Cytokine Adsorption in Severe, Refractory Septic Shock

Septic Shock Clinical Trial

Official title:

Cytokine Adsorption in Severe, Refractory Septic Shock

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04910893
• Other study ID #: Cytosorb
• Status: Completed
• Phase: N/A
• Start date: November 27, 2014
• Est. completion date: December 31, 2018

Study information

• Verified date: June 2021
• Source: University of Zurich
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 48
• Est. completion date: December 31, 2018
• Est. primary completion date: August 24, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Cytokine Storm
• Septic Shock
• Shock
• Shock, Septic

Intervention

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:
• Standard of Care
Standard intensive care of patients suffering septic shock

Locations

Country	Name	City	State
n/a

Sponsors (2)

Lead Sponsor	Collaborator
University of Zurich	CytoSorbents Europe GmbH

References & Publications (8)

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).

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. — View 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. — View 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. — View 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. — View Citation

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. — View Citation

Taniguchi T. Cytokine adsorbing columns. Contrib Nephrol. 2010;166:134-141. doi: 10.1159/000314863. Epub 2010 May 7. — View 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. Review. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	Cumulative intensive care mortality at 30 days	Intensive care mortality assessment at day 30 between groups	30 days post fulfillment of inclusion criteria
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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