active treatment was decided on admission

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Prophylactic antibiotic; Amoxicillin-Clavulanic acid 1.2g every 8h	Drug: Amoxicillin-Clavulanic acid; Patients without evidence of tracheobronchial aspiration were randomized to immediate prophylactic Amoxicillin-Clavulanic acid 1,2 gr/8h; Other Names: Amoksiklav, Augmentin
NO_INTERVENTION: Clinically-driven antibiotics; Administration of antibiotics in clinically-driven group was at the discretion of attending intensivist. Selection of antibiotic in clinically-driven group was empirical or based on the results of bacterial cultures if already available.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Value of C-reactive protein (CRP) at day three	Expressed in milligram/litre (normal <5 mg/L)	Three days after admission to Intensive care unit (ICU)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Severity of systemic inflammatory response estimated by peak white blood cell count (WBC)	Expressed in number of white blood cells x 109 per litre (L)	First measurement at admission in hospital and afterwards in 24 hours intervals during stay in the intensive care unite (ICU) but not longer then first seven days
Severity of systemic inflammatory response estimated by peak value of procalcitonin (PCT)	Expressed in microgram/litre (normal <0.5 microgram/L)	First measurement at admission in hospital and afterwards in 24 hours intervals during stay in the intensive care unite (ICU) but not longer then first seven days
Severity of systemic inflammatory response estimated by peak value of neutrophil Cluster of differentiation 64 (CD 64)	Neutrophil CD 64 expression was used as an index of sepsis with >1.2 indicating greater likelihood of sepsis	First measurement at admission in hospital and afterwards in 24 hours intervals in the first three days
Appearance of pneumonia on chest X ray		Chest X ray was taken on admission and afterwards on daily basis during the stay in the intensive care unite but not longer than first week
Incidence of positive blind mini bronchoalveolar lavage (Mini-BAL) on day 3		Mini-BAL was performed on the third day after the sudden cardiac arrest
Incidence of positive hemocultures		From the admission until the patient was transferred to the ward. This was always during the ICU stay-one month
Duration of tracheal intubation	Duration of intubation was expressed as days of intubation started with admission until the extubation. Because this is being done in intensive care unite, the time frame is duration of ICU stay	From the day of admission until the extubation. This was always during the ICU stay- one month
Duration of mechanical ventilation	Duration of mechanical ventilation was expressed as days the patient needed the mechanical support for breathing regardless of mode of support	From the admission until spontaneous breathing . This was during ICU stay-one month
ICU stay		From the admission until the patient was transferred to ward, usually less than one month
Survival with good neurological outcome	Good neurological outcome was characterised using cerebral performance category (CPC) with 1-2 indicating good neurological recovery.	Up to six months after the event

Collaborators and Investigators

• Sponsor: University Medical Centre Ljubljana
• Investigators: Principal Investigator: Marko Noč, MD, PhD, University Medical Centre Ljubljana

Publications and helpful links

General Publications

• Tomte O, Andersen GO, Jacobsen D, Draegni T, Auestad B, Sunde K. Strong and weak aspects of an established post-resuscitation treatment protocol-A five-year observational study. Resuscitation. 2011 Sep;82(9):1186-93. doi: 10.1016/j.resuscitation.2011.05.003. Epub 2011 May 14.
• Stub D, Hengel C, Chan W, Jackson D, Sanders K, Dart AM, Hilton A, Pellegrino V, Shaw JA, Duffy SJ, Bernard S, Kaye DM. Usefulness of cooling and coronary catheterization to improve survival in out-of-hospital cardiac arrest. Am J Cardiol. 2011 Feb 15;107(4):522-7. doi: 10.1016/j.amjcard.2010.10.011. Epub 2010 Dec 22.
• Kocjancic ST, Jazbec A, Noc M. Impact of intensified postresuscitation treatment on outcome of comatose survivors of out-of-hospital cardiac arrest according to initial rhythm. Resuscitation. 2014 Oct;85(10):1364-9. doi: 10.1016/j.resuscitation.2014.06.028. Epub 2014 Jul 8.
• Perbet S, Mongardon N, Dumas F, Bruel C, Lemiale V, Mourvillier B, Carli P, Varenne O, Mira JP, Wolff M, Cariou A. Early-onset pneumonia after cardiac arrest: characteristics, risk factors and influence on prognosis. Am J Respir Crit Care Med. 2011 Nov 1;184(9):1048-54. doi: 10.1164/rccm.201102-0331OC.
• Mongardon N, Perbet S, Lemiale V, Dumas F, Poupet H, Charpentier J, Pene F, Chiche JD, Mira JP, Cariou A. Infectious complications in out-of-hospital cardiac arrest patients in the therapeutic hypothermia era. Crit Care Med. 2011 Jun;39(6):1359-64. doi: 10.1097/CCM.0b013e3182120b56.
• Gajic O, Festic E, Afessa B. Infectious complications in survivors of cardiac arrest admitted to the medical intensive care unit. Resuscitation. 2004 Jan;60(1):65-9. doi: 10.1016/j.resuscitation.2003.08.005.
• Woo JH, Lim YS, Yang HJ, Park WB, Cho JS, Kim JJ, Hyun SY, Lee G. Factors associated with pneumonia in post-cardiac arrest patients receiving therapeutic hypothermia. Am J Emerg Med. 2014 Feb;32(2):150-5. doi: 10.1016/j.ajem.2013.10.035. Epub 2013 Oct 26.
• Ribaric SF, Turel M, Knafelj R, Gorjup V, Stanic R, Gradisek P, Cerovic O, Mirkovic T, Noc M. Prophylactic versus clinically-driven antibiotics in comatose survivors of out-of-hospital cardiac arrest-A randomized pilot study. Resuscitation. 2017 Feb;111:103-109. doi: 10.1016/j.resuscitation.2016.11.025. Epub 2016 Dec 14.

Study record dates

Study Major Dates

• Study Start: September 1, 2013
• Primary Completion (ACTUAL): March 1, 2015
• Study Completion (ACTUAL): April 1, 2015

Study Registration Dates

• First Submitted: June 30, 2016
• First Submitted That Met QC Criteria: September 8, 2016
• First Posted (ESTIMATE): September 14, 2016

Study Record Updates

• Last Update Posted (ESTIMATE): September 14, 2016
• Last Update Submitted That Met QC Criteria: September 8, 2016
• Last Verified: August 1, 2016

More Information

Terms related to this study

• Keywords: Out-of-hospital cardiac arrest; Prophylactic antibiotics
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Heart Arrest; Out-of-Hospital Cardiac Arrest; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Anti-Bacterial Agents; beta-Lactamase Inhibitors; Amoxicillin; Clavulanic Acid; Clavulanic Acids; Amoxicillin-Potassium Clavulanate Combination
• Other Study ID Numbers: P3-0331

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO