blood purification in sepsis

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.

22

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?

33


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?

44


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

55


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

66


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

77


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

88


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

99


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

1010


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

1111


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

1212


Mechanisms of Clearance Mechanisms of Clearance of Mediatorsof Mediators

• diffusiondiffusion

• convectionconvection

• adsorptionadsorption

• decreased production decreased production

– ? “feedback” effect? “feedback” effect

1313


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

1414


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

1515


What is the Evidence for Blood Purification?What is the Evidence for Blood Purification?

1616


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

1717


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

1818


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

1919


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

2020


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

2121


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

2222


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

2323


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

2424


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

2525


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


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


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

2626


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?

2727


The way of the future?The way of the future?

• AdsorptionAdsorption

• Continuous Plasma Filtration Adsorption Continuous Plasma Filtration Adsorption (CPFA)(CPFA)

2828


Coupled Plasma Filtration Adsorption Coupled Plasma Filtration Adsorption (CPFA)(CPFA)

PLASMA FILTERPLASMA FILTER HEMODIAFILTERHEMODIAFILTER

SORBENTSORBENT

DIALYSATEDIALYSATE

BLOOD BLOOD

IN IN

BLOOD BLOOD

OUTOUT

2929


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

3030


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)

3131


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

3232


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

3333


ConclusionsConclusions

• ““tip of the iceburg”?tip of the iceburg”?

• potentially important adjunctive therapypotentially important adjunctive therapy

• do no harm vs. improving outcome ?do no harm vs. improving outcome ?

blood purification in sepsis

Documents

tnf monomer

tnf trimer

efficacythe future

sirsmechanisms of clearance

known mediators

evil humorsorrestore

bc childrens hospital

peter skippen