The effect of a novel extracorporeal cytokine hemoadsorption device on IL-6 elimination in septic patients: A randomized controlled trial

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Abstract

Objective

We report on the effect of hemoadsorption therapy to reduce cytokines in septic patients with respiratory failure.

Methods

This was a randomized, controlled, open-label, multicenter trial. Mechanically ventilated patients with severe sepsis or septic shock and acute lung injury or acute respiratory distress syndrome were eligible for study inclusion. Patients were randomly assigned to either therapy with CytoSorb hemoperfusion for 6 hours per day for up to 7 consecutive days (treatment), or no hemoperfusion (control). Primary outcome was change in normalized IL-6-serum concentrations during study day 1 and 7.

Results

97 of the 100 randomized patients were analyzed. We were not able to detect differences in systemic plasma IL-6 levels between the two groups (n = 75; p = 0.15). Significant IL-6 elimination, averaging between 5 and 18% per blood pass throughout the entire treatment period was recorded. In the unadjusted analysis, 60-day-mortality was significantly higher in the treatment group (44.7%) compared to the control group (26.0%; p = 0.039). The proportion of patients receiving renal replacement therapy at the time of enrollment was higher in the treatment group (31.9%) when compared to the control group (16.3%). After adjustment for patient morbidity and baseline imbalances, no association of hemoperfusion with mortality was found (p = 0.19).

Conclusions

In this patient population with predominantly septic shock and multiple organ failure, hemoadsorption removed IL-6 but this did not lead to lower plasma IL-6-levels. We did not detect statistically significant differences in the secondary outcomes multiple organ dysfunction score, ventilation time and time course of oxygenation.

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Most cited references 29

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American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference: definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis.

(1992)

To define the terms "sepsis" and "organ failure" in a precise manner. Review of the medical literature and the use of expert testimony at a consensus conference. American College of Chest Physicians (ACCP) headquarters in Northbrook, IL. Leadership members of ACCP/Society of Critical Care Medicine (SCCM). An ACCP/SCCM Consensus Conference was held in August of 1991 with the goal of agreeing on a set of definitions that could be applied to patients with sepsis and its sequelae. New definitions were offered for some terms, while others were discarded. Broad definitions of sepsis and the systemic inflammatory response syndrome were proposed, along with detailed physiologic variables by which a patient could be categorized. Definitions for severe sepsis, septic shock, hypotension, and multiple organ dysfunction syndrome were also offered. The use of severity scoring methods were recommended when dealing with septic patients as an adjunctive tool to assess mortality. Appropriate methods and applications for the use and testing of new therapies were recommended. The use of these terms and techniques should assist clinicians and researchers who deal with sepsis and its sequelae.

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Multiple organ dysfunction score: a reliable descriptor of a complex clinical outcome.

J C Marshall, D J Cook, N V Christou … (1995)

To develop an objective scale to measure the severity of the multiple organ dysfunction syndrome as an outcome in critical illness. Systematic literature review; prospective cohort study. Surgical intensive care unit (ICU) of a tertiary-level teaching hospital. All patients (n = 692) admitted for > 24 hrs between May 1988 and March 1990. None. Computerized database review of MEDLINE identified clinical studies of multiple organ failure that were published between 1969 and 1993. Variables from these studies were evaluated for construct and content validity to identify optimal descriptors of organ dysfunction. Clinical and laboratory data were collected daily to evaluate the performance of these variables individually and in aggregate as an organ dysfunction score. Seven systems defined the multiple organ dysfunction syndrome in more than half of the 30 published reports reviewed. Descriptors meeting criteria for construct and content validity could be identified for five of these seven systems: a) the respiratory system (Po2/FIO2 ratio); b) the renal system (serum creatinine concentration); c) the hepatic system (serum bilirubin concentration); d) the hematologic system (platelet count); and e) the central nervous system (Glasgow Coma Scale). In the absence of an adequate descriptor of cardiovascular dysfunction, we developed a new variable, the pressure-adjusted heart rate, which is calculated as the product of the heart rate and the ratio of central venous pressure to mean arterial pressure. These candidate descriptors of organ dysfunction were then evaluated for criterion validity (ICU mortality rate) using the clinical database. From the first half of the database (the development set), intervals for the most abnormal value of each variable were constructed on a scale from 0 to 4 so that a value of 0 represented essentially normal function and was associated with an ICU mortality rate of or = 50%. These intervals were then tested on the second half of the data set (the validation set). Maximal scores for each variable were summed to yield a Multiple Organ Dysfunction Score (maximum of 24). This score correlated in a graded fashion with the ICU mortality rate, both when applied on the first day of ICU admission as a prognostic indicator and when calculated over the ICU stay as an outcome measure. For the latter, ICU mortality was approximately 25% at 9 to 12 points, 50% at 13 to 16 points, 75% at 17 to 20 points, and 100% at levels of > 20 points. The score showed excellent discrimination, as reflected in areas under the receiver operating characteristic curve of 0.936 in the development set and 0.928 in the validation set. The incremental increase in scores over the course of the ICU stay (calculated as the difference between maximal scores and those scores obtained on the first day [i.e., the delta Multiple Organ Dysfunction Score]) also demonstrated a strong correlation with the ICU mortality rate. In a logistic regression model, this incremental increase in scores accounted for more of the explanatory power than admission severity indices. This multiple organ dysfunction score, constructed using simple physiologic measures of dysfunction in six organ systems, mirrors organ dysfunction as the intensivist sees it and correlates strongly with the ultimate risk of ICU mortality and hospital mortality. The variable, delta Multiple Organ Dysfunction Score, reflects organ dysfunction developing during the ICU stay, which therefore is potentially amenable to therapeutic manipulation. (ABSTRACT TRUNCATED)

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Early use of polymyxin B hemoperfusion in patients with septic shock due to peritonitis: a multicenter randomized control trial

Didier M. Payen, Joëlle Guilhot, Yoann Launey … (2015)

Purpose To test whether the polymyxin B hemoperfusion (PMX HP) fiber column reduces mortality and organ failure in peritonitis-induced septic shock (SS) from abdominal infections. Method Prospective, multicenter, randomized controlled trial in 18 French intensive care units from October 2010 to March 2013, enrolling 243 patients with SS within 12 h after emergency surgery for peritonitis related to organ perforation. The PMX HP group received conventional therapy plus two sessions of PMX HP. Primary outcome was mortality on day 28; secondary outcomes were mortality on day 90 and a reduction in the severity of organ failures based on Sequential Organ Failure Assessment (SOFA) scores. Results Primary outcome: day 28 mortality in the PMX HP group (n = 119) was 27.7 versus 19.5 % in the conventional group (n = 113), p = 0.14 (OR 1.5872, 95 % CI 0.8583–2.935). Secondary endpoints: mortality rate at day 90 was 33.6 % in PMX-HP versus 24 % in conventional groups, p = 0.10 (OR 1.6128, 95 % CI 0.9067–2.8685); reduction in SOFA score from day 0 to day 7 was −5 (−11 to 6) in PMX-HP versus −5 (−11 to 9), p = 0.78. Comparable results were observed in the predefined subgroups (presence of comorbidity; adequacy of surgery, <2 sessions of hemoperfusion) and for SOFA reduction from day 0 to day 3. Conclusion This multicenter randomized controlled study demonstrated a non-significant increase in mortality and no improvement in organ failure with PMX HP treatment compared to conventional treatment of peritonitis-induced SS. Electronic supplementary material The online version of this article (doi:10.1007/s00134-015-3751-z) contains supplementary material, which is available to authorized users.

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Author and article information

Contributors

Dirk Schädler:

ORCID: http://orcid.org/0000-0002-5745-4797

Role: Data curationRole: Funding acquisitionRole: InvestigationRole: ResourcesRole: ValidationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing

Christine Pausch: Role: Data curationRole: Formal analysisRole: ResourcesRole: SoftwareRole: VisualizationRole: Writing – original draftRole: Writing – review & editing

Daniel Heise: Role: Data curationRole: InvestigationRole: ResourcesRole: Writing – review & editing

Andreas Meier-Hellmann: Role: Data curationRole: InvestigationRole: ResourcesRole: Writing – review & editing

Jörg Brederlau: Role: Data curationRole: InvestigationRole: ResourcesRole: Writing – review & editing

Norbert Weiler: Role: Data curationRole: InvestigationRole: ResourcesRole: Writing – review & editing

Gernot Marx: Role: Data curationRole: InvestigationRole: ResourcesRole: Writing – review & editing

Christian Putensen: Role: Data curationRole: InvestigationRole: ResourcesRole: Writing – review & editing

Claudia Spies: Role: Data curationRole: InvestigationRole: ResourcesRole: Writing – review & editing

Achim Jörres: Role: Data curationRole: InvestigationRole: ResourcesRole: Writing – review & editing

Michael Quintel: Role: Data curationRole: InvestigationRole: ResourcesRole: Writing – review & editing

Christoph Engel: Role: Data curationRole: Formal analysisRole: ResourcesRole: SoftwareRole: VisualizationRole: Writing – review & editing

John A. Kellum: Role: ConceptualizationRole: Data curationRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: ResourcesRole: SupervisionRole: ValidationRole: VisualizationRole: Writing – review & editing

Martin K. Kuhlmann: Role: ConceptualizationRole: Data curationRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: ValidationRole: VisualizationRole: Writing – review & editing

Kathrin Eller: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, CA USA )

ISSN (Electronic): 1932-6203

Publication date (Electronic): 30 October 2017

Publication date Collection: 2017

Volume: 12

Issue: 10

Electronic Location Identifier: e0187015

Affiliations

[1 ] Department of Anesthesiology and Intensive Care Medicine, University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany

[2 ] Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany

[3 ] Centre of Anaesthesiology, Emergency and Intensive Care Medicine, University Hospital Göttingen, Göttingen, Germany

[4 ] Department of Anesthesiology and Intensive Care Medicine, HELIOS Klinikum, Erfurt, Germany

[5 ] Department of Intensive Care Medicine, Helios Hospital Berlin-Buch, Berlin, Germany

[6 ] Department of Intensive Care and Intermediate Care, RWTH University Hospital Aachen, Aachen, Germany

[7 ] Department of Anesthesiology and Intensive Care Medicine, University of Bonn, Bonn, Germany

[8 ] Anaesthesiology and Intensive Care Medicine, Campus Charité Mitte and Campus Charité Virchow-Klinikum, Charité - University Medicine Berlin, Berlin, Germany

[9 ] Department of Medicine I - Nephrology, Transplantation & Medical Intensive Care, University Witten/Herdecke, Medical Center Cologne-Merheim, Cologne, Germany

[10 ] Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America

[11 ] Department of Nephrology, Vivantes Klinikum im Friedrichshain, Berlin, Germany

Medizinische Universitat Graz, AUSTRIA

Author notes

Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: MKK received a research grant for study administration and coordination by Cytosorbents. GM has received honorary from Cytosorbents. DS and MKK received refunds of travelling expenses by Cytosorbents. The remaining authors have declared that no competing interests exist. The study was supported by Cytosorbents Corporation, New Jersey, United States and investigated a product marketed by Cytosorbents. This does not alter our adherence to PLOS ONE policies on sharing data and materials. Cytosorbents does not employ and does not pay consultancies to any of the authors.

* E-mail: dirk.schaedler@ 123456uksh.de

Author information

Dirk Schädler http://orcid.org/0000-0002-5745-4797

Article

Publisher ID: PONE-D-17-09665

DOI: 10.1371/journal.pone.0187015

PMC ID: 5662220

PubMed ID: 29084247

SO-VID: 20e07027-ba08-4b84-a252-1f886b7fd09b

License:

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 author and source are credited.

History

Date received : 11 March 2017

Date accepted : 10 October 2017

Page count

Figures: 6, Tables: 6, Pages: 19

Funding

The study was supported by Cytosorbents Corporation, New Jersey, United States. Cytosorbents was involved in study design and data collection. Cytosorbents had no role in analysis, decision to publish or preparation of the manuscript.

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Data Availability All relevant data are within the paper and its Supporting Information files.

The effect of a novel extracorporeal cytokine hemoadsorption device on IL-6 elimination in septic patients: A randomized controlled trial

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Abstract

Objective

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Results

Conclusions

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Most cited references 29

American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference: definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis.

Multiple organ dysfunction score: a reliable descriptor of a complex clinical outcome.

Early use of polymyxin B hemoperfusion in patients with septic shock due to peritonitis: a multicenter randomized control trial

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