Circulating Microvesicles Are Elevated Acutely following Major Burns Injury and Associated with Clinical Severity.

Microvesicles are cell-derived signaling particles emerging as important mediators and biomarkers of systemic inflammation, but their production in severe burn injury patients has not been described. In this pilot investigation, we measured circulating microvesicle levels following severe burns, with severe sepsis patients as a comparator group. We hypothesized that levels of circulating vascular cell-derived microvesicles are elevated acutely following burns injury, mirroring clinical severity due to the early onset and prevalence of systemic inflammatory response syndrome (SIRS) in these patients. Blood samples were obtained from patients with moderate to severe thermal injury burns, with severe sepsis, and from healthy volunteers. Circulating microvesicles derived from total leukocytes, granulocytes, monocytes, and endothelial cells were quantified in plasma by flow cytometry. All circulating microvesicle subpopulations were elevated in burns patients on day of admission (day 0) compared to healthy volunteers (leukocyte-microvesicles: 3.5-fold, p = 0.005; granulocyte-microvesicles: 12.8-fold, p<0.0001; monocyte-microvesicles: 20.4-fold, p<0.0001; endothelial- microvesicles: 9.6-fold, p = 0.01), but decreased significantly by day 2. Microvesicle levels were increased with severe sepsis, but less consistently between patients. Leukocyte- and granulocyte-derived microvesicles on day 0 correlated with clinical assessment scores and were higher in burns ICU non-survivors compared to survivors (leukocyte MVs 4.6 fold, p = 0.002; granulocyte MVs 4.8 fold, p = 0.003). Mortality prediction analysis of area under receiver operating characteristic curve was 0.92 (p = 0.01) for total leukocyte microvesicles and 0.85 (p = 0.04) for granulocyte microvesicles. These findings demonstrate, for the first time, acute increases in circulating microvesicles following burns injury in patients and point to their potential role in propagation of sterile SIRS-related pathophysiology.

eLearning to facilitate the education and implementation of the Chelsea Critical Care Physical Assessment: a novel measure of function in critical illness.

OBJECTIVE: To evaluate the efficacy of eLearning in the widespread standardised teaching, distribution and implementation of the Chelsea Critical Care Physical Assessment (CPAx) tool-a validated tool to assess physical function in critically ill patients. DESIGN: Prospective educational study. An eLearning module was developed through a conceptual framework, using the four-stage technique for skills teaching to teach clinicians how to use the CPAx. Example and test video case studies of CPAx assessments were embedded within the module. The CPAx scores for the test case studies and demographic data were recorded in a secure area of the website. Data were analysed for inter-rater reliability using intraclass correlation coefficients (ICCs) to see if an eLearning educational package facilitated consistent use of the tool. A utility and content validity questionnaire was distributed after 1 year to eLearning module registrants (n=971). This was to evaluate uptake of the CPAx in clinical practice and content validity of the CPAx from the perspective of clinical users. SETTING: The module was distributed for use via professional forums (n=2) and direct contacts (n=95). PARTICIPANTS: Critical care clinicians. PRIMARY OUTCOME MEASURE: ICC of the test case studies. RESULTS: Between July and October 2014, 421 candidates from 15 countries registered for the eLearning module. The ICC for case one was 0.996 (95% CI 0.990 to 0.999; n=207). The ICC for case two was 0.988 (0.996 to 1.000; n=184). The CPAx has a strong total scale content validity index (s-CVI) of 0.94 and is well used. CONCLUSIONS: eLearning is a useful and reliable way of teaching psychomotor skills, such as the CPAx. The CPAx is a well-used measure with high content validity rated by clinicians.

The responsiveness of the Chelsea Critical Care Physical Assessment tool in measuring functional recovery in the burns critical care population: an observational study.

INTRODUCTION: Severe burn leads to a state of hypercatabolism, resulting in rapid muscle loss and long-term disability. As survival rates from severe burn are improving, early rehabilitation is essential to facilitate functional recovery. However, there is no way of measuring the degree of disability in the acute stages, and hence, no marker of functional recovery. This hampers both communication and research into interventions to improve functional outcomes. The Chelsea Critical Care Physical Assessment tool (CPAx) is a simple objective measure of function, designed and validated in the general Intensive Care Unit (ICU) cohort. The aim of this study was to test the responsiveness of the CPAx in the burns ICU (BICU) cohort and validate its use. METHODS: Observational study of 52 BICU patients admitted for over 48h. All patients were assessed on the CPAx retrospectively for pre-admission, and prospectively at ICU admission, ICU discharge (or final ICU assessment for non-survivors) and hospital discharge. Analysis of variance, post hoc between group differences in median CPAx score, and floor and ceiling effect (i.e. the percentage of patients scoring full marks (50), or zero) for the four time points were completed. Minimal clinically important difference (MCID) was estimated as half of the standard deviation of the CPAx score at ICU discharge. RESULTS: A total of 30 patients were included in the final analysis; mean age was 47.1 years (SD 21.2), 63.3% were male, with a median burn total body surface area (TBSA) of 30% (IQR 11.3-48.8). There was a significant difference in the analysis of variance in median CPAx scores at all four time points (p<.001). In survivors, the differences in CPAx scores post hoc were significant for all time points (p<.05), aside from ICU discharge and hospital discharge. The CPAx MCID for BICU patients was six. Twenty-three (86.7%) patients scored full marks or zero on the CPAx pre-admission. For survivors, no patients scored full marks or zero on the CPAx at ICU and hospital discharge. On ICU admission 66.7% (n=20) scored zero on the CPAx and no patients scored 50. CONCLUSIONS: The CPAx score appears to be able to detect improvements in physical function as patients recover from acute severe burn. It has a limited floor and ceiling effect in the acute setting and a change in CPAx score of 6 represents clinically important progress. Further work is required in a larger cohort.

Construct validity of the Chelsea critical care physical assessment tool: an observational study of recovery from critical illness.

INTRODUCTION: Intensive care unit-acquired weakness (ICU-AW) is common in survivors of critical illness, resulting in global weakness and functional deficit. Although ICU-AW is well described subjectively in the literature, the value of objective measures has yet to be established. This project aimed to evaluate the construct validity of the Chelsea Critical Care Physical Assessment tool (CPAx) by analyzing the association between CPAx scores and hospital-discharge location, as a measure of functional outcome. METHODS: The CPAx was integrated into practice as a service-improvement initiative in an 11-bed intensive care unit (ICU). For patients admitted for more than 48 hours, between 10 May 2010 and 13 November 2013, the last CPAx score within 24 hours of step down from the ICU or death was recorded (n = 499). At hospital discharge, patients were separated into seven categories, based on continued rehabilitation and care needs. Descriptive statistics were used to explore the association between ICU discharge CPAx score and hospital-discharge location. RESULTS: Of the 499 patients, 171 (34.3%) returned home with no ongoing rehabilitation or care input; 131 (26.2%) required community support; 28 (5.6%) went to inpatient rehabilitation for <6 weeks; and 25 (5.0%) went to inpatient rehabilitation for >6 weeks; 27 (5.4%) required nursing home level of care; 80 (16.0%) died in the ICU, and 37 (7.4%) died in hospital. A significant difference was found in the median CPAx score between groups (P < 0.0001). Four patients (0.8%) scored full marks (50) on the CPAx, all of whom went home with no ongoing needs; 16 patients (3.2%) scored 0 on the CPAx, all of whom died within 24 hours. A 0.8% ceiling effect and a 3.2% floor effect of the CPAx is found in the ICU. Compliance with completion of the CPAx stabilized at 78% of all ICU admissions. CONCLUSION: The CPAx score at ICU discharge has displayed construct validity by crudely discriminating between groups with different functional needs at hospital discharge. The CPAx has a limited floor and ceiling effect in survivors of critical illness. A significant proportion of patients had a requirement for postdischarge care and rehabilitation.

Reactive oxygen species and p38 mitogen-activated protein kinase mediate tumor necrosis factor α-converting enzyme (TACE/ADAM-17) activation in primary human monocytes.

Tumor necrosis factor α-converting enzyme (TACE) is responsible for the shedding of cell surface TNF. Studies suggest that reactive oxygen species (ROS) mediate up-regulation of TACE activity by direct oxidization or modification of the protein. However, these investigations have been largely based upon nonphysiological stimulation of promonocytic cell lines which may respond and process TACE differently from primary cells. Furthermore, investigators have relied upon TACE substrate shedding as a surrogate for activity quantification. We addressed these concerns, employing a direct, cell-based fluorometric assay to investigate the regulation of TACE catalytic activity on freshly isolated primary human monocytes during LPS stimulation. We hypothesized that ROS mediate up-regulation of TACE activity indirectly, by activation of intracellular signaling pathways. LPS up-regulated TACE activity rapidly (within 30 min) without changing cell surface TACE expression. Scavenging of ROS or inhibiting their production by flavoprotein oxidoreductases significantly attenuated LPS-induced TACE activity up-regulation. Exogenous ROS (H(2)O(2)) also up-regulated TACE activity with similar kinetics and magnitude as LPS. H(2)O(2)- and LPS-induced TACE activity up-regulation were effectively abolished by a variety of selective p38 MAPK inhibitors. Activation of p38 was redox-sensitive as H(2)O(2) caused p38 phosphorylation, and ROS scavenging significantly reduced LPS-induced phospho-p38 expression. Inhibition of the p38 substrate, MAPK-activated protein kinase 2, completely attenuated TACE activity up-regulation, whereas inhibition of ERK had little effect. Lastly, inhibition of cell surface oxidoreductases prevented TACE activity up-regulation distal to p38 activation. In conclusion, our data indicate that in primary human monocytes, ROS mediate LPS-induced up-regulation of TACE activity indirectly through activation of the p38 signaling pathway.