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      Sepsis biomarkers in unselected patients on admission to intensive or high-dependency care

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          Abstract

          Introduction

          Although many sepsis biomarkers have shown promise in selected patient groups, only C-reactive protein and procalcitonin (PCT) have entered clinical practice. The aim of this study was to evaluate three promising novel sepsis biomarkers in unselected patients at admission to intensive care. We assessed the performance of pancreatic stone protein (PSP), soluble CD25 (sCD25) and heparin binding protein (HBP) in distinguishing patients with sepsis from those with a non-infective systemic inflammatory response and the ability of these markers to indicate severity of illness.

          Methods

          Plasma levels of the biomarkers, PCT and selected inflammatory cytokines were measured in samples taken from 219 patients during the first six hours of admission to intensive or high dependency care. Patients with a systemic inflammatory response were categorized as having sepsis or a non-infective aetiology, with or without markers of severity, using standard diagnostic criteria.

          Results

          Both PSP and sCD25 performed well as biomarkers of sepsis irrespective of severity of illness. For both markers the area under the receiver operating curve (AUC) was greater than 0.9; PSP 0.927 (0.887 to 0.968) and sCD25 0.902 (0.854 to 0.949). Procalcitonin and IL6 also performed well as markers of sepsis whilst in this intensive care unit (ICU) population, HBP did not: PCT 0.840 (0.778 to 0.901), IL6 0.805 (0.739 to 0.870) and HBP 0.607 (0.519 to 0.694). Levels of both PSP and PCT reflected severity of illness and both markers performed well in differentiating patients with severe sepsis from severely ill patients with a non-infective systemic inflammatory response: AUCs 0.955 (0.909 to 1) and 0.837 (0.732 to 0.941) respectively. Although levels of sCD25 did not correlate with severity, the addition of sCD25 to either PCT or PSP in a multivariate model improved the diagnostic accuracy of either marker alone.

          Conclusions

          PSP and sCD25 perform well as sepsis biomarkers in patients with suspected sepsis at the time of admission to intensive or high dependency care. These markers warrant further assessment of their prognostic value. Whereas previously published data indicate HBP has clinical utility in the emergency department, it did not perform well in an intensive-care population.

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          Most cited references16

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          Hospitalizations, costs, and outcomes of severe sepsis in the United States 2003 to 2007.

          To assess trends in number of hospitalizations, outcomes, and costs of severe sepsis in the United States. Temporal trends study using the Nationwide Inpatient Sample. Adult patients with severe sepsis (defined as a diagnosis of sepsis and organ dysfunction) diagnosed between 2003 and 2007. We determined the weighted frequency of patients hospitalized with severe sepsis. We calculated age- and sex-adjusted population-based mortality rates for severe sepsis per 100,000 population and also used logistic regression to adjust in-hospital mortality rates for patient characteristics. We calculated inflation-adjusted costs using hospital-specific cost-to-charge ratios. We identified a rapid steady increase in the number of cases of severe sepsis, from 415,280 in 2003 to 711,736 in 2007 (a 71% increase). The total hospital costs for all patients with severe sepsis increased from $15.4 billion in 2003 to $24.3 billion in 2007 (57% increase). The proportion of patients with severe sepsis and only a single organ dysfunction decreased from 51% in 2003 to 45% in 2007 (p < .001), whereas the proportion of patients with three or four or more organ dysfunctions increased 1.19-fold and 1.51-fold, respectively (p < .001). During the same time period, we observed 2% decrease per year in hospital mortality for patients with severe sepsis (p < .001), as well as a slight decrease in the length of stay (9.9 days to 9.2 days; p < .001) and a significant decrease in the geometric mean cost per case of severe sepsis ($20,210 per case in 2003 and $19,330 in 2007; p = .025). The increase in the number of hospitalizations for severe sepsis coupled with declining in-hospital mortality and declining geometric mean cost per case may reflect improvements in care or increases in discharges to skilled nursing facilities; however, these findings more likely represent changes in documentation and hospital coding practices that could bias efforts to conduct national surveillance.
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            Accuracy of procalcitonin for sepsis diagnosis in critically ill patients: systematic review and meta-analysis.

            Procalcitonin is widely reported as a useful biochemical marker to differentiate sepsis from other non-infectious causes of systemic inflammatory response syndrome. In this systematic review, we estimated the diagnostic accuracy of procalcitonin in sepsis diagnosis in critically ill patients. 18 studies were included in the review. Overall, the diagnostic performance of procalcitonin was low, with mean values of both sensitivity and specificity being 71% (95% CI 67-76) and an area under the summary receiver operator characteristic curve of 0.78 (95% CI 0.73-0.83). Studies were grouped into phase 2 studies (n=14) and phase 3 studies (n=4) by use of Sackett and Haynes' classification. Phase 2 studies had a low pooled diagnostic odds ratio of 7.79 (95% CI 5.86-10.35). Phase 3 studies showed significant heterogeneity because of variability in sample size (meta-regression coefficient -0.592, p=0.017), with diagnostic performance upwardly biased in smaller studies, but moving towards a null effect in larger studies. Procalcitonin cannot reliably differentiate sepsis from other non-infectious causes of systemic inflammatory response syndrome in critically ill adult patients. The findings from this study do not lend support to the widespread use of the procalcitonin test in critical care settings.
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              Biomarkers of sepsis.

              A complex network of biological mediators underlies the clinical syndrome of sepsis. The nonspecific physiologic criteria of sepsis syndrome or the systemic inflammatory response syndrome do not adequately identify patients who might benefit from either conventional anti-infective therapies or from novel therapies that target specific mediators of sepsis. Validated biomarkers of sepsis may improve diagnosis and therapeutic decision making for these high-risk patients. To develop a methodologic framework for the identification and validation of biomarkers of sepsis. A small group meeting of experts in clinical epidemiology, biomarker development, and sepsis clinical trials; selective narrative review of the biomarker literature. The utility of a biomarker is a function of the degree to which it adds value to the available clinical information in the domains of screening, diagnosis, risk stratification, and monitoring of the response to therapy. We identified needs for greater standardization of biomarker methodologies, greater methodologic rigor in biomarker studies, wider integration of biomarkers into clinical studies (in particular, early phase studies), and increased collaboration among investigators, pharmaceutical industry, biomarker industry, and regulatory agencies. Biomarkers promise to transform sepsis from a physiologic syndrome to a group of distinct biochemical disorders. This transformation could aid therapeutic decision making, and hence improve the prognosis for patients with sepsis, but will require an unprecedented degree of systematic investigation and collaboration.
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                Author and article information

                Contributors
                Journal
                Crit Care
                Crit Care
                Critical Care
                BioMed Central
                1364-8535
                1466-609X
                2013
                26 March 2013
                : 17
                : 2
                : R60
                Affiliations
                [1 ]Brighton and Sussex Medical School, Falmer, BN1 9PS, UK
                [2 ]Brighton and Sussex University Hospitals NHS Trust, Brighton BN2 5BE, UK
                [3 ]Abbott GmbH & Co.KG, Abbott Diagnostics Division, Discovery Research, Max-Planck Ring 2, 65205 Wiesbaden, Germany
                [4 ]Lascco SA, Frédéric Lajaunias, 8 Rue de la Rôtisserie, 1211 Geneva 3, Switzerland
                [5 ]Klinik für Viszeral- and Transplantationschirurgie, Rämistrasse 100, Universitätsspital Zürich, 8091 Zürich, Switzerland
                Article
                cc12588
                10.1186/cc12588
                3672658
                23531337
                c964d549-17a3-4ab5-8788-fd1fda09866a
                Copyright ©2013 Llewelyn et al.; licensee BioMed Central Ltd.

                This is an open access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 31 October 2012
                : 19 February 2013
                : 18 March 2013
                Categories
                Research

                Emergency medicine & Trauma
                Emergency medicine & Trauma

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