Blood Purification in Sepsis

1
Blood Purification in Sepsis

• Dr. Peter Skippen, PICU.
• BC Childrens Hospital,
• Vancouver. CANADA.

2
Outline

• Basic concepts of SIRS and therapies
• Rationale for blood purification
• Types of blood purification
• Evidence for efficacy
• The future?

3
What are we doing?

• Remove the evil humors
• OR
• Restore the balance
• OR
• Both
• OR
• Neither

4
Synopsis of SIRS
infecting Organism
immune Status
HOST
genetic map
systemic insult
Stereotypical host response
cellular response
humoral 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
5
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
6
Stereotypical Response
sepsis trauma panceatitis
Similar cellular inflammatory response
Similar clinical response
TNF
TLR
CELL MEMBRANE
Fever Hypotension Respiratory distress Oliguria E
levated liver enzymes
CD14
CD11b upregulation
kinases
oxidative stress
Mitochondrial oxidative stress
HSF
NF-kB
TNF mRNA/HSP mRNA
NUCLEUS
7
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
8
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

9
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
10
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 gt 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

11
Types of Blood Purification

• hemofilters
• regular pore size (MW lt 40,000D)
• Low flux
• High flux
• large pore filtration (MW lt 100,000D)
• open pore plasma filters
• plasma exchange
• plasmapheresis
• adsorption
• coupled plasma filtration / adsorption
• combinations

12
Mechanisms of Clearance of Mediators

• diffusion
• convection
• adsorption
• decreased production
• ? feedback effect

13
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

14
Problems with the Concept

• what do the plasma levels of mediators
  really mean?
• animal studies not clinically applicable to
  human sepsis

15
What is the Evidence for Blood Purification?
16
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

17
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

18
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

19
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

20
Experimental Studies In Vivo

• REGULAR PORE SIZE INDIRECT MEDIATOR
  REMOVAL
• Author Model Results Reference
• Stein 90 pig endotoxemia ? hemodynamics Int
  Care Med 16494-9
• Gomez 90 dog sepsis ? LV contractility Anesthes
  iol 73671-85
• Stein 91 pig endotoxemia ? lung
  compliance Int Care Med 17293-8
• Grootendorst 92 pig endotoxemia ? CO, RVEF Int
  Care Med 18235-40
• Grootendorst 93 pig endotoxemia effluent causes
  shock J Crit Care 8161-9
• Lee 93 pig, sepsis ? survival Crit Care Med
  21914
• Heideman 94 rat endotoxemia ? survival Circ
  Shock 44183-7
• Bellomo 95 dog endotoxemia ? CO,
  hemodynamics AJRCCM 151A318
• Mink 95 dog sepsis ? hemodynamics Anesthesiol
  83178-90
• Flynn 94 pig endotoxemia ? LV contractility
  Anesth Analg 80S129
• Freeman 95 dog sepsis no effect J Am Coll
  Surg 180286-92
• Bottoms 96 pig endotoxemia no effect Shock
  5149-54
• Murpy 97 pig endotoxemia no effect J Vet Res
  58408-13
• Mink 99 dog sepsis no effect Int Care Med
  25733-43

21
Experimental Studies In Vivo

• REGULAR PORE SIZE DIRECT MEDIATOR REMOVAL
• Author Model Results Reference
• Bellomo 93 human sepsis IL-1, TNF Crit Care
  Med 21522-6
• Tonnesen 93 human sepsis IL-1, IL-6, TNF Anaes
  Int Care 21752-8
• Andreasson 93 human CPB cytokines Ann Thor Surg
  561499-1502
• Journois 94 human CPB IL-6, TNF Anesthesiol
  811181-9
• Hoffman 94 human sepsis C3, C5a Int Care Med
  20A73
• Heideman 94 rat endotoxemia PGF, TxB2 Circ
  Shock 44183-7
• Hoffman 95 human sepsis Kidney Int
  481563-1570
• Bellomo 95 human sepsis IL-6, IL-8 Ren Fail
  17457-466
• Van Bommel 95 human sepsis TNF, IL_1,
  IL-6 Contrib Nephrol 11662-75
• Hoffman 96 human sepsis Int Care Med
  261360-1367
• Kellum 96 dog endotoxemia endothelin,
  PGF AJRCCM 153A838
• Heering 97 human sepsis cytokines Int Care Med
  23288-96
• Kellum 98 human sepsis TNF, IL-6 Crit Care Med
  261995-2000
• Bellomo 98 human sepsis C3a Kidney Int
  53S182-5
• Ishihara 99 pig endotoxemia TNF, PGF, TxB J of
  Trauma 46894-99
• Hoffman 99 human sepsis UF cardiotoxins Shock
  12174-80

22
Experimental Studies In Vivo

• HIGH VOLUME HF
• Author Model Results Reference
• Grootendorst 92 pig endotoxemia ?
  hemodynamics Int Care Med 18235-40
• Grootendorst 94 pig gut ischemia ?
  hemodynamics Shock 272-8
• Rogiers 99 dog endotoxemia ? hemodynamics Crit
  Care Med 271848-55
• Bellomo 2000 dog endotoxemia ? MAP no ?
  CO AJRCCM 1611429-36
• LARGE PORE FILTRATION
• Lee 98 pig septicemia ? hemodynamics,
  survival Crit Care Med 26730-37
• Kline 99 dog endotoxemia ? hemodynamics,
  survival Crit Care Med 27588-96

23
Plasmapheresis

• Plasmapheresis (PP)

• Plasma exchange (PE)
• centrifugation
• membrane

Plasma
PLASMA FILTER
PLASMA FILTER
Plasma
ADSORBANT COLUMN
FFP/colloid/IgG
Patient
Patient
24
Plasmapheresis Clinical Studies

• ANIMAL STUDIES
• Author Results Reference
• Busund 91 no survival advantage Arch Surg
  126591-7
• Natanson 93 no survival advantage Transfusion
  33243-48
• HUMAN STUDIES
• Author Type of Study Results Reference
• Van Deuren 92 observational no benefit Clin
  Infect Dis 15424-30
• Reeves 95 retrospective no benefit Int Care Med
  21500-4
• Berlot 97 observational no benefit Blood Purif
  1545-53
• Kumar 98 observational no benefit Nephrol Dial
  Trans 13484-7
• Reeves 99 RCT no benefit Crit Care Med
  272096-104
• Schmidt 2000 observational no benefit Int Care
  Med 26532-7

25
Human Clinical Studies of High Volume CVVH
Level 1 Studies Author Design Results R
eference Ronco 2000 PRCT improved
outcome Lancet 35526-30 Level 2
Studies Cosentino 91 RCT (ARDS) no difference
Contrib Nephrol 9394-97 Braun 95 RCT (SIRS) ?
Apache III score Contrib Nephrol
11689-98 Reigel 95 RCT (trauma) attenuates
CO Contrib Nephrol 11656-61 Sander 97 RCT
(SIRS) no difference CVS Int Care Med
23878-884 Riera 97 RCT (trauma) ?
CVS/oxygenation Surgery 122902-908
Level 3 Studies Wakabayashi 96 cross
over Br J Surg 83393-4 Jacob 96 Review no
difference Nephrol Dial Transp 111250-55 Honore
97 cohort improved CVS Int Care Med
23S77 Bellomo 98 cohort reduced
inotropes Kidney Int 53S182-5 Oudmans
99 cohort improved mortality Int Care Med
25814-21
26
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?

27
The way of the future?

• Adsorption
• Continuous Plasma Filtration Adsorption (CPFA)

28
Coupled Plasma Filtration Adsorption (CPFA)
PLASMA FILTER
HEMODIAFILTER
BLOOD IN
BLOOD OUT
DIALYSATE
SORBENT
29
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

30
PMX-F Hemoperfusion

• Adsorbs endotoxin

Animal Models Author Model Survival Referenc
e 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 35341-43 Hanasawa 89 dog e-toxemia 83 vs.
0 Surg Gyn Obstet 168323-331 Kodama 90 dog
e-toxemia 75 vs. 0 Jpn J Artif Org
17277-79 Shoji 93 dog e-toxemia 60 vs. 20
Jpn J Artif Org 22204-11 Sato 93 dog
e-toxemia 80 vs.0 ASAIO Trans
39M790-M793 Human Studies (all
uncontrolled) Aoki 94 observational ET
clearance /? inotropes Am J Surg
167412-17 Kodama 97 phase II/III survival/ET
clearance Shock 7 supp6 (abstract)
31
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 281526-33, 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 9A0655,
  1998)
• improved hemodynamics SVR
• reduced inotrope requirements
• improved monocyte responsiveness

32
The Past and the Future

• CRRT
• mid 1960s Henderson first demonstrated
  pumped ultrafiltration
• 1977 Kramer first performed CAVH
• early 1990s 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

33
Conclusions

• tip of the iceburg?
• potentially important adjunctive therapy
• do no harm vs. improving outcome ?