Jean Antonelli

C5a-mediated neutrophil dysfunction is RhoA-dependent and predicts infection in critically ill patients

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 PI3Kδ. 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.

Predictive value of cell-surface markers in infections in critically ill patients: protocol for an observational study (ImmuNe FailurE in Critical Therapy (INFECT) Study)

Introduction Critically ill patients are at high risk of nosocomial infections, with between 20% and 40% of patients admitted to the intensive care unit (ICU) acquiring infections. These infections result in increased antibiotic use, and are associated with morbidity and mortality. Although critical illness is classically associated with hyperinflammation, the high rates of nosocomial infection argue for an importance of effect of impaired immunity. Our group recently demonstrated that a combination of 3 measures of immune cell function (namely neutrophil CD88, monocyte HLA-DR and % regulatory T cells) identified a patient population with a 2.4–5-fold greater risk for susceptibility to nosocomial infections. Methods and analysis This is a prospective, observational study to determine whether previously identified markers of susceptibility to nosocomial infection can be validated in a multicentre population, as well as testing several novel markers which may improve the risk of nosocomial infection prediction. Blood samples from critically ill patients (those admitted to the ICU for at least 48 hours and requiring mechanical ventilation alone or support of 2 or more organ systems) are taken and undergo whole blood staining for a range of immune cell surface markers. These samples undergo analysis on a standardised flow cytometry platform. Patients are followed up to determine whether they develop nosocomial infection. Infections need to meet strict prespecified criteria based on international guidelines; where these criteria are not met, an adjudication panel of experienced intensivists is asked to rule on the presence of infection. Secondary outcomes will be death from severe infection (sepsis) and change in organ failure. Ethics and dissemination Ethical approval including the involvement of adults lacking capacity has been obtained from respective English and Scottish Ethics Committees. Results will be disseminated through presentations at scientific meetings and publications in peer-reviewed journals. Trial registration number NCT02186522; Pre-results.

Development of Process Control Methodology for Tracking the Quality and Safety of Pain, Agitation, and Sedation Management in Critical Care Units.

Objective:To develop sedation, pain, and agitation quality measures using process control methodology and evaluate their properties in clinical practice. Design:A Sedation Quality Assessment Tool was developed and validated to capture data for 12-hour periods of nursing care. Domains included pain/discomfort and sedation-agitation behaviors; sedative, analgesic, and neuromuscular blocking drug administration; ventilation status; and conditions potentially justifying deep sedation. Predefined sedation-related adverse events were recorded daily. Using an iterative process, algorithms were developed to describe the proportion of care periods with poor limb relaxation, poor ventilator synchronization, unnecessary deep sedation, agitation, and an overall optimum sedation metric. Proportion charts described processes over time (2 monthly intervals) for each ICU. The numbers of patients treated between sedation-related adverse events were described with G charts. Automated algorithms generated charts for 12 months of sequential data. Mean values for each process were calculated, and variation within and between ICUs explored qualitatively. Setting:Eight Scottish ICUs over a 12-month period. Patients:Mechanically ventilated patients. Interventions:None. Measurements and Main Results:The Sedation Quality Assessment Tool agitation-sedation domains correlated with the Richmond Sedation Agitation Scale score (Spearman &rgr; = 0.75) and were reliable in clinician-clinician (weighted kappa; &kgr; = 0.66) and clinician-researcher (&kgr; = 0.82) comparisons. The limb movement domain had fair correlation with Behavioral Pain Scale (&rgr; = 0.24) and was reliable in clinician-clinician (&kgr; = 0.58) and clinician-researcher (&kgr; = 0.45) comparisons. Ventilator synchronization correlated with Behavioral Pain Scale (&rgr; = 0.54), and reliability in clinician-clinician (&kgr; = 0.29) and clinician-researcher (&kgr; = 0.42) comparisons was fair-moderate. Eight hundred twenty-five patients were enrolled (range, 59–235 across ICUs), providing 12,385 care periods for evaluation (range 655–3,481 across ICUs). The mean proportion of care periods with each quality metric varied between ICUs: excessive sedation 12–38%; agitation 4–17%; poor relaxation 13–21%; poor ventilator synchronization 8–17%; and overall optimum sedation 45–70%. Mean adverse event intervals ranged from 1.5 to 10.3 patients treated. The quality measures appeared relatively stable during the observation period. Conclusions:Process control methodology can be used to simultaneously monitor multiple aspects of pain-sedation-agitation management within ICUs. Variation within and between ICUs could be used as triggers to explore practice variation, improve quality, and monitor this over time.

Early PREdiction of Severe Sepsis (ExPRES-Sepsis) study: protocol for an observational derivation study to discover potential leucocyte cell surface biomarkers

Introduction Sepsis is an acute illness resulting from infection and the host immune response. Early identification of individuals at risk of developing life-threatening severe sepsis could enable early triage and treatment, and improve outcomes. Currently available biomarkers have poor predictive value for predicting subsequent clinical course in patients with suspected infection. Circulating leucocytes provide readily accessible tissues that reflect many aspects of the complex immune responses described in sepsis. We hypothesise that measuring cellular markers of immune responses by flow cytometry will enable early identification of infected patients at risk of adverse outcomes. We aim to characterise leucocyte surface markers (biomarkers) and their abnormalities in a population of patients presenting to the hospital emergency department with suspected sepsis, and explore their ability to predict subsequent clinical course. Methods and analysis We will conduct a prospective, multicentre, clinical, exploratory, cohort observational study. To answer our study question, 3 patient populations will be studied. First, patients with suspected sepsis from the emergency department (n=300). To assess performance characteristics of potential tests, critically ill patients with established sepsis, and age and gender matched patients without suspicion of infection requiring hospital admission (both n=100) will be recruited as comparator populations. In all 3 groups, we plan to assess circulating biomarker profiles using flow cytometry. We will select candidate biomarkers by cross-cohort comparison, and then explore their predictive value for clinical outcomes within the cohort with suspected sepsis. Ethics and dissemination The study will be carried out based on the principles in the Declaration of Helsinki and the International Conference on Harmonisation Good Clinical Practice. Ethics approval has been granted from the Scotland A Research Ethics Committee (REC) and Oxford C REC. On conclusion of this study, the results will be disseminated via peer-reviewed journals. Trial registration number NCT02188992; Pre-results.

Rationale, design and methodology of a trial evaluating three strategies designed to improve sedation quality in intensive care units (DESIST study)

Objectives To describe the rationale, design and methodology for a trial of three novel interventions developed to improve sedation-analgesia quality in adult intensive care units (ICUs). Participants and Setting 8 clusters, each a Scottish ICU. All mechanically ventilated sedated patients were potentially eligible for inclusion in data analysis. Design Cluster randomised design in 8 ICUs, with ICUs randomised after 45 weeks baseline data collection to implement one of four intervention combinations: a web-based educational programme (2 ICUs); education plus regular sedation quality feedback using process control charts (2 ICUs); education plus a novel sedation monitoring technology (2 ICUs); or all three interventions. ICUs measured sedation-analgesia quality, relevant drug use and clinical outcomes, during a 45-week preintervention and 45-week postintervention period separated by an 8-week implementation period. The intended sample size was >100 patients per site per study period. Main Outcome measures The primary outcome was the proportion of 12 h care periods with optimum sedation-analgesia, defined as the absence of agitation, unnecessary deep sedation, poor relaxation and poor ventilator synchronisation. Secondary outcomes were proportions of care periods with each of these four components of optimum sedation and rates of sedation-related adverse events. Sedative and analgesic drug use, and ICU and hospital outcomes were also measured. Analytic approach Multilevel generalised linear regression mixed models will explore the effects of each intervention taking clustering into account, and adjusting for age, gender and APACHE II score. Sedation-analgesia quality outcomes will be explored at ICU level and individual patient level. A process evaluation using mixed methods including quantitative description of intervention implementation, focus groups and direct observation will provide explanatory information regarding any effects observed. Conclusions The DESIST study uses a novel design to provide system-level evaluation of three contrasting complex interventions on sedation-analgesia quality. Recruitment is complete and analysis ongoing. Trial registration number NCT01634451.

Challenges in the design and analysis of a factorial-design cluster randomised trial

Optimising sedation quality in mechanically ventilated intensive care patients is important because excessive sedation is associated with increased hospital acquired infections, longer intensive care (ICU) and hospital stay, and possibly higher mortality. The Development and Evaluation of Strategies to Improve Sedation Quality in InTensive Care (DESIST) study aims to optimise sedation practice. Here we focus on the study design, statistical analysis plan, performing the analysis and issues that occurred. DESIST randomised eight ICUs in pairs to four different combinations of sedation-related quality improvement interventions. The primary outcome assessed optimum sedation within each 12 hour nursing shift (referred to as a DESIST care period). This resulted in a three-level hierarchical data structure: DESIST care periods within admissions, within ICU.