title: Effectiveness of biomarker-based exclusion of ventilator-acquired pneumonia to reduce antibiotic use (VAPrapid-2): study protocol for a randomised controlled trial.
abstract: Ventilator-acquired pneumonia (VAP) is a common reason for antimicrobial therapy in the intensive care unit (ICU). Biomarker-based diagnostics could improve antimicrobial stewardship through rapid exclusion of VAP. Bronchoalveloar lavage (BAL) fluid biomarkers have previously been shown to allow the exclusion of VAP with high confidence.
  
  
  
  This is a prospective, multi-centre, randomised, controlled trial to determine whether a rapid biomarker-based exclusion of VAP results in fewer antibiotics and improved antimicrobial management. Patients with clinically suspected VAP undergo BAL, and VAP is confirmed by growth of a potential pathogen at [≥] 10(4) colony-forming units per millilitre (CFU/ml). Patients are randomised 1:1, to either a 'biomarker-guided recommendation on antibiotics' in which BAL fluid is tested for IL-1β and IL-8 in addition to routine microbiology testing, or to 'routine use of antibiotics' in which BAL undergoes routine microbiology testing only. Clinical teams are blinded to intervention until 6 hours after randomisation, when biomarker results are reported to the clinician. The primary outcome is a change in the frequency distribution of antibiotic-free days (AFD) in the 7 days following BAL. Secondary outcome measures include antibiotic use at 14 and 28 days; ventilator-free days; 28-day mortality and ICU mortality; sequential organ failure assessment (SOFA) at days 3, 7 and 14; duration of stay in critical care and the hospital; antibiotic-associated infections; and antibiotic-resistant pathogen cultures up to hospital discharge, death or 56 days. A healthcare-resource-utilisation analysis will be calculated from the duration of critical care and hospital stay. In addition, safety data will be collected with respect to performing BAL. A sample size of 210 will be required to detect a clinically significant shift in the distribution of AFD towards more patients having fewer antibiotics and therefore more AFD.
  
  
  
  This trial will test whether a rapid biomarker-based exclusion of VAP results in rapid discontinuation of antibiotics and therefore improves antibiotic management in patients with suspected VAP.
  
  
  
  ISRCTN65937227 . Registered on 22 August 2013. ClinicalTrials.gov, NCT01972425 . Registered on 24 October 2013.
authors.affiliation: Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK. t.p.hellyer@ncl.ac.uk.
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Hellyer
authors.affiliation: Centre for Population Health Sciences, University of Edinburgh, Medical School, Edinburgh, UK.
authors.forename: Niall H
authors.initials: NH
authors.lastname: Anderson
authors.affiliation: Newcastle Clinical Trials Unit, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Jennie
authors.initials: J
authors.lastname: Parker
authors.affiliation: Institute of Inflammation and Repair, University of Manchester, Manchester Academic Health Sciences Centre & Intensive Care Unit, Salford Royal NHS Foundation Trust, Greater Manchester, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Dark
authors.affiliation: Becton Dickinson Biosciences, Erembodegem, Aalst, Belgium.
authors.forename: Tina
authors.initials: T
authors.lastname: Van Den Broeck
authors.affiliation: Intensive Care Unit, Chelsea and Westminster Hospital, Imperial College London, London, UK.
authors.forename: Suveer
authors.initials: S
authors.lastname: Singh
authors.affiliation: Department of Medical Microbiology, Kelvin Building, The Royal Hospitals, Belfast, UK.
authors.forename: Ronan
authors.initials: R
authors.lastname: McMullan
authors.affiliation: Northern Ireland Clinical Trials Unit, Elliot Dynes Building, The Royal Hospitals, Belfast, UK.
authors.forename: Ashley M
authors.initials: AM
authors.lastname: Agus
authors.affiliation: Centre for Experimental Medicine, Queen's University Belfast, Belfast, UK.
authors.forename: Lydia M
authors.initials: LM
authors.lastname: Emerson
authors.affiliation: Centre for Experimental Medicine, Queen's University Belfast, Belfast, UK.
authors.forename: Bronagh
authors.initials: B
authors.lastname: Blackwood
authors.affiliation: Public Health Laboratory, Heart of England NHS Foundation Trust, Birmingham, UK.
authors.forename: Savita
authors.initials: S
authors.lastname: Gossain
authors.affiliation: MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh, UK.
authors.forename: Tim S
authors.initials: TS
authors.lastname: Walsh
authors.affiliation: University of Warwick and Heart of England NHS Foundation Trust, Coventry, UK.
authors.forename: Gavin D
authors.initials: GD
authors.lastname: Perkins
authors.affiliation: Division of Anaesthesia, Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge Biomedical Campus, Cambridge, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Conway Morris
authors.affiliation: Northern Ireland Clinical Trials Unit, Elliot Dynes Building, The Royal Hospitals, Belfast, UK.|Centre for Experimental Medicine, Queen's University Belfast, Belfast, UK.|Regional Intensive Care Unit, Royal Victoria Hospital, Grosvenor Road, Belfast, UK.
authors.forename: Daniel F
authors.initials: DF
authors.lastname: McAuley
authors.affiliation: Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: A John
authors.initials: AJ
authors.lastname: Simpson
mesh_terms: D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D000073602:Antimicrobial Stewardship; D001419:Bacteria / Q000254:growth & development / Q000302:isolation & purification; D015415:Biomarkers / Q000032:analysis; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry* / Q000382:microbiology; D002985:Clinical Protocols; D015169:Colony Count, Microbial; D017052:Hospital Mortality; D006801:Humans; D053583:Interleukin-1beta / Q000032:analysis*; D016209:Interleukin-8 / Q000032:analysis*; D007902:Length of Stay; D063305:Organ Dysfunction Scores; D018579:Patient Selection; D018410:Pneumonia, Bacterial / Q000175:diagnosis* / Q000188:drug therapy / Q000382:microbiology / Q000401:mortality; D053717:Pneumonia, Ventilator-Associated / Q000175:diagnosis* / Q000188:drug therapy / Q000382:microbiology / Q000401:mortality; D011237:Predictive Value of Tests; D011446:Prospective Studies; D012107:Research Design; D012121:Respiration, Artificial; D013997:Time Factors; D006113:United Kingdom; D019564:Unnecessary Procedures
chemical_list: D000900:Anti-Bacterial Agents; D015415:Biomarkers; C508606:CXCL8 protein, human; C508585:IL1B protein, human; D053583:Interleukin-1beta; D016209:Interleukin-8
keywords: Antibiotic stewardship; Biomarker; Randomised controlled trial; Ventilator-acquired pneumonia