UK Efficacy and Mechanism Evaluation Programme and National Institutes of Health.

Critically ill patients are at heightened risk for nosocomial infections. The anaphylatoxin C5a impairs phagocytosis by neutrophils. However, the mechanisms by which this occurs and the relevance for acquisition of nosocomial infection remain undetermined. We aimed to characterize mechanisms by which C5a inhibits phagocytosis in vitro and in critically ill patients, and to define the relationship between C5a-mediated dysfunction and acquisition of nosocomial infection. In healthy human neutrophils, C5a significantly inhibited RhoA activation, preventing actin polymerization and phagocytosis. RhoA inhibition was mediated by PI3K␦. The effects on RhoA, actin, and phagocytosis were fully reversed by GM-CSF. Parallel observations were made in neutrophils from critically ill patients, that is, impaired phagocytosis was associated with inhibition of RhoA and actin polymerization, and reversed by GM-CSF. Among a cohort of 60 critically ill patients, C5a-mediated neutrophil dysfunction (as determined by reduced CD88 expression) was a strong predictor for subsequent acquisition of nosocomial infection (relative risk, 5.8; 95% confidence interval, 1.5-22; P ‫؍‬ .0007), and remained independent of time effects as assessed by survival analysis (hazard ratio, 5.0; 95% confidence interval, 1.3-8.3; P ‫؍‬ .01). In conclusion, this study provides new insight into the mechanisms underlying immunocompromise in critical illness and suggests novel avenues for therapy and prevention of nosocomial infection. (Blood. 2011;117(19):5178-5188) IntroductionThe systemic inflammatory response syndrome (SIRS) is classically characterized by profound immune activation, accompanying massive cytokinemia and organ damage. 1,2 However, SIRS is accompanied by a counter-regulatory immune suppression sometimes termed the compensatory anti-inflammatory response syndrome (CARS). 3 This relative immune suppression is considered important for effective resolution of inflammation but may extend to maladaptive counter-regulatory anti-inflammatory responses. 4,5 The consequences of impaired immune function include enhanced susceptibility to nosocomial infection 6 or death from sepsis. 7 Neutrophils are the major front-line cellular defense against bacterial pathogens, and acquired defects in neutrophil function have been identified in both animal and human sepsis 8,9 as well as sterile SIRS. 10,11 However, the mediators driving these defects, and the mechanisms involved, remain uncertain.Animal studies have implicated uncontrolled activation of the complement system in the pathogenesis of sepsis and sterile SIRS. [12][13][14] The key components mediating vasodilatation and vascular leak-the hallmarks of septic shock-are the anaphylatoxins. These are activated forms of complement factors 3 (C3a) and 5 (C5a). 14,15 Animal models of sepsis have also implicated C5a in neutrophil dysfunction. 8 Because of the rapid clearance (2-to 3-minute half life) of C5a from the circulation, measurement of plasma concentrations gives an imprecise account of neutrophil expos...

PurposeCellular immune dysfunctions, which are common in intensive care patients, predict a number of significant complications. In order to effectively target treatments, clinically applicable measures need to be developed to detect dysfunction. The objective was to confirm the ability of cellular markers associated with immune dysfunction to stratify risk of secondary infection in critically ill patients.MethodsMulti-centre, prospective observational cohort study of critically ill patients in four UK intensive care units. Serial blood samples were taken, and three cell surface markers associated with immune cell dysfunction [neutrophil CD88, monocyte human leucocyte antigen-DR (HLA-DR) and percentage of regulatory T cells (Tregs)] were assayed on-site using standardized flow cytometric measures. Patients were followed up for the development of secondary infections.ResultsA total of 148 patients were recruited, with data available from 138. Reduced neutrophil CD88, reduced monocyte HLA-DR and elevated proportions of Tregs were all associated with subsequent development of infection with odds ratios (95% CI) of 2.18 (1.00–4.74), 3.44 (1.58–7.47) and 2.41 (1.14–5.11), respectively. Burden of immune dysfunction predicted a progressive increase in risk of infection, from 14% for patients with no dysfunction to 59% for patients with dysfunction of all three markers. The tests failed to risk stratify patients shortly after ICU admission but were effective between days 3 and 9.ConclusionsThis study confirms our previous findings that three cell surface markers can predict risk of subsequent secondary infection, demonstrates the feasibility of standardized multisite flow cytometry and presents a tool which can be used to target future immunomodulatory therapies.Trial registrationThe study was registered with clinicaltrials.gov (NCT02186522).Electronic supplementary materialThe online version of this article (10.1007/s00134-018-5247-0) contains supplementary material, which is available to authorized users.

Dysfunctions of T-cells, monocytes, and neutrophils predict acquisition of nosocomial infection, and combine additively to stratify risk of nosocomial infection in the critically ill.

Walsh, T. S. et al. (2016) Staff education, regular sedation and analgesia quality feedback, and a sedation monitoring technology for improving sedation and analgesia quality for critically ill, mechanically ventilated patients: a cluster randomised trial. Lancet Respiratory Medicine, 4(10), pp. 807-817. (doi:10.1016/S2213-2600(16)30178-3) This is the author's final accepted version.There may be differences between this version and the published version. You are advised to consult the publisher's version if you wish to cite from it.

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ObjectivesVarious strategies to promote light sedation are highly recommended in recent guidelines, as deep sedation is associated with suboptimum patient outcomes. Yet, the challenges met by clinicians in delivering high-quality analgosedation is rarely addressed. As part of the evaluation of a cluster-randomised quality improvement trial in eight Scottish intensive care units (ICUs), we aimed to understand the challenges to optimising sedation in the Scottish ICU settings prior to the trial. This article reports on the findings.DesignA qualitative exploratory design: We conducted focus groups (FG) with clinicians during the preintervention period. Setting and participants: Eight Scottish ICUs. Nurses, physiotherapists and doctors working in each ICU volunteered to participate. FG were recorded and verbatim transcribed and inserted in NVivo V.10 for analysis. Qualitative thematic analysis was undertaken to develop emergent themes from the patterns identified in relation to sedation practice. Ethical approval was secured by Scotland A Research ethics committee.ResultsThree themes emerged from the inductive analysis: (a) a recent shift in sedation practice, (b) uncertainty in decision-making and (c) system-level factors including the ICU environment, organisational factors and educational gaps. Clinicians were challenged daily to manage agitated or difficult-to-sedate patients in the era of a progressive mantra of ‘just sedate less’ imposed by the pain–agitation–delirium guidelines.ConclusionsThe current implementation of guidelines does not support behaviour change strategies to allow a patient-focused approach to sedation management, which obstructs optimum sedation–analgesia management. Recognition of the various challenges when mandating less sedation needs to be considered and novel sedation–analgesia strategies should allow a system-level approach to improve sedation–analgesia quality.DESIST registration number NCT01634451