Cytokine Adsorption in Severe, Refractory Septic Shock

Septic shock and the underlying dysregulated inflammatory host-response remain a major contributor to mortality in critically ill patients. Cytokine adsorption represents an attractive approach to the treatment of septic shock. Nevertheless, its effect on circulating cytokine levels, as well as on the course of disease remains largely unassessed.

Study Overview

• Status: Completed
• Conditions: Septic Shock; Cytokine Storm
• Intervention / Treatment: Device: Cytokine Adsorption; Other: Standard of Care

Detailed Description

Cytokine-release plays an important role in the physiology of immune response to pathologic influences by recruiting immune cells to the pathogenic loci, be they of infectious or of non-infectious nature. Once at the focus, the activated immune cells can in turn release more cytokines if a more extensive immune response is needed. This extremely important mechanism for the organism, can however become pathological if the positive feedback loop between immune cells and cytokines, for any reason, overshoots in form of a so called cytokine storm and substantial amounts of released cytokines gain a systemic influence. The acute complication of this immune over-reaction is a SIRS, which can critically escalate into a potentially lethal multiple organ dysfunction syndrome, thus requiring immediate intensive care treatment.

It is, having this framework in mind, the reason why the CytoSorb-Adsorber has been developed as a new therapeutic milestone. Essentially a haemoperfusion-filter, which through its layering with polymer beads (Divinylbenzene/ Polyvinylpyrrolidone) can adsorb cytokines as well as multiple inflammatory mediators and thus effectively remove them from the bloodstream, reducing their possible systemic influence and hence improving the outcome for patients being treated with it.

The CytoSorb-Adsorber is an already CE-approved product, which has demonstrated its capacity to significantly reduce cytokine-levels such as IL-6, IL-8, IL-10, TNFα, HMGB-1, IL-1ra in a variety of pre-clinical studies. As well as in a clinical randomised multicentre study, which tested the CytoSorb-Adsorber on a cohort of ALI/ ARDS and severely septic/ septically shocked patients. The results of the later study can be very positively assessed, first of all and most importantly showing, that no security concerns had to be had in regard to the haemoperfusion-filter, as no adverse-effects attributable to the device were found. And further, by proving an effect on systemic cytokine-levels in form of a significant reduction in IL-6, IL-8, MCP-1 and IL-1ra, as well as a reduction in mortality of those patients with high initial cytokine levels, effectively reducing the 60 day mortality rate from 60% to 17% in a pool of 14 patients.

With the intention to further elucidate the usefulness and clinical importance of this device this study proposes a prospective recruitment of patients in severe refractory septic shock to test the efficiency of this device.

• Study Type: Interventional
• Enrollment (Actual): 48
• Phase: Not Applicable

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

Patients diagnosed septic shock in the 24 hours ensuing diagnosis:

(I) severe, refractory septic shock defined as:

1. an acute SOFA score increase ≥2 points consequent to a presumed or proven infection
2. volume resuscitation of at least 30ml/kg in the last 24 hours
3. a Vasopressor Dependency Index11 (VPI) above or equal to 3
4. a persistently elevated serum lactate level >2mmol/l (II) Interleukin-6 levels equal or above 1000 ng/l (III) were above 18 years of age.

Exclusion Criteria:

1. Contraindication on ethical grounds
2. child bearing or breastfeeding women
3. terminal patients
4. human immunodeficiency virus with a CD4 cell count <0.2 106/l
5. allergy to Polystyrene/ Divinylbenzene, Polycarbonate, Polypropylene, Silicon or Polyester
6. need for extra-corporeal membrane oxygenation
7. no given consent.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cytokine Adsorption Arm; Intervention with CytoSorb	Device: Cytokine Adsorption; Cytokine adsorption therapy will be provided continuously for 72 hours by means of the CytoSorb® (CytoSorbents Corporation, Monmouth Junction, USA) column, run in series to a veno-venous continuous hemodialysis system, which will be exchanged every 24 hours.; Other Names: CytoSorb
Other: Historical Comparison; Patients extracted from a septic shock population treated at the same institution between 2010 and 2018 and matched to the intervention group.	Other: Standard of Care; Standard intensive care of patients suffering septic shock

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in circulating Interleukin-6 levels over time	Change in circulating Interleukin-6 levels, stratified by groups, over the initial 72 hours ensuing fulfillment of inclusion criteria	Mixed Model Assessment at timepoints 0, 24, 48, 72 hours
Change in Vasopressor requirements over time	Change in the Vasopressor Dependency Index, stratified by groups, over the initial 72 hours ensuing fulfillment of inclusion criteria	Mixed Model Assessment at timepoints 0, 2, 4, 8, 12 , 24, 48, 72 hours
Cumulative intensive care mortality at 30 days	Intensive care mortality assessment at day 30 between groups	30 days post fulfillment of inclusion criteria

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in C-reactive protein levels over time	Change in C-reactive protein levels, stratified by groups, over the initial 72 hours ensuing fulfillment of inclusion criteria	Mixed Model Assessment at timepoints 0, 24, 48, 72 hours
Change in Procalcitonin levels over time	Change in Procalcitonin levels, stratified by groups, over the initial 72 hours ensuing fulfillment of inclusion criteria	Mixed Model Assessment at timepoints 0, 24, 48, 72 hours
Change in SOFA Score over time	Change in SOFA Score, stratified by groups, over the initial 72 hours ensuing fulfillment of inclusion criteria	Mixed Model Assessment at timepoints 0, 24, 48, 72 hours
Change in arterial lactate levels over time	Change in arterial lactate levels, stratified by groups, over the initial 72 hours ensuing fulfillment of inclusion criteria	Mixed Model Assessment at timepoints 0, 2, 4, 8, 12 , 24, 48, 72 hours
Change in cardiac index over time	Change in cardiac index, stratified by groups, over the initial 72 hours ensuing fulfillment of inclusion criteria	Mixed Model Assessment at timepoints 0, 2, 4, 8, 12 , 24, 48, 72 hours
Change in Extra Vascular Lung Water Index over time	Change in Extra Vascular Lung Water Index, stratified by groups, over the initial 72 hours ensuing fulfillment of inclusion criteria	Mixed Model Assessment at timepoints 0, 24, 48, 72 hours
Change in daily Infused Volume over time	Change in daily Infused Volume, stratified by groups, over the initial 72 hours ensuing fulfillment of inclusion criteria	Mixed Model Assessment at timepoints 0, 24, 48, 72 hours
Change in PaO2/ FiO2 Ratio over time	Change in PaO2/ FiO2 Ratio, stratified by groups, over the initial 72 hours ensuing fulfillment of inclusion criteria	Mixed Model Assessment at timepoints 0, 2, 4, 8, 12 , 24, 48, 72 hours
Change in Serum Albumin levels over time	Change in Serum Albumin levels, stratified by groups, over the initial 72 hours ensuing fulfillment of inclusion criteria	Mixed Model Assessment at timepoints 0, 24, 48, 72 hours
Change in Bilirubin levels over time	Change in Bilirubin levels, stratified by groups, over the initial 72 hours ensuing fulfillment of inclusion criteria	Mixed Model Assessment at timepoints 0, 24, 48, 72 hours

Collaborators and Investigators

• Sponsor: University of Zurich
• Collaborators: CytoSorbents Europe GmbH
• Investigators: Principal Investigator: Marco Maggiorini, MD, Medizinische Intensivstation D-HOER 27, UniversitatsSpital Zürich

Publications and helpful links

General Publications

• Wang H, Ma S. The cytokine storm and factors determining the sequence and severity of organ dysfunction in multiple organ dysfunction syndrome. Am J Emerg Med. 2008 Jul;26(6):711-5. doi: 10.1016/j.ajem.2007.10.031.
• Taniguchi T. Cytokine adsorbing columns. Contrib Nephrol. 2010;166:134-141. doi: 10.1159/000314863. Epub 2010 May 7.
• Morris C, Gray L, Giovannelli M. Early report: The use of Cytosorb haemabsorption column as an adjunct in managing severe sepsis: initial experiences, review and recommendations. J Intensive Care Soc. 2015 Aug;16(3):257-264. doi: 10.1177/1751143715574855. Epub 2015 Mar 18.
• Rimmelé T, Kellum JA. Clinical review: blood purification for sepsis. Crit Care. 2011;15(1):205. doi: 10.1186/cc9411. Epub 2011 Feb 16. Review.
• Reiter K, Bordoni V, Dall'Olio G, Ricatti MG, Soli M, Ruperti S, Soffiati G, Galloni E, D'Intini V, Bellomo R, Ronco C. In vitro removal of therapeutic drugs with a novel adsorbent system. Blood Purif. 2002;20(4):380-8. doi: 10.1159/000063108.
• Kellum JA, Song M, Venkataraman R. Hemoadsorption removes tumor necrosis factor, interleukin-6, and interleukin-10, reduces nuclear factor-kappaB DNA binding, and improves short-term survival in lethal endotoxemia. Crit Care Med. 2004 Mar;32(3):801-5. doi: 10.1097/01.ccm.0000114997.39857.69.
• Peng ZY, Carter MJ, Kellum JA. Effects of hemoadsorption on cytokine removal and short-term survival in septic rats. Crit Care Med. 2008 May;36(5):1573-7. doi: 10.1097/CCM.0b013e318170b9a7.
• D Schädler, C Porzelius, A Jörres, G Marx, A Meier-Hellmann, C Putensen, M Quintel, C Spies, C Engel, NWeiler, M Kuhlmann. A multicenter randomized controlled study of an extracorporeal cytokine hemoadsorption device in septic patients. Critical Care 2013, 17(Suppl 2):P62 (19 March 2013).

Study record dates

Study Major Dates

• Study Start (Actual): November 27, 2014
• Primary Completion (Actual): August 24, 2018
• Study Completion (Actual): December 31, 2018

Study Registration Dates

• First Submitted: May 27, 2021
• First Submitted That Met QC Criteria: May 27, 2021
• First Posted (Actual): June 2, 2021

Study Record Updates

• Last Update Posted (Actual): June 10, 2021
• Last Update Submitted That Met QC Criteria: June 7, 2021
• Last Verified: June 1, 2021

More Information

Terms related to this study

• Keywords: Septic Shock; Cytokine Adsorption; Hemadsorption; extracorporeal removal
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Sepsis; Shock, Septic; Shock; Cytokine Release Syndrome
• Other Study ID Numbers: Cytosorb

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No