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Clinical utility of biomarkers of endothelial activation in sepsis-a systematic review

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      A strong biologic rationale exists for targeting markers of endothelial cell (EC) activation as clinically informative biomarkers to improve diagnosis, prognostic evaluation or risk-stratification of patients with sepsis.


      The objective was to review the literature on the use of markers of EC activation as prognostic biomarkers in sepsis. MEDLINE was searched for publications using the keyword 'sepsis' and any of the identified endothelial-derived biomarkers in any searchable field. All clinical studies evaluating markers reflecting activation of ECs were included. Studies evaluating other exogenous mediators of EC dysfunction and studies of patients with malaria and febrile neutropenia were excluded.


      Sixty-one studies were identified that fulfilled the inclusion criteria. Overall, published studies report positive correlations between multiple EC-derived molecules and the diagnosis of sepsis, supporting the critical role of EC activation in sepsis. Multiple studies also reported positive associations for mortality and severity of illness, although these results were less consistent than for the presence of sepsis. Very few studies, however, reported thresholds or receiver operating characteristics that would establish these molecules as clinically-relevant biomarkers in sepsis.


      Multiple endothelial-derived molecules are positively correlated with the presence of sepsis in humans, and variably correlated to other clinically-important outcomes. The clinical utility of these biomarkers is limited by a lack of assay standardization, unknown receiver operating characteristics and lack of validation. Additional large-scale prospective clinical trials will be required to determine the clinical utility of biomarkers of endothelial activation in the management of patients with sepsis.

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      Most cited references 101

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      GRADE: an emerging consensus on rating quality of evidence and strength of recommendations.

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        APACHE II: a severity of disease classification system.

        This paper presents the form and validation results of APACHE II, a severity of disease classification system. APACHE II uses a point score based upon initial values of 12 routine physiologic measurements, age, and previous health status to provide a general measure of severity of disease. An increasing score (range 0 to 71) was closely correlated with the subsequent risk of hospital death for 5815 intensive care admissions from 13 hospitals. This relationship was also found for many common diseases. When APACHE II scores are combined with an accurate description of disease, they can prognostically stratify acutely ill patients and assist investigators comparing the success of new or differing forms of therapy. This scoring index can be used to evaluate the use of hospital resources and compare the efficacy of intensive care in different hospitals or over time.
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          Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care.

          To determine the incidence, cost, and outcome of severe sepsis in the United States. Observational cohort study. All nonfederal hospitals (n = 847) in seven U.S. states. All patients (n = 192,980) meeting criteria for severe sepsis based on the International Classification of Diseases, Ninth Revision, Clinical Modification. None. We linked all 1995 state hospital discharge records (n = 6,621,559) from seven large states with population and hospital data from the U.S. Census, the Centers for Disease Control, the Health Care Financing Administration, and the American Hospital Association. We defined severe sepsis as documented infection and acute organ dysfunction using criteria based on the International Classification of Diseases, Ninth Revision, Clinical Modification. We validated these criteria against prospective clinical and physiologic criteria in a subset of five hospitals. We generated national age- and gender-adjusted estimates of incidence, cost, and outcome. We identified 192,980 cases, yielding national estimates of 751,000 cases (3.0 cases per 1,000 population and 2.26 cases per 100 hospital discharges), of whom 383,000 (51.1%) received intensive care and an additional 130,000 (17.3%) were ventilated in an intermediate care unit or cared for in a coronary care unit. Incidence increased >100-fold with age (0.2/1,000 in children to 26.2/1,000 in those >85 yrs old). Mortality was 28.6%, or 215,000 deaths nationally, and also increased with age, from 10% in children to 38.4% in those >85 yrs old. Women had lower age-specific incidence and mortality, but the difference in mortality was explained by differences in underlying disease and the site of infection. The average costs per case were $22,100, with annual total costs of $16.7 billion nationally. Costs were higher in infants, nonsurvivors, intensive care unit patients, surgical patients, and patients with more organ failure. The incidence was projected to increase by 1.5% per annum. Severe sepsis is a common, expensive, and frequently fatal condition, with as many deaths annually as those from acute myocardial infarction. It is especially common in the elderly and is likely to increase substantially as the U.S. population ages.

            Author and article information

            [1 ]Division of Hematology, University of British Columbia, Vancouver General Hospital, 855 12th Ave W, Vancouver, BC V5Z 1M9, Canada
            [2 ]Divisions of Pediatric Infectious Disease and Critical Care, University of Toronto, Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G 1X8, Canada
            [3 ]McLaughlin-Rotman Centre for Global Health, University Health Network, 101 College Street, Suite 406 Toronto, ON M5G 1L7, Canada
            [4 ]Department of Medicine, University of Toronto, 1 King's College Circle Medical Sciences Building-Room 2109, Toronto, ON M5S 1A8, Canada
            [5 ]Interdepartmental Division of Critical Care Medicine, University of Toronto, Queen Street Wing, Room 4-042, 30 Bond Street, Toronto, ON M5B 1W8, Canada
            Crit Care
            Crit Care
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            BioMed Central
            16 January 2012
            : 16
            : 1
            : R7
            Copyright ©2012 Xing et al.; licensee BioMed Central Ltd.

            This is an open access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


            Emergency medicine & Trauma

            coagulation, endothelium, biomarker, sepsis, angiopoietin


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