Cytokine Adsorption in Severe, Refractory Septic Shock

Study Overview
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Brief Summary
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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
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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.

Official Title
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Cytokine Adsorption in Severe, Refractory Septic Shock

Conditions
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Septic Shock, Cytokine Storm

Intervention / Treatment
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* Device: Cytokine Adsorption
* Other: Standard of Care


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Prospective interventional study with comparative matched septic shock cohort
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cytokine Adsorption Arm<br>Intervention with CytoSorb | Device: Cytokine Adsorption<br>* 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.<br>* Other names: CytoSorb;|
| Other: Historical Comparison<br>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<br>* Standard intensive care of patients suffering septic shock<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hemadsorption, Septic Shock, Cytokine Adsorption, extracorporeal removal