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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-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.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-1β 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.Funding: UK Department of Health and the Wellcome Trust.

ObjectiveThis audit aimed to improve the speed and completeness of delivery of treatment to urology patients at risk of sepsis in the hospital.Patients and methodsPatients were prospectively included if they developed a new-onset systemic inflammatory response syndrome, were reviewed by a doctor who thought this was due to infection and prescribed antibiotics. We measured median time to antibiotic administration (TTABx) as the primary outcome. Factors associated with delays in management were identified, targeted quality improvement interventions implemented and then reaudited.ResultsThere were 74 patients in the baseline cohort and 69 following interventions. Median TTABx fell from 3.6 (1.9–6.9) hours to 1.7 (1.0–3.8) pConclusionA period of baseline prospective study, followed by tailored quality improvement initiatives, can significantly improve the speed and quality of sepsis management for inpatients on an acute hospital ward.

Expression of inflammatory mediators is controlled in part at the transcriptional level via nuclear factor-kappa B. Inhibition of nuclear factor-kappa B activation may be beneficial in critically ill patients. N-acetylcysteine is an antioxidant that inhibits nuclear factor-kappa B activation in vitro. In this pilot study we investigated the effect of N-acetylcysteine on nuclear factor-kappa B activation and circulating cytokine and adhesion molecules in patients with sepsis.Prospective, randomized, double blind, placebo-controlled pilot trial.Eight-bed intensive care unit in a university teaching hospital.Twenty consecutive patients within 12 hrs of fulfilling the consensus criteria for sepsis.A bolus of 150 mg/kg N-acetylcysteine in 100 mL of 0.9% saline over 15 mins, then 50 mg/kg in 100 mL of 0.9% saline over 4 hrs as a loading dose, and then a maintenance infusion of 50 mg/kg in 200 mL of 0.9% saline over each 24-hr period for a total of 72 hrs, or an equivalent volume of saline.Nuclear factor-kappa B activation was measured in mononuclear leukocytes using electrophoretic mobility shift assay, at baseline and 24, 48, 72, and 96 hrs later. Activation decreased significantly in patients treated with N-acetylcysteine (p =.016) but not placebo and was significantly reduced at 72 hrs compared with both preinfusion values (p =.028) and patients receiving placebo (p =.01). Plasma interleukin-6, interleukin-8, and soluble intercellular adhesion molecule-1 concentrations were measured using enzyme immunoassay. Interleukin-6 concentrations were high initially and then decreased in all patients, regardless of whether they received N-acetylcysteine or placebo. Interleukin-8 decreased significantly only in those who received N-acetylcysteine (p =.0081). Soluble intercellular adhesion molecule-1 concentrations remained unchanged in all patients.Administration of N-acetylcysteine results in decreased nuclear factor-kappa B activation in patients with sepsis, associated with decreases in interleukin-8 but not interleukin-6 or soluble intercellular adhesion molecule-1. These pilot data suggest that antioxidant therapy with N-acetylcysteine may be useful in blunting the inflammatory response to sepsis. Further studies are warranted.

Quinolone antibiotics such as ciprofloxacin modify immune and inflammatory responses in some cells. We have shown previously that ciprofloxacin decreases the accumulation of interleukin (IL)-6 protein from a human endothelial cell line, whilst IL-8 protein production was increased. It is not known whether this occurs through effects on transcription and mRNA expression. We therefore investigated the effect of ciprofloxacin on mRNA for IL-6 and IL-8, and on three transcription factors known to be involved in the regulation of these cytokines. We investigated the effect of ciprofloxacin on tumour necrosis factor α- and IL-1β-mediated activation of the transcription factors nuclear factor κB (NFκB), activator protein-1 (AP-1) and nuclear factor IL-6 (NF-IL-6) using an electrophoretic mobility shift assay, and the effect on expression of mRNA for IL-6 and IL-8 by reverse transcriptase–PCR in the EAhy926 endothelial cell line. Ciprofloxacin decreased IL-6 mRNA (P < 0.05) and increased IL-8 mRNA (P < 0.05) expression. Ciprofloxacin did not modulate activation of NFκB or AP-1. However, NF-IL-6 binding was decreased in the presence of 100 µg/ml ciprofloxacin (P < 0.05). The study shows that ciprofloxacin-mediated decreased IL-6 release by a human endothelial cell line is reflected by decreased mRNA expression and decreased NF-IL-6 but not NFkB or AP-1 activation. Increased IL-8 mRNA in response to ciprofloxacin was not reflected by altered transcription factor activation and may represent increased mRNA stability.

OBJECTIVES To determine nuclear factor kappa B (NF-kappa B) activation in mononuclear and neutrophils from critically ill patients and to compare NF-kappa B activation with circulating concentrations of interleukin (IL)-6, IL-8, and soluble intercellular adhesion molecule (sICAM)-1. DESIGN Observational study. SETTING University Teaching Hospital, eight-bed intensive care unit in northeast Scotland. PATIENTS Ten patients admitted to the intensive care unit who fulfilled the criteria for systemic inflammatory response syndrome were studied at 0, 24, 48, and 72 hrs. Six healthy volunteers were also studied. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS NF-kappa B activation was significantly higher in patients compared to healthy volunteers in both neutrophils (p = .001) and mononuclear leukocytes (p = .013). In the six patients who survived to 96 hrs, the level of NF-kappa B activation in mononuclear cells remained constant (p = .9). However, in the four patients who died before 96 hrs, mononuclear cell NF-kappa B activation increased markedly and was significantly higher before death than in those who survived to 96 hrs (p = .0105). NF-kappa B activation in neutrophils similarly remained constant in patients who survived to 96 hrs (p = .4) but did not show the same increase before death. Circulating concentrations of IL-6, IL-8, and sICAM-1 were elevated but were unrelated to leukocyte NF-kappa B activation. CONCLUSIONS We found NF-kappa B activation in mononuclear and neutrophils in patients with systemic inflammatory response syndrome, which increased markedly before death in mononuclear leukocytes and was not related to plasma IL-6, IL-8, and sICAM-1 concentrations. These data support the need for further study of the role of NF-kappa B activation in mortality from systemic inflammatory response syndrome and sepsis.