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      Adsorptive Modulation of Inflammatory Mediators Dampens Endothelial Cell Activation

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          Abstract

          Aim: In this study, the effect of specific or selective adsorption of inflammatory mediators on endothelial activation was assessed. Methods: Conditioned medium was obtained by stimulation of monocytic THP-1 cells with lipopolysaccharide and treated either with an adsorbent specific for tumour necrosis factor-α or with an albumin-coated polystyrene-divinylbenzene copolymer which selectively binds a range of cytokines. Thereafter, the conditioned medium was applied to endothelial cells in culture. Results: Adsorption of inflammatory mediators resulted in significantly decreased endothelial cell activation, as shown by reduced interleukin (IL)-6 and IL-8 secretion from endothelial cells as well as reduced surface expression of the adhesion molecules intercellular adhesion molecule-1 and E-selectin. The effect was more pronounced the earlier the mediator modulation was performed. Conclusion: Adsorptive modulation of inflammatory mediators dampens endothelial cell activation and may thus be beneficial as supportive therapy in sepsis.

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          Effectiveness of polymyxin B-immobilized fiber column in sepsis: a systematic review

          Introduction Severe sepsis and septic shock are common problems in the intensive care unit and carry a high mortality. Endotoxin, one of the principal components on the outer membrane of gram-negative bacteria, is considered important to their pathogenesis. Polymyxin B bound and immobilized to polystyrene fibers (PMX-F) is a medical device that aims to remove circulating endotoxin by adsorption, theoretically preventing the progression of the biological cascade of sepsis. We performed a systematic review to describe the effect in septic patients of direct hemoperfusion with PMX-F on outcomes of blood pressure, use of vasoactive drugs, oxygenation, and mortality reported in published studies. Methods We searched PubMed, the Cochrane Collaboration Database, and bibliographies of retrieved articles and consulted with experts to identify relevant studies. Prospective and retrospective observational studies, pre- and post-intervention design, and randomized controlled trials were included. Three authors reviewed all citations. We identified a total of 28 publications – 9 randomized controlled trials, 7 non-randomized parallel studies, and 12 pre-post design studies – that reported at least one of the specified outcome measures (pooled sample size, 1,425 patients: 978 PMX-F and 447 conventional medical therapy). Results Overall, mean arterial pressure (MAP) increased by 19 mm Hg (95% confidence interval [CI], 15 to 22 mm Hg; p < 0.001), representing a 26% mean increase in MAP (range, 14% to 42%), whereas dopamine/dobutamine dose decreased by 1.8 μg/kg per minute (95% CI, 0.4 to 3.3 μg/kg per minute; p = 0.01) after PMX-F. There was significant intertrial heterogeneity for these outcomes (p < 0.001), which became non-significant when analysis was stratified for baseline MAP. The mean arterial partial pressure of oxygen/fraction of inspired oxygen (PaO2/FiO2) ratio increased by 32 units (95% CI, 23 to 41 units; p < 0.001). PMX-F therapy was associated with significantly lower mortality risk (risk ratio, 0.53; 95% CI, 0.43 to 0.65). The trials assessed had suboptimal method quality. Conclusion Based on this critical review of the published literature, direct hemoperfusion with PMX-F appears to have favorable effects on MAP, dopamine use, PaO2/FiO2 ratio, and mortality. However, publication bias and lack of blinding need to be considered. These findings support the need for further rigorous study of this therapy.
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            Hemoadsorption removes tumor necrosis factor, interleukin-6, and interleukin-10, reduces nuclear factor-kappaB DNA binding, and improves short-term survival in lethal endotoxemia.

            Previous studies have shown that inflammatory mediators can be removed from the circulation with hemofiltration and that adsorption plays an important role. Because adsorptive capacity of hollow-fiber dialyzers is limited, we sought to determine whether hemoadsorption using high surface area beads would result in greater mediator removal and improved survival in experimental sepsis. Randomized controlled laboratory experiment. University laboratory. Sixty-six adult Sprague-Dawley rats. We conducted two ex vivo and two in vivo experiments. For in vivo experiments, we administered Escherichia coli endotoxin (20 mg/kg) by intravenous infusion and then randomized each animal to receive either hemoadsorption or a sham circuit for 4 hrs. Hemoadsorption was performed for 4 hrs using an arterial-venous circuit and a CytoSorb cartridge containing 10 g of polystyrene divinyl benzene copolymer beads with a biocompatible polyvinylpyrrolidone coating. Survival time was measured to a maximum of 12 hrs. In a separate set of experiments, we studied 12 animals using the same protocol except that we killed all animals at 4 hrs and removed standardized sections of liver for analysis of nuclear factor-kappaB DNA binding. Mean survival time among hemoadsorption-treated animals was 629+/-114 vs. 518+/-120 mins for sham-treated animals (p <.01). Overall survival (defined at 12 hrs) was also significantly better in the hemoadsorption group, seven of 20 vs. one of 20 (p <.05). Plasma interleukin-6 and interleukin-10 concentrations and liver nuclear factor-kappaB DNA binding were significantly reduced by hemoadsorption. Ex vivo experiments showed no endotoxin adsorption but strengthened our in vivo observations by showing rapid adsorption of tumor necrosis factor, interleukin-6, and interleukin-10. Hemoadsorption was associated with reduced inflammation and improved survival in this murine model of septic shock.
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              A pilot study of coupled plasma filtration with adsorption in septic shock.

              To test the hypothesis that nonselective plasma adsorption by a hydrophobic resin (coupled plasmafiltration and adsorption) could improve hemodynamics and restore leukocyte responsiveness in patients with septic shock. Prospective, pilot, crossover clinical trial. General intensive care unit in a teaching hospital. Ten patients with hyperdynamic septic shock. Patients were randomly allocated to 10 hrs of either coupled plasma filtration adsorption plus hemodialysis (treatment A) or continuous venovenous hemodiafiltration (treatment B) in random order. We measured the change in mean arterial pressure, norepinephrine requirements, and leukocyte tumor necrosis factor-alpha (TNF-alpha) production (both spontaneous and lipopolysaccharide-stimulated) after 10 hrs of each treatment. We also tested TNF-alpha production from normal human adherent monocytes incubated with patients' plasma obtained before and after the resin, both with or without incubation with an anti-interleukin-10 monoclonal antibody. Mean arterial pressure increased after 10 hr by 11.8 mm Hg with treatment A and by 5.5 mm Hg with treatment B (p =.001). There was an average decrease of norepinephrine requirement of 0.08 microg/kg/min with treatment A and 0.0049 microg/kg/min with treatment B (p =.003). All patients but one survived. Spontaneous and lipopolysaccharide-induced TNF-alpha production from patients' whole blood increased over time with treatment A. This increase was more marked in blood drawn after the device (plasmafiltrate-sorbent plus hemodialyzer) (p =.009). Preresin plasma suppressed lipopolysaccharide-stimulated production of TNF-alpha by 1 x 10(6)cultured adherent monocytes from healthy donors. This suppressive effect was significantly reduced after passage of plasma through the resin (p =.019) and after incubation with anti-interleukin-10 monoclonal antibodies (p =.028). In patients with septic shock, coupled plasmafiltration-adsorption combined with hemodialysis was associated with improved hemodynamics compared with continuous venovenous hemodiafiltration. This result might be related to its ability to restore leukocyte responsiveness to lipopolysaccharide. These findings suggest a potential role for blood purification in the treatment of septic shock.
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                Author and article information

                Journal
                BPU
                Blood Purif
                10.1159/issn.0253-5068
                Blood Purification
                S. Karger AG
                0253-5068
                1421-9735
                2011
                November 2011
                26 August 2011
                : 32
                : 4
                : 286-295
                Affiliations
                Department for Clinical Medicine and Biotechnology, Danube University Krems, Krems, Austria
                Author notes
                *Viktoria Weber, Department for Clinical Medicine and Biotechnology, Danube University Krems, Dr.-Karl-Dorrek-Strasse 30, AT–3500 Krems (Austria), Tel. +43 2732 893 2632, E-Mail viktoria.weber@donau-uni.ac.at
                Article
                330329 Blood Purif 2011;32:286–295
                10.1159/000330329
                21876351
                d8131a79-5742-40a3-ba55-d411218a513e
                © 2011 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                History
                : 13 January 2011
                : 24 June 2011
                Page count
                Figures: 6, Pages: 10
                Categories
                Original Paper

                Cardiovascular Medicine,Nephrology
                Adsorption,Polymers,Blood purification,Endothelial cell activation,Sepsis

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