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-1β 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-1β and IL-8 could effectively and safely improve antibiotic stewardship in patients with clinically suspected ventilator-associated pneumonia.
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 One patient in the biomarker-guided recommendation group was withdrawn by the clinical team before bronchoscopy and so was excluded from the intention-to-treat analysis.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.
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.
UK Department of Health and the Wellcome Trust.
Evidence before this study
We searched Medline between Jan 1, 1996, and April 30, 2019, with the MeSH terms “Pneumonia”; “Pneumonia, bacterial”; “Pneumonia, Ventilator-Associated”; “Respiratory Tract Infections”; “Biomarkers”; “Protein Precursors”; and “Anti-bacterial Agents”. Although several trials investigated the role of procalcitonin in reducing antibiotic use in lower respiratory tract infections, to our knowledge, few trials have been done in patients with ventilator-associated pneumonia. A multicentre trial of a procalcitonin-guided intervention to discontinue antibiotics in patients with ventilator-associated pneumonia reported a significant improvement in antibiotic-free days at 28 days. However, the duration of antibiotics in both the intervention and the control groups of the trial were longer than the 8-day duration recommended in international guidelines. A further single-centre trial used a combination of the Clinical Pulmonary Infection Score and procalcitonin to guide antibiotic discontinuation in patients who had already completed 7 days of antibiotic therapy. Although patients in the procalcitonin group had more antibiotic-free days at 28 days versus the control group, the duration of antibiotics in both groups was longer than 8 days. These studies focused on discontinuation of antibiotics once empirical treatment was established. To our knowledge, there are no published trials in which antibiotic stewardship is based on early exclusion of ventilator-associated pneumonia.
Added value of this study
To our knowledge, VAPrapid2 is the first trial to use a validated biomarker in a cohort of patients with clinically suspected ventilator-associated pneumonia, with an aim to determine whether early exclusion of ventilator-associated pneumonia could improve antibiotic stewardship. Furthermore, our trial included a process evaluation that aimed to understand clinical behaviours and implementation of the trial protocol. This trial showed that, although the biomarker test could accurately exclude ventilator-associated pneumonia, the trial recommendation regarding antibiotic discontinuation was seldom followed by clinicians, resulting in no difference in antibiotic use between the intervention and control groups. The results of this trial highlight entrenched behaviours in antibiotic prescribing practice and barriers to adopting new, unfamiliar technologies.
Implications of all the available evidence
Previous trials of procalcitonin have influenced the duration of antibiotic treatment in patients with ventilator-associated pneumonia. However, most patients with suspected ventilator-associated pneumonia do not actually have it, subjecting them to unnecessary antibiotic treatment while the true cause of respiratory compromise potentially goes untreated. Avoiding antibiotic use in such patients remains an important goal for antibiotic stewardship in intensive care units. The VAPrapid2 trial showed no influence on antibiotic prescribing practices in this patient group. Future studies should differentiate suspected from confirmed ventilator-associated pneumonia, aim to reduce antibiotics in patients who do not have confirmed infection, and dissect complex mechanisms that influence prescribing practices.
and is associated with substantial mortality, particularly in the ageing ICU population.
Broad-spectrum antibiotic use is recommended in suspected ventilator-associated pneumonia.
- Torres A
- Niederman MS
- Chastre J
- et al.
However, diagnosis of this infection remains notoriously difficult, and pulmonary infection is typically confirmed in only 20–60% of suspected cases.
Consequently, antibiotics are overused for suspected ventilator-associated pneumonia, potentially exposing patients to adverse effects, detracting from alternative causes of respiratory compromise, increasing costs, and driving emergence of antimicrobial resistance.
The association between increased antibiotic use and emergence of antimicrobial resistance in ICUs is well established.
In the setting of hospital-acquired pneumonia, adherence to guidelines that promote broad-spectrum empirical antibiotics has been associated with adverse outcomes.
This background has driven a need to rationalise antibiotic prescribing in ICUs.
a process evaluation study was embedded in this trial.
Study design and participants
VAPrapid2 was a multicentre, randomised controlled trial in patients admitted to the ICU with suspected ventilator-associated pneumonia. The trial was done in 24 ICUs from 17 National Health Service (NHS) hospital trusts across England, Scotland, and Northern Ireland.
Additionally, clinicians had to consider eligible patients unlikely to have extrapulmonary infection requiring antibiotic treatment (ie, early discontinuation of antibiotics would be appropriate if ventilator-associated pneumonia was confidently excluded).
Patients were excluded if they fulfilled the criteria predicting poor tolerance of bronchoscopy and bronchoalveolar lavage: PaO2 less than 8 kPa on FiO2 greater than 0·7, positive end-expiratory pressure greater than 15 cmH2O, peak airway pressure greater than 35 cmH2O, heart rate greater than 140 beats per minute, mean arterial pressure less than 65 mm Hg, bleeding diathesis (platelet count <20 × 109/L or international normalised ratio >3), intracranial pressure greater than 20 mm Hg, and ICU consultant considered bronchoscopy and bronchoalveolar lavage to be unsafe for the patient.
Patients or their relatives or representatives gave written informed consent for inclusion in the study.
Randomisation and masking
Samples were transported at 4°C to one of six testing laboratories (appendix p 5), with a transport time of up to 1·5 h.
and an automated calculation was made available to the laboratory staff processing bronchoalveolar lavage fluid samples. Instructions were communicated to clinicians by telephone immediately after results became available. For patients randomly assigned to the biomarker-guided group, the instruction relayed to clinicians was either, “Biomarker result above cutoff. Ventilator-associated pneumonia cannot be excluded, consider continuing antibiotics,” or “Biomarker result below cutoff. The negative predictive value is 1 and ventilator-associated pneumonia is very unlikely. Consider discontinuation of antibiotics.” For patients randomly assigned to routine use of antibiotics the instruction given to clinicians was, “Patient in routine use of antibiotics group.” If assays did not meet internal quality control criteria, clinicians were advised to default to routine care. The median negative predictive value previously calculated for the combination of IL-1β and IL-8 was 1·0 (95% CI 0·92–1·0).
Microbiology testing was done in accredited NHS or Public Health England microbiology laboratories. Standard operating procedures for semiquantitative culture were done in accordance with the 2012 UK Standards for Microbiology Investigation, issued by the Health Protection Agency. This strategy allowed samples to be quantified as having no growth, 1–10 CFU/mL, 10–102 CFU/mL, 102–103 CFU/mL, 103–104 CFU/mL, 104–105 CFU/mL, and so on, allowing simple and clear demarcation of bacteria grown at 104 CFU/mL or more (ventilator-associated pneumonia) and less than 104 CFU/mL.
Investigators visited all ICUs before recruitment commenced, providing educational sessions on the diagnostic performance of the biomarkers and on the trial intervention. Key components of trial design were reinforced through regular communication. Additional training was done in testing laboratories with respect to laboratory processes and biomarker measurement. Before the trial commenced, clinicians were again made aware of the biomarker test and were encouraged to follow the biomarker-guided recommendations. However, antibiotic use decisions were not mandated and were at clinicians’ discretion.
The primary outcome was the distribution of antibiotic-free days in the 7 days following bronchoalveolar lavage. Antibiotic-free days were handled as an integer, with patients classified in one of eight categories (0–7 antibiotic-free days, inclusive).
Predefined secondary outcomes were antibiotic-free days at days 14 and 28, antibiotic days at days 7, 14, and 28, ventilator-free days at 28 days, 28-day mortality and ICU mortality, sequential organ failure assessment (SOFA) score at days 3, 7 and 14, duration of critical care (level 2 and level 3 care) and hospital stay, antibiotic-associated infections (Clostridium difficile and meticillin-resistant Staphylococcus aureus) up to hospital discharge, death, or 56 days, antibiotic-resistant pathogens (resistant to two or more antibiotics) cultured up to hospital discharge, death, or 56 days, and health-care resource use calculated from length of critical care and hospital stay up to discharge, death, or 56 days. When considering outcomes at days 7, 14, and 28, antibiotics refers to all antibiotics given for treatment of infection; prophylactic antibiotics were not considered.
Since adverse clinical events are common in ICUs, the trial protocol mandated reporting of adverse events within 2 h of bronchoscopy. Clinical team members reported any further events after 2 h if they were considered clinically significant or related to the trial.
We deemed effect sizes in the region 0·07–0·08 to be of a clinically relevant magnitude. These effect sizes represent an approximate change in median antibiotic-free days from 0 (IQR 0·0–2·5) to 1·5 (0·0–3·5). Therefore, we proposed a recruitment target of 90 patients per group, with an α of 0·05 and β of 0·20. Allowing for attrition of 14·3%, the target sample size was 210 patients. The primary analysis was done on the intention-to-treat population. We analysed the primary outcome by χ2 test on a 2 × 8 table of trial group versus antibiotic-free days. Sensitivity analyses were done using a discrete-time Cox proportional hazards model with centre and randomisation group as covariates, censored for death or end of follow-up at 7 days. We did a further sensitivity analysis, redefining antibiotic-free days as zero if death occurred within 7 days, as a more conservative approach.
We assessed the prevalence of missing data during a masked review after database lock, which was judged to be of sufficiently low frequency as to not require imputation for all variables. However, as prespecified in the Statistical Analysis Plan, SOFA scores were based on the last evaluable score. Unadjusted CIs and p values are reported for multiplicity.
Role of the funding source
The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.
Table 1Baseline characteristics
Data are mean (SD), n (%), or median (IQR). APACHE=acute physiology and chronic health evaluation. SOFA=sequential organ failure assessment. ICU=intensive care unit.
Table 2Microorganisms isolated in bronchoalveolar lavage fluid
Data are n of isolates (in some bronchoalveolar lavage samples, more than one organism was isolated). 68 patients in the non-ventilator-associated pneumonia column had no growth. CFU=colony-forming units.
Table 3Antibiotic-free days for the intention-to-treat and per-protocol analyses
Table 4Secondary outcome measures
Data are median (IQR), n (%), or mean (SD), unless otherwise indicated. The last row of the table excludes a single observation in the biomarker-guided group recorded as having multiple pathogens (more than twice any other patient). HR=hazard ratio. ICU=intensive car e unit. OR=odds ratio. SOFA=sequential organ failure assessment. RR=risk ratio.
Table 5Patients with reported adverse events or serious adverse events
Data are number of patients (%); multiple events were reported in some patients.
Serum procalcitonin has been studied widely in the ICU (outside the specific context of ventilator-associated pneumonia) and this approach showed varying success for safely adjusting antibiotic use.
However, procalcitonin is ineffective for the exclusion of ventilator-associated pneumonia,
which was the focus of our approach. Inconsistent effects of procalcitonin on antibiotic use have also been described for lower respiratory tract infection outside the ICU.
Enthusiasm for a procalcitonin strategy in the ICU is offset by high non-compliance with procalcitonin guidance in general, and durations of procalcitonin-guided antibiotic use in ventilator-associated pneumonia that exceed the widely accepted standard of 8 days.
- Torres A
- Niederman MS
- Chastre J
- et al.
Given that confirmation of ventilator-associated pneumonia is low in cases in which it is suspected,
we reasoned that persuasive early evidence for the absence of ventilator-associated pneumonia might have a greater effect on antibiotic duration. Proof of concept for this general strategy had been provided by a single-centre study that used preliminary microbiology culture results to stop antibiotics around 1 day after bronchoalveolar lavage.
This second, independent validation of their performance in 24 ICUs under real-life conditions supports their diagnostic utility. This study yielded opportunities to discontinue antibiotics, but advice was only followed in four (24%) of 17 cases.
Our data suggest that the observed absence of effect was more likely to be explained by clinicians’ behaviour than by poor test performance. Before the trial commenced, the negative predictive value of the test was estimated at 1·0 (95% CI 0·92–1·00),
therefore, the lower confidence limit could have affected clinicians’ confidence. However, the process evaluation did not provide evidence to support this theory. The process evaluation suggested that deeply entrenched prescribing characteristics probably underlie the lack of effect, as described in other settings.
We attempted to mitigate non-compliance by including ICUs committed to the principle of accepting a recommendation to stop antibiotics. However, dissociation between intention and action in prescribing has been previously described.
our process evaluation provided valuable and unexpected insights into influences that might affect delivery of a trial. The process evaluation suggested that recruitment often did not proceed because of identification of restricted availability of bronchoalveolar lavage or laboratory processing on the day, or because clinicians habitually preferred to complete antibiotic courses (thereby precluding enrolment). However, the main barrier to recruitment was clinician scepticism around the additional diagnostic value and safety of bronchoalveolar lavage. The role of bronchoalveolar lavage in the diagnosis of ventilator-associated pneumonia remains contentious.
Bronchoalveolar lavage is not a gold standard diagnostic for ventilator-associated pneumonia—simultaneous histological analysis and microbiological culture of alveolar tissue would give ideal diagnostic precision, but is neither practical nor ethical. We considered bronchoalveolar lavage the most pragmatic and accurate alternative, while recognising it to be an imperfect reference standard.
Considerable lack of familiarity with bronchoalveolar lavage in ICUs has been highlighted previously.
The validation of test accuracy suggests that protocolised bronchoalveolar lavage was done to a high and uniform standard in this study. Furthermore, bronchoalveolar lavage was generally safe, although was associated with a small, transient increase in oxygen requirements, which has been noted elsewhere.
Finally, the process evaluation strongly suggested that permanent research champions and ICU-trained research nurses devoted to the trial enhanced all aspects of recruitment and trial delivery. In units without research champions, attrition of recruitment over time was pronounced and self-perpetuating.
or ventilator-associated pneumonia severity scores,
and we did not ascertain why patients who were taking corticosteroids had been prescribed these.
The argument that Candida is not a pathogen in ventilator-associated pneumonia has been strengthened by a recent prospective study,
although the diagnosis of infection was partly based on endotracheal aspirate cultures. Our decision to consider the presence of such organisms at 104 CFU/mL or more in bronchoalveolar lavage fluid as ventilator-associated pneumonia was based on our previous studies and large clinical trials in suspected ventilator-associated pneumonia reporting substantial growth of these organisms.
However, we acknowledge that many clinicians would not consider fungi, yeasts, or Enterococci as pathogens in ventilator-associated pneumonia.
We elected to include such patients on the grounds that our derivation and validation studies had similar ventilator-associated pneumonia rates (24% and 35%, respectively), with the derivation study excluding and the validation study including such patients. The similar ventilator-associated pneumonia rate in the current study (34%) provides evidence that inclusion of such patients did not materially alter ventilator-associated pneumonia rates. However, although there was only one false negative result identified for our test, it remains theoretically possible that bronchoalveolar lavage fluid samples might be sterile for technical reasons, such as inadequate sampling or delays in analysis, as has been described for blood cultures.
We attempted to mitigate this risk by implementing a protocolised bronchoalveolar lavage, ensuring timely delivery of samples and having quality control checks within the biomarker assay.
This study was confined to a single timepoint based on our previous data, the desire to provide results well before bronchoalveolar lavage fluid culture results were available to clinicians, and because the mild inflammation associated with bronchoalveolar lavage would confound results from subsequent lavages. However, we cannot be certain that we used the optimum timepoint(s) for sampling.
In conclusion, biomarker-guided exclusion of ventilator-associated pneumonia did not reduce antibiotic use in centres that had committed to following test recommendations. Process evaluation suggested that lack of adoption of the technology and clinician behaviour had a greater influence on trial outcomes than did test performance. Antibiotic prescribing behaviours appear entrenched and recalcitrant to change. Future trials of diagnostic tests for ventilator-associated pneumonia should incorporate detailed implementation strategies informed by prior characterisation of factors that influence prescribing and diagnostic decision making.
TSW, DFM, NA (the study statistician), ACM, SS, GDP, RM, CMO’K, DWJK, and AJS designed the study. DFM, TSW, NA, ACM, SS, GDP, RM, CMO’K, DWJK, and AJS secured funding for the study. TPH coordinated the study. JP was the trial manager for the study. SAB was the trial project manager. RM provided microbiological support for the study. LME and BB designed the process evaluation for the study. TPH, DFM, TSW, ACM, SS, PD, AIR, GDP, LME, SEW, KK, SVB, RLP, AJR, AA, JB-S, NMR, IDW, CB, BY, CS, SKL, JH, SB, VL, and JSo collected the data. TVDB and GB analysed laboratory data and supervised quality control for assays. JSc did laboratory assays. TPH, NA, AJA, GP, and AJS analysed the data. TPH, DFM, TSW, ACM, SS, PD, GDP, LME, BB, AA, AJA, GP, and AJS interpreted the data. TPH, DFM, TSW, NA, ACM, SS, PD, GDP, LME, and AJS wrote the manuscript. All authors revised the manuscript and approved the final version for publication.
Declaration of interests
DFM reports a grant from the Wellcome Trust and UK Department of Health (for the conduct of the study); personal fees from consultancy for GlaxoSmithKline, Boehringer Ingelheim, and Bayer, all outside of the current work; that his institution has received funds from grants from the UK National Institute for Health Research (NIHR), Wellcome Trust, Innovate UK, the UK Medical Research Council, Northern Ireland Health and Social Care Research and Development Division Research, the National Institutes of Health, and the Health Research Board (Ireland); and that he is a Director of Research for the Intensive Care Society and Programme Director of the NIHR Efficacy and Mechanism Evaluation programme. TSW reports a grant from the Wellcome Trust and UK Department of Health (for the conduct of the study). ACM is a member of the advisory board for Serendex Pharmaceuticals. SS has received fees from Ambu for key opinion leader meetings. PD reports clinical advisory board membership with DNA Electronics and receipt of grants relating to sepsis and severe infection from the UK NIHR, all outside of the submitted work. CMO’K reports a grant from the Wellcome Trust and UK Department of Health (for the conduct of the study); and that her spouse has received personal fees from consultancy for GlaxoSmithKline, Boehringer Ingelheim, and Bayer, outside of the submitted work. TVDB, GB, and DWJK were employees of Becton Dickinson Biosciences during the study. AJS reports a grant from the Wellcome Trust and UK Department of Health (for the conduct of the study); that his institution has received funds from grants surrounding sepsis and pneumonia from the UK Medical Research Council, and UK NIHR; and that he is Director of the NIHR Newcastle In Vitro Diagnostics Co-operative. All other authors declare no competing interests.
This publication presents independent research supported by the Health Innovation Challenge Fund ( HICF-510-078; 094949/Z/10/X ), a parallel funding partnership between the UK Department of Health and Wellcome Trust. The views expressed in this publication are those of the authors and not necessarily those of the UK Department of Health or Wellcome Trust. The study was also supported by the National Institute for Health Research (NIHR) Newcastle Biomedical Research Centre ( IS-BRC-1215-20001 ) and the Medical Research Council SHIELD antimicrobial resistance consortium ( MR/N02995X/1 ). ACM is supported by a Clinical Research Career Development Fellowship from the Wellcome Trust ( WT 2055214/Z/16/Z ). GDP is an NIHR Senior Investigator. Trial delivery was supported by the NIHR National Clinical Research Network in Critical Care, the Northern Ireland Clinical Research Network, and the UK Intensive Care Foundation.
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Published: December 03, 2019
© 2019 The Author(s). Published by Elsevier Ltd.