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Treatment of Sepsisby Extracorporeal Blood Purification Systems (EBPS)

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0

50.000

100.000

150.000

200.000

250.000

Dea

ths/

Year

Severe SepsisIncidence and Mortality Compared with Other Major Diseases

††National Center for Health Statistics, 2001. National Center for Health Statistics, 2001. §§American Cancer Society, 2001. *American Heart Association. 2000.American Cancer Society, 2001. *American Heart Association. 2000. ‡ ‡Angus DC et al. Angus DC et al. Crit Care Med.Crit Care Med. 2001 . 2001 .

0

50

100

150

200

250

300

AIDS*AIDS* ColonColon BreastBreastCancerCancer§§

CHFCHF†† Severe Severe SepsisSepsis‡‡

Cas

es/1

00,0

00C

ases

/100

,000

Incidence of Severe SepsisIncidence of Severe Sepsis Mortality of Severe SepsisMortality of Severe Sepsis

AIDS*AIDS* SevereSevereSepsisSepsis‡‡

AMIAMI††Breast Breast CancerCancer§§

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Sepsis Continuum

1.1. Bone et al. Chest 1992; 101: 1644. *American College of Chest Physicians **Society of Critical Care Medicine Bone et al. Chest 1992; 101: 1644. *American College of Chest Physicians **Society of Critical Care Medicine22. Brun-Buisson C. Intensive Care Med 2000; 26: S64. . Brun-Buisson C. Intensive Care Med 2000; 26: S64.

Infection/Infection/TraumaTrauma

Systemic Inflammatory Response SyndromeSystemic Inflammatory Response Syndrome11: : defined by fulfills two of the following criteria:defined by fulfills two of the following criteria: Temperature > 38°C or < 36°CTemperature > 38°C or < 36°C Heart rate ≥ 90 bpm Heart rate ≥ 90 bpm Respiratory rate ≥ 20/min or Respiratory rate ≥ 20/min or pCO pCO22 < 32 mmHg < 32 mmHg Leucocytes > 12.000/mmLeucocytes > 12.000/mm33 or or

≤ 4000/mm ≤ 4000/mm33 or or > 10 % immature forms > 10 % immature forms

SIRSSIRS SepsisSepsis severe Sepsissevere Sepsis

SIRS+ suspected or evident infection

Shock

Sepsis with ≥ 1 organ dysfunctionSepsis with ≥ 1 organ dysfunction CardiovascularCardiovascular (volume refractory hypotension)(volume refractory hypotension) RenalRenal RespiratoryRespiratory HepaticHepatic HaematologicHaematologic CNSCNS Metabolic acidosis without Metabolic acidosis without

identifiable reason identifiable reason

28 day letality28 day letality22 20 %20 % 40 %40 % up toup to 80 % 80 %

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Endotoxin

Endotoxemia is associated with sepsis

Sources of Endotoxin are:

Gram negative organisms, Impaired permeability of the gut due to infection with gram positive, fungal, viral organisms or to non-infective causes

(inner)(inner)

Core glycolipidCore glycolipid

O-specific O-specific oligosaccharide oligosaccharide subunitsubunit

Lipid-ALipid-A

(outer)(outer)

O-specific polysaccharide chainO-specific polysaccharide chain

nn

Gram-negative bacterial endotoxin (lipopolysaccharide, {LPS})Gram-negative bacterial endotoxin (lipopolysaccharide, {LPS})

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Intervention strategy for Sepsis Therapy

nn

EndotoxinEndotoxinTranslocation Translocation from the gutfrom the gut

Infection:Infection:Release of toxinsRelease of toxins

Modified by Cohen J, Nature 2002

Supportive Therapy Supportive Therapy of organ failuresof organ failures

Supportive Therapy Supportive Therapy of organ failuresof organ failures

Removal of Endotoxin Removal of Endotoxin and Cytokines by and Cytokines by Extracorporeal Blood Extracorporeal Blood Purification Purification SystemcircuitSystemcircuit

Elimination of septic focusElimination of septic focusAnti-infectious therapyAnti-infectious therapy

Elimination of septic focusElimination of septic focusAnti-infectious therapyAnti-infectious therapy

Hypoxemia, Burning,Hypoxemia, Burning,TraumaTrauma

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Pro-inflammatoric cytokines:TNF, IL-1, IL-6, IL-8, IFN, O-, C3a, C5a, pro-coagulation factors

SHOCK MOF

Anti-inflammatoric counterreaction („immuno-paralysis“):TGF, IL-10

Inactivation of immunity and inflammatory system

Monocytes/Macrophages

Infection, hypoxemia, burning, trauma

SIRS

Inactivation of Monocytes/Macrophages, O-

1.

2.

Sepsis & SIRS

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Conditions for Reduction of Endotoxin and Cytikines by EBPS

• Molecular Weight

• Protein Binding

• Distribution Volume

• Endogenous Clearance

• Water soluble

• Resynthesis

• Rebound

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heparinV

V

PV

PA

Disadvantages complex machinery

expensive

Advantage no arterial access

blood flow sufficient

good elimination of large molecules

exact filtration

UF R

BLD

SAD

heater

high-flu

x

CVVH Continuous veno-venous hemofiltration

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H2O water soluble molecules

F

mmHg

mmHgB

B

high-flu

x

High Volume Haemofitration (HVHF)

S

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0

40

80

120

10 102 103 104 105

urea creatinine Vit. B12 ß2-M albumine

clearance ml/min

MW dalton

HF

Kidney

Cut-off

IL-1 TNFIL-6IL-8

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0

20

40

80

60

2 310 4

0

500

1000

1500

IL-6

TNF

IL-1

IL-8

TNF (U/ml) IL-1 (pg/ml) IL-6 (U/ml) IL-8 (pg/ml)

t/h

Plasma concentrations in sepsis patients durin high-volume HF (Hoffmann, 1997)

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Further Clinical Studies

Heering et al. (1997)

Oudemans et al. (1999)

Ronco et al. (2000)

Bellomo et al. (2001):

Convective and adsorbtive Technics like HVHF show better, but still small extration of middle molecules…. „Such adsorption can temporarily reduce the concentration of some cytokines and complement anaphylatoxins and could have biological and clinical significans“

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Advantages

rel. simple technic wide spectrum of indication rel. low costs

Heparin

V

V

PV

PA

Pl. S

BLD

SAD

Heater

Plasm

a Filter

PPL

SAC

Bilance

PEX Therapeutic Plasma Exchange

Disadvantages

non-selective

substitution complications no chronic application

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35 patients with „Immuno-paralysis“ (control-group 41 patients)

Deactivated monocytes (HLA-DR-Antigen-Expression)

No. of PEX 3 on 3 following days

Treated Plasmavolume 3 litres

Substitution FFP

Result: Survival Rate 48% vs. 20%

Conclusion: the recovery of the immuno-competence is an important condition of good prognosis in sepsis

(Reinke, 1997)

PEX in Sepsis Patients

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Further Clinical Studies

Berlot et al. (1997)

Exchange of 1 plasma volume.

Improvement of cardiac index and other cardiovascular parameters.

Reeves et al. (1999)

Continuous exchange of 5 volumes of plasma by FFP, colloids and cristalloids within 30-36 h.

Reduction of CRP, C3, haptoglobin, 1-antitrypsin, but less of IL-6, thromboxane B2 and GSF.

Conclusions are not clear!

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Advantages

selective

chronic application

Heparin

V

V

PV

PA

BLD

SAD

Heater

Plasm

a Filter

PPL

SAC

PAP Plasma Adsorption

Disadvantages

expensive

complex machinery

Plasm

a AdsorberParticle Filter

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Plasma Adsorption/Perfusion (PAP)

Shoji et al. (1998)

Adsortion of Endotoxin by Polymyxin B cartridge.

Ronco et al. (2000)

Coupled Plasma Filtration Adsorption (CPFA) by using synthetic resin cartridge and haemodialyzer.

Results

Increased cardiovascular resistance, reduction of vasopressor drugs, improved oxygenesation index, cardiac index and left ventricular stroke work index.

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Selective Adsorption system For Endotoxin (S.A.F.E.)- Extracorporeal Plasma Perfusion System -

Blood pumpBlood pump60 … 120 ml/min60 … 120 ml/min

Plasma filter Plasma filter HEMOSELECT 0,3m² HEMOSELECT 0,3m²

air detection andair detection andprotection systemprotection system

blood leak blood leak controllercontroller Plasma pumpPlasma pump

15 … 30 ml/min15 … 30 ml/min

Adsorption columnAdsorption columnS.A.F.E.-ColumnS.A.F.E.-Column

Material: Membranous polyamide matrix with functional groups made from di ethyl amino ethyl Binding capacity: > 3.000 ng LPS

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S.A.F.E. AdsorberS.A.F.E. Adsorber Principe of AdsorptionPrincipe of Adsorption

pore

membrane

AAdsorptive dsorptive PPorous orous SSystemsystems

Tentacle:Tentacle:DEAE-groupDEAE-group

LPS

PottingPotting

HousingHousing

target target substance substance

PlasmaPlasmaDead-End Design with Hollow FibersDead-End Design with Hollow Fibers

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Clinical Study:Elimination and Safety Profile of the Selective Adsorption system for Endotoxin (S.A.F.E.) in healthy volunteers

Study design Open prospective study; one study site 6 male healthy volunteers

Part A: In-vitro-adsorption profile from fresh donated heparine anticoagulated human plasma

Part B: Influence of the S.A.F.E. on vital signs and laboratory parameters in healthy volunteers

Aim of the studyEssential performance of the adsorption column (in vitro)Safety of the Medical Device System “S.A.F.E.” under regular clinical conditions of two procedures for two days running

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Diapact CRRT

HIGHRESOLUTION

SCREEN

HEATER

PUMP PANEL

FILTERHOLDER

WEIGHINGSYSTEM

IV POLE

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Diapact CRRT - a versatile system

No other equipment currently on the market offers the same range of therapy modes as the Diapact CRRT:

Plasma therapies: PEX, PAP

Intermittent therapies: HF, HD, HFD

Continuous therapies: SCUF, CVVH, CVVHD, CVVHFD

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Conclusions

• A final conclusion on the efficacy of EBPS in treating sepsis is not possible due to the heterogenous sepsis petient.

• The EBPS shows an effective reduction of endotoxin and several cytokines.

• The EBPS seams to be well tollerated, but side effects have to be considered.

• The treatment by EBPS has shown a clinical improvement of cardio-circulatory parameters.

• Further clinical studies are needed, because a sure conclusion about any positive influence on mortality rate is actually not possible yet.