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      The influence of corticosteroids on the release of novel biomarkers in human endotoxemia

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          Abstract

          Objective

          Sepsis intervention studies need better patient stratification methods, and one way to realize this is the introduction of stable biomarkers. A set of recently developed novel biomarkers, based upon precursor-fragments of short-lived hormones, was previously shown to be increased during sepsis. However, it is not known whether these biomarkers are influenced by sepsis intervention strategies. Therefore we investigated the markers in a model of human endotoxemia intervened by increasing doses of prednisolone.

          Design and setting

          Prospective, open-label study in a specialized clinical research unit of a university hospital.

          Subjects

          Thirty-two healthy male volunteers.

          Interventions

          Subjects received prednisolone orally at doses of 0, 3, 10 or 30 mg ( n = 8 per group) at 2 h before intravenous injection of Escherichia coli lipopolysaccharide (LPS) (4 ng/kg). Blood samples were drawn during 24 h after LPS injection.

          Measurements and results

          LPS injection caused an increase in levels of midregional pro-adrenomedullin (MR-proADM), midregional pro-atrial natriuretic peptide (MR-proANP), C-terminal pro-arginine–vasopressin (CT-proAVP) and procalcitonin (PCT). Prednisolone caused a dose dependent inhibition of MR-proADM, MR-proANP and CT-proAVP levels.

          Conclusions

          These results show that a set of novel, highly stable sepsis biomarkers was increased during human endotoxemia and was dose-dependently inhibited by corticosteroid pre-treatment.

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          Most cited references 17

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          Procalcitonin as a diagnostic test for sepsis in critically ill adults and after surgery or trauma: a systematic review and meta-analysis.

          To quantify the accuracy of serum procalcitonin as a diagnostic test for sepsis, severe sepsis, or septic shock in adults in intensive care units or after surgery or trauma, alone and compared with C-reactive protein. To draw and compare the summary receiver operating characteristics curves for procalcitonin and C-reactive protein from the literature. MEDLINE (keywords: procalcitonin, intensive care, sepsis, postoperative sepsis, trauma); screening of the literature. Meta-analysis of all 49 published studies in medical, surgical, or polyvalent intensive care units or postoperative wards. Children, medical patients, and immunocompromised patients were excluded. Thirty-three studies fulfilled inclusion criteria (3,943 patients, 1,828 males, 922 females; mean age: 56.1 yrs; 1,825 patients with sepsis, severe sepsis, or septic shock; 1,545 with only systemic inflammatory response syndrome); eight studies could not be analyzed statistically. Global mortality rate was 29.3%. Global odds ratios for diagnosis of infection complicated by systemic inflammation were 15.7 for the 25 studies (2,966 patients) using procalcitonin (95% confidence interval, 9.1-27.1) and 5.4 for the 15 studies (1,322 patients) using C-reactive protein (95% confidence interval, 3.2-9.2). The summary receiver operating characteristics curve for procalcitonin was better than for C-reactive protein. In the 15 studies using both markers, the Q* value (intersection of summary receiver operating characteristics curve with the diagonal line where sensitivity equals specificity) was significantly higher for procalcitonin than for C-reactive protein (0.78 vs. 0.71, p = .02), the former test showing better accuracy. Procalcitonin represents a good biological diagnostic marker for sepsis, severe sepsis, or septic shock, difficult diagnoses in critically ill patients. Procalcitonin is superior to C-reactive protein. Procalcitonin should be included in diagnostic guidelines for sepsis and in clinical practice in intensive care units.
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            Measurement of midregional proadrenomedullin in plasma with an immunoluminometric assay.

            Adrenomedullin (ADM) is a potent vasodilatory peptide, and circulating concentrations have been described for several disease states, including dysfunction of the cardiovascular system and sepsis. Reliable quantification has been hampered by the short half-life, the existence of a binding protein, and physical properties. Here we report the technical evaluation of an assay for midregional pro-ADM (MR-proADM) that does not have these problems. MR-proADM was measured in a sandwich immunoluminometric assay using 2 polyclonal antibodies to amino acids 45-92 of proADM. The reference interval was defined in EDTA plasma of 264 healthy individuals (117 male, 147 female), and increased MR-proADM concentrations were found in 95 patients with sepsis and 54 patients with cardiovascular disease. The assay has an analytical detection limit of 0.08 nmol/L, and the interassay CV was 0.12 nmol/L. The assay was linear on dilution with undisturbed recovery of the analyte. EDTA-, heparin-, and citrate-plasma samples were stable (<20% loss of analyte) for at least 3 days at room temperature, 14 days at 4 degrees C, and 1 year at -20 degrees C. MR-proADM values followed a gaussian distribution in healthy individuals with a mean (SD) of 0.33 (0.07) nmol/L (range, 0.10-0.64 nmol/L), without significant difference between males or females. The correlation coefficient for MR-proADM vs age was 0.50 (P < 0.001). MR-proADM was significantly (P < 0.001) increased in patients with cardiovascular disease [median (range), 0.56 (0.08-3.9) nmol/L] and patients with sepsis [3.7 (0.72-25.4) nmol/L]. MR-proADM is stable in plasma of healthy individuals and patients. MR-proADM measurements may be useful for evaluating patients with sepsis, systemic inflammation, or heart failure.
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              Immunoluminometric assay for the midregion of pro-atrial natriuretic peptide in human plasma.

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                Author and article information

                Contributors
                m.d.dekruif@amc.uva.nl
                Journal
                Intensive Care Med
                Intensive Care Medicine
                Springer-Verlag (Berlin/Heidelberg )
                0342-4642
                1432-1238
                14 December 2007
                March 2008
                : 34
                : 3
                : 518-522
                Affiliations
                [1 ]Center for Experimental and Molecular Medicine, Room G2-132, Academic Medical Center, Meibergdreef 9, 1105 Amsterdam, AZ The Netherlands
                [2 ]Department of Anesthesiology, University Medical Center Utrecht, P.O. Box 85500, 3508 Utrecht, GA The Netherlands
                [3 ]Center for Infection and Immunity Amsterdam, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 Amsterdam, AZ The Netherlands
                [4 ]Research Department, Brahms AG, Neuendorfstrasse 25, 16761 Hennigsdorf/Berlin, Germany
                [5 ]CombinatoRx, Inc., 245 st., 16th floor, 02142 Cambridge, MA USA
                [6 ]Sirtris Pharmaceuticals, 790 Memorial Drive, 02139 Cambridge, MA USA
                Article
                955
                10.1007/s00134-007-0955-x
                2244699
                18080111
                © The Author(s) 2007
                Categories
                Brief Report
                Custom metadata
                © Springer-Verlag 2008

                Emergency medicine & Trauma

                endotoxin, corticosteroids, biological markers, sepsis

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