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Sepsis:Sepsis:
Evolving ConceptsEvolving Concepts
John C. Marshall, MD FRCSCJohn C. Marshall, MD FRCSC
St. Michael’s HospitalSt. Michael’s Hospital University of TorontoUniversity of Toronto
HippocratesHippocrates460 – 370 BC460 – 370 BC
SepsisSepsis
PepsisPepsis
Louis PasteurLouis Pasteur1822 - 18951822 - 1895
Fermentation Fermentation caused by living caused by living
organismsorganisms
Germ theoryGerm theoryof diseaseof disease
ConsequencesConsequences
• Public healthPublic health
• ImmunizationImmunization
• SterilizationSterilization
• AntibioticsAntibiotics
Susceptibility to LPS is Susceptibility to LPS is
Transferred with Bone Marrow CellsTransferred with Bone Marrow Cells
C3H HeJ C3H HeJ
(Resistant)(Resistant)C3H HeN C3H HeN
(Sensitive)(Sensitive)
- Michalek, - Michalek, J.Infect.Dis.J.Infect.Dis. 141:55, 1980 141:55, 1980
Susceptibility to LPS is Susceptibility to LPS is
Transferred with Bone Marrow CellsTransferred with Bone Marrow Cells
C3H HeJ C3H HeJ
(Resistant)(Resistant)C3H HeN C3H HeN
(Sensitive)(Sensitive)IRRADIATION IRRADIATION
CROSSOVER BONE MARROW TRANSPLANTCROSSOVER BONE MARROW TRANSPLANT
+ + LPSLPS
- Michalek, - Michalek, J.Infect.Dis.J.Infect.Dis. 141:55, 1980 141:55, 1980
Susceptibility to LPS is Susceptibility to LPS is
Transferred with Bone Marrow CellsTransferred with Bone Marrow Cells
C3H HeJ C3H HeJ
(Resistant)(Resistant)C3H HeN C3H HeN
(Sensitive)(Sensitive)
HeN Marrow DieHeN Marrow Die
HeJ Marrow LiveHeJ Marrow Live
IRRADIATION IRRADIATION
CROSSOVER BONE MARROW TRANSPLANTCROSSOVER BONE MARROW TRANSPLANT
+ + LPSLPS
- Michalek, - Michalek, J.Infect.Dis.J.Infect.Dis. 141:55, 1980 141:55, 1980
Bruce BeutlerBruce Beutler
““Passive immunization Passive immunization
against tumor necrosis against tumor necrosis
factor/cachectin protects factor/cachectin protects
mice from the lethal effects mice from the lethal effects
of endotoxin.”of endotoxin.”
Beutler, Milsark, & CeramiBeutler, Milsark, & Cerami
ScienceScience 229:869, 1985 229:869, 1985
ConsequencesConsequences
• New diseasesNew diseases
• New therapeutic targetsNew therapeutic targets
• Response is the diseaseResponse is the disease
• Not unique to infectionNot unique to infection
InfectionInfectionSepsisSepsis
Systemic InflammatorySystemic InflammatoryResponse SyndromeResponse Syndrome
SIRSSIRSTraumaTrauma
PancreatitisPancreatitis
BurnsBurns
ACCP/SCCM Consensus Conference 1991ACCP/SCCM Consensus Conference 1991
Rates of Sepsis, U.S. 1979 - 2001Rates of Sepsis, U.S. 1979 - 2001
- Martin, - Martin, N Engl J MedN Engl J Med 348:1546, 2003 348:1546, 2003
- - Crit Care MedCrit Care Med 32:858, 2004 32:858, 2004
- - Crit Care Med Crit Care Med 36:296, 200836:296, 2008
CVPCVP
Mean Arterial PressureMean Arterial Pressure>> 8 8
<8<8
FluidsFluids
ScvOScvO22
>> 65 65<65<65
PressorsPressors
Goals achievedGoals achieved>> 70 70Transfusion,Transfusion,
InotropesInotropes
The Impact of Goal-Directed Therapy
Rivers E, et al. N Engl J Med 2001;345:1368Rivers E, et al. N Engl J Med 2001;345:1368
00
1010
2020
3030
4040
5050
6060 Standard Therapy Standard Therapy
Goal-directed Goal-directed
Hospital Hospital Mortality Mortality
28 Day 28 Day Mortality Mortality
60 Day 60 Day MortalityMortality
NNT to prevent 1 death = 6-8NNT to prevent 1 death = 6-8
Mort
ality
(%
)M
ort
ality
(%
)
1-2
1-2
2-3
2-3
3-4
3-4
4-5
4-5
5-6
5-6
6-9
6-9
9-12
9-12
12-2
412
-24
24-3
624
-36
>36
>36
Od
ds
Rat
io f
or
Dea
thO
dd
s R
atio
fo
r D
eath
(95%
CI)
(95%
CI)
11
1010
100100
Time from Onset of HypotensionTime from Onset of Hypotension (Hours)(Hours)
-Kumar, -Kumar, Crit Care Med 34:1589, 2006Crit Care Med 34:1589, 2006
Impact of Delayed Antibiotic Impact of Delayed Antibiotic Therapy on Clinical OutcomeTherapy on Clinical Outcome
Impact of Source Control inImpact of Source Control in1170 Patients with Sepsis1170 Patients with Sepsis
28 Day Mortality28 Day Mortality
AdequateAdequate Inadequate p.Inadequate p.
31.4% 31.4% (303/964)(303/964) 42.7% 42.7% (88/206)(88/206) 0.003 0.003
Odds Ratio 0.61 (0.45-0.83)Odds Ratio 0.61 (0.45-0.83)
Despite conventional Despite conventional
treatment, 30 to 40% of septic treatment, 30 to 40% of septic
patients die of a process patients die of a process
characterized by persistent characterized by persistent
inflammation and non-resolving inflammation and non-resolving
organ dysfunction.organ dysfunction.
Lipopolysaccharide (LPS)Lipopolysaccharide (LPS)
Susceptibility to LPS is Susceptibility to LPS is
Transferred with Bone Marrow CellsTransferred with Bone Marrow Cells
C3H HeJ C3H HeJ
(Resistant)(Resistant)C3H HeN C3H HeN
(Sensitive)(Sensitive)
HeN Marrow DieHeN Marrow Die
HeJ Marrow LiveHeJ Marrow Live
IRRADIATION IRRADIATION
CROSSOVER BONE MARROW TRANSPLANTCROSSOVER BONE MARROW TRANSPLANT
+ + LPSLPS
- Michalek, - Michalek, J.Infect.Dis.J.Infect.Dis. 141:55, 1980 141:55, 1980
TLR2TLR2 Lipoteichoic acid, bacterial Lipoteichoic acid, bacterial lipoprotein, lipoprotein, Injured tissueInjured tissue
TLR3TLR3 Double-stranded RNADouble-stranded RNATLR4TLR4 Endotoxin, Endotoxin, elastase, heparan, elastase, heparan,
HSP60, oxidized phospholipidsHSP60, oxidized phospholipids TLR5TLR5 FlagellinFlagellinTLR6TLR6 MycoplasmaMycoplasma lipopeptide lipopeptideTLR7TLR7 Imiquod, viral DNAImiquod, viral DNATLR8TLR8 Viral DNA, single-strand RNAViral DNA, single-strand RNATLR9TLR9 Bacterial DNABacterial DNA
Toll-like ReceptorsToll-like Receptors
Baseline 4 Hours
PM
N/M
ou
se (
X 1
06 )
0
2
4
6
8
10
C3H/HeNC3H HeJ
Day 1 Day 7L
og
cfu
/Gm
kid
ney
0
2
4
6
8C3H HeNC3H/HeJ
**
****
Clearance of Clearance of CandidaCandida is Impaired is Impairedin TLR4 Mutant C3H/HeJ Micein TLR4 Mutant C3H/HeJ Mice
- Netea, - Netea, J Infect DisJ Infect Dis 185:1483, 2002 185:1483, 2002
Mediators ofMediators ofLethality in Murine EndotoxemiaLethality in Murine Endotoxemia
CytokinesCytokines IL-1, IL-12, IL-18, IL-27, TNF, IFNIL-1, IL-12, IL-18, IL-27, TNF, IFN, TGF, TGFββ, , LIF,MIF, G-LIF,MIF, G-CSF, HMGB-1, MIP-1CSF, HMGB-1, MIP-1αα, , MFP-14, LBP, PTH-RPMFP-14, LBP, PTH-RP
IL-1ra, IL-4, IL-10, IL-13, IFNIL-1ra, IL-4, IL-10, IL-13, IFNαα, , HGF, LIF, CRP, MCP-1, HGF, LIF, CRP, MCP-1, BPI, CAP18, TSG-14, VLDL, VIP, C3, C4, melatoninBPI, CAP18, TSG-14, VLDL, VIP, C3, C4, melatonin
ReceptorsReceptors TNFr p55, IL-1r, PAFr, LECAM-1, TREM-1, LDLr, TNFr p55, IL-1r, PAFr, LECAM-1, TREM-1, LDLr, CD11a, CD14CD11a, CD14VIPr, Adenosine A3rVIPr, Adenosine A3r
Non-proteinsNon-proteins PAF, PLAPAF, PLA22
Vitamin B12, Vitamin D3Vitamin B12, Vitamin D3
Signal Signal hck, COX-2, p38, jnk, NFhck, COX-2, p38, jnk, NFκκB, iNOS, caspase-3B, iNOS, caspase-3
transductiontransduction Stat4, Stat6, IStat4, Stat6, IκκB, HSP70, hemoxygenaseB, HSP70, hemoxygenase
CoagulationCoagulation PAI 1, Tissue FactorPAI 1, Tissue Factor
FactorsFactors TFPI, APCTFPI, APC
- Marshall - Marshall Nature Rev Drug Disc Nature Rev Drug Disc 2:391, 20032:391, 2003
Search Advanced search NatureJournal home > Archive > Letter > Full text > Figure 1FIGURE 1. Gene expression profiles of circulating leukocytes in response to bacterial endotoxin infusion.From the following article:A network-based analysis of systemic inflammation in humans
Steve E. Calvano, Wenzhong Xiao, Daniel R. Richards, Ramon M. Felciano, Henry V. Baker, Raymond J. Cho, Richard O. Chen, Bernard H. Brownstein, J. Perren Cobb, S. Kevin Tschoeke, Carol Miller-Graziano, Lyle L. Moldawer, Michael N. Mindrinos, Ronald W. Davis, Ronald G. Tompkins, Stephen F. Lowry and Inflamm and Host Response to Injury Large Scale Collab. Res. ProgramNature 437, 1032-1037 (13 October 2005) doi: 10.1038/nature03985BACK TO ARTICLE
Samples from eight healthy volunteers were tested at baseline (0 h) and 2, 4, 6, 9 and 24 h after intravenous administration of endotoxin (four subjects) or vehicle (four subjects). a, Significant (false discovery rate of <0.1%) probe sets (5,093) were subjected to K-means clustering into ten bins (0–9). Probe sets for which the abundance was above the mean are shown in red, below the mean are shown in blue, and equivalent to the mean are in white. b, Principal component plot of the significant probe sets at the indicated times after endotoxin administration.Next figure | Figures & Tables index BACK TO ARTICLETopNatureISSN: 0028-0836EISSN: 1476-4687•About NPG •Contact NPG •Nature jobs.com •Privacy policy •Legal notice •Accessibility statement •RSS web feeds •Help © 2006 Nature Publishing Group – partner of AGORA, HINARI, Cross Ref and COUNTER
LPS challenge in LPS challenge in
human volunteers human volunteers
causes altered causes altered
expression of 3714 expression of 3714
distinct genes. distinct genes.
- Calvano, - Calvano, NatureNature 437:1032, 2005 437:1032, 2005
TLR4TLR4CD14CD14
EndotoxinEndotoxin
IRAKIRAKMyD88MyD88
TRAF2TRAF2
NFkBNFkB
MAP Kinases: MAP Kinases: Erk, p38, JnkErk, p38, JnkPI3 KinasePI3 Kinase
Pro-inflammatory genes:Pro-inflammatory genes:IL-1, TNFIL-1, TNF
PAF, Nitric oxide, PAF, Nitric oxide, CoagulationCoagulation
Tissue ischemia,Tissue ischemia,Cell necrosis, Cell necrosis,
ApoptosisApoptosis
TLR4TLR4CD14CD14
EndotoxinEndotoxin
IRAKIRAKMyD88MyD88
TRAF2TRAF2
NFkBNFkB
MAP Kinases: Erk, p38, JnkMAP Kinases: Erk, p38, JnkPI3 KinasePI3 Kinase
Pro-inflammatory genes:Pro-inflammatory genes:IL-1, TNFIL-1, TNF
PAF, Nitric oxide, PAF, Nitric oxide, CoagulationCoagulation
Tissue ischemia,Tissue ischemia,Cell necrosis, Cell necrosis,
ApoptosisApoptosis
TLR4 AntagonistsTLR4 Antagonists E5564 (Eisai)E5564 (Eisai)
OthersOthers
CD14 AntagonistsCD14 Antagonists IC14IC14
Anti-LPS StrategiesAnti-LPS Strategies Antibodies:Antibodies:
J5, HA-1A, E5J5, HA-1A, E5
rBPIrBPI2121
Polymyxin B dextranPolymyxin B dextran
HDL, taurolidineHDL, taurolidine
Alkaline phosphataseAlkaline phosphatase
Lipid emulsionLipid emulsion
Extracorporeal removalExtracorporeal removal
Therapies Targeting EndotoxinTherapies Targeting Endotoxin
TLR4TLR4CD14CD14
EndotoxinEndotoxin
IRAKIRAKMyD88MyD88
TRAF2TRAF2
NFkBNFkB
MAP Kinases: Erk, p38, JnkMAP Kinases: Erk, p38, JnkPI3 KinasePI3 Kinase
Pro-inflammatory genes:Pro-inflammatory genes:IL-1, TNFIL-1, TNF
PAF, Nitric oxide, PAF, Nitric oxide, CoagulationCoagulation
Tissue ischemia,Tissue ischemia,Cell necrosis, Cell necrosis,
ApoptosisApoptosis
TLR4TLR4CD14CD14
EndotoxinEndotoxin
IRAKIRAKMyD88MyD88
TRAF2TRAF2
NFkBNFkB
MAP Kinases: Erk, p38, JnkMAP Kinases: Erk, p38, JnkPI3 KinasePI3 Kinase
Pro-inflammatory genes:Pro-inflammatory genes:IL-1, TNFIL-1, TNF
PAF, Nitric oxide, PAF, Nitric oxide, CoagulationCoagulation
Tissue ischemia,Tissue ischemia,Cell necrosis, Cell necrosis,
ApoptosisApoptosis
Neutralization of Pro-InflammatoryNeutralization of Pro-InflammatoryCytokines in SepsisCytokines in Sepsis
Interleukin-1 Receptor Antagonist Interleukin-1 Receptor Antagonist
3 Studies; 1688 patients3 Studies; 1688 patients
28 Day Mortality28 Day Mortality Odds Ratio: 0.80 (0.65-0.99)Odds Ratio: 0.80 (0.65-0.99)
p=0.04p=0.04
Anti-TNF AntibodiesAnti-TNF Antibodies8 Studies; 6500 patients8 Studies; 6500 patients
28 Day Mortality28 Day Mortality
Odds Ratio: 0.93 (0.87-0.99)Odds Ratio: 0.93 (0.87-0.99)
p=0.02p=0.02
Neutralization of Pro-InflammatoryNeutralization of Pro-InflammatoryCytokines in SepsisCytokines in Sepsis
TLR4TLR4CD14CD14
EndotoxinEndotoxin
IRAKIRAKMyD88MyD88
TRAF2TRAF2
NFkBNFkB
MAP Kinases: Erk, p38, JnkMAP Kinases: Erk, p38, JnkPI3 KinasePI3 Kinase
Pro-inflammatory genes:Pro-inflammatory genes:IL-1, TNFIL-1, TNF
PAF, Nitric oxide, PAF, Nitric oxide, CoagulationCoagulation
Tissue ischemia,Tissue ischemia,Cell necrosis, Cell necrosis,
ApoptosisApoptosis
Recombinant PAF AcetylhydrolaseRecombinant PAF Acetylhydrolase
Phase II Trial (N = 240)Phase II Trial (N = 240)
28 Day Mortality (%)
Placebo Treated p.
Overall 28.4 14.5 0.03
Severe Sepsis 44.2 21.4 0.03
Trauma 10.5 5.9 NS
- Shuster, - Shuster, Crit Care MedCrit Care Med 31:1612, 2003 31:1612, 2003
Day of Study
Per
cen
t S
urv
ivin
g
0
20
40
60
80
100
0 7 14 21 280 7 14 21 28
PlaceboPlacebo
L-NMMAL-NMMAp<0.001p<0.001WilcoxonWilcoxon
Effects of L-NMMA on SurvivalEffects of L-NMMA on Survivalin Septic Shockin Septic Shock
- Lopez, - Lopez, Crit Care MedCrit Care Med 32:21, 2004 32:21, 2004
rhAPC Reduces Mortality in SepsisrhAPC Reduces Mortality in Sepsis
-Bernard et al; -Bernard et al; NEJM NEJM 344:649, 2001344:649, 2001
TLR4TLR4CD14CD14
EndotoxinEndotoxin
IRAKIRAKMyD88MyD88
TRAF2TRAF2
NFkBNFkB
MAP Kinases: MAP Kinases: Erk, p38, JnkErk, p38, JnkPI3 KinasePI3 Kinase
Pro-inflammatory genes:Pro-inflammatory genes:IL-1, TNFIL-1, TNF
PAF, Nitric oxide, PAF, Nitric oxide, CoagulationCoagulation
Tissue ischemia,Tissue ischemia,Cell necrosis, Cell necrosis,
ApoptosisApoptosis
Annane D Annane D BMJBMJ 2004;329:480 2004;329:480
Corticosteroids in Septic Shock:Corticosteroids in Septic Shock:A Meta-analysisA Meta-analysis
0.6 0.7 0.8 0.9 1.0 1.1 1.2 1.30.6 0.7 0.8 0.9 1.0 1.1 1.2 1.3
Experimental Agent Better Placebo BetterExperimental Agent Better Placebo Better
Anti-TNF AntibodiesAnti-TNF Antibodies10 Trials; 6821 Patients10 Trials; 6821 Patients
Anti-endotoxin TherapyAnti-endotoxin Therapy9 trials; 3057 Patients9 trials; 3057 Patients
IL-1raIL-1ra3 Trials; 1688 Patients3 Trials; 1688 Patients
Intravenous immune globulinIntravenous immune globulin20 Trials; 2621 Patients20 Trials; 2621 Patients
Activated Protein C; All PatientsActivated Protein C; All Patients2 Trials 4303 Patients2 Trials 4303 Patients
Activated Protein C; Patients with MOFActivated Protein C; Patients with MOF2 Trials; 2133 Patients2 Trials; 2133 Patients
Adjuvant Therapy in SepsisAdjuvant Therapy in Sepsis
- Marshall, - Marshall, J Leukoc BiolJ Leukoc Biol 83:471, 2008 83:471, 2008
But …But …• Impact is modestImpact is modest
• Indications for use poorly Indications for use poorly defineddefined
0 1 2 3 4 5 60 1 2 3 4 5 6
Study Drug BetterStudy Drug Better
All dosesAll doses
<5 mg/kg/hr<5 mg/kg/hr
> 5mg/kg/hr> 5mg/kg/hr
Dose-dependent Effects of L-NMMADose-dependent Effects of L-NMMAon Survivalon Survival
- Lopez, - Lopez, Crit Care MedCrit Care Med 32:21, 2004 32:21, 2004
TNF Levels Following InfusionTNF Levels Following Infusion
Hours Post-InfusionHours Post-Infusion
PrePre 22 2424 7272
TN
F (
ng
/ml)
TN
F (
ng
/ml)
00
11
22
33
44
55
66
77
88
TNF MAbTNF MAbPlaceboPlacebo
Sepsis SyndromeSepsis Syndrome(Bone et al; 1987)(Bone et al; 1987)
Suspected or proven infection, in Suspected or proven infection, in association with:association with:
• TachycardiaTachycardia• TachypneaTachypnea• Hyper- or hypothermiaHyper- or hypothermia• Dysfunction of one or more organsDysfunction of one or more organs
Sepsis Syndrome Sepsis Syndrome
• 24 year old man with penetrating 24 year old man with penetrating injury to coloninjury to colon
• 86 year old woman with CHF and 86 year old woman with CHF and Enterococcal UTIEnterococcal UTI
• 51 year old man with COPD 51 year old man with COPD exacerbation; exacerbation; CandidaCandida in sputum in sputum
The PIRO ConceptThe PIRO Concept
• PredispositionPredisposition
• InsultInsult
• ResponseResponse
• Organ dysfunctionOrgan dysfunction
- Crit Care Med 31:1250, 2003- Crit Care Med 31:1250, 2003
Cancer staging Cancer staging
stratifies by:stratifies by:
• PrognosisPrognosis
• Potential to Potential to
respond respond
to to
treatmenttreatment
Inflammatory OrganInflammatory OrganInsult Response DysfunctionInsult Response Dysfunction Infection Adaptive Injurious InflammationInfection Adaptive Injurious Inflammation Injury, IschemiaInjury, Ischemia Iatrogenic Iatrogenic
Risk of Death: Risk of Death: Cause of Death of Biologic ParentCause of Death of Biologic Parent
RRRR 95% CI95% CI
All causesAll causes 1.711.71 1.14 – 2.57 1.14 – 2.57
Natural causesNatural causes 1.981.98 1.25 – 3.12 1.25 – 3.12
InfectionInfection 5.815.81 2.47 – 13.7 2.47 – 13.7
CardiovascularCardiovascular 4.524.52 1.32 – 15.4 1.32 – 15.4
CancerCancer 1.191.19 0.16 – 8.99 0.16 – 8.99
- Sorensen et al - Sorensen et al N Engl J MedN Engl J Med 318:727, 1988 318:727, 1988
Tumor Necrosis Factor Tumor Necrosis Factor ααG A; -308 (Promoter)G A; -308 (Promoter)
Author DiseaseAuthor Disease Cases Controls p. Cases Controls p.
NadelNadel Meningococcemia 0.56 0.29 0.03 Meningococcemia 0.56 0.29 0.03(deaths)(deaths)
MiraMira Septic shock Septic shock 0.52 0.52 0.24 0.0080.24 0.008(deaths)(deaths)
TangTang Septic shock Septic shock 0.40 0.40 0.080.08 <0.05 <0.05 (deaths)(deaths)
Mea
n C
han
ge
in D
AS
28M
ean
Ch
ang
e in
DA
S28
-4
-3
-2
-1
0
1 GGGG GAGA
AAAA
Etanercept Etanercept (N=455)(N=455) Infliximab Infliximab (N=453)(N=453)
*p=0.001*p=0.001
**
The TNF -308A/G Polymorphism ModifiesThe TNF -308A/G Polymorphism Modifiesthe Response to Anti-TNF Therapythe Response to Anti-TNF Therapy
- Maxwell, - Maxwell, Hum Mol GenetHum Mol Genet 17:3532, 2008 17:3532, 2008
Absolute Risk Reduction (%)Absolute Risk Reduction (%)-40 -20 0 20 40 60
S. pneumoniaeS. pneumoniae
Grp. B Strep.Grp. B Strep.
S. aureusS. aureus
CLPCLP
E. coliE. coli
LPSLPS N=256N=256
N=56N=56
N=23N=23
N=14N=14
N=10N=10
N=21N=21
Influence of Infectious Challenge onInfluence of Infectious Challenge onResponse to Neutralization of TNFResponse to Neutralization of TNFαα
- Lorente & Marshall, - Lorente & Marshall, ShockShock 24 (Suppl):107, 2005 24 (Suppl):107, 2005
Absolute Risk Reduction (%)Absolute Risk Reduction (%)
-40-40 -30-30 -20-20 -10-10 00 1010 2020 3030
M. tuberculosisM. tuberculosis
ListeriaListeria
CandidaCandida
SalmonellaSalmonella N=11N=11
N=14N=14
N=10N=10
N=11N=11
- Lorente & Marshall, - Lorente & Marshall, ShockShock 24 (Suppl):107, 2005 24 (Suppl):107, 2005
OR for 95%OR for 95%
Infectious Focus N Mortality CIInfectious Focus N Mortality CI
Intra-abdominalIntra-abdominal 31 1.38 0.56-3.40 31 1.38 0.56-3.40
PneumoniaPneumonia 30 1.82 0.74-4.47 30 1.82 0.74-4.47
BacteremiaBacteremia 57 1.83 0.79-4.26 57 1.83 0.79-4.26
Urinary Tract Urinary Tract 23 0.49 0.15-1.6023 0.49 0.15-1.60
Impact of Infection-Related VariablesImpact of Infection-Related Variableson ICU Outcomeon ICU Outcome
Source Control MortalitySource Control Mortality
Adequate 126 (23.1%) Adequate 126 (23.1%) (N=545)(N=545)
Inadequate 48 (39.7%)* Inadequate 48 (39.7%)* (N=121)(N=121)
* p<0.001* p<0.001
Impact of Source Control inImpact of Source Control inPatients with Low IL-6 LevelsPatients with Low IL-6 Levels
Source Control MortalitySource Control Mortality
Adequate 177 (42.3%) Adequate 177 (42.3%) (N=419)(N=419)
Inadequate 40 (47.1%)* Inadequate 40 (47.1%)* (N=85)(N=85)
* p=0.49* p=0.49
Impact of Source Control inImpact of Source Control inPatients with Patients with High High IL-6 LevelsIL-6 Levels
Impact of Organ DysfunctionImpact of Organ Dysfunctionon Response to Antibioticson Response to Antibiotics
ICU MortalityICU Mortality Adequate Inadequate p.Adequate Inadequate p.
LOD > 4LOD > 4 (N=72)(N=72) 21/36 (59%) 20/36 (56%) 0.81 21/36 (59%) 20/36 (56%) 0.81
LODLOD << 4 4 (N=70) 2/27 (7%) 16/43 (37%)(N=70) 2/27 (7%) 16/43 (37%) 0.0060.006
- Clec’h, - Clec’h, Intensive Care Med Intensive Care Med 30:1327, 2004 30:1327, 2004
* p=0.003;* p=0.003;OR 0.51 (0.32-0.80)OR 0.51 (0.32-0.80)
Baseline MOD ScoreBaseline MOD Score
0-40-4 5-85-8 9-129-12 13-1613-16 17-2017-20 21-2421-24
28 D
ay M
ort
alit
y (P
er c
ent)
28 D
ay M
ort
alit
y (P
er c
ent)
00
2020
4040
6060
8080
100100
PlaceboPlacebo
AfelimomabAfelimomab
**
Anti-TNF is Most Efficacious inAnti-TNF is Most Efficacious inPatients without Organ DysfunctionPatients without Organ Dysfunction
.5 .6 .7 .8 .9 1.0 1.1 1.2 1.3 1.4.5 .6 .7 .8 .9 1.0 1.1 1.2 1.3 1.4
16901690
418418
543543
432432
235235
6161
Response to Drotrecogin Response to Drotrecogin αα as a as aFunction of Number of Organ FailuresFunction of Number of Organ Failures
All patientsAll patients
One OFOne OF
2 OF2 OF
3 OF3 OF
4 OF4 OF
5 OF5 OF
ConclusionsConclusions
• Improved understanding of biology Improved understanding of biology
of response to injuryof response to injury
• Can be translated into effective new Can be translated into effective new
therapiestherapies
• The obstacle is our intrinsic The obstacle is our intrinsic
conceptual conservatismconceptual conservatism
Thank you!Thank you!