Observational Trial on Cytokine Adsorption in Sepsis
Observational Trial on Cytokine Adsorption in Sepsis
To determine the specific population of critically ill septic patients who benefit most from
 cytokine adsorption therapy with the HA-380 cartridge. Benefit of the treatment will be
 assessed on the basis of:

 -  The scope of the effect of cytokine adsorption therapy in this specific population of
 critically ill patients expressed by cytokine variability within the patients

 -  The scope of cytokine changes in passing the adsorption cartridge my measuring cytokine
 levels in the patient's blood directly before passing through the cartridge and directly
 after having passed through the cartridge.

 -  The scope of changes in organ dysfunction expressed by SOFA scores that are repeatedly
 calculated during the treatment with cytokine adsorption and then daily until day 7 of
 the ICU treatment.

 -  The scope of changes on cellular function on immune cells in serum samples taken before
 and after cytokine adsorption therapy.

 -  The scope of removal of anti-infective drugs from the blood in passing through the
 cytokine adsorption cartridge by measuring antibiotic drug levels in the patients blood
 during the cytokine adsorption therapy

 -  30 day and 90 day mortality and location status in survivors
1. Medical Problem Sepsis, a syndrome of physiologic, pathologic, and biochemical
 abnormalities induced by infection. It is a major public health concern, accounting for
 more than $20 billion (5.2%) of total US hospital costs in 2011 (1). Sepsis has shown an
 increase in incidence most likely due to a combination of aging patient populations with
 more comorbidities and greater recognition (2,3). Sepsis is by conservative estimates a
 leading cause of mortality and morbidity in critical illness with long term sequelae for
 survivors (4,5).

 Underlying to sepsis is a multifaceted host response to an infecting pathogen that may
 be significantly amplified by endogenous factors and is defined by a nonhomeostatic,
 dysregulated host response to the infection with a potential lethality that is
 considerably in excess of that straightforward infection. In the early phases, an
 overshoot of pro-inflammatory mediators is often observed, caused by pathogen-associated
 molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). High levels
 of pro- and anti-inflammatory cytokines are both associated with increased mortality
 (6). Blocking of overproduction of these cytokines using monoclonal anti- bodies
 targeting specific cytokines such as tumor necrosis factor-α (anti-TNF-α) have not
 demonstrated mortality benefits in larger trials (7).

 Therefore, an approach to decrease cytokine overproduction by using extracorporeal blood
 purification has previously been examined. Initial trials using Polymyxin B showed
 favorable results for markers of critical care treatment with a reduction of vasopressor
 dosage and higher ratios oxygen partial pressure to inspired oxygen (8). A larger
 randomized trial by Payenne however did not show any improvement of organ dysfunction or
 reduction in mortality by using Polymycin B hemoperfusion (9).

 A recent trial on the effect of the CytoSorb adsorption device using IL-6 levels as
 marker of efficacy did also not find an effect of mortality, improved organ dysfunction
 or in fact a reduction of circulating IL-6 levels. However, in this trial the baseline
 cytokine levels were only moderately increased to begin with suggesting use of a device
 within a suboptimal patient population (10).

 As no more approved specific therapies to treat sepsis, exist following the withdrawal
 of recombinant activated protein C (Xigris; Eli Lilly, USA) from the market in 2011
 following the results of the PROWESS-SHOCK trial and the pathophysiologic basis for
 mechanisms in sepsis due to an excess cytokine release are sound, the extracorporeal
 removal of cytokines remains a promising therapeutic target given the correct patient
 population (11).

 2. Principal research question and novel aspects Within the trials addressing removal of
 excess cytokines, the selection of patients and timing of the intervention has been
 difficult, and results have not been conclusive. Data on the patient population which
 might benefit most in regard to the aspects of cytokine levels removed and organ failure
 or progressive organ dysfunction averted are sparse or non-existent. Even the largest
 randomised trial so far was active for 3 years in recruiting 100 patients out of 580
 patients screened (10). This trial failed to show a positive effect on the primary
 endpoint of IL-6 removal as well as on secondary endpoints of morbidity or 30 day
 mortality. However, in this small trial there was a very low median cytokine level
 measured at baseline and randomisation which might be associated with the consecutive
 failure to detect a reduction in circulating cytokines. The question remains, whether
 this trial identified a patient population that was going to benefit from such a therapy
 to begin with. Post-hoc analyses of another trial, the Euphrates trial (12) showed that
 there might be positive signal for reduced mortality in patients with an endotoxin
 activity that was in a mid-range and not at the highest end of the spectrum.

 We therefore aim to undertake an observational trial to examine the effect of treating
 sepsis according to the surviving sepsis campaign guidelines and using extracorporeal
 cytokine removal looking at circulating cytokine levels and development of new or
 worsening organ dysfunction in patients with sepsis or septic shock who show highly
 increased IL-6 levels.

 3. HA 330 and HA 380 Hemoperfusion Cartridge The HA type resin cartridge (Jafron
 Industries, China) is an extracorporeal hemoperfusion device that uses neutral
 microporous resin, and it has been proven to specifically absorb different media- tors
 such as bilirubin and cytokines (13 ).

 The HA380 HA 330 and HA 380 resin cartridges haves the ability to absorb various medium-sized
 factors, including most inflammatory cytokines (IL-1, IL-6, IL-8, IL-10 and TNF-a) and haves
 therefore lately been used in the treatment of patients with sepsis in China with several
 case reports demonstrating promising results on the clinical course of treated patients
 (14,15). Furthermore, there pooled there is emerging data that this therapeutic concept is
 efficienct and helpful in adequately selected patient populations (16,17).

 The HA 380 cartridge is the CE-labeled updated version of the HA-330 cartridge which features
 a larger surface area of the resin beads increasing the overall capacity and thus potential
 efficacy of the device.

 The HA 380 Hemoperfusion Cartridge works using Van der Waals interaction between resin
 molecular groups and adsorbed substances. Unlike the CytoSorb device, these are incorporated
 into the resin molecule by a molecular sieve effect of the 3D network structure and the
 lipophilic hydrophobicity of the molecular group. Therefore, the pass-through effect in
 removing cytokines is expected to be larger and more sustained, as previously adsorbed
 cytokines will not again be released by continued blood flow or movement of the device. The
 range of adsorption is shown in figure 1. The device described has a CE label and is approved
 for treatment in a variety of clinically situations including but not limited to
 intra-operative use in cardiac surgery, intoxication, liver failure and sepsis. Compared to
 other available devices which could be used in the same settings this cartridge offers
 superior flow characteristics, less flow resistance and a higher capacity of cytokine
 removal. The effect of combining a standard treatment course of sepsis according to the
 Surviving Sepsis Campaign guidelines with extracorporeal cytokine removal however is not well
 examined overall.

 In our center we have therefore undertaken a retrospective pilot observational trial of 15
 patients in which the using the HA 380 330 device was used as a rescue therapy in therapy in
 15 patients with septic shock and multi-organ failure refractory to conventional treatment.
 In this trial of extremely ill patients we found a significant difference between hospital
 survivors and non-survivors in circulating IL-6, IL-10 and TNF-alpha levels after 8 hours of
 treatment with the HLA 3380 cartridge. However, the overall variation of cytokine levels at
 baseline and the variation of changes from baseline during therapy were rather large. The
 sample size was too small to infer any causality or undertake multi-variate analysis
Inclusion Criteria:

 1. >18 years of age

 2. diagnosis of sepsis or septic shock with at least 2 organ-dysfunctions defined by SOFA
 score

 3. baseline serum IL-6 > 1000 pg/ml, IL-10 levels >250 pg/ml or TNF-alpha levels > 100
 ng/l. The baseline IL-6 measurement must be on the same calendar day that the cytokine
 adsorption is started, the baseline IL-10 or TNF-alpha can be taken up to 36h before
 because of higher turn-around times for these tests.

 4. need for CRRT or ECMO therapy

 Exclusion Criteria:

 1. Solid organ malignancies with or without treatment

 2. Participation or enrollment in another clinical study within 30 day

 3. Pregnant and lactating females If women of childbearing potential will be enrolled, a
 pregnancy test will be performed by assessing the value of ß-HCG in the routinely
 drawn blood and or urine.

 4. Patient has been committed to an institution by legal or regulatory order

 5. Participation in a parallel interventional clinical trial

 6. The subject received an investigational drug within 30 days prior to inclusion into
 this project