Severe Sepsis and

1
Severe Sepsis and Septic Shock
John C. Marshall, MD FRCSC
December 2, 2008
St. Michaels Hospital
University of Toronto
2
Sepsis Pepsis
Hippocrates 460 370 BC
3
Fermentation caused by living organisms
Germ theory of disease
Louis Pasteur 1822 - 1895
4
An extract of the cell wall of Vibrio
cholera Endotoxin - 1894
Richard Pfeiffer
5
- MMWR 48621,1999
6
Rates of Sepsis, U.S. 1979 - 2001
- Martin, N Engl J Med 3481546, 2003
7
Epidemiology

• 750,000 cases a year
• 211,000 deaths annually

- Angus et al Crit. Care Med. 291303, 2001
8
Mortality of Sepsis
- Martin, N Engl J Med 3481546, 2003
9
Microbiology of Sepsis
- Martin, N Engl J Med 3481546, 2003
10
Sepsis
The presence of pus-forming organisms in the
bloodstream. - Stedmans Dictionary,
1974 The systemic host response to invasive
infection - ACCP/SCCM, 1992
11
ACCP/SCCM Consensus Conference 1991
Trauma
Infection
SIRS
Sepsis
Burns
Pancreatitis
Systemic Inflammatory Response Syndrome
12
Sepsis The systemic host response to
infection Severe Sepsis Sepsis organ
dysfunction Septic Shock Sepsis
hemodynamic instability
- Bone et al Crit Care Med 22864, 1992
13
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

14
How does sepsis kill?
15
Lipopolysaccharide (Endotoxin)
16
Susceptibility to LPS is Transferred with Bone
Marrow Cells
C3H HeJ (Resistant)
C3H HeN (Sensitive)
- Michalek, J.Infect.Dis. 14155, 1980
17
Susceptibility to LPS is Transferred with Bone
Marrow Cells
C3H HeJ (Resistant)
C3H HeN (Sensitive)
IRRADIATION CROSSOVER BONE MARROW TRANSPLANT
LPS
- Michalek, J.Infect.Dis. 14155, 1980
18
Susceptibility to LPS is Transferred with Bone
Marrow Cells
C3H HeJ (Resistant)
C3H HeN (Sensitive)
IRRADIATION CROSSOVER BONE MARROW TRANSPLANT
LPS
HeJ Marrow Live
HeN Marrow Die
- Michalek, J.Infect.Dis. 14155, 1980
19
Toll-like Receptors
TLR2 Lipoteichoic acid, Bacterial
lipoprotein, Injured tissue TLR3 Double-stranded
RNA TLR4 Endotoxin, elastase, heparan,
HSP60 TLR5 Flagellin TLR6 Mycoplasma
lipopeptide TLR7 Imiquod, viral DNA TLR8 Viral
DNA, single-strand RNA TLR9 Bacterial DNA
20
Activation of NF?B by LPS
TLR4
MD-2
Cytoplasm
MyD88
IRAK
TRAF6
TAK1/TAB1
NIK
IKK?/IKK?
I?B?
Ubiquitination degradation
p65
p50
NF?B
Nucleus
21
(No Transcript)
22
Mediators of Lethality in Murine Endotoxemia
Cytokines IL-1, IL-12, IL-18 TNF, IFN?, TGFß,
LIF,MIF, G-CSF, HMGB-1, MIP-1a, MFP-14, LBP,
PTH-RP IL-1ra, IL-4, IL-10, IL-13, IFNa, 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 PAF,
PLA2 Vitamin B12, Vitamin D3 Signal hck,
COX-2, p38, jnk, NF?B, iNOS, caspase-3
transduction Stat4, Stat6, I?B, HSP70,
hemoxygenase Coagulation PAI 1, Tissue
Factor Factors TFPI, APC
- Marshall Nature Rev Drug Disc 2391, 2003
23
The Multiple Organ Dysfunction Syndrome (MODS)
.. The major limiting factor after injury in
patients who do not have brain injury is not so
much a system, but rather a combination of events
that can best be called multiple systems
failure.
- A.E. Baue, Arch Surg 110779-781, 1975
24
Treatment of Sepsis

• Intravenous fluids
• Vasoactive drugs
• Antibiotics
• Surgical source control
• Organ system support
• ??? Therapy targeting biologic mediators

25
Sepsis Management Guidelines

• International Sepsis Forum

Intensive Care Medicine 27 (Suppl) 2001
www.sepsisforum.org
Surviving Sepsis Campaign
ESICM/SCCM/ISF
26
Early Goal-directed Therapy for Septic Shock
Standard Goal-Directed (N133)
(N130) MVO2 65.311.4
70.410.7 APACHE II
15.96.4 13.06.3 Mortality
46.5 30.5

plt0.02
- Rivers, N Engl J Med 3451368, 2001
27
(No Transcript)
28
Ventilation with lower tidal volumes as compared
with traditional tidal volumes for acute lung
injury and the acute respiratory distress syndrome
Mortality ()
Controls 39.8 Volume-limited 31.0
P0.007
ARDSNet NEJM 3421301, 2000
29
(No Transcript)
30
(No Transcript)
31
Endotoxin Activity (ICU Patients)
32
Randomized Trial of HA-1A in Sepsis
Mortality
Placebo HA-1A p.
All patients 43 39
0.24 Gram negative 49
32 0.014 Gm -ve shock 57
33 0.017
- Ziegler, N.Engl.J.Med. 324429, 1991
33
Followup Study of HA-1A (2199 Patients)
14 Day Mortality
Placebo HA-1A p.
All patients 36 38
0.19 Gram negative 32 33
0.86 Gram positive 37 41
0.07
- McCloskey, Ann.Intern.Med. 1211, 1994
34
TNFa TNFß (lymphotoxin)

• 26 kDa cell surface molecule
• 17 kDa secreted molecule
• Two receptors TNFR1 (p55), TNFR2 (p75)

35
The Cytokine Response to Endotoxin Challenge
36
Survival of Baboons Following Challenge with E.
coli
Gentamicin 0/6 Gentamicin Bay
x1351 6/6
- Hinshaw, Circ Shock 30279, 1990
37
Cytokine Levels in Human Sepsis
Median (pg/ml) Range TNF 83
7 57,151 IL-6 965 8
1,553,435 IL-8 2130 16 651,338
- MONARCS, Unpublished
38
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)
p0.02
39
Influence of Infectious Challenge on Response to
Neutralization of TNFa
LPS
N256
E. coli
N56
CLP
N23
S. aureus
N14
Grp. B Strep.
N10
S. pneumoniae
N21
-40
-20
0
20
40
60
Absolute Risk Reduction ()
- Lorente Marshall, Shock 24 (Suppl)107, 2005
40
Salmonella
N11
Candida
N14
Listeria
N10
M. tuberculosis
N11
-40
-30
-20
-10
0
10
20
30
Absolute Risk Reduction ()
- Lorente Marshall, Shock 24 (Suppl)107, 2005
41
Nature 2000404518
Protein C

• Hepatic synthesis
• Activated by thrombinthrombomodulin
• Inhibits Factors Va, VIIIa

42
Actions of Activated Protein C

• Anti-thrombotic Inhibits microvascular
  coagulopathy
• Anti-inflammatory EPCR transduces
  anti-inflammatory signal
• Anti-apoptotic Inhibits endothelial cell
  apoptosis

43
rhAPC Reduces Mortality in Sepsis
-Bernard et al NEJM 344649, 2001
44
Bleeding Complications
Placebo 2.0 rhAPC 3.5
P0.06
45
- Davidson et al N Engl J Med 3471036, 2002
46
Corticosteroids in Septic Shock
Non-responders to corticotropin (N 229)
Placebo Steroids p. Mortality
63 53 0.02 Shock Reversal
40 57 0.001
-Annane et al JAMA 288862, 2002
47
Effects of L-NMMA on Survival in Septic Shock
100
80
Placebo
60
Percent Surviving
40
L-NMMA
plt0.001 Wilcoxon
20
0
0 7 14
21 28
Day of Study
- Lopez, Crit Care Med 3221, 2004
48
Dose-dependent Effects of L-NMMA on Survival
All doses
lt5 mg/kg/hr
gt 5mg/kg/hr
0 1 2 3
4 5 6
Study Drug Better
- Lopez, Crit Care Med 3221, 2004
49
Mortality Reduction in Human Sepsis
Target RRR () Endotoxin
6 TNF 9 IL-1 15 Activated
Protein C 20 Steroids 16
50
Survival of Baboons Following Challenge with E.
coli
Gentamicin 0/6 Gentamicin Bay x1351
6/6
- Hinshaw et al, Circ Shock 30279, 1990
51
Sepsis Syndrome (Bone et al 1987)

• Suspected or proven infection, in association
  with
• Tachycardia
• Tachypnea
• Hyper- or hypothermia
• Dysfunction of one or more organs

52
Staging in Oncology Stratifies by

• Risk of adverse outcome
• Potential to benefit from therapy

53
The PIRO Staging System

• Pre-existing conditions
• Insult
• Response
• Organ dysfunction

SCCM/ESICM Conference, Dec. 2001
54
Genetic and environmental influences on
premature death in adult adoptees - Sorensen
TI et al N Engl J Med 318727, 1988

• 960 Danish families
• Children born 1924 1926
• Early adoption into biologically unrelated
  family
• Early deaths in children and parents

55
Risk of Death Cause of Death of Adoptive Parent
RR 95 CI All causes 1 Natural
causes 1 Infection 1 Cardiovascular 3.0
2 0.72 12.8 Cancer 5.16 1.20 22.2
- Sorensen et al N Engl J Med 318727, 1988
56
Risk of Death Cause of Death of Biologic Parent
RR 95 CI All causes 1.71 1.14
2.57 Natural causes 1.98 1.25
3.12 Infection 5.81 2.47
13.7 Cardiovascular 4.52 1.32
15.4 Cancer 1.19 0.16 8.99
- Sorensen et al N Engl J Med 318727, 1988
57
Insult

• Infection primary, secondary, tertiary
• Endotoxin
• Injury, ischemia

58
Followup Study of HA-1A (2199 Patients)
14 Day Mortality
Placebo HA-1A p.
All patients 36 38
0.19 Gram negative 32 33
0.86 Gram positive 37 41
0.07
- McCloskey, Ann.Intern.Med. 1211, 1994
59
(No Transcript)
60
Corticosteroids in Septic Shock
Non-responders to corticotropin (N 229)
Placebo Steroids p. Mortality
63 53 0.02 Shock Reversal
40 57 0.001
-Annane et al JAMA 288862, 2002
61
Impact of Source Control in Patients with Low
IL-6 Levels
Source Control Mortality Adequate
126 (23.1) (N545) Inadequate
48 (39.7) (N121)
plt0.001
62
Impact of Source Control in Patients with High
IL-6 Levels
Source Control Mortality Adequate
177 (42.3) (N419) Inadequate
40 (47.1) (N85)
p0.49
63
Impact of Baseline Organ Dysfunction on Response
to Therapy with TNF Antibody
p 0.003 OR 0.51 (0.32 - 0.80)
64
Response to Drotrecogin a as a Function of Number
of Organ Failures
1690
All patients One OF 2 OF 3 OF 4 OF 5 OF
418
543
432
235
61
65
Challenges for Sepsis Research

• Description What is the disease?
• Staging Who should be treated, with what?
• Markers How do we titrate therapy?
• Organization Sepsis societies
• Education Clinicians and health care workers
• Public

66
Thank you!