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Severe Sepsis and Severe Sepsis and
Septic ShockSeptic ShockJohn C. Marshall, MD FRCSCJohn C. Marshall, MD FRCSC
December 2, 2008December 2, 2008
St. Michael’s HospitalSt. Michael’s Hospital University of TorontoUniversity of Toronto
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HippocratesHippocrates460 – 370 BC460 – 370 BC
SepsisSepsis
PepsisPepsis
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Louis PasteurLouis Pasteur1822 - 18951822 - 1895
Fermentation Fermentation caused by living caused by living
organismsorganisms
Germ theoryGerm theoryof diseaseof disease
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Richard PfeifferRichard Pfeiffer
An extract of An extract of the cell wall of the cell wall of Vibrio choleraVibrio cholera::
EndotoxinEndotoxin
- 1894- 1894
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- - MMWRMMWR 48:621,1999 48:621,1999
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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
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EpidemiologyEpidemiology
• 750,000 cases a year750,000 cases a year
• 211,000 deaths annually211,000 deaths annually
- Angus et al Crit. Care Med. 29:1303, 2001- Angus et al Crit. Care Med. 29:1303, 2001
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Mortality of SepsisMortality of Sepsis
- Martin, - Martin, N Engl J MedN Engl J Med 348:1546, 2003 348:1546, 2003
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Microbiology of SepsisMicrobiology of Sepsis
- Martin, - Martin, N Engl J MedN Engl J Med 348:1546, 2003 348:1546, 2003
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SepsisSepsis
“ “ The presence of pus-forming The presence of pus-forming organisms in the bloodstream….organisms in the bloodstream….
- - Stedman’s Dictionary, 1974Stedman’s Dictionary, 1974
“ “ The systemic host response to The systemic host response to invasive infection…”invasive infection…”
- ACCP/SCCM, 1992- ACCP/SCCM, 1992
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InfectionInfectionSepsisSepsis
Systemic InflammatorySystemic InflammatoryResponse SyndromeResponse Syndrome
SIRSSIRSTraumaTrauma
PancreatitisPancreatitis
BurnsBurns
ACCP/SCCM Consensus Conference 1991ACCP/SCCM Consensus Conference 1991
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SepsisSepsis The systemic host The systemic host response to infectionresponse to infection
Severe SepsisSevere Sepsis Sepsis + organ Sepsis + organ dysfunctiondysfunction
Septic ShockSeptic Shock Sepsis + Sepsis + hemodynamic hemodynamic instabilityinstability
- Bone et al - Bone et al Crit Care Med Crit Care Med 22:864, 199222:864, 1992
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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
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How doesHow does
sepsis kill?sepsis kill?
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LipopolysaccharideLipopolysaccharide (Endotoxin)(Endotoxin)
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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
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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
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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
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TLR2TLR2 Lipoteichoic acid, Bacterial Lipoteichoic acid, Bacterial lipoprotein, Injured tissue lipoprotein, Injured tissue
TLR3TLR3 Double-stranded RNADouble-stranded RNATLR4TLR4 Endotoxin, elastase, heparan, Endotoxin, elastase, heparan,
HSP60HSP60TLR5TLR5 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
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CD14CD14
LPSLPS
Activation of NFB by LPS
MD
-2
Ubiquitination + degradation
NucleusNucleus
CytoplasmCytoplasm
TRAF6TRAF6
TAK1/TAB1TAK1/TAB1
NIKNIK
IKKIKK/IKK/IKK
p50p50 p65p65
IIBBpp pp
IRAKIRAK
TLR4TLR4
NFNFBB
MyD88MyD88
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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
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Mediators ofMediators ofLethality in Murine EndotoxemiaLethality in Murine Endotoxemia
CytokinesCytokines IL-1, IL-12, IL-18 TNF, IFNIL-1, IL-12, IL-18 TNF, IFN, TGF, TGFββ, , LIF,MIF, G-CSF, LIF,MIF, G-CSF, HMGB-1, MIP-1HMGB-1, MIP-1αα, , MFP-14, LBP, PTH-RPMFP-14, LBP, PTH-RPIL-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
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“…“….. .. The major limiting The major limiting
factor after injury in patients factor after injury in patients
who do not have brain injury who do not have brain injury
is not so much a system, but is not so much a system, but
rather a combination of rather a combination of
events that can best be called events that can best be called
multiple systems failure….”multiple systems failure….”
- A.E. Baue, - A.E. Baue, Arch Surg Arch Surg 110:779-781, 1975110:779-781, 1975
The Multiple Organ The Multiple Organ Dysfunction Dysfunction
Syndrome (MODS)Syndrome (MODS)
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Treatment of SepsisTreatment of Sepsis
• Intravenous fluidsIntravenous fluids
• Vasoactive drugsVasoactive drugs
• AntibioticsAntibiotics
• Surgical source controlSurgical source control
• Organ system supportOrgan system support
• ??? Therapy targeting biologic ??? Therapy targeting biologic
mediatorsmediators
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Sepsis Management GuidelinesSepsis Management Guidelines
International Sepsis ForumInternational Sepsis Forum
Intensive Care MedicineIntensive Care Medicine27 (Suppl) 200127 (Suppl) 2001
www.sepsisforum.orgwww.sepsisforum.org
Surviving Sepsis CampaignSurviving Sepsis Campaign
ESICM/SCCM/ISFESICM/SCCM/ISF
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Early Goal-directed TherapyEarly Goal-directed Therapyfor Septic Shockfor Septic Shock
StandardStandard Goal-DirectedGoal-Directed (N=133) (N=130)(N=133) (N=130)
MVOMVO22 65.3 65.3++11.411.4 70.4 70.4++10.7*10.7*
APACHE II 15.9APACHE II 15.9++6.4 13.06.4 13.0++6.3*6.3*
Mortality 46.5% 30.5%*Mortality 46.5% 30.5%* * p<0.02* p<0.02 - Rivers, - Rivers, N Engl J MedN Engl J Med 345:1368, 2001 345:1368, 2001
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Ventilation with lower tidal volumes as compared Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury with traditional tidal volumes for acute lung injury
and the acute respiratory distress syndromeand the acute respiratory distress syndrome
Mortality (%)Mortality (%)
ControlsControls 39.839.8
Volume-limitedVolume-limited 31.0*31.0*
ARDSNet; NEJM 342:1301, 2000
*P=0.007
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sTNFR1 sTNFR2 IL-1ra
Ser
um
Lev
els
(ng
/ml)
0
10
20
30
40
50
60
70
Conventional
Protective
**
**
p<0.001p<0.001
Mechanical Ventilation Evokes Mechanical Ventilation Evokes a Systemic Cytokine Responsea Systemic Cytokine Response
- Ranieri, - Ranieri, JAMAJAMA 282:54, 1999 282:54, 1999
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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
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Endotoxin Activity Level(ICU Patients)
0.0 0.2 0.4 0.6 0.8 1.0
Nu
mb
er
of
Su
bje
cts
0
10
20
30
40
50
60
70
Endotoxin Activity (ICU Patients)Endotoxin Activity (ICU Patients)
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Randomized Trial of HA-1A in SepsisRandomized Trial of HA-1A in Sepsis
All patients 43% 39% 0.24All patients 43% 39% 0.24
Gram negative 49% 32% 0.014Gram negative 49% 32% 0.014
Gm -ve shock 57% 33% 0.017Gm -ve shock 57% 33% 0.017
Placebo HA-1A p.Placebo HA-1A p.MortalityMortality
- Ziegler, - Ziegler, N.Engl.J.Med. N.Engl.J.Med. 324:429, 1991324:429, 1991
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Followup Study of HA-1AFollowup Study of HA-1A(2199 Patients)(2199 Patients)
All patients 36% 38% 0.19All patients 36% 38% 0.19
Gram negative 32% 33% 0.86Gram negative 32% 33% 0.86
Gram positive 37% 41% 0.07Gram positive 37% 41% 0.07
Placebo HA-1A p.Placebo HA-1A p.14 Day Mortality14 Day Mortality
- McCloskey, - McCloskey, Ann.Intern.Med.Ann.Intern.Med. 121:1, 1994 121:1, 1994
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TNFTNFαα
TNFTNFββ (lymphotoxin)(lymphotoxin)
• 26 kDa cell surface molecule26 kDa cell surface molecule
• 17 kDa secreted molecule17 kDa secreted molecule
• Two receptors TNFR1 (p55), TNFR2 (p75)Two receptors TNFR1 (p55), TNFR2 (p75)
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Time (Hours)Time (Hours)
0 5 10 15 20
Cy
tok
ine
lev
els
(p
g/m
l)C
yto
kin
e le
vel
s (
pg
/ml)
0
50
100
150
200
250TNFIL-1
IL-6
The Cytokine Response toThe Cytokine Response toEndotoxin ChallengeEndotoxin Challenge
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Gentamicin 0/6
Gentamicin + Bay x1351 6/6
- Hinshaw, Circ Shock 30:279, 1990
Survival of Baboons FollowingSurvival of Baboons FollowingChallenge with Challenge with E. coliE. coli
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Median (pg/ml) RangeMedian (pg/ml) Range
TNFTNF 83 83 7 – 57,151 7 – 57,151
IL-6IL-6 965 965 8 – 1,553,435 8 – 1,553,435
IL-8IL-8 2130 2130 16 – 651,338 16 – 651,338
Cytokine Levels in Human SepsisCytokine Levels in Human Sepsis
- MONARCS, Unpublished- MONARCS, Unpublished
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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
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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
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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
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Nature 2000;404:518
Protein CProtein C
• Hepatic synthesisHepatic synthesis
• Activated by thrombin:thrombomodulinActivated by thrombin:thrombomodulin
• Inhibits Factors Va, VIIIaInhibits Factors Va, VIIIa
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Actions of Activated Protein CActions of Activated Protein C
• Anti-thrombotic:Anti-thrombotic: Inhibits Inhibits
microvascular coagulopathymicrovascular coagulopathy
• Anti-inflammatory: Anti-inflammatory: EPCR EPCR
transduces anti-inflammatory signaltransduces anti-inflammatory signal
• Anti-apoptotic: Anti-apoptotic: Inhibits endothelial Inhibits endothelial
cell apoptosiscell apoptosis
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rhAPC Reduces Mortality in SepsisrhAPC Reduces Mortality in Sepsis
-Bernard et al; -Bernard et al; NEJM NEJM 344:649, 2001344:649, 2001
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Bleeding ComplicationsBleeding Complications
PlaceboPlacebo 2.0%2.0%
rhAPCrhAPC 3.5%3.5%
P=0.06P=0.06
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- Davidson et al; - Davidson et al; N Engl J Med N Engl J Med 347:1036, 2002347:1036, 2002
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Corticosteroids in Septic ShockCorticosteroids in Septic Shock
Placebo Steroids p.Placebo Steroids p.
MortalityMortality 63% 53% 0.02 63% 53% 0.02
Shock Reversal 40% 57% 0.001Shock Reversal 40% 57% 0.001
Non-responders to corticotropin Non-responders to corticotropin (N = 229)(N = 229)
-Annane et al -Annane et al JAMAJAMA 288:862, 2002 288:862, 2002
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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
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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
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Mortality Reduction in Human SepsisMortality Reduction in Human Sepsis
TargetTarget RRR (%) RRR (%)
EndotoxinEndotoxin 6 6
TNFTNF 9 9
IL-1IL-1 15 15
Activated Protein C 20 Activated Protein C 20
SteroidsSteroids 16 16
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Survival of Baboons FollowingSurvival of Baboons FollowingChallenge with Challenge with E. coli E. coli
GentamicinGentamicin 0/6 0/6
Gentamicin + Bay x1351Gentamicin + Bay x1351 6/6 6/6
- Hinshaw et al, - Hinshaw et al, Circ Shock 30:279, 1990Circ Shock 30:279, 1990
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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
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Staging in Oncology Stratifies by:Staging in Oncology Stratifies by:
• Risk of adverse outcomeRisk of adverse outcome
• Potential to benefit from Potential to benefit from therapytherapy
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The PIRO Staging SystemThe PIRO Staging System
• Pre-existing conditionsPre-existing conditions
• InsultInsult
• ResponseResponse
• Organ dysfunctionOrgan dysfunction
SCCM/ESICM Conference, Dec. 2001SCCM/ESICM Conference, Dec. 2001
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““Genetic and environmental influences Genetic and environmental influences on premature death in adult adoptees”on premature death in adult adoptees”
- Sorensen TI et al; - Sorensen TI et al; N Engl J MedN Engl J Med 318:727, 1988 318:727, 1988
• 960 Danish families960 Danish families
• Children born 1924 – 1926Children born 1924 – 1926
• Early adoption into biologically Early adoption into biologically
unrelated familyunrelated family
• Early deaths in children and parentsEarly deaths in children and parents
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Risk of Death: Risk of Death: Cause of Death of Adoptive ParentCause of Death of Adoptive Parent
RRRR 95% CI95% CI
All causesAll causes 1 1
Natural causesNatural causes 1 1
InfectionInfection 1 1
CardiovascularCardiovascular 3.023.02 0.72 – 12.8 0.72 – 12.8
CancerCancer 5.165.16 1.20 – 22.2 1.20 – 22.2
- Sorensen et al - Sorensen et al N Engl J MedN Engl J Med 318:727, 1988 318:727, 1988
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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
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InsultInsult
• Infection – primary, secondary, Infection – primary, secondary,
tertiarytertiary
• EndotoxinEndotoxin
• Injury, ischemiaInjury, ischemia
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Followup Study of HA-1AFollowup Study of HA-1A(2199 Patients)(2199 Patients)
All patients 36% 38% 0.19All patients 36% 38% 0.19
Gram negative 32% 33% 0.86Gram negative 32% 33% 0.86
Gram positive 37% 41% 0.07Gram positive 37% 41% 0.07
Placebo HA-1A p.Placebo HA-1A p.14 Day Mortality14 Day Mortality
- McCloskey, - McCloskey, Ann.Intern.Med.Ann.Intern.Med. 121:1, 1994 121:1, 1994
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Corticosteroids in Septic ShockCorticosteroids in Septic Shock
Placebo Steroids p.Placebo Steroids p.
MortalityMortality 63% 53% 0.02 63% 53% 0.02
Shock Reversal 40% 57% 0.001Shock Reversal 40% 57% 0.001
Non-responders to corticotropin Non-responders to corticotropin (N = 229)(N = 229)
-Annane et al -Annane et al JAMAJAMA 288:862, 2002 288:862, 2002
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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
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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
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Baseline MOD Score
0-4 5-8 9-12 13-16 17-20 21-24
28 D
ay M
ort
ali
ty (
Per
cen
t)
0
20
40
60
80
100
PlaceboAfelimomab
*
Impact of Baseline Organ Dysfunction onImpact of Baseline Organ Dysfunction onResponse to Therapy with ~TNF AntibodyResponse to Therapy with ~TNF Antibody
*p = 0.003*p = 0.003 OR: 0.51OR: 0.51(0.32 - 0.80)(0.32 - 0.80)
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.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
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Challenges for Challenges for
Sepsis ResearchSepsis Research
• DescriptionDescription What is the disease?What is the disease?
• Staging Staging Who should be treated, with what?Who should be treated, with what?
• MarkersMarkers How do we titrate therapy?How do we titrate therapy?
• OrganizationOrganization Sepsis societiesSepsis societies
• Education Education * Clinicians and health care workers* Clinicians and health care workers
* Public* Public
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Thank you!Thank you!