Blood purification in sepsis
This presentation is the property of its rightful owner.
Sponsored Links
1 / 33

Blood Purification in Sepsis PowerPoint PPT Presentation


  • 170 Views
  • Uploaded on
  • Presentation posted in: General

Blood Purification in Sepsis. Dr. Peter Skippen, PICU. BC Children’s Hospital, Vancouver. CANADA. Outline. Basic concepts of SIRS and therapies Rationale for blood purification Types of blood purification Evidence for efficacy The future?. What are we doing?.

Download Presentation

Blood Purification in Sepsis

An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.


- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -

Presentation Transcript


Blood purification in sepsis

Blood Purification in Sepsis

Dr. Peter Skippen, PICU.

BC Children’s Hospital,

Vancouver. CANADA.


Outline

Outline

  • Basic concepts of SIRS and therapies

  • Rationale for blood purification

  • Types of blood purification

  • Evidence for efficacy

  • The future?


What are we doing

What are we doing?

Remove the “evil humors”

OR

Restore the balance

OR

Both

OR

Neither


Synopsis of sirs

Synopsis of SIRS

immune Status

infecting Organism

HOST

genetic map

systemic insult

Stereotypical host response

humoral response

cellular response

ENDOTHELIUM

Mediators spills over into circulation

pro-inflammatory

systemic inflammation

local inflammation

anti-inflammatory

complement

  • Bound

  • Nonspecific protein bound

  • Soluble receptor bound

Unbound

phospholipase A2 dependent products

coagulation

fibrinolysis / anticoagulation

  • CLEARANCE

  • non-specific

  • cpecific

    • cell bonud

    • circulating

  • REMOTE INJURY

  • ARDS

  • renal dysfunction

  • liver dysfunction

Death

or

Recovery


Sirs evolution

SIRS Evolution

TNF-

IL-1ß

IL-6

IL-8

PAF

iNOS

COX2

Clinical presentation

Biologic sequelae

IL-1 ra

IL-10

sTNFr-1/11

TGF-

IL-4

Sepsis

SIRS

Monocyte activation

PROINFLAMMATORY

ANTI-INFLAMMATORY

IL-1 ra

IL-10

sTNFr-1/11

TGF-

IL-4

TNF-

IL-1ß

IL-6

IL-8

PAF

iNOS

COX2

Monocyte deactivation

SEPTIC SHOCK

PROINFLAMMATORY

ANTI-INFLAMMATORY + CELL HYPORESPONSIVENESS / IMMUNOPARALYSIS


Stereotypical response

Stereotypical Response

sepsis

trauma

panceatitis

Similar cellular inflammatory response

Similar clinical response

TNF

TLR

CELL MEMBRANE

Fever

Hypotension

Respiratory distress

Oliguria

Elevated liver enzymes

CD14

CD11b upregulation

kinases

oxidative stress

Mitochondrial oxidative stress

HSF

NF-kB

TNF mRNA/HSP mRNA

NUCLEUS


Sepsis therapy

Sepsis Therapy

Bacterial sepsis

exotoxin

LPS

mediators

antibiotics / surgical drainage

general ICU support

IMMUNOMODULATION

monoclonal antibodies

other anti-inflammatories

steroids

- high dose

- low dose

mediator adsorption / removal


What are the targets

most known mediators are water soluble

possible contenders

500-60,000D (“middle molecules”)

cytokines

anti/pro-coagulants

other molecules

complement

phospholipase A-2 dependent products

likely many unknown contenders

What are the targets?


Convective removal of mediators

Convective Removal of Mediators

ß2 microglobulin

myoglobin

creatinine

IL-6

sucrose

inulin

urea

albumin

IL-8

ionic compounds

Vit B12

TNF

IL-1

10102103104105

MW (Daltons)

Filter cutoff


Convective removal of mediators1

Convective Removal of Mediators

MEDIATORMW (Daltons)SIEVING COEFFICIENT

AA metabolites+/- 6000.5-0.9

Bradykinin+/- 1100

Endothelin+/- 2,5000.19

C3a/C5a+/- 11,0000.11-0.77

MDS+/- 600-30,000

Endotoxin> 106

LPS+/- 67,000

TNF monomer+/- 17,0000-0.2

TNF trimer+/- 54,000

IL-1+/- 17,5000.07-0.42

IL-6+/- 22,000

IL-8+/- 8,0000.48

IL-10+/- 18,0000

INF+/- 20,000


Types of blood purification

Types of Blood Purification

  • hemofilters

    • regular pore size (MW < 40,000D)

      • Low flux

      • High flux

    • large pore filtration (MW < 100,000D)

  • open pore plasma filters

    • plasma exchange

    • plasmapheresis

  • adsorption

  • coupled plasma filtration / adsorption

  • combinations


Mechanisms of clearance of mediators

Mechanisms of Clearance of Mediators

  • diffusion

  • convection

  • adsorption

  • decreased production

    • ? “feedback” effect


Potential adverse effects of blood purification

Potential Adverse Effects of Blood Purification

  • interaction of immune system with foreign surface of circuit

    • cellulosic vs. biocompatible

      • complement activation

      • bradykinin generation

      • leukocyte activation / adhesins?

  • clearance of anti-inflammatory mediators

  • clearance of unknown “good” mediators


Problems with the concept

Problems with the Concept

  • what do the plasma levels of mediators really mean?

  • animal studies not clinically applicable to human sepsis


What is the evidence for blood purification

What is the Evidence for Blood Purification?


Systematic review levels of evidence

Systematic Review: Levels of Evidence

Level 1: randomized clinical trials with substantial treatment effects

Level 2: randomized clinical trials with smaller treatment effects

Level 3: prospective, controlled, non-randomized, cohort studies

Level 4: historic, non-randomized, cohort studies

Level 5: case series, no control group

Level 6: animal studies

Level 7: extrapolations from existing data

Level 8: rational conjecture, common practices


Types of studies on blood purification in sepsis

indirect evidence

cytokines in ultrafiltrate

adverse effects of reinfused ultrafiltrate

direct evidence

animal studies

human improved ventricular function

human improved lung compliance

human survival advantage

Types of Studies on Blood Purification in Sepsis


Level of evidence

Level of Evidence

  • mediator clearance

    • in-vitro

    • in-vivo

      • all level 5 or 6

  • animal studies (level 6)

    • many

  • clinical studies

    • 2 level 1 studies (Ronco et al & Reeves et al)

    • 5 level 2 studies

    • remainder level 3 or 4


Experimental studies in vivo

Experimental Studies in-Vivo

  • Detection of mediators in ultrafiltrate

  • Detection of changes in serum levels of mediators

  • Detection of changes of hemodynamics / resp. function septic animals

  • Detection of effects of UF on hemodynamics of normal animals

  • Detection of effects of UF on lymphocyte activation in-vitro


Experimental studies in vivo1

Experimental Studies In Vivo

REGULAR PORE SIZE: INDIRECT MEDIATOR REMOVAL

AuthorModelResultsReference

Stein 90pig endotoxemia hemodynamicsInt Care Med 16:494-9

Gomez 90dog sepsis LV contractilityAnesthesiol 73:671-85

Stein 91pig endotoxemia lung complianceInt Care Med 17:293-8

Grootendorst 92pig endotoxemia CO, RVEFInt Care Med 18:235-40

Grootendorst 93pig endotoxemiaeffluent causes shockJ Crit Care 8:161-9

Lee 93pig, sepsis survivalCrit Care Med 21:914

Heideman 94rat endotoxemia survivalCirc Shock 44:183-7

Bellomo 95dog endotoxemia CO, hemodynamicsAJRCCM 151:A318

Mink 95dog sepsis hemodynamicsAnesthesiol 83:178-90

Flynn 94pig endotoxemia  LV contractility Anesth Analg 80:S129

Freeman 95dog sepsisno effectJ Am Coll Surg 180:286-92

Bottoms 96pig endotoxemiano effectShock 5:149-54

Murpy 97pig endotoxemiano effectJ Vet Res 58:408-13

Mink 99dog sepsisno effect Int Care Med 25:733-43


Experimental studies in vivo2

Experimental Studies In Vivo

REGULAR PORE SIZE: DIRECT MEDIATOR REMOVAL

AuthorModelResultsReference

Bellomo 93human sepsisIL-1, TNFCrit Care Med 21:522-6

Tonnesen 93human sepsisIL-1, IL-6, TNFAnaes Int Care 21:752-8

Andreasson 93human CPBcytokinesAnn Thor Surg 56:1499-1502

Journois 94human CPBIL-6, TNFAnesthesiol 81:1181-9

Hoffman 94human sepsisC3, C5a Int Care Med 20:A73

Heideman 94rat endotoxemiaPGF, TxB2Circ Shock 44:183-7

Hoffman 95human sepsis Kidney Int 48:1563-1570

Bellomo 95human sepsisIL-6, IL-8Ren Fail 17:457-466

Van Bommel 95human sepsisTNF, IL_1, IL-6Contrib Nephrol 116:62-75

Hoffman 96human sepsisInt Care Med 26:1360-1367

Kellum 96dog endotoxemiaendothelin, PGFAJRCCM 153:A838

Heering 97human sepsiscytokinesInt Care Med 23:288-96

Kellum 98human sepsisTNF, IL-6Crit Care Med 26:1995-2000

Bellomo 98human sepsisC3aKidney Int 53:S182-5

Ishihara 99pig endotoxemiaTNF, PGF, TxBJ of Trauma 46:894-99

Hoffman 99human sepsis UFcardiotoxinsShock 12:174-80

Lonnemann 99human sepsis TNFKidney Int 56:S84-87


Experimental studies in vivo3

Experimental Studies In Vivo

HIGH VOLUME HF

AuthorModelResultsReference

Grootendorst 92pig endotoxemia hemodynamicsInt Care Med 18:235-40

Grootendorst 94pig gut ischemia hemodynamicsShock 2:72-8

Rogiers 99dog endotoxemia hemodynamicsCrit Care Med 27:1848-55

Bellomo 2000dog endotoxemia MAP; no ∆ COAJRCCM 161:1429-36

LARGE PORE FILTRATION

Lee 98pig septicemia hemodynamics, survivalCrit Care Med 26:730-37

Kline 99dog endotoxemia hemodynamics, survival Crit Care Med 27:588-96


Plasmapheresis

Plasma exchange (PE)

centrifugation

membrane

Plasmapheresis (PP)

Plasmapheresis

Plasma

PLASMA FILTER

PLASMA FILTER

Plasma

ADSORBANT COLUMN

FFP/colloid/IgG

Patient

Patient


Plasmapheresis clinical studies

Plasmapheresis: Clinical Studies

ANIMAL STUDIES

AuthorResultsReference

Busund 91no survival advantageArch Surg 126:591-7

Natanson 93no survival advantageTransfusion 33:243-48

HUMAN STUDIES

AuthorType of StudyResultsReference

Van Deuren 92observationalno benefitClin Infect Dis 15:424-30

Reeves 95retrospectiveno benefitInt Care Med 21:500-4

Berlot 97observationalno benefitBlood Purif 15:45-53

Kumar 98 observationalno benefitNephrol Dial Trans 13:484-7

Reeves 99RCTno benefitCrit Care Med 27:2096-104

Schmidt 2000observationalno benefitInt Care Med 26:532-7


Human clinical studies of high volume cvvh

Human Clinical Studies of High Volume CVVH

Level 1 Studies

AuthorDesignResultsReference

Ronco 2000 PRCTimproved outcomeLancet 355:26-30

Level 2 Studies

Cosentino 91 RCT (ARDS)no difference Contrib Nephrol 93:94-97

Braun 95RCT (SIRS) Apache III scoreContrib Nephrol 116:89-98

Reigel 95RCT (trauma)attenuates COContrib Nephrol 116:56-61

Sander 97RCT (SIRS)no difference CVSInt Care Med 23:878-884

Riera 97RCT (trauma) CVS/oxygenationSurgery 122:902-908

Level 3 Studies

Wakabayashi 96cross overBr J Surg 83:393-4

Jacob 96 Reviewno differenceNephrol Dial Transp 11:1250-55

Honore 97cohort improved CVSInt Care Med 23:S77

Bellomo98cohortreduced inotropesKidney Int 53:S182-5

Oudmans 99cohortimproved mortalityInt Care Med 25:814-21


Problems

Problems?

  • Can accuracy of machines handle high flows for pediatric patients?

  • Will there be prospective randomized controlled studies?

  • Will one filter fit all comers?

    • What about unique genetic makeup?

  • Cost?


The way of the future

The way of the future?

  • Adsorption

  • Continuous Plasma Filtration Adsorption (CPFA)


Coupled plasma filtration adsorption cpfa

Coupled Plasma Filtration Adsorption (CPFA)

PLASMA FILTER

HEMODIAFILTER

BLOOD IN

BLOOD OUT

DIALYSATE

SORBENT


Adsorbents

Adsorbents

  • non selective

    • charcoal

      • coated

      • uncoated

    • uncharged resins

    • liposomes (+ Vit C & Vit E)

  • selective

    • hydrophobic resins

    • powdered adsorbent

    • microsphere based detoxification system

    • engineered matrices

      • polymyxin B

      • polyethyleneimine

  • specific

    • antibody-coated microspheres detoxification system

      • anti-TNF MDS

      • anti-IL-1 MDS


Pmx f hemoperfusion

PMX-F Hemoperfusion

Animal Models

AuthorModelSurvival%Reference

Rx vs control

Hanasawa 84dog e-toxemia83 vs 12.5Therapeutic Apheresis, P 167-70

Hanasawa 89live e-coli60 vs 0ASAIO Trans 35:341-43

Hanasawa 89dog e-toxemia83 vs. 0Surg Gyn Obstet 168:323-331

Kodama 90dog e-toxemia75 vs. 0Jpn J Artif Org 17:277-79

Shoji 93dog e-toxemia60 vs. 20 Jpn J Artif Org 22:204-11

Sato 93dog e-toxemia80 vs.0 ASAIO Trans 39:M790-M793

Human Studies (all uncontrolled)

Aoki 94observational ET clearance / inotropesAm J Surg 167:412-17

Kodama 97phase II/IIIsurvival/ET clearanceShock 7 supp:6 (abstract)

  • Adsorbs endotoxin


Cpfa experimental studies

CPFA: Experimental Studies

  • In-Vitro studies

    • much more efficient clearance of cytokines

  • Animal Studies

    • rabbit model of LPS septic shock (Tetta C, Coupled plasma filtration-adsorption in a rabbit model of endotoxic shock. Crit Care Med 28:1526-33, 2000)

      • 85% survival in rabbits supported with CPFA

      • 80% mortality in control rabbits

  • Human Clinical Study (Brendolan A, Coupled plasma filtration-adsorption technique in sepsis-associated acute renal failure: hemodynamic effects. J Am Soc Nephrol 9:A0655, 1998)

    • improved hemodynamics SVR

    • reduced inotrope requirements

    • improved monocyte responsiveness


The past and the future

The Past and the Future

CRRT

  • mid 1960’s Henderson first demonstrated pumped ultrafiltration

    • 1977 Kramer first performed CAVH

    • early 1990’s pumped continuous hemofiltration (CVVH)

  • 2002:

    • wide range of customized machinery

    • synthetic biocompatible membrane

      Blood Purification

  • 1990:

    • initial studies demonstrating mediator clearance

  • ?2020

    • specific therapy for sepsis / SIRS


Conclusions

Conclusions

  • “tip of the iceburg”?

  • potentially important adjunctive therapy

  • do no harm vs. improving outcome ?


  • Login