Transcript Current Technology for CRRT

Blood Purification
in Sepsis
Dr. Peter Skippen, PICU.
BC Children’s Hospital,
Vancouver. CANADA.
Blood Purification in SIRS
Outline
• Basic concepts of SIRS and therapies
• Rationale for blood purification
• Types of blood purification
• Evidence for efficacy
• The future?
2
Blood Purification in SIRS
What are we doing?
Remove the “evil humors”
OR
Restore the balance
OR
Both
OR
Neither
3
Blood Purification in SIRS
Synopsis of SIRS
immune Status
HOST
infecting Organism
genetic map
cellular response
systemic insult
Stereotypical host response
humoral response
ENDOTHELIUM
Mediators spills over into circulation
local inflammation
Unbound
pro-inflammatory
systemic inflammation
anti-inflammatory
complement
Bound
phospholipase A2 dependent products
•Nonspecific protein bound
•Soluble receptor bound
coagulation
fibrinolysis / anticoagulation
REMOTE INJURY
•ARDS
•renal dysfunction
•liver dysfunction
Death
or
Recovery
CLEARANCE
•non-specific
•cpecific
•cell bonud
•circulating
4
Blood Purification in SIRS
Clinical presentation
Sepsis
SIRS
SEPTIC SHOCK
TNF-
IL-1ß
IL-6
IL-8
PAF
iNOS
COX2
SIRS Evolution
PROINFLAMMATORY
TNF-
IL-1ß
IL-6
IL-8
PAF
iNOS
COX2
PROINFLAMMATORY
Biologic sequelae
IL-1 ra
IL-10
sTNFr-1/11
TGF-
IL-4
ANTI-INFLAMMATORY
Monocyte activation
IL-1 ra
IL-10
sTNFr-1/11
TGF-
IL-4
Monocyte deactivation
ANTI-INFLAMMATORY + CELL
HYPORESPONSIVENESS / IMMUNOPARALYSIS
5
Blood Purification in SIRS
Stereotypical Response
sepsis
trauma
panceatitis
Similar cellular inflammatory
response
Similar clinical
response
TNF
CELL
MEMBRANE
CD14
TLR
CD11b upregulation
kinases
oxidative stress
NF-kB
HSF
Fever
Hypotension
Respiratory distress
Oliguria
Elevated liver enzymes
Mitochondrial oxidative
stress
TNF mRNA/HSP mRNA
6
NUCLEUS
Blood Purification in SIRS
Sepsis Therapy
Bacterial sepsis
exotoxin
LPS
antibiotics / surgical drainage
general ICU support
monoclonal antibodies
mediators
IMMUNOMODULATION
other anti-inflammatories
steroids
- high dose
- low dose
mediator adsorption / removal
7
Blood Purification in SIRS
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
8
Blood Purification in SIRS
Convective Removal of Mediators
ß2 microglobulin
myoglobin
IL-6
creatinine
sucrose
urea
ionic compounds
inulin
albumin
IL-8
Vit B12
IL-1
10
102
103
104
TNF
105
MW (Daltons)
Filter cutoff
9
Blood Purification in SIRS
Convective Removal of Mediators
MEDIATOR
MW (Daltons)
AA metabolites
Bradykinin
Endothelin
C3a/C5a
MDS
Endotoxin
LPS
TNF monomer
TNF trimer
IL-1
IL-6
IL-8
IL-10
INF
+/- 600
+/- 1100
+/- 2,500
+/- 11,000
+/- 600-30,000
> 106
+/- 67,000
+/- 17,000
+/- 54,000
+/- 17,500
+/- 22,000
+/- 8,000
+/- 18,000
+/- 20,000
SIEVING COEFFICIENT
0.5-0.9
0.19
0.11-0.77
0-0.2
0.07-0.42
0.48
0
10
Blood Purification in SIRS
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
11
Blood Purification in SIRS
Mechanisms of Clearance of Mediators
• diffusion
• convection
• adsorption
• decreased production
– ? “feedback” effect
12
Blood Purification in SIRS
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
13
Blood Purification in SIRS
Problems with the Concept
• what do the plasma levels of mediators really mean?
• animal studies not clinically applicable to human sepsis
14
Blood Purification in SIRS
What is the Evidence for Blood Purification?
15
Blood Purification in SIRS
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
16
Blood Purification in SIRS
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
17
Blood Purification in SIRS
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
18
Blood Purification in SIRS
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
19
Blood Purification in SIRS
Experimental Studies In Vivo
Author
REGULAR PORE SIZE: INDIRECT MEDIATOR REMOVAL
Model
Results
Reference
Stein 90
Gomez 90
Stein 91
Grootendorst 92
Grootendorst 93
Lee 93
Heideman 94
Bellomo 95
Mink 95
Flynn 94
Freeman 95
Bottoms 96
Murpy 97
Mink 99
pig endotoxemia
dog sepsis
pig endotoxemia
pig endotoxemia
pig endotoxemia
pig, sepsis
rat endotoxemia
dog endotoxemia
dog sepsis
pig endotoxemia
dog sepsis
pig endotoxemia
pig endotoxemia
dog sepsis
 hemodynamics
 LV contractility
 lung compliance
 CO, RVEF
effluent causes shock
 survival
 survival
 CO, hemodynamics
 hemodynamics
 LV contractility
no effect
no effect
no effect
no effect
Int Care Med 16:494-9
Anesthesiol 73:671-85
Int Care Med 17:293-8
Int Care Med 18:235-40
J Crit Care 8:161-9
Crit Care Med 21:914
Circ Shock 44:183-7
AJRCCM 151:A318
Anesthesiol 83:178-90
Anesth Analg 80:S129
J Am Coll Surg 180:286-92
Shock 5:149-54
J Vet Res 58:408-13
Int Care Med 25:733-43
20
Blood Purification in SIRS
Experimental Studies In Vivo
Author
REGULAR PORE SIZE: DIRECT MEDIATOR REMOVAL
Model
Results
Reference
Bellomo 93
Tonnesen 93
Andreasson 93
Journois 94
Hoffman 94
Heideman 94
Hoffman 95
Bellomo 95
Van Bommel 95
Hoffman 96
Kellum 96
Heering 97
Kellum 98
Bellomo 98
Ishihara 99
Hoffman 99
Lonnemann 99
human sepsis
human sepsis
human CPB
human CPB
human sepsis
rat endotoxemia
human sepsis
human sepsis
human sepsis
human sepsis
dog endotoxemia
human sepsis
human sepsis
human sepsis
pig endotoxemia
human sepsis UF
human sepsis
IL-1, TNF
IL-1, IL-6, TNF
cytokines
IL-6, TNF
C3, C5a
PGF, TxB2
IL-6, IL-8
TNF, IL_1, IL-6
endothelin, PGF
cytokines
TNF, IL-6
C3a
TNF, PGF, TxB
cardiotoxins
TNF
Crit Care Med 21:522-6
Anaes Int Care 21:752-8
Ann Thor Surg 56:1499-1502
Anesthesiol 81:1181-9
Int Care Med 20:A73
Circ Shock 44:183-7
Kidney Int 48:1563-1570
Ren Fail 17:457-466
Contrib Nephrol 116:62-75
Int Care Med 26:1360-1367
AJRCCM 153:A838
Int Care Med 23:288-96
Crit Care Med 26:1995-2000
Kidney Int 53:S182-5
J of Trauma 46:894-99
Shock 12:174-80
Kidney Int 56:S84-87
21
Blood Purification in SIRS
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
 hemodynamics, survival Crit Care Med 26:730-37
Lee 98
pig septicemia
Kline 99
dog endotoxemia  hemodynamics, survival Crit Care Med 27:588-96
22
Blood Purification in SIRS
Plasmapheresis
• Plasma exchange (PE)
– centrifugation
– membrane
• Plasmapheresis (PP)
Plasma
PLASMA FILTER
PLASMA FILTER
Plasma
ADSORBANT
COLUMN
FFP/colloid/IgG
Patient
Patient
23
Blood Purification in SIRS
Plasmapheresis: Clinical Studies
ANIMAL STUDIES
Author
Results
Reference
Busund 91
Natanson 93
no survival advantage
no survival advantage
Arch Surg 126:591-7
Transfusion 33:243-48
HUMAN STUDIES
Author
Type of Study
Results
Reference
Van Deuren 92
Reeves 95
Berlot 97
Kumar 98
Reeves 99
Schmidt 2000
observational
retrospective
observational
observational
RCT
observational
no benefit
no benefit
no benefit
no benefit
no benefit
no benefit
Clin Infect Dis 15:424-30
Int Care Med 21:500-4
Blood Purif 15:45-53
Nephrol Dial Trans 13:484-7
Crit Care Med 27:2096-104
Int Care Med 26:532-7
24
Blood Purification in SIRS
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
Braun 95
Reigel 95
Sander 97
Riera 97
RCT (ARDS)
RCT (SIRS)
RCT (trauma)
RCT (SIRS)
RCT (trauma)
no difference
 Apache III score
attenuates CO
no difference CVS
 CVS/oxygenation
Contrib Nephrol 93:94-97
Contrib Nephrol 116:89-98
Contrib Nephrol 116:56-61
Int Care Med 23:878-884
Surgery 122:902-908
Level 3 Studies
Wakabayashi 96
Jacob 96
Honore 97
Bellomo 98
Oudmans 99
cross over
Review
cohort
cohort
cohort
no difference
improved CVS
reduced inotropes
improved mortality
Br J Surg 83:393-4
Nephrol Dial Transp 11:1250-55
Int Care Med 23:S77
Kidney Int 53:S182-5
Int Care Med 25:814-21
25
Blood Purification in SIRS
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?
26
Blood Purification in SIRS
The way of the future?
• Adsorption
• Continuous Plasma Filtration Adsorption (CPFA)
27
Blood Purification in SIRS
Coupled Plasma Filtration Adsorption (CPFA)
PLASMA FILTER
HEMODIAFILTER
BLOOD
BLOOD
IN
OUT
DIALYSATE
SORBENT
28
Blood Purification in SIRS
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
29
Blood Purification in SIRS
PMX-F Hemoperfusion
• Adsorbs endotoxin
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)
30
Blood Purification in SIRS
CPFA: Experimental Studies
• In-Vitro studies
– much more efficient clearance of cytokines
• Animal Studies
– rabbit model of LPS septic shock (Tetta C, Coupled plasma filtrationadsorption 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
31
Blood Purification in SIRS
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
32
Blood Purification in SIRS
Conclusions
• “tip of the iceburg”?
• potentially important adjunctive therapy
• do no harm vs. improving outcome ?
33