Safety aspects and effects of CytoSorb on the immune system · SEPSIS Other Therapies Convective Therapies Perfusion/ Adsorption Hybrid Therapies RAD SCD CytoSorb CPFA Conventional

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


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


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


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)


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)


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

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


Dep. of Intensive Care MedicineEmail: [email protected]

Safety aspects and effects of CytoSorb on the immune system · SEPSIS Other Therapies Convective Therapies Perfusion/ Adsorption Hybrid Therapies RAD SCD CytoSorb CPFA Conventional

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