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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?.

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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

10 102 103 104 105

MW (Daltons)

Filter cutoff


Convective removal of mediators1
Convective Removal of Mediators

MEDIATOR MW (Daltons) SIEVING COEFFICIENT

AA metabolites +/- 600 0.5-0.9

Bradykinin +/- 1100

Endothelin +/- 2,500 0.19

C3a/C5a +/- 11,000 0.11-0.77

MDS +/- 600-30,000

Endotoxin > 106

LPS +/- 67,000

TNF monomer +/- 17,000 0-0.2

TNF trimer +/- 54,000

IL-1 +/- 17,500 0.07-0.42

IL-6 +/- 22,000

IL-8 +/- 8,000 0.48

IL-10 +/- 18,000 0

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



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

Author Model Results Reference

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

Gomez 90 dog sepsis  LV contractility Anesthesiol 73:671-85

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

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

Grootendorst 93 pig endotoxemia effluent causes shock J Crit Care 8:161-9

Lee 93 pig, sepsis  survival Crit Care Med 21:914

Heideman 94 rat endotoxemia  survival Circ Shock 44:183-7

Bellomo 95 dog endotoxemia  CO, hemodynamics AJRCCM 151:A318

Mink 95 dog sepsis  hemodynamics Anesthesiol 83:178-90

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

Freeman 95 dog sepsis no effect J Am Coll Surg 180:286-92

Bottoms 96 pig endotoxemia no effect Shock 5:149-54

Murpy 97 pig endotoxemia no effect J Vet Res 58:408-13

Mink 99 dog sepsis no effect Int Care Med 25:733-43


Experimental studies in vivo2
Experimental Studies In Vivo

REGULAR PORE SIZE: DIRECT MEDIATOR REMOVAL

Author Model Results Reference

Bellomo 93 human sepsis IL-1, TNF Crit Care Med 21:522-6

Tonnesen 93 human sepsis IL-1, IL-6, TNF Anaes Int Care 21:752-8

Andreasson 93 human CPB cytokines Ann Thor Surg 56:1499-1502

Journois 94 human CPB IL-6, TNF Anesthesiol 81:1181-9

Hoffman 94 human sepsis C3, C5a Int Care Med 20:A73

Heideman 94 rat endotoxemia PGF, TxB2 Circ Shock 44:183-7

Hoffman 95 human sepsis Kidney Int 48:1563-1570

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

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

Hoffman 96 human sepsis Int Care Med 26:1360-1367

Kellum 96 dog endotoxemia endothelin, PGF AJRCCM 153:A838

Heering 97 human sepsis cytokines Int Care Med 23:288-96

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

Bellomo 98 human sepsis C3a Kidney Int 53:S182-5

Ishihara 99 pig endotoxemia TNF, PGF, TxB J of Trauma 46:894-99

Hoffman 99 human sepsis UF cardiotoxins Shock 12:174-80

Lonnemann 99 human sepsis TNF Kidney Int 56:S84-87


Experimental studies in vivo3
Experimental Studies In Vivo

HIGH VOLUME HF

Author Model Results Reference

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

Grootendorst 94 pig gut ischemia  hemodynamics Shock 2:72-8

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

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

LARGE PORE FILTRATION

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

Kline 99 dog 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

Author Results Reference

Busund 91 no survival advantage Arch Surg 126:591-7

Natanson 93 no survival advantage Transfusion 33:243-48

HUMAN STUDIES

Author Type of Study Results Reference

Van Deuren 92 observational no benefit Clin Infect Dis 15:424-30

Reeves 95 retrospective no benefit Int Care Med 21:500-4

Berlot 97 observational no benefit Blood Purif 15:45-53

Kumar 98 observational no benefit Nephrol Dial Trans 13:484-7

Reeves 99 RCT no benefit Crit Care Med 27:2096-104

Schmidt 2000 observational no benefit Int Care Med 26:532-7


Human clinical studies of high volume cvvh
Human Clinical Studies of High Volume CVVH

Level 1 Studies

Author Design Results Reference

Ronco 2000 PRCT improved outcome Lancet 355:26-30

Level 2 Studies

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

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

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

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

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

Level 3 Studies

Wakabayashi 96 cross over Br J Surg 83:393-4

Jacob 96 Review no difference Nephrol Dial Transp 11:1250-55

Honore 97 cohort improved CVS Int Care Med 23:S77

Bellomo 98 cohort reduced inotropes Kidney Int 53:S182-5

Oudmans 99 cohort improved mortality Int 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

Author Model Survival % Reference

Rx vs control

Hanasawa 84 dog e-toxemia 83 vs 12.5 Therapeutic Apheresis, P 167-70

Hanasawa 89 live e-coli 60 vs 0 ASAIO Trans 35:341-43

Hanasawa 89 dog e-toxemia 83 vs. 0 Surg Gyn Obstet 168:323-331

Kodama 90 dog e-toxemia 75 vs. 0 Jpn J Artif Org 17:277-79

Shoji 93 dog e-toxemia 60 vs. 20 Jpn J Artif Org 22:204-11

Sato 93 dog e-toxemia 80 vs.0 ASAIO Trans 39:M790-M793

Human Studies (all uncontrolled)

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

Kodama 97 phase II/III survival/ET clearance Shock 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 ?


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