Effectiveness of biomarker-based exclusion of ventilator-acquired pneumonia to reduce antibiotic use (VAPrapid-2): study protocol for a randomised controlled trial

Effectiveness of biomarker-based exclusion of ventilator-acquired pneumonia to reduce antibiotic use (VAPrapid-2): study protocol for a randomised controlled trial

Trials, July 2016

27422026

Thomas P. Hellyer, Niall H. Anderson, Jennie Parker, Paul Dark, Tina Van Den Broeck, Suveer Singh, Ronan McMullan, Ashley M. Agus, Lydia M. Emerson, Bronagh Blackwood, Savita Gossain, Tim S. Walsh, Gavin D. Perkins, Andrew Conway Morris, Daniel F. McAuley, A. John Simpson

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.