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      Cytokine Removal with a Novel Adsorbent Polymer

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          Abstract

          Background/Aims: We sought to characterize a novel adsorbent polymer in terms of cytokine removal. Methods: We challenged 50 rats with lipopolysaccharide to obtain cytokine-rich blood and circulated this through cartridges containing polymer. In separate experiments, cell-free supernatants were passed through cartridges containing polymer. We measured tumor necrosis factor alpha, interleukin 10 and interleukin 6 concentrations under a variety of conditions to evaluate adsorption kinetics. Results: All three cytokines were rapidly removed from the blood with less than 50% of the initial concentrations present after 1 h of circulation through the cartridge. There was no significant difference in the effect across a range of blood flows and Ca<sup>2+</sup> concentrations. Adsorption was decreased somewhat by extremely low temperature (4°C). Conclusion: The adsorbent polymer removes cytokines with high efficiency, and binding is relatively unaffected by a variety of physical conditions.

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          Most cited references 13

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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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            Continuous veno-venous hemofiltration with dialysis removes cytokines from the circulation of septic patients.

            To determine whether continuous veno-venous hemofiltration with dialysis leads to extraction of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta) from the circulation of critically ill patients with sepsis and acute renal failure and to quantitate the clearance and removal rates of these cytokines and their effect on serum cytokine concentrations. Prospective, controlled study of TNF-alpha IL-1 beta extraction by continuous veno-venous hemofiltration with dialysis in patients with septic acute renal failure. Intensive care unit of a tertiary institution. Eighteen critically ill patients with sepsis and acute renal failure. Control group of six patients experiencing an acute illness while undergoing chronic hemodialysis. Collection of blood samples before continuous veno-venous hemofiltration with hemodialysis. Simultaneous collection of prefilter blood and ultradiafiltrate after 4 and 24 hrs of treatment. TNF-alpha and IL-1 beta concentrations were measured in blood and ultradiafiltrate. Their clearances and daily extraction were calculated and compared with a control group. TNF-alpha was detected in 66.6% of serum samples of patients with septic acute renal failure; IL-1 beta was detected in 55% of patients' sera samples. Both TNF-alpha and IL-1 beta were cleared by the hemofilter during continuous veno-venous hemofiltration with dialysis. The mean clearance for TNF-alpha was 30.7 L/day (95% confidence interval 22.4 to 39) with a daily mean excretion of 14.1 micrograms (95% confidence interval 1.7 to 26.5). Mean IL-1 beta clearance was 36.1 L/day (95% confidence interval 25.4 to 46.8) equivalent to a mean daily IL-1 beta excretion of 1 microgram (95% confidence interval 0.9 to 1.1). No measurable concentrations of TNF-alpha or IL-1 beta were found in the serum or ultrafiltrate specimens of control patients. These findings demonstrate that continuous veno-venous hemofiltration with dialysis can remove both TNF-alpha and IL-1 beta from the circulation of septic, critically ill patients. This cytokine extraction may prove to be of benefit in attenuating the progression of multiple organ dysfunction in patients with sepsis-associated renal failure, who are receiving continuous veno-venous hemofiltration with dialysis. This potential benefit of existing hemofiltration therapies supports their preferential implementation in patients with renal failure associated with severe sepsis. These observations may stimulate the modification of filtration membrane design seeking to specifically augment the clearance from the circulation of a variety of such cytokines.
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              Cytokine removal and cardiovascular hemodynamics in septic patients with continuous venovenous hemofiltration.

              To determine whether continuous venovenous hemofiltration leads to extraction of tumor necrosis factor alpha (TNF alpha) and cytokines from the circulation of critically ill patients with sepsis and acute renal failure and to quantitate the clearance and the removal rate of these cytokines and their effect on serum cytokine concentrations. Prospective, controlled study in patients with continuous venovenous hemofiltration (24 1/24 h) using a polysulphone membrane in patients with acute renal failure. 33 ventilated patients with acute renal failure of septic (n = 18) and cardiovascular origin (n = 15) were studied. Hemodynamic monitoring and collection of blood and ultrafiltrate samples before and during the first 72 h of continuous hemofiltration. Cardiovascular hemodynamics (Swan-Ganz catheter), Acute Physiology and Chronic Health Evaluation II score, creatinine, electrolytes, and blood urea nitrogen were recorded daily. Cytokines (TNF alpha, TNF alpha-RII, interleukin (IL) 1beta, IL1RA, IL2, IL2R, IL6, IL6R, IL8, IL10) were measured in prefilter blood and in ultrafiltrate immediately preceding and 12, 24, 48, and 72 h after initiating continuous venovenous hemofiltration (CVVH). Septic patients showed elevated cardiovascular values for cardiac output (7.2 +/- 2.1 l/min), cardiac index (4.2 +/- 1.3 l/min per m2), and stroke volume (67 +/- 23 ml) and reduced values for systemic vascular resistance (540 +/- 299 dyn x s x cm(-5)). All hemodynamic values normalized within the first 24 h after initiating CVVH treatment. TNF alpha was 1833 +/- 1217 pg/ml in septic patients and 42.9 +/- 6.3 pg/ml in nonseptic patients (p < 0.05) prior to CVVH. TNF alpha was detected in ultrafiltrate but did not decrease in blood during treatment with CVVH. There was no difference in IL 1beta between septic (3.8 +/- 1.9 pg/ml) and nonseptic patients (1.7 +/- 0.5 pg/ml). No significant elimination of cytokines was achieved in the present study by CVVH treatment. These findings demonstrate that CVVH can remove TNF alpha and special cytokines from the circulation of critically ill patients. Cardiovascular hemodynamics seemed to improve in septic patients after induction of hemofiltration treatment, although there was no evidence that extracorporeal removal of cytokines achieved a reduction in blood levels. The study indicates that low volume continuous hemofiltration with polysulphone membranes in patients with acute renal failure is not able to induce significant removal of cytokines.
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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
                2004
                November 2004
                17 November 2004
                : 22
                : 5
                : 428-434
                Affiliations
                aThe MANTRA Laboratories, Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pa., bRenalTech International, New York, N.Y., USA
                Article
                80235 Blood Purif 2004;22:428–434
                10.1159/000080235
                15316198
                © 2004 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.

                Page count
                Figures: 6, References: 22, Pages: 7
                Product
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/80235
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