UniversitätsklinikumHamburg-Eppendorf
Safety aspects and effects of
CytoSorb on the immune system
A. Nierhaus
Dr. Axel Nierhaus MD, EDICSenior Consultant Intensivist
Vice Chair
Dept. of Critical Care Medicine
International CytoSorb Users‘ Meeting
Brussels
March 20, 2017
COI – Statement
Research funding, travel reimbursement and lecture honoraria from
Fresenius Medical Care
CytoSorbents Europe
Biotest
Thermo Fisher Scientific
Novalung
SEPSISOther
Therapies
Convective
Therapies
Perfusion/
Adsorption
Hybrid
Therapies
RAD
SCD
CytoSorb
CPFA
Conventional
CRRT
High
VolumeHigh Cut-Off
PMX
CPFA: coupled plasma filtration adsorption
RAD: renal tubule cell assist device
SCD: selective cytapheretic device
Potential Extracorporeal Methods
for Severe Sepsis and Septic Shock
Plasma
Exchange
Extracorporeal
Therapies in Sepsis:
e.g.
CVVHD (Citrate-Anticoag.)
+CytoSorb
TNFα 52000
IL-6 28000
IL-1ß 18000
0 kDa10 20 30 40 50 60 70
TNF-α Trimer
IFN-γ dimer
IL-6sFas Ligand
MCP-1(Glycosylated)
Albumin
IL-8MIP-1α
IL-18
sTNFR
G-CSFIL-4
Free Hemoglobin
Myoglobin
Bilirubin
Dialysis
HMGB1TGF-β
MCP-1IL-13
IL-10
IL-1aTNF-α MonomerIFN-γ Monomer
IL-1Ra
7
IL-6 and IL-10 in patients with pneumonia
Elevated levels of IL-6 AND IL-10 increase the risk of death
Kellum JA et al. Arch Intern Med. 2007 Aug 13-27;167(15):1655-63
Survival analysis Risk of death
TOXIC
Organ failure
Time
Recovery
Excessive cytokinemia
UniversitätsklinikumHamburg-Eppendorf
Sigrun Friesecke MD
Stephanie S. Stecher MD
Axel Nierhaus MD, EDIC
CytoSorb in refractory septic shock
Study HypothesisCan cytokine absorption therapy affect hemodynamics in
established refractory septic shock? German Clinical Trials Register D R K S N o . 0 0 0 0 5 1 4 9
• Septic shock (Il-6 > 1000 pg/ml)
• Guideline-oriented treatment for 4-6 h completed
• persisting hemodynamic shock with tendency to further
deterioration:
- Further increase of lactate concentration OR
- Further increase of noradrenaline requirements (> 0,3 µg/kg/min)
Patients (n=22)
Friesecke S et al. (2017) under review
Study protocol: Intervention, Endpoints
▪ Hämadsorption
▪ Anticoagulation heparin or citrate
▪ Antibiotic dose x1.5
1. Change of noradrenaline
requirements after 6 and 12 h
2. Lactate clearance / SOFA-
Score / shock resolution
Endpoints
Friesecke S et al. (2017) under review
Results | Study cohort
No. included 22
Age (mean±SD) 59.6±19.2
m : f 18:4
Focus of
infection
Pneumonia
Abdomen
UTI
other
non-infectious SIRS
11
7
1
2
2
Blood culture positive (n) 12
SOFA-Score 15±3
IL-6 (pg/ml; mean±SD) 87039±126869
PCT (µg/l; mean±SD) 89±182
Friesecke S et al. (2017) under review
1
10
100
1.000
10.000
100.000
d0 d1 d2 d3 d4 d5 d6 d7
Time (days)
Il-6
(p
g/m
l)Il-6 Plasma Concentrations (N=22)
Friesecke S et al. (2017) under review
0
5
10
15
20
Time (h)
Lac
tate
(m
mo
l/l)
-80
-60
-40
-20
0
20
40
hour -6 - 0 hour 0 - 6 hour 6 - 12 hour 12 - 18 hour 18 - 24
Lact
ate
cle
aran
ce(%
)
Lactate clearance
Arterial Lactate Concentrations (N=22)
Friesecke S et al. (2017) under review
Results | Shock resolution and survival
NOR ≤ 0,005 µg/kg/min
Lactate < 2,2 mmol/l
refractory
shock
(n=22)
no shock reversal,
early death (n=7, 32%)
Shock reversal
(n=15, 68%)
Adsorber
therapy
Late non-survivors
(n=6, 27%)
Survivors
(n=9, 41%)
Maximum
SOFA ScoreMortality
0 to 6 < 10%
7 to 9 15 - 20%
10 to 12 40 - 50%
13 to 14 50 - 60%
15 > 80%
15 to 24 > 90%Friesecke S et al. (2017) under review
Open Questions
? Reproducibility
? Frequency of adsorber exchange
? Treatment duration
? Drug absorption
? Control group
Safety Considerations
Direct
• Effectiveness
• Biocompatibility
Blood trauma?
Pro-coagulatory?
Pro-inflammatory?
• Simplicity/Feasibility
Indirect
• Drug adsorption
• Endocrine effects
• Leukosequestration
• Thrombopenia
• Immunodepression
→ Risk/Benefit ratio?
Reduction of cytokine levels
Schädler D et al. Critical Care 2013, 17(Suppl 2)
Control
CytoSorb
Safety
• All 100 patients were included in the safety-analysis
• No adverse and device-related events in > 300 treatments
• No significant changes of electrolyte levels
• No deterioration of organ dysfunctions
• No problems with anticoagulation
• Minimal loss of albumin (
Monocyte function and outcome
Lekkou A et al. 2004
Survival
Death
1 2 3 4 5 6 7 8 9 10 11 12 13 14
Time (d)
250
200
150
100
50
300
350
400Nonsurvivors (N=15)
Survivors (N=25)
Mean
Flu
ore
scence
Inte
nsity
* **
* **
450
Spontaneous recovery of HLA-DR is associated with survival
Nierhaus A et al., Crit Care Med 2005 (Abstr.)
Cheron A et al. Crit Care 2010
* *
Lack of recovery in monocyte human leukocyte antigen-DR
expression is independently associated with the development of
sepsis after major trauma (prospect. observ. study, N=105)
no sepsis
sepsis
Ex-vivo LPS-stimulation
+ 500 pg endotoxin
+ PBS
250 µl whole blood
4 h at 37°CTNFα
in supernatant
0
25
50
75
100
group 196 %
group 265 %
%
p=0.007
TNF- release
< 200 pg/ml > 48 h
N=25
Low TNFex-vivo-production and secondary infectionsN=45, Sepsis & Severe Sepsis, Mortality 36%, median SAPS II 39, no difference
between groups 1 & 2, no difference in antibiotic exposure
TNF- release
>200 pg/ml or < 200 < 48 h
N=20
Nierhaus A et al. (2014), Abstract
Patients
infe
cte
don IC
U
Group 1
N=25
96%
Group 2
N=20
53%
0
5000
10000
15000
20000
25000
1 2 3 4
IL-6 (pg/ml)
0
2
4
6
8
10
12
14
1 2 3 4
Noradrenaline Lactate
Noradrenaline (mcg/kg/min)
Lactate (mmol/l)
Cytosorb Haemoperfusion
Postop. SIRS, ShockPat. J.N., ♂, 54 J., abdomino-thoracic esophagectomy
3
2
1
0
6
4
2
0
0
100
200
300
400
500
600
700
800
900
1000
1 2 3 4 5
LPS-induced TNFα ex-vivo Production
TN
Fα
(pg/
(ml)
0
1
2
3
4
1 2 3 4 5
Noradrenaline (µg/kg/min)
0
10000
20000
30000
40000
50000
60000
70000
1 2 3 4 5
Il-6 (pg/ml)
Cytosorb Haemoperfusion
Meningococcal MeningitisPat. E.K., ♀, 24 J., microbiolog. proven meningococcemia (BSI & CSF)
0
100
200
300
400
500
600
700
800
900
1000
1 2 3 4 5
LPS-induced TNFα ex-vivo Production
TN
Fα
(pg/
(ml)
Hämadsorptionsbehandlung nach ECCN=16, kardiog./distributiver Schock, ANV
Träger K et al. 2016
Träger K et al. 2016
David S et al. Journal of Intensive Care (2017) 5:12
David S et al. Journal of Intensive Care (2017) 5:12
David S et al. Journal of Intensive Care (2017) 5:12
New sepsis trials should consider the substantial heterogeneity in the patients and type of infections usually included in sepsis trials as well as the phase of the immune response, in which the patient is at time of inclusion
Wiersinga WJ et al. Virulence 4(8) 2013
Safety Considerations
Direct
• Effectiveness
• Biocompatibility
Blood trauma
Pro-coagulatory
Pro-inflammatory
• Simplicity/Feasibility
Indirect
• Drug adsorption
• Endocrine effects
• Leukosequestration
• Thrombopenia
• Immunodepression
Potential indications
• sept. shock
• post-operative excessive inflammatory response
• Intra-operative (e.g. HLM procedures > 2 hours)
• ARDSPancreatitis
Rhabdomyolysis
Burns and inhalation injury
Organ transplantation /
Brain death (donors), ABO-Incompatibilities
Thank you
UniversitätsklinikumHamburg-Eppendorf
Dep. of Intensive Care MedicineEmail: [email protected]