Transcript Sepsis Surgery Residents 2010

Sepsis:
Evolving Concepts
John C. Marshall, MD FRCSC
St. Michael’s Hospital
University of Toronto
Sepsis
Pepsis
Hippocrates
460 – 370 BC
Fermentation
caused by living
organisms
Germ theory
of disease
Louis Pasteur
1822 - 1895
Consequences
• Public health
• Immunization
• Sterilization
• Antibiotics
Susceptibility to LPS is
Transferred with Bone Marrow Cells
C3H HeJ
C3H HeN
(Resistant)
(Sensitive)
- Michalek, J.Infect.Dis. 141:55, 1980
Susceptibility to LPS is
Transferred with Bone Marrow Cells
C3H HeJ
(Resistant)
C3H HeN
IRRADIATION
(Sensitive)
CROSSOVER BONE MARROW TRANSPLANT
+ LPS
- Michalek, J.Infect.Dis. 141:55, 1980
Susceptibility to LPS is
Transferred with Bone Marrow Cells
C3H HeJ
C3H HeN
(Resistant)
IRRADIATION
(Sensitive)
CROSSOVER BONE MARROW TRANSPLANT
+ LPS
HeJ Marrow Live
HeN Marrow Die
- Michalek, J.Infect.Dis. 141:55, 1980
“Passive immunization
against tumor necrosis
factor/cachectin protects
mice from the lethal effects
of endotoxin.”
Bruce Beutler
Beutler, Milsark, & Cerami
Science 229:869, 1985
Consequences
• New diseases
• New therapeutic targets
• Response is the disease
• Not unique to infection
ACCP/SCCM Consensus Conference 1991
Infection
Sepsis
Trauma
SIRS
Burns
Pancreatitis
Systemic Inflammatory
Response Syndrome
Rates of Sepsis, U.S. 1979 - 2001
- Martin, N Engl J Med 348:1546, 2003
- Crit Care Med 32:858, 2004
- Crit Care Med 36:296, 2008
<8
Fluids
CVP
>8
Mean Arterial Pressure
<65
Pressors
> 65
ScvO2
Transfusion,
Inotropes
> 70
Goals achieved
The Impact of Goal-Directed
Therapy
NNT to prevent 1 death = 6-8
Mortality (%)
60
50
Standard Therapy
Goal-directed
40
30
20
10
0
Hospital
Mortality
28 Day
Mortality
60 Day
Mortality
Rivers E, et al. N Engl J Med 2001;345:1368
100
(95% CI)
Odds Ratio for Death
Impact of Delayed Antibiotic
Therapy on Clinical Outcome
10
1
Time from Onset of Hypotension
(Hours)
-Kumar, Crit Care Med 34:1589, 2006
Impact of Source Control in
1170 Patients with Sepsis
28 Day Mortality
Adequate Inadequate
31.4% (303/964)
42.7% (88/206)
Odds Ratio 0.61 (0.45-0.83)
p.
0.003
Despite conventional
treatment, 30 to 40% of septic
patients die of a process
characterized by persistent
inflammation and non-resolving
organ dysfunction.
Lipopolysaccharide (LPS)
Susceptibility to LPS is
Transferred with Bone Marrow Cells
C3H HeJ
C3H HeN
(Resistant)
IRRADIATION
(Sensitive)
CROSSOVER BONE MARROW TRANSPLANT
+ LPS
HeJ Marrow Live
HeN Marrow Die
- Michalek, J.Infect.Dis. 141:55, 1980
Toll-like Receptors
TLR2
TLR3
TLR4
TLR5
TLR6
TLR7
TLR8
TLR9
Lipoteichoic acid, bacterial
lipoprotein, Injured tissue
Double-stranded RNA
Endotoxin, elastase, heparan,
HSP60, oxidized phospholipids
Flagellin
Mycoplasma lipopeptide
Imiquod, viral DNA
Viral DNA, single-strand RNA
Bacterial DNA
Clearance of Candida is Impaired
in TLR4 Mutant C3H/HeJ Mice
Log cfu/Gm kidney
PMN/Mouse (X 106)
8
10
8
*
6
4
C3H HeN
C3H/HeJ
*
6
*
4
2
0
Day 1
C3H/HeN
C3H HeJ
Day 7
2
0
Baseline
4 Hours
- Netea, J Infect Dis 185:1483, 2002
Mediators of
Lethality in Murine Endotoxemia
Cytokines
IL-1, IL-12, IL-18, IL-27, TNF, IFN, TGFβ, LIF,MIF, GCSF, HMGB-1, MIP-1α, MFP-14, LBP, PTH-RP
IL-1ra, IL-4, IL-10, IL-13, IFNα, HGF, LIF, CRP, MCP-1,
BPI, CAP18, TSG-14, VLDL, VIP, C3, C4, melatonin
Receptors
TNFr p55, IL-1r, PAFr, LECAM-1, TREM-1, LDLr,
CD11a, CD14
VIPr, Adenosine A3r
Non-proteins
Signal
transduction
Coagulation
Factors
PAF, PLA2
Vitamin B12, Vitamin D3
hck, COX-2, p38, jnk, NFκB, iNOS, caspase-3
Stat4, Stat6, IκB, HSP70, hemoxygenase
PAI 1, Tissue Factor
TFPI, APC
- Marshall Nature Rev Drug Disc 2:391, 2003
LPS challenge in
human volunteers
causes altered
expression of 3714
distinct genes.
- Calvano, Nature 437:1032, 2005
Endotoxin
TLR4
MyD88
CD14
IRAK
TRAF2
MAP Kinases: Erk, p38, Jnk
PI3 Kinase
NFkB
Pro-inflammatory genes:
IL-1, TNF
Tissue ischemia,
Cell necrosis,
Apoptosis
PAF, Nitric oxide,
Coagulation
Endotoxin
TLR4
MyD88
CD14
IRAK
TRAF2
MAP Kinases: Erk, p38, Jnk
PI3 Kinase
NFkB
Pro-inflammatory genes:
IL-1, TNF
Tissue ischemia,
Cell necrosis,
Apoptosis
PAF, Nitric oxide,
Coagulation
Therapies Targeting Endotoxin
TLR4 Antagonists
E5564 (Eisai)
Others
CD14 Antagonists
IC14
Anti-LPS Strategies
Antibodies:
J5, HA-1A, E5
rBPI21
Polymyxin B dextran
HDL, taurolidine
Alkaline phosphatase
Lipid emulsion
Extracorporeal removal
Endotoxin
TLR4
MyD88
CD14
IRAK
TRAF2
MAP Kinases: Erk, p38, Jnk
PI3 Kinase
NFkB
Pro-inflammatory genes:
IL-1, TNF
Tissue ischemia,
Cell necrosis,
Apoptosis
PAF, Nitric oxide,
Coagulation
Endotoxin
TLR4
MyD88
CD14
IRAK
TRAF2
MAP Kinases: Erk, p38, Jnk
PI3 Kinase
NFkB
Pro-inflammatory genes:
IL-1, TNF
Tissue ischemia,
Cell necrosis,
Apoptosis
PAF, Nitric oxide,
Coagulation
Neutralization of Pro-Inflammatory
Cytokines in Sepsis
Interleukin-1 Receptor Antagonist
3 Studies; 1688 patients
28 Day Mortality
Odds Ratio: 0.80 (0.65-0.99)
p=0.04
Neutralization of Pro-Inflammatory
Cytokines in Sepsis
Anti-TNF Antibodies
8 Studies; 6500 patients
28 Day Mortality
Odds Ratio:
0.93 (0.87-0.99)
p=0.02
Endotoxin
TLR4
MyD88
CD14
IRAK
TRAF2
MAP Kinases: Erk, p38, Jnk
PI3 Kinase
NFkB
Pro-inflammatory genes:
IL-1, TNF
Tissue ischemia,
Cell necrosis,
Apoptosis
PAF, Nitric oxide,
Coagulation
Recombinant PAF Acetylhydrolase
Phase II Trial (N = 240)
28 Day Mortality (%)
Placebo
Treated
p.
28.4
14.5
0.03
Severe Sepsis
44.2
21.4
0.03
Trauma
10.5
5.9
NS
Overall
- Shuster, Crit Care Med 31:1612, 2003
Effects of L-NMMA on Survival
in Septic Shock
Percent Surviving
100
80
Placebo
60
40
L-NMMA
p<0.001
Wilcoxon
20
0
0
7
14
21
28
Day of Study
- Lopez, Crit Care Med 32:21, 2004
rhAPC Reduces Mortality in Sepsis
-Bernard et al; NEJM 344:649, 2001
Endotoxin
TLR4
MyD88
CD14
IRAK
TRAF2
MAP Kinases: Erk, p38, Jnk
PI3 Kinase
NFkB
Pro-inflammatory genes:
IL-1, TNF
Tissue ischemia,
Cell necrosis,
Apoptosis
PAF, Nitric oxide,
Coagulation
Corticosteroids in Septic Shock:
A Meta-analysis
Annane D BMJ 2004;329:480
Adjuvant Therapy in Sepsis
Anti-endotoxin Therapy
9 trials; 3057 Patients
Anti-TNF Antibodies
10 Trials; 6821 Patients
IL-1ra
3 Trials; 1688 Patients
Intravenous immune globulin
20 Trials; 2621 Patients
Activated Protein C; All Patients
2 Trials 4303 Patients
Activated Protein C; Patients with MOF
2 Trials; 2133 Patients
0.6
0.7
0.8
0.9
Experimental Agent Better
1.0
1.1
1.2
1.3
Placebo Better
- Marshall, J Leukoc Biol 83:471, 2008
But …
• Impact is modest
• Indications for use poorly
defined
Dose-dependent Effects of L-NMMA
on Survival
All doses
<5 mg/kg/hr
> 5mg/kg/hr
0
1
2
3
4
5
6
Study Drug Better
- Lopez, Crit Care Med 32:21, 2004
TNF Levels Following Infusion
8
7
TNF (ng/ml)
6
TNF MAb
Placebo
5
4
3
2
1
0
Pre
2
24
Hours Post-Infusion
72
Sepsis Syndrome
(Bone et al; 1987)
Suspected or proven infection, in
association with:
•
•
•
•
Tachycardia
Tachypnea
Hyper- or hypothermia
Dysfunction of one or more organs
Sepsis Syndrome
• 24 year old man with penetrating
injury to colon
• 86 year old woman with CHF and
Enterococcal UTI
• 51 year old man with COPD
exacerbation; Candida in sputum
The PIRO Concept
• Predisposition
• Insult
• Response
• Organ dysfunction
- Crit Care Med 31:1250, 2003
Cancer staging
stratifies by:
• Prognosis
• Potential to
respond to
treatment
Insult
Inflammatory
Response
Infection
Adaptive Injurious
Injury, Ischemia
Organ
Dysfunction
Inflammation
Iatrogenic
Risk of Death:
Cause of Death of Biologic Parent
All causes
Natural causes
Infection
Cardiovascular
Cancer
RR
95% CI
1.71
1.98
5.81
4.52
1.19
1.14 – 2.57
1.25 – 3.12
2.47 – 13.7
1.32 – 15.4
0.16 – 8.99
- Sorensen et al N Engl J Med 318:727, 1988
Tumor Necrosis Factor α
G
A; -308 (Promoter)
Author
Disease
Cases Controls p.
Nadel
Meningococcemia
(deaths)
0.56
0.29
0.03
Mira
Septic shock
(deaths)
0.52
0.24
0.008
Tang
Septic shock
(deaths)
0.40
0.08
<0.05
Mean Change in DAS28
The TNF -308A/G Polymorphism Modifies
the Response to Anti-TNF Therapy
GG
GA
AA
1
*p=0.001
0
-1
-2
*
-3
-4
Etanercept (N=455)
Infliximab (N=453)
- Maxwell, Hum Mol Genet 17:3532, 2008
Influence of Infectious Challenge on
Response to Neutralization of TNFα
LPS
N=256
E. coli
N=56
CLP
N=23
S. aureus
N=14
Grp. B Strep.
N=10
S. pneumoniae
N=21
-40
-20
0
20
40
60
Absolute Risk Reduction (%)
- Lorente & Marshall, Shock 24 (Suppl):107, 2005
Salmonella
N=11
Candida
N=14
Listeria
N=10
M. tuberculosis
N=11
-40
-30
-20
-10
0
10
20
30
Absolute Risk Reduction (%)
- Lorente & Marshall, Shock 24 (Suppl):107, 2005
Impact of Infection-Related Variables
on ICU Outcome
Infectious Focus
N
OR for
Mortality
95%
CI
Intra-abdominal
31
1.38
0.56-3.40
Pneumonia
30
1.82
0.74-4.47
Bacteremia
57
1.83
0.79-4.26
Urinary Tract
23
0.49
0.15-1.60
Impact of Source Control in
Patients with Low IL-6 Levels
Source Control
Adequate
Mortality
126 (23.1%)
(N=545)
Inadequate
48 (39.7%)*
(N=121)
* p<0.001
Impact of Source Control in
Patients with High IL-6 Levels
Source Control
Adequate
Mortality
177 (42.3%)
(N=419)
Inadequate
40 (47.1%)*
(N=85)
* p=0.49
Impact of Organ Dysfunction
on Response to Antibiotics
ICU Mortality
Adequate Inadequate
p.
LOD > 4
(N=72)
21/36 (59%)
20/36 (56%)
0.81
LOD < 4
(N=70)
2/27 (7%)
16/43 (37%)
0.006
- Clec’h, Intensive Care Med 30:1327, 2004
28 Day Mortality (Per cent)
Anti-TNF is Most Efficacious in
Patients without Organ Dysfunction
100
* p=0.003;
OR 0.51 (0.32-0.80)
80
Placebo
Afelimomab
60
40
20
*
0
0-4
5-8
9-12
13-16
17-20
21-24
Baseline MOD Score
Response to Drotrecogin α as a
Function of Number of Organ Failures
1690
All patients
418
One OF
543
2 OF
432
3 OF
235
4 OF
61
.5
5 OF
.6
.7
.8
.9
1.0 1.1 1.2
1.3 1.4
Conclusions
• Improved understanding of biology
of response to injury
• Can be translated into effective new
therapies
• The obstacle is our intrinsic
conceptual conservatism
Thank you!