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!