20.06.05 Dr. M. Susca 1/23
Treatment of Sepsisby Extracorporeal Blood Purification Systems (EBPS)
20.06.05 Dr. M. Susca 2/23
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§§
20.06.05 Dr. M. Susca 3/23
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 %
20.06.05 Dr. M. Susca 4/23
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})
20.06.05 Dr. M. Susca 5/23
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
20.06.05 Dr. M. Susca 6/23
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
20.06.05 Dr. M. Susca 7/23
Conditions for Reduction of Endotoxin and Cytikines by EBPS
• Molecular Weight
• Protein Binding
• Distribution Volume
• Endogenous Clearance
• Water soluble
• Resynthesis
• Rebound
20.06.05 Dr. M. Susca 8/23
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
20.06.05 Dr. M. Susca 9/23
H2O water soluble molecules
F
mmHg
mmHgB
B
high-flu
x
High Volume Haemofitration (HVHF)
S
20.06.05 Dr. M. Susca 10/23
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
20.06.05 Dr. M. Susca 11/23
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)
20.06.05 Dr. M. Susca 12/23
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“
20.06.05 Dr. M. Susca 13/23
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
20.06.05 Dr. M. Susca 14/23
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
20.06.05 Dr. M. Susca 15/23
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!
20.06.05 Dr. M. Susca 16/23
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
20.06.05 Dr. M. Susca 17/23
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.
20.06.05 Dr. M. Susca 18/23
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
20.06.05 Dr. M. Susca
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
20.06.05 Dr. M. Susca 20/23
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
20.06.05 Dr. M. Susca 21/23
Diapact CRRT
HIGHRESOLUTION
SCREEN
HEATER
PUMP PANEL
FILTERHOLDER
WEIGHINGSYSTEM
IV POLE
20.06.05 Dr. M. Susca 22/23
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
20.06.05 Dr. M. Susca 23/23
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.