Download - Blood Purification in Sepsis Dr. Peter Skippen, PICU. BC Children’s Hospital, Vancouver. CANADA
Blood Purification Blood Purification
in Sepsisin Sepsis
Dr. Peter Skippen, PICU. Dr. Peter Skippen, PICU.
BC Children’s Hospital,BC Children’s Hospital,
Vancouver. CANADA.Vancouver. CANADA.
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Blood Purification in SIRSBlood Purification in SIRS
OutlineOutline
• Basic concepts of SIRS and therapiesBasic concepts of SIRS and therapies
• Rationale for blood purificationRationale for blood purification
• Types of blood purificationTypes of blood purification
• Evidence for efficacyEvidence for efficacy
• The future?The future?
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Blood Purification in SIRSBlood Purification in SIRS
Remove the “evil humors”Remove the “evil humors”
OROR
Restore the balanceRestore the balance
OROR
BothBoth
OROR
NeitherNeither
What are we doing?What are we doing?
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Blood Purification in SIRSBlood Purification in SIRS
Synopsis of SIRSSynopsis of SIRS
local inflammationlocal inflammation systemic inflammationsystemic inflammation
infecting Organism infecting Organism
cellular responsecellular response humoral responsehumoral response
pro-inflammatory
anti-inflammatory
complement
coagulation
fibrinolysis / anticoagulation
ENDOTHELIUMENDOTHELIUM
phospholipase A2 dependent products
HOSTHOSTimmune Statusimmune Status
genetic mapgenetic map
Stereotypical host responseStereotypical host response
Mediators spills over into circulationMediators spills over into circulation
UnboundUnbound
REMOTE INJURYREMOTE INJURY•ARDSARDS•renal dysfunctionrenal dysfunction•liver dysfunctionliver dysfunction
CLEARANCECLEARANCE•non-specificnon-specific•cpecificcpecific
•cell bonudcell bonud•circulatingcirculating
systemic insultsystemic insult
BoundBound•Nonspecific protein boundNonspecific protein bound•Soluble receptor boundSoluble receptor bound
DeathDeathoror
RecoveryRecovery
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Clinical presentationClinical presentation
SepsisSepsisSIRSSIRS
SEPTIC SHOCKSEPTIC SHOCK
Biologic sequelaeBiologic sequelae
Monocyte activationMonocyte activation
Monocyte deactivationMonocyte deactivation
TNF-TNF-IL-1ßIL-1ßIL-6IL-6IL-8IL-8PAFPAFiNOSiNOSCOX2COX2
IL-1 raIL-1 raIL-10IL-10sTNFr-1/11sTNFr-1/11TGF-TGF-IL-4IL-4
PROINFLAMMATORYPROINFLAMMATORY
PROINFLAMMATORYPROINFLAMMATORY
ANTI-INFLAMMATORYANTI-INFLAMMATORY
ANTI-INFLAMMATORY + CELL ANTI-INFLAMMATORY + CELL HYPORESPONSIVENESS / IMMUNOPARALYSISHYPORESPONSIVENESS / IMMUNOPARALYSIS
TNF-TNF-IL-1ßIL-1ßIL-6IL-6IL-8IL-8PAFPAFiNOSiNOSCOX2COX2
IL-1 raIL-1 raIL-10IL-10sTNFr-1/11sTNFr-1/11TGF-TGF-IL-4IL-4
SIRS EvolutionSIRS Evolution
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Stereotypical ResponseStereotypical Response
Similar Similar clinical clinical responseresponse
Similar Similar cellularcellular inflammatory inflammatory response response
sepsissepsistraumatraumapanceatitispanceatitis
TNFTNF
CD14CD14 TLRTLR
oxidative stressoxidative stress
NF-kBNF-kB
TNF mRNA/HSP mRNATNF mRNA/HSP mRNA
Mitochondrial oxidative Mitochondrial oxidative stressstress
HSFHSF
NUCLEUSNUCLEUS
kinaseskinasesCD11b upregulationCD11b upregulation
FeverFeverHypotensionHypotensionRespiratory distressRespiratory distressOliguriaOliguriaElevated liver enzymesElevated liver enzymes
CELL CELL MEMBRANEMEMBRANE
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Blood Purification in SIRSBlood Purification in SIRS
Sepsis TherapySepsis Therapy
antibiotics / surgical drainageantibiotics / surgical drainage general ICU supportgeneral ICU support
steroidssteroids- high dose- high dose- low dose- low dose
Bacterial sepsisBacterial sepsis
exotoxinexotoxin LPSLPS mediatorsmediators
IMMUNOMODULATIONIMMUNOMODULATION
monoclonal antibodiesmonoclonal antibodies other anti-inflammatoriesother anti-inflammatories
mediator adsorption / removalmediator adsorption / removal
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Blood Purification in SIRSBlood Purification in SIRS
What are the targets?What are the targets?
• most known mediators are water solublemost known mediators are water soluble
• possible contenderspossible contenders
– 500-60,000D (“middle molecules”)500-60,000D (“middle molecules”)
• cytokinescytokines
• anti/pro-coagulantsanti/pro-coagulants
– other moleculesother molecules
• complementcomplement
• phospholipase A-2 dependent productsphospholipase A-2 dependent products
• likely many unknown contenderslikely many unknown contenders
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Convective Removal of MediatorsConvective Removal of Mediators
1010 101022 101033 101044 101055
ionic compoundsionic compounds
ureaurea
creatininecreatinine
sucrosesucrose
Vit BVit B1212
inulininulin
IL-8IL-8
IL-6IL-6
TNFTNF
albuminalbumin
myoglobinmyoglobin
IL-1IL-1
ß2 microglobulinß2 microglobulin
MW (Daltons)MW (Daltons)
Filter cutoffFilter cutoff
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Convective Removal of MediatorsConvective Removal of Mediators
MEDIATORMEDIATOR MW (Daltons)MW (Daltons) SIEVING COEFFICIENTSIEVING COEFFICIENT
AA metabolitesAA metabolites +/- 600+/- 600 0.5-0.90.5-0.9BradykininBradykinin +/- 1100+/- 1100EndothelinEndothelin +/- 2,500+/- 2,500 0.190.19C3a/C5aC3a/C5a +/- 11,000+/- 11,000 0.11-0.770.11-0.77MDSMDS +/- 600-30,000+/- 600-30,000EndotoxinEndotoxin > 10> 1066
LPSLPS +/- 67,000+/- 67,000TNF monomerTNF monomer +/- 17,000+/- 17,000 0-0.20-0.2TNF trimerTNF trimer +/- 54,000+/- 54,000IL-1IL-1 +/- 17,500+/- 17,500 0.07-0.420.07-0.42IL-6IL-6 +/- 22,000+/- 22,000IL-8IL-8 +/- 8,000+/- 8,000 0.480.48IL-10IL-10 +/- 18,000+/- 18,000 00INFINF +/- 20,000+/- 20,000
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Types of Blood PurificationTypes of Blood Purification
• hemofiltershemofilters
– regular pore size (MW < 40,000D)regular pore size (MW < 40,000D)
• Low fluxLow flux
• High fluxHigh flux
– large pore filtration (MW < 100,000D)large pore filtration (MW < 100,000D)
• open pore plasma filters open pore plasma filters
– plasma exchangeplasma exchange
– plasmapheresisplasmapheresis
• adsorptionadsorption
• coupled plasma filtration / adsorptioncoupled plasma filtration / adsorption
• combinationscombinations
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Mechanisms of Clearance Mechanisms of Clearance of Mediatorsof Mediators
• diffusiondiffusion
• convectionconvection
• adsorptionadsorption
• decreased production decreased production
– ? “feedback” effect? “feedback” effect
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Potential Adverse Effects of Blood PurificationPotential Adverse Effects of Blood Purification
• interaction of immune system with foreign surface of circuitinteraction of immune system with foreign surface of circuit
– cellulosic vs. biocompatiblecellulosic vs. biocompatible
• complement activationcomplement activation
• bradykinin generationbradykinin generation
• leukocyte activation / adhesins?leukocyte activation / adhesins?
• clearance of anti-inflammatory mediatorsclearance of anti-inflammatory mediators
• clearance of unknown “good” mediatorsclearance of unknown “good” mediators
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Problems with the ConceptProblems with the Concept
• what do the plasma levels of mediators really mean?what do the plasma levels of mediators really mean?
• animal studies not clinically applicable to human sepsisanimal studies not clinically applicable to human sepsis
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What is the Evidence for Blood Purification?What is the Evidence for Blood Purification?
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Systematic Review: Levels of EvidenceSystematic Review: Levels of Evidence
Level 1:Level 1: randomized clinical trials with substantial treatment effects randomized clinical trials with substantial treatment effects
Level 2:Level 2: randomized clinical trials with smaller treatment effects randomized clinical trials with smaller treatment effects
Level 3:Level 3: prospective, controlled, non-randomized, cohort studies prospective, controlled, non-randomized, cohort studies
Level 4:Level 4: historic, non-randomized, cohort studies historic, non-randomized, cohort studies
Level 5:Level 5: case series, no control group case series, no control group
Level 6:Level 6: animal studies animal studies
Level 7:Level 7: extrapolations from existing data extrapolations from existing data
Level 8:Level 8: rational conjecture, common practices rational conjecture, common practices
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Types of Studies on Blood Types of Studies on Blood Purification in SepsisPurification in Sepsis
• indirect evidenceindirect evidence
– cytokines in ultrafiltratecytokines in ultrafiltrate
– adverse effects of reinfused ultrafiltrateadverse effects of reinfused ultrafiltrate
• direct evidencedirect evidence
– animal studiesanimal studies
– human improved ventricular functionhuman improved ventricular function
– human improved lung compliancehuman improved lung compliance
– human survival advantagehuman survival advantage
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Level of Evidence Level of Evidence
• mediator clearancemediator clearance– in-vitroin-vitro
– in-vivoin-vivo
• all level 5 or 6all level 5 or 6
• animal studies (level 6)animal studies (level 6)– manymany
• clinical studiesclinical studies– 2 level 1 studies (Ronco et al & Reeves et al) 2 level 1 studies (Ronco et al & Reeves et al)
– 5 level 2 studies5 level 2 studies
– remainder level 3 or 4remainder level 3 or 4
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Experimental Studies in-VivoExperimental Studies in-Vivo
• Detection of mediators in ultrafiltrateDetection of mediators in ultrafiltrate
• Detection of changes in serum levels of mediatorsDetection of changes in serum levels of mediators
• Detection of changes of hemodynamics / resp. function septic animalsDetection of changes of hemodynamics / resp. function septic animals
• Detection of effects of UF on hemodynamics of normal animalsDetection of effects of UF on hemodynamics of normal animals
• Detection of effects of UF on lymphocyte activation in-vitroDetection of effects of UF on lymphocyte activation in-vitro
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Blood Purification in SIRSBlood Purification in SIRS
Experimental Studies In VivoExperimental Studies In Vivo
REGULAR PORE SIZE: INDIRECT MEDIATOR REMOVALREGULAR PORE SIZE: INDIRECT MEDIATOR REMOVALAuthorAuthor ModelModel ResultsResults ReferenceReference
Stein 90Stein 90 pig endotoxemiapig endotoxemia hemodynamics hemodynamics Int Care Med 16:494-9Int Care Med 16:494-9Gomez 90Gomez 90 dog sepsisdog sepsis LV contractility LV contractility Anesthesiol 73:671-85Anesthesiol 73:671-85Stein 91Stein 91 pig endotoxemiapig endotoxemia lung compliance lung compliance Int Care Med 17:293-8Int Care Med 17:293-8Grootendorst 92Grootendorst 92 pig endotoxemiapig endotoxemia CO, RVEF CO, RVEF Int Care Med 18:235-40 Int Care Med 18:235-40 Grootendorst 93Grootendorst 93 pig endotoxemiapig endotoxemia effluent causes shockeffluent causes shock J Crit Care 8:161-9J Crit Care 8:161-9Lee 93Lee 93 pig, sepsispig, sepsis survival survival Crit Care Med 21:914Crit Care Med 21:914Heideman 94Heideman 94 rat endotoxemiarat endotoxemia survival survival Circ Shock 44:183-7Circ Shock 44:183-7Bellomo 95Bellomo 95 dog endotoxemiadog endotoxemia CO, hemodynamics CO, hemodynamics AJRCCM 151:A318AJRCCM 151:A318Mink 95Mink 95 dog sepsisdog sepsis hemodynamics hemodynamics Anesthesiol 83:178-90Anesthesiol 83:178-90Flynn 94Flynn 94 pig endotoxemia pig endotoxemia LV contractility LV contractility Anesth Analg 80:S129Anesth Analg 80:S129Freeman 95Freeman 95 dog sepsisdog sepsis no effectno effect J Am Coll Surg 180:286-92J Am Coll Surg 180:286-92Bottoms 96Bottoms 96 pig endotoxemiapig endotoxemia no effectno effect Shock 5:149-54Shock 5:149-54Murpy 97Murpy 97 pig endotoxemiapig endotoxemia no effectno effect J Vet Res 58:408-13J Vet Res 58:408-13Mink 99Mink 99 dog sepsisdog sepsis no effect no effect Int Care Med 25:733-43Int Care Med 25:733-43
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Experimental Studies In VivoExperimental Studies In VivoREGULAR PORE SIZE: DIRECT MEDIATOR REMOVALREGULAR PORE SIZE: DIRECT MEDIATOR REMOVAL
AuthorAuthor ModelModel ResultsResults ReferenceReference
Bellomo 93Bellomo 93 human sepsishuman sepsis IL-1, TNFIL-1, TNF Crit Care Med 21:522-6Crit Care Med 21:522-6Tonnesen 93Tonnesen 93 human sepsishuman sepsis IL-1, IL-6, TNFIL-1, IL-6, TNF Anaes Int Care 21:752-8 Anaes Int Care 21:752-8 Andreasson 93Andreasson 93 human CPBhuman CPB cytokinescytokines Ann Thor Surg 56:1499-1502Ann Thor Surg 56:1499-1502Journois 94Journois 94 human CPBhuman CPB IL-6, TNFIL-6, TNF Anesthesiol 81:1181-9Anesthesiol 81:1181-9Hoffman 94Hoffman 94 human sepsishuman sepsis CC33, C, C5a5a Int Care Med 20:A73Int Care Med 20:A73Heideman 94Heideman 94 rat endotoxemiarat endotoxemia PGF, TxB2PGF, TxB2 Circ Shock 44:183-7Circ Shock 44:183-7Hoffman 95Hoffman 95 human sepsis human sepsis Kidney Int 48:1563-1570Kidney Int 48:1563-1570Bellomo 95Bellomo 95 human sepsishuman sepsis IL-6, IL-8IL-6, IL-8 Ren Fail 17:457-466Ren Fail 17:457-466Van Bommel 95Van Bommel 95 human sepsishuman sepsis TNF, IL_1, IL-6TNF, IL_1, IL-6 Contrib Nephrol 116:62-75Contrib Nephrol 116:62-75Hoffman 96Hoffman 96 human sepsishuman sepsis Int Care Med 26:1360-1367Int Care Med 26:1360-1367Kellum 96Kellum 96 dog endotoxemiadog endotoxemia endothelin, PGFendothelin, PGF AJRCCM 153:A838AJRCCM 153:A838Heering 97Heering 97 human sepsishuman sepsis cytokinescytokines Int Care Med 23:288-96Int Care Med 23:288-96Kellum 98Kellum 98 human sepsishuman sepsis TNF, IL-6TNF, IL-6 Crit Care Med 26:1995-2000Crit Care Med 26:1995-2000Bellomo 98Bellomo 98 human sepsishuman sepsis C3aC3a Kidney Int 53:S182-5Kidney Int 53:S182-5Ishihara 99Ishihara 99 pig endotoxemiapig endotoxemia TNF, PGF, TxBTNF, PGF, TxB J of Trauma 46:894-99J of Trauma 46:894-99Hoffman 99Hoffman 99 human sepsis UFhuman sepsis UF cardiotoxinscardiotoxins Shock 12:174-80Shock 12:174-80Lonnemann 99Lonnemann 99 human sepsis human sepsis TNFTNF Kidney Int 56:S84-87Kidney Int 56:S84-87
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Blood Purification in SIRSBlood Purification in SIRS
Experimental Studies In VivoExperimental Studies In Vivo
HIGH VOLUME HFHIGH VOLUME HF
AuthorAuthor ModelModel ResultsResults ReferenceReference
Grootendorst 92Grootendorst 92 pig endotoxemiapig endotoxemia hemodynamics hemodynamics Int Care Med 18:235-40Int Care Med 18:235-40
Grootendorst 94Grootendorst 94 pig gut ischemiapig gut ischemia hemodynamics hemodynamics Shock 2:72-8Shock 2:72-8
Rogiers 99Rogiers 99 dog endotoxemiadog endotoxemia hemodynamics hemodynamics Crit Care Med 27:1848-55Crit Care Med 27:1848-55
Bellomo 2000Bellomo 2000 dog endotoxemiadog endotoxemia MAP; no ∆ CO MAP; no ∆ CO AJRCCM 161:1429-36AJRCCM 161:1429-36
LARGE PORE FILTRATIONLARGE PORE FILTRATION
Lee 98Lee 98 pig septicemiapig septicemia hemodynamics, survival hemodynamics, survival Crit Care Med 26:730-37Crit Care Med 26:730-37
Kline 99Kline 99 dog endotoxemiadog endotoxemia hemodynamics, survival hemodynamics, survival Crit Care Med 27:588-96Crit Care Med 27:588-96
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PlasmapheresisPlasmapheresis
• Plasma exchange (PE)Plasma exchange (PE)– centrifugationcentrifugation– membranemembrane
• Plasmapheresis (PP)Plasmapheresis (PP)
FFP/colloid/IgGFFP/colloid/IgG
PlasmaPlasma
PatientPatient
PlasmaPlasma
PatientPatient
PLASMA FILTERPLASMA FILTER PLASMA FILTERPLASMA FILTER
ADSORBANT ADSORBANT COLUMNCOLUMN
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Plasmapheresis: Clinical StudiesPlasmapheresis: Clinical Studies
ANIMAL STUDIESANIMAL STUDIES
AuthorAuthor ResultsResults ReferenceReference
Busund 91Busund 91 no survival advantageno survival advantage Arch Surg 126:591-7Arch Surg 126:591-7Natanson 93Natanson 93 no survival advantageno survival advantage Transfusion 33:243-48Transfusion 33:243-48
HUMAN STUDIESHUMAN STUDIES
AuthorAuthor Type of StudyType of Study ResultsResults ReferenceReference
Van Deuren 92Van Deuren 92 observationalobservational no benefitno benefit Clin Infect Dis 15:424-30Clin Infect Dis 15:424-30Reeves 95Reeves 95 retrospectiveretrospective no benefitno benefit Int Care Med 21:500-4Int Care Med 21:500-4Berlot 97Berlot 97 observationalobservational no benefitno benefit Blood Purif 15:45-53Blood Purif 15:45-53Kumar 98 Kumar 98 observationalobservational no benefitno benefit Nephrol Dial Trans 13:484-7Nephrol Dial Trans 13:484-7Reeves 99Reeves 99 RCTRCT no benefitno benefit Crit Care Med 27:2096-104Crit Care Med 27:2096-104Schmidt 2000Schmidt 2000 observationalobservational no benefitno benefit Int Care Med 26:532-7Int Care Med 26:532-7
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Blood Purification in SIRSBlood Purification in SIRS
Human Clinical Studies of High Volume CVVHHuman Clinical Studies of High Volume CVVH
Level 1 StudiesLevel 1 Studies
AuthorAuthor DesignDesign ResultsResults ReferenceReference
Ronco 2000 Ronco 2000 PRCTPRCT improved outcomeimproved outcome Lancet 355:26-30Lancet 355:26-30
Level 2 StudiesLevel 2 Studies
Cosentino 91 Cosentino 91 RCT (ARDS)RCT (ARDS) no difference no difference Contrib Nephrol 93:94-97Contrib Nephrol 93:94-97Braun 95Braun 95 RCT (SIRS)RCT (SIRS) Apache III score Apache III score Contrib Nephrol 116:89-98Contrib Nephrol 116:89-98Reigel 95Reigel 95 RCT (trauma)RCT (trauma) attenuates COattenuates CO Contrib Nephrol 116:56-61Contrib Nephrol 116:56-61Sander 97Sander 97 RCT (SIRS)RCT (SIRS) no difference CVSno difference CVS Int Care Med 23:878-884Int Care Med 23:878-884Riera 97Riera 97 RCT (trauma)RCT (trauma) CVS/oxygenation CVS/oxygenation Surgery 122:902-908Surgery 122:902-908
Level 3 StudiesLevel 3 Studies
Wakabayashi 96Wakabayashi 96 cross overcross over Br J Surg 83:393-4Br J Surg 83:393-4Jacob 96 Jacob 96 ReviewReview no differenceno difference Nephrol Dial Transp 11:1250-55Nephrol Dial Transp 11:1250-55Honore 97Honore 97 cohort cohort improved CVSimproved CVS Int Care Med 23:S77Int Care Med 23:S77BellomoBellomo 9898 cohortcohort reduced inotropesreduced inotropes Kidney Int 53:S182-5Kidney Int 53:S182-5Oudmans 99Oudmans 99 cohortcohort improved mortalityimproved mortality Int Care Med 25:814-21Int Care Med 25:814-21
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Problems?Problems?
• Can accuracy of machines handle high flows Can accuracy of machines handle high flows
for pediatric patients?for pediatric patients?
• Will there be prospective randomized Will there be prospective randomized
controlled studies?controlled studies?
• Will one filter fit all comers?Will one filter fit all comers?
– What about unique genetic makeup?What about unique genetic makeup?
• Cost?Cost?
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Blood Purification in SIRSBlood Purification in SIRS
The way of the future?The way of the future?
• AdsorptionAdsorption
• Continuous Plasma Filtration Adsorption Continuous Plasma Filtration Adsorption (CPFA)(CPFA)
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Blood Purification in SIRSBlood Purification in SIRS
Coupled Plasma Filtration Adsorption Coupled Plasma Filtration Adsorption (CPFA)(CPFA)
PLASMA FILTERPLASMA FILTER HEMODIAFILTERHEMODIAFILTER
SORBENTSORBENT
DIALYSATEDIALYSATE
BLOOD BLOOD
IN IN
BLOOD BLOOD
OUTOUT
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AdsorbentsAdsorbents
• non selectivenon selective– charcoalcharcoal
• coatedcoated• uncoateduncoated
– uncharged resinsuncharged resins– liposomes (+ Vit C & Vit E)liposomes (+ Vit C & Vit E)
• selectiveselective– hydrophobic resinshydrophobic resins– powdered adsorbentpowdered adsorbent– microsphere based detoxification systemmicrosphere based detoxification system– engineered matricesengineered matrices
• polymyxin Bpolymyxin B• polyethyleneiminepolyethyleneimine
• specificspecific– antibody-coated microspheres detoxification systemantibody-coated microspheres detoxification system
• anti-TNF MDSanti-TNF MDS• anti-IL-1 MDSanti-IL-1 MDS
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PMX-F HemoperfusionPMX-F Hemoperfusion• Adsorbs endotoxinAdsorbs endotoxin
Animal ModelsAnimal Models
AuthorAuthor ModelModel SurvivalSurvival %% ReferenceReference
Rx vs controlRx vs control
Hanasawa 84Hanasawa 84 dog e-toxemiadog e-toxemia 83 vs 12.583 vs 12.5 Therapeutic Apheresis, P 167-70Therapeutic Apheresis, P 167-70
Hanasawa 89Hanasawa 89 live e-colilive e-coli 60 vs 060 vs 0 ASAIO Trans 35:341-43ASAIO Trans 35:341-43
Hanasawa 89Hanasawa 89 dog e-toxemiadog e-toxemia 83 vs. 083 vs. 0 Surg Gyn Obstet 168:323-331Surg Gyn Obstet 168:323-331
Kodama 90Kodama 90 dog e-toxemiadog e-toxemia 75 vs. 075 vs. 0 Jpn J Artif Org 17:277-79Jpn J Artif Org 17:277-79
Shoji 93Shoji 93 dog e-toxemiadog e-toxemia 60 vs. 2060 vs. 20 Jpn J Artif Org 22:204-11 Jpn J Artif Org 22:204-11
Sato 93Sato 93 dog e-toxemiadog e-toxemia 80 vs.080 vs.0 ASAIO Trans 39:M790-M793 ASAIO Trans 39:M790-M793
Human Studies (all uncontrolled)Human Studies (all uncontrolled)
Aoki 94Aoki 94 observationalobservational ET clearance / ET clearance / inotropes inotropes Am J Surg 167:412-17Am J Surg 167:412-17
Kodama 97Kodama 97 phase II/IIIphase II/III survival/ET clearancesurvival/ET clearance Shock 7 supp:6 (abstract)Shock 7 supp:6 (abstract)
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Blood Purification in SIRSBlood Purification in SIRS
CPFA: Experimental StudiesCPFA: Experimental Studies
• In-Vitro studiesIn-Vitro studies– much more efficient clearance of cytokinesmuch more efficient clearance of cytokines
• Animal Studies Animal Studies – rabbit model of LPS septic shock rabbit model of LPS septic shock (Tetta C, Coupled plasma filtration-(Tetta C, Coupled plasma filtration-
adsorption in a rabbit model of endotoxic shock. Crit Care Med 28:1526-33, adsorption in a rabbit model of endotoxic shock. Crit Care Med 28:1526-33, 2000)2000)
• 85% survival in rabbits supported with CPFA85% survival in rabbits supported with CPFA
• 80% mortality in control rabbits80% mortality in control rabbits
• Human Clinical Study Human Clinical Study (Brendolan A, Coupled plasma filtration-(Brendolan A, Coupled plasma filtration-adsorption technique in sepsis-associated acute renal failure: hemodynamic adsorption technique in sepsis-associated acute renal failure: hemodynamic effects. J Am Soc Nephrol 9:A0655, 1998) effects. J Am Soc Nephrol 9:A0655, 1998)
– improved hemodynamics SVRimproved hemodynamics SVR
– reduced inotrope requirementsreduced inotrope requirements
– improved monocyte responsivenessimproved monocyte responsiveness
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Blood Purification in SIRSBlood Purification in SIRS
The Past and the FutureThe Past and the Future
CRRTCRRT• mid 1960’s Henderson first demonstrated pumped ultrafiltrationmid 1960’s Henderson first demonstrated pumped ultrafiltration
– 1977 Kramer first performed CAVH1977 Kramer first performed CAVH
– early 1990’s pumped continuous hemofiltration (CVVH)early 1990’s pumped continuous hemofiltration (CVVH)
• 2002: 2002:
– wide range of customized machinerywide range of customized machinery
– synthetic biocompatible membranesynthetic biocompatible membrane
Blood PurificationBlood Purification• 1990:1990:
– initial studies demonstrating mediator clearanceinitial studies demonstrating mediator clearance
• ?2020?2020
– specific therapy for sepsis / SIRS specific therapy for sepsis / SIRS