Biomarker-guided antibiotic stewardship in suspected ventilator-associated pneumonia (VAPrapid2): a randomised controlled trial and process evaluation

被引:72
作者
Hellyer, Thomas P. [1 ]
McAuley, Daniel F. [4 ,5 ]
Walsh, Timothy S. [7 ,8 ]
Anderson, Niall [9 ]
Morris, Andrew Conway [10 ]
Singh, Suveer [11 ]
Dark, Paul [12 ]
Roy, Alistair, I [13 ]
Perkins, Gavin D. [14 ,15 ]
McMullan, Ronan [4 ]
Emerson, Lydia M. [4 ]
Blackwood, Bronagh [4 ]
Wright, Stephen E. [16 ]
Kefala, Kallirroi [8 ]
O'Kane, Cecilia M. [4 ]
Baudouin, Simon, V [17 ]
Paterson, Ross L. [18 ]
Rostron, Anthony J. [1 ,13 ]
Agus, Ashley [6 ]
Bannard-Smith, Jonathan [19 ]
Robin, Nicole M. [20 ]
Welters, Ingeborg D. [21 ]
Bassford, Christopher [22 ]
Yates, Bryan [23 ]
Spencer, Craig [24 ]
Laha, Shondipon K. [24 ]
Hulme, Jonathan [25 ]
Bonner, Stephen [26 ]
Linnett, Vanessa [27 ]
Sonksen, Julian [28 ]
Van Den Broeck, Tina [29 ]
Boschman, Gert [29 ]
Keenan, D. W. James [29 ]
Scott, Jonathan [1 ]
Allen, A. Joy [2 ]
Phair, Glenn [6 ]
Parker, Jennie [3 ]
Bowett, Susan A. [3 ]
Simpson, A. John [1 ,2 ]
机构
[1] Newcastle Univ, Translat & Clin Res Inst, Newcastle NE2 4HH, England
[2] Newcastle Univ, Natl Inst Hlth Res Newcastle Vitro Diagnost Coope, Newcastle, England
[3] Newcastle Univ, Newcastle Clin Trials Unit, Newcastle, England
[4] Queens Univ Belfast, Wellcome Wolfson Ctr Expt Med, Belfast, Antrim, North Ireland
[5] Royal Hosp, Reg Intens Care Unit, Belfast, Antrim, North Ireland
[6] Royal Hosp, Northern Ireland Clin Trials Unit, Belfast, Antrim, North Ireland
[7] Univ Edinburgh, Queens Med Res Inst, Anaesthesia Crit Care & Pain Med, Edinburgh, Midlothian, Scotland
[8] Royal Infirm Edinburgh NHS Trust, Intens Care Unit, Edinburgh, Midlothian, Scotland
[9] Univ Edinburgh, Usher Inst, Edinburgh, Midlothian, Scotland
[10] Univ Cambridge, Addsenbrookes Hosp, Dept, Div Anaesthesia, Cambridge, England
[11] Imperial Coll London, Dept Canc & Surg, London, England
[12] Univ Manchester, Natl Inst Hlth Res, Biomed Res Ctr, Div Infect Immun & Resp Med,Manchester Natl Inst, Manchester, Lancs, England
[13] City Hosp Sunderland NHS Fdn Trust, Sunderland Royal Hosp, Integrated Crit Care Unit, Sunderland, England
[14] Univ Warwick, Warwick Med Sch, Coventry, W Midlands, England
[15] Univ Hosp Birmingham NHS Fdn Trust, Heartlands Hosp, Intens Care Unit, Birmingham, W Midlands, England
[16] Newcastle Tyne Hosp NHS Fdn Trust, Freeman Hosp, Integrated Crit Care Unit, Newcastle, England
[17] Newcastle Tyne Hosp NHS Fdn Trust, Royal Victoria Infirm, Intens Care Unit, Newcastle, England
[18] Western Gen Hosp, Intens Care Unit, Edinburgh, Midlothian, Scotland
[19] Manchester Univ NHS Fdn Trust, Manchester Royal Infirm, Intens Care Unit, Manchester, Lancs, England
[20] Countess Chester NHS Fdn Trust, Intens Care Unit, Chester, Cheshire, England
[21] Univ Liverpool, Inst Ageing & Chron Dis, Liverpool, Merseyside, England
[22] Univ Hosp Coventry & Warwickshire NHS Trust, Univ Hosp Coventry, Care Unit, Coventry, W Midlands, England
[23] Northumbria Specialist Emergency Care Hosp, Intens Care Unit, Cramlington, England
[24] Lancashire Teaching Hosp NHS Fdn Trust, Preston Royal Hosp, Intens Care Unit, Preston, Lancs, England
[25] Sandwell & West Birmingham Hosp NHSTrust, Sandwell Gen Hosp, Intens Care Unit, West Bromwich, England
[26] South Tees Hosp NHS Fdn Trust, James Cook Univ Hosp, Intens Care Unit, Middlesbrough, Cleveland, England
[27] Gateshead NHS Fdn Trust, Queen Elizabeth Hosp, Intens Care Unit, Gateshead, England
[28] Dudley Grp NHS Fdn Trust, Russells Hall Hosp, Intens Care Unit, Dudley, England
[29] Becton Dickinson Biosci Europe, Erembodegem, Belgium
基金
英国惠康基金; 美国国家卫生研究院; 英国医学研究理事会;
关键词
CLINICAL-PRACTICE GUIDELINES; RESPIRATORY-TRACT INFECTION; INTENSIVE-CARE UNITS; PROCALCITONIN; PREVALENCE; MORTALITY; ICU; STRATEGIES; MANAGEMENT; DIAGNOSIS;
D O I
10.1016/S2213-2600(19)30367-4
中图分类号
R4 [临床医学];
学科分类号
1002 ; 100602 ;
摘要
Background Ventilator-associated pneumonia is the most common intensive care unit (ICU)-acquired infection, yet accurate diagnosis remains difficult, leading to overuse of antibiotics. Low concentrations of IL-1 beta and IL-8 in bronchoalveolar lavage fluid have been validated as effective markers for exclusion of ventilator-associated pneumonia. The VAPrapid2 trial aimed to determine whether measurement of bronchoalveolar lavage fluid IL-1 beta and IL-8 could effectively and safely improve antibiotic stewardship in patients with clinically suspected ventilator-associated pneumonia. Methods VAPrapid2 was a multicentre, randomised controlled trial in patients admitted to 24 ICUs from 17 National Health Service hospital trusts across England, Scotland, and Northern Ireland. Patients were screened for eligibility and included if they were 18 years or older, intubated and mechanically ventilated for at least 48 h, and had suspected ventilator-associated pneumonia. Patients were randomly assigned (1:1) to biomarker-guided recommendation on antibiotics (intervention group) or routine use of antibiotics (control group) using a web-based randomisation service hosted by Newcastle Clinical Trials Unit. Patients were randomised using randomly permuted blocks of size four and six and stratified by site, with allocation concealment. Clinicians were masked to patient assignment for an initial period until biomarker results were reported. Bronchoalveolar lavage was done in all patients, with concentrations of IL-1 beta and IL-8 rapidly determined in bronchoalveolar lavage fluid from patients randomised to the biomarker-based antibiotic recommendation group. If concentrations were below a previously validated cutoff, clinicians were advised that ventilator-associated pneumonia was unlikely and to consider discontinuing antibiotics. Patients in the routine use of antibiotics group received antibiotics according to usual practice at sites. Microbiology was done on bronchoalveolar lavage fluid from all patients and ventilator-associated pneumonia was confirmed by at least 104 colony forming units per mL of bronchoalveolar lavage fluid. The primary outcome was the distribution of antibiotic-free days in the 7 days following bronchoalveolar lavage. Data were analysed on an intention-to-treat basis, with an additional per-protocol analysis that excluded patients randomly assigned to the intervention group who defaulted to routine use of antibiotics because of failure to return an adequate biomarker result. An embedded process evaluation assessed factors influencing trial adoption, recruitment, and decision making. This study is registered with ISRCTN, ISRCTN65937227, and ClinicalTrials.gov, NCT01972425. Findings Between Nov 6, 2013, and Sept 13, 2016, 360 patients were screened for inclusion in the study. 146 patients were ineligible, leaving 214 who were recruited to the study. Four patients were excluded before randomisation, meaning that 210 patients were randomly assigned to biomarker-guided recommendation on antibiotics (n=104) or routine use of antibiotics (n=106). One patient in the biomarker-guided recommendation group was withdrawn by the clinical team before bronchoscopy and so was excluded from the intention-to-treat analysis. We found no significant difference in the primary outcome of the distribution of antibiotic-free days in the 7 days following bronchoalveolar lavage in the intention-to-treat analysis (p=0.58). Bronchoalveolar lavage was associated with a small and transient increase in oxygen requirements. Established prescribing practices, reluctance for bronchoalveolar lavage, and dependence on a chain of trial-related procedures emerged as factors that impaired trial processes. Interpretation Antibiotic use remains high in patients with suspected ventilator-associated pneumonia. Antibiotic stewardship was not improved by a rapid, highly sensitive rule-out test. Prescribing culture, rather than poor test performance, might explain this absence of effect. Copyright (C) 2019 The Author(s). Published by Elsevier Ltd.
引用
收藏
页码:182 / 191
页数:10
相关论文
共 44 条
[21]   Implementation of guidelines for management of possible multidrug-resistant pneumonia in intensive care: an observational, multicentre cohort study [J].
Kett, Daniel H. ;
Cano, Ennie ;
Quartin, Andrew A. ;
Mangino, Julie E. ;
Zervos, Marcus J. ;
Peyrani, Paula ;
Cely, Cynthia M. ;
Ford, Kimbal D. ;
Scerpella, Ernesto G. ;
Ramirez, Julio A. .
LANCET INFECTIOUS DISEASES, 2011, 11 (03) :181-189
[22]   Categorical Risk Perception Drives Variability in Antibiotic Prescribing in the Emergency Department: A Mixed Methods Observational Study [J].
Klein, Eili Y. ;
Martinez, Elena M. ;
May, Larissa ;
Saheed, Mustapha ;
Reyna, Valerie ;
Broniatowski, David A. .
JOURNAL OF GENERAL INTERNAL MEDICINE, 2017, 32 (10) :1083-1089
[23]   Procalcitonin usefulness for the initiation of antibiotic treatment in intensive care unit patients [J].
Layios, Nathalie ;
Lambermont, Bernard ;
Canivet, Jean-Luc ;
Morimont, Philippe ;
Preiser, Jean-Charles ;
Garweg, Christophe ;
Ledoux, Didier ;
Frippiat, Frederic ;
Piret, Sonia ;
Giot, Jean-Baptiste ;
Wiesen, Patricia ;
Meuris, Christelle ;
Massion, Paul ;
Leonard, Philippe ;
Nys, Monique ;
Lancellotti, Patrizio ;
Chapelle, Jean-Paul ;
Damas, Pierre .
CRITICAL CARE MEDICINE, 2012, 40 (08) :2304-2309
[24]   The Ventilator-Associated Pneumonia PIRO Score A Tool for Predicting ICU Mortality and Health-Care Resources Use in Ventilator-Associated Pneumonia [J].
Lisboa, Thiago ;
Diaz, Emili ;
Sa-Borges, Marcio ;
Socias, Antonia ;
Sole-Violan, Jordi ;
Rodriguez, Alejandro ;
Rello, Jordi .
CHEST, 2008, 134 (06) :1208-1216
[25]   Information leaflet and antibiotic prescribing strategies for acute lower respiratory tract infection - A randomized controlled trial [J].
Little, P ;
Rumsby, K ;
Kelly, J ;
Watson, L ;
Moore, M ;
Warner, G ;
Fahey, T ;
Williamson, I .
JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION, 2005, 293 (24) :3029-3035
[26]   Usefulness of procalcitonin for the diagnosis of ventilator-associated pneumonia [J].
Luyt, Charles-Edouard ;
Combes, Alain ;
Reynaud, Catherine ;
Hekimian, Guillaume ;
Nieszkowska, Ania ;
Tonnellier, Marc ;
Aubry, Alexandra ;
Trouillet, Jean-Louis ;
Bernard, Maguy ;
Chastre, Jean .
INTENSIVE CARE MEDICINE, 2008, 34 (08) :1434-1440
[27]   Multistate Point- Prevalence Survey of Health Care- Associated Infections [J].
Magill, Shelley S. ;
Edwards, Jonathan R. ;
Bamberg, Wendy ;
Beldavs, Zintars G. ;
Dumyati, Ghinwa ;
Kainer, Marion A. ;
Lynfield, Ruth ;
Maloney, Meghan ;
McAllister-Hollod, Laura ;
Nadle, Joelle ;
Ray, Susan M. ;
Thompson, Deborah L. ;
Wilson, Lucy E. ;
Fridkin, Scott K. .
NEW ENGLAND JOURNAL OF MEDICINE, 2014, 370 (13) :1198-1208
[28]   THE STANDARDIZATION OF BRONCHOSCOPIC TECHNIQUES FOR VENTILATOR-ASSOCIATED PNEUMONIA [J].
MEDURI, GU ;
CHASTRE, J .
CHEST, 1992, 102 (05) :S557-S564
[29]   A randomized controlled trial of an antibiotic discontinuation policy for clinically suspected ventilator-associated pneumonia [J].
Micek, S ;
Ward, S ;
Fraser, VJ ;
Kollef, MH .
CHEST, 2004, 125 (05) :1791-1799
[30]   Predicting Mortality in Patients with Ventilator-Associated Pneumonia: The APACHE II Score versus the New IBMP-10 Score [J].
Mirsaeidi, Mehdi ;
Peyrani, Paula ;
Ramirez, Julio A. .
CLINICAL INFECTIOUS DISEASES, 2009, 49 (01) :72-77