Cytokine Adsorption in Severe, Refractory Septic Shock
Primary Purpose
Septic Shock, Cytokine Storm
Status
Completed
Phase
Not Applicable
Locations
Study Type
Interventional
Intervention
Cytokine Adsorption
Standard of Care
Sponsored by
About this trial
This is an interventional treatment trial for Septic Shock focused on measuring Septic Shock, Cytokine Adsorption, Hemadsorption, extracorporeal removal
Eligibility Criteria
Inclusion Criteria:
Patients diagnosed septic shock in the 24 hours ensuing diagnosis:
(I) severe, refractory septic shock defined as:
- an acute SOFA score increase ≥2 points consequent to a presumed or proven infection
- volume resuscitation of at least 30ml/kg in the last 24 hours
- a Vasopressor Dependency Index11 (VPI) above or equal to 3
- 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:
- Contraindication on ethical grounds
- child bearing or breastfeeding women
- terminal patients
- human immunodeficiency virus with a CD4 cell count <0.2 106/l
- allergy to Polystyrene/ Divinylbenzene, Polycarbonate, Polypropylene, Silicon or Polyester
- need for extra-corporeal membrane oxygenation
- no given consent.
Sites / Locations
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Other
Arm Label
Cytokine Adsorption Arm
Historical Comparison
Arm Description
Intervention with CytoSorb
Patients extracted from a septic shock population treated at the same institution between 2010 and 2018 and matched to the intervention group.
Outcomes
Primary Outcome Measures
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
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
Cumulative intensive care mortality at 30 days
Intensive care mortality assessment at day 30 between groups
Secondary Outcome Measures
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
Change in Procalcitonin levels over time
Change in Procalcitonin levels, stratified by groups, over the initial 72 hours ensuing fulfillment of inclusion criteria
Change in SOFA Score over time
Change in SOFA Score, stratified by groups, over the initial 72 hours ensuing fulfillment of inclusion criteria
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
Change in cardiac index over time
Change in cardiac index, stratified by groups, over the initial 72 hours ensuing fulfillment of inclusion criteria
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
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
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
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
Change in Bilirubin levels over time
Change in Bilirubin levels, stratified by groups, over the initial 72 hours ensuing fulfillment of inclusion criteria
Full Information
NCT ID
NCT04910893
First Posted
May 27, 2021
Last Updated
June 7, 2021
Sponsor
University of Zurich
Collaborators
CytoSorbents Europe GmbH
1. Study Identification
Unique Protocol Identification Number
NCT04910893
Brief Title
Cytokine Adsorption in Severe, Refractory Septic Shock
Official Title
Cytokine Adsorption in Severe, Refractory Septic Shock
Study Type
Interventional
2. Study Status
Record Verification Date
June 2021
Overall Recruitment Status
Completed
Study Start Date
November 27, 2014 (Actual)
Primary Completion Date
August 24, 2018 (Actual)
Study Completion Date
December 31, 2018 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of Zurich
Collaborators
CytoSorbents Europe GmbH
4. Oversight
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
Data Monitoring Committee
No
5. Study Description
Brief Summary
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.
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Septic Shock, Cytokine Storm
Keywords
Septic Shock, Cytokine Adsorption, Hemadsorption, extracorporeal removal
7. Study Design
Primary Purpose
Treatment
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Model Description
Prospective interventional study with comparative matched septic shock cohort
Masking
ParticipantOutcomes Assessor
Allocation
Non-Randomized
Enrollment
48 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Cytokine Adsorption Arm
Arm Type
Experimental
Arm Description
Intervention with CytoSorb
Arm Title
Historical Comparison
Arm Type
Other
Arm Description
Patients extracted from a septic shock population treated at the same institution between 2010 and 2018 and matched to the intervention group.
Intervention Type
Device
Intervention Name(s)
Cytokine Adsorption
Other Intervention Name(s)
CytoSorb
Intervention Description
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.
Intervention Type
Other
Intervention Name(s)
Standard of Care
Intervention Description
Standard intensive care of patients suffering septic shock
Primary Outcome Measure Information:
Title
Change in circulating Interleukin-6 levels over time
Description
Change in circulating Interleukin-6 levels, stratified by groups, over the initial 72 hours ensuing fulfillment of inclusion criteria
Time Frame
Mixed Model Assessment at timepoints 0, 24, 48, 72 hours
Title
Change in Vasopressor requirements over time
Description
Change in the Vasopressor Dependency Index, stratified by groups, over the initial 72 hours ensuing fulfillment of inclusion criteria
Time Frame
Mixed Model Assessment at timepoints 0, 2, 4, 8, 12 , 24, 48, 72 hours
Title
Cumulative intensive care mortality at 30 days
Description
Intensive care mortality assessment at day 30 between groups
Time Frame
30 days post fulfillment of inclusion criteria
Secondary Outcome Measure Information:
Title
Change in C-reactive protein levels over time
Description
Change in C-reactive protein levels, stratified by groups, over the initial 72 hours ensuing fulfillment of inclusion criteria
Time Frame
Mixed Model Assessment at timepoints 0, 24, 48, 72 hours
Title
Change in Procalcitonin levels over time
Description
Change in Procalcitonin levels, stratified by groups, over the initial 72 hours ensuing fulfillment of inclusion criteria
Time Frame
Mixed Model Assessment at timepoints 0, 24, 48, 72 hours
Title
Change in SOFA Score over time
Description
Change in SOFA Score, stratified by groups, over the initial 72 hours ensuing fulfillment of inclusion criteria
Time Frame
Mixed Model Assessment at timepoints 0, 24, 48, 72 hours
Title
Change in arterial lactate levels over time
Description
Change in arterial lactate levels, stratified by groups, over the initial 72 hours ensuing fulfillment of inclusion criteria
Time Frame
Mixed Model Assessment at timepoints 0, 2, 4, 8, 12 , 24, 48, 72 hours
Title
Change in cardiac index over time
Description
Change in cardiac index, stratified by groups, over the initial 72 hours ensuing fulfillment of inclusion criteria
Time Frame
Mixed Model Assessment at timepoints 0, 2, 4, 8, 12 , 24, 48, 72 hours
Title
Change in Extra Vascular Lung Water Index over time
Description
Change in Extra Vascular Lung Water Index, stratified by groups, over the initial 72 hours ensuing fulfillment of inclusion criteria
Time Frame
Mixed Model Assessment at timepoints 0, 24, 48, 72 hours
Title
Change in daily Infused Volume over time
Description
Change in daily Infused Volume, stratified by groups, over the initial 72 hours ensuing fulfillment of inclusion criteria
Time Frame
Mixed Model Assessment at timepoints 0, 24, 48, 72 hours
Title
Change in PaO2/ FiO2 Ratio over time
Description
Change in PaO2/ FiO2 Ratio, stratified by groups, over the initial 72 hours ensuing fulfillment of inclusion criteria
Time Frame
Mixed Model Assessment at timepoints 0, 2, 4, 8, 12 , 24, 48, 72 hours
Title
Change in Serum Albumin levels over time
Description
Change in Serum Albumin levels, stratified by groups, over the initial 72 hours ensuing fulfillment of inclusion criteria
Time Frame
Mixed Model Assessment at timepoints 0, 24, 48, 72 hours
Title
Change in Bilirubin levels over time
Description
Change in Bilirubin levels, stratified by groups, over the initial 72 hours ensuing fulfillment of inclusion criteria
Time Frame
Mixed Model Assessment at timepoints 0, 24, 48, 72 hours
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Patients diagnosed septic shock in the 24 hours ensuing diagnosis:
(I) severe, refractory septic shock defined as:
an acute SOFA score increase ≥2 points consequent to a presumed or proven infection
volume resuscitation of at least 30ml/kg in the last 24 hours
a Vasopressor Dependency Index11 (VPI) above or equal to 3
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:
Contraindication on ethical grounds
child bearing or breastfeeding women
terminal patients
human immunodeficiency virus with a CD4 cell count <0.2 106/l
allergy to Polystyrene/ Divinylbenzene, Polycarbonate, Polypropylene, Silicon or Polyester
need for extra-corporeal membrane oxygenation
no given consent.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Marco Maggiorini, MD
Organizational Affiliation
Medizinische Intensivstation D-HOER 27, UniversitatsSpital Zürich
Official's Role
Principal Investigator
12. IPD Sharing Statement
Plan to Share IPD
No
Citations:
PubMed Identifier
18606328
Citation
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.
Results Reference
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PubMed Identifier
20473001
Citation
Taniguchi T. Cytokine adsorbing columns. Contrib Nephrol. 2010;166:134-141. doi: 10.1159/000314863. Epub 2010 May 7.
Results Reference
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PubMed Identifier
28979423
Citation
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.
Results Reference
background
PubMed Identifier
21371356
Citation
Rimmele T, Kellum JA. Clinical review: blood purification for sepsis. Crit Care. 2011;15(1):205. doi: 10.1186/cc9411. Epub 2011 Feb 16.
Results Reference
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PubMed Identifier
12169849
Citation
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.
Results Reference
background
PubMed Identifier
15090965
Citation
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.
Results Reference
background
PubMed Identifier
18434884
Citation
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.
Results Reference
background
Citation
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).
Results Reference
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Cytokine Adsorption in Severe, Refractory Septic Shock
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