Get documents about "Intracellular signaling pathways of Innate Immunity “to Toll-Like
Document Sample
The Treatment of Sepsis:
Slow progress, but
continued hope
S. M. Opal, MD
ID noon time lecture
Aug 27, 2007
Martin et al. N Engl J Med 2003;348:1546 3 fold increase
21 yr CDC study: 10
million cases of
severe sepsis in USA
Incidence of Severe Sepsis by Age
120,000 30
Incidence/1,000 Population
100,000 Number of cases 25
Incidence rate
80,000 20
Cases
60,000 15
40,000 10
20,000 5
0 0
<1 1 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85+
Age/Years
35% decrease in
I----27.8%---I overall mortality
rate over 22 years
I----17.9%---I
LPS Mj
Early Signaling Events
of Innate Immunity
3’
DNA NFkB nuclear
localization
sequence
5’
5’
3’
Host response-antimicrobial
defense programs
TLR LPS signaling pathways
LPS 4
in human monocytes
LBP CD
14
MD2
TRAM
IFNb
MyD88 Mal P
IRAK4 IRAK1
“Fast” LPS
RIP-1
signaling
TRAF6 TAB1,2
pathway JAK
PI3K TAK1 “Slow” LPS
IKK g signaling
TRAF6
MKK6 a b pathway P
NFkB IRAK1
MKK7 Stat 1
p65 p50
TBK1
IkB JNK
P38, ERK1
p300
IRF-3
P
p65 p50 c-Jun p300
p300
IRF-3 IRF-3
Cytokines,
CD80, CD83 APP, NOS IFN-response genes
OMP, PGN LPS
flagellin TLR Pathogen –
BLP MALP TLR 4 RP associated
5 105 Molecular
TLR TLR CD
2 6 MD2 14 CD pattern
19
CD MD1 receptors
TLR 36
1
B cells
CD
14
Endosome
Cytosol PGN-DAP
CpG DNA
dsRNA
CARD NOD LRR ssRNA
NOD1 TLR ssRNA TLR
3 TLR 9
NOD2 7/8
PGN-MDP
m/h
NFkB JNK
p38
p300
IRF-3
p65 p50 c-Jun p300
creb torc IRF-3 IRF-3
Cyokines,
CD80, CD83 APP, NOS IFN-response genes
Polymorphisms in TLR4
Hypothetical
Model of TLR4
With common
polymorphisms at
D299G and T399I
WT Double mutant
Rallabhandi et al
J Immunol
2006;177:322
Docking
site?
Clotting and innate immunity are highly
integrated and contribute to sepsis
Hepatic Microcirculation-
baseline
30 min post sublethal dose LPS
Intravascular fibrin
PMN-platelet
aggregates
Receptor downregulation (TLR 4, TNFR, HLA-DR)
Soluble (sIL1,6,TNFr) and decoy receptors (IL-1R2)
Receptor antagonists (IL-1ra)
Anti-inflammatory cytokines (IL-4,10,13)
Intracellular inhibitors (SOCS, IkB, Tollip, MyD88s)
Cellular apoptosis of B cells CD4 T cells and FDCs
Sepsis-induced immunosuppression
(Hotchkiss and Karl N Engl J Med 2003;348:138)
The Diagnosis of Sepsis
• No single lab test, biomarker, clinical finding or
hemodynamic event is sufficient to make a unequivocal
diagnosis for sepsis
• Clinical Diagnosis of an invasive infection (with or without
bloodstream invasion) + a deleterious host response - fever
(or hypothermia), leukocytosis (or neutropenia), tissue
hypoperfusion with or without systemic hypotension
– multiorgan involvement- DIC, ATN, ARDS, CNS
dysfunction, Lactic acidosis, hepatic dysfunction
– Shock- fluid non-responsive hypotension (BP<90/60) with
early hyperdynamic cardiovascular response (high CO,
normal Lt Atrial filling pressure, Low SVR)
Surviving Sepsis Campaign - Evidence based review of the
medical literature - 2007
Initial evaluation and resuscitation (The golden Six Hours)
• Measure blood lactate
• Blood cultures before antibiotics
• Broad spectrum antibiotics to cover likely pathogens
within 1 hour of presentation
• If systolic BP<90 mmHg, or MAP<65 mmHg or lactate
>4 mmolar, initial fluid resuscitation with 20-40 ml/kg
• Vasopressors for hypotension during & after initial
fluid resuscitation
• Inotropic agents (and/or PRBCs if Hct <30%)
delivered for ScVO2<70% if CVP>8
• 6 hour Goals: CVP 8-12 mmHg; ScVO2>70%; MAP>65
mmHg and blood Lactate normalizing
Septic Shock: Flow-dependent O2 Uptake in the
microcirculation-failure of autoregulation
Diffuse vasodilation,
Distributive
inflammation,
hypoxia followed
intravascular fibrin, tissue
by tissue dysoxia
hypoperfusion,
and cytopathic
myocardial depression
hypoxia
Arterial Hemoglobin-
Mixed venous
O2 saturation-Normal
hemoglobin-O2
> 95%
saturation (SVO2) <70%
O2 content high
O2 content very low
microcirculation
Early Goal-Directed Therapy for Severe Sepsis/Septic Shock
60
EGT in patients Standard Therapy EGT
with severe 50
Mortality (%)
sepsis produced 40
the following:
– 42% in relative 30
risk of 28-day
mortality (P=0.009) 20
– 33% in relative
risk of death at 60 10
days (P=0.03)
• NNT to prevent 1 0
death = 6-8 In-hospital 28-day mortality 60-day mortality
mortality (all
patients) SVO2 >70% and MAP 65 mm Hg in 6 hr
1o end-point
Rivers E, et al. N Engl J Med 2001;345:1368-77
5-10% increase in mortality for every hour delay of
antibiotic Rx after onset of septic shock
(95% Confidence Interval)
100
Odds Ratio of Death
10
1
1-
2-
3-
4-
5-
6-
9-
12
24
>3
1.
2.
3.
4.
5.
8.
11
-2
-3
6
99
99
99
99
99
99
3.
5.
.9
9
99
99
(N=2731 ICU patients)
Time (hrs)
Kumar et al. Crit Care Med 2006; 34: 1458
Current targets for therapeutic intervention in sepsis
1 PAMP’s Microbial Mediators
Phospholipids
Immune effector
cells
Early host Chemokines
2 mediators
Cytokines
3 Platelet-fibrin
clots Late host
4 mediators
MIF HMGB-1 Proteases
5
24 Hour Sepsis Bundle:
• Intensive Insulin Rx in Critically Ill Patients
– NEJM 2001;345:1359-67; NEJM 2006;354:449
• Low T V ventilation; keep the lungs dry post-resuscitation
– NEJM 2000;342:1301-8; NEJM 2006;354:2564
• Activated Protein C for Severe Sepsis
– NEJM 2001; 344:699-709; NEJM 2005;353:1332; Lancet 2007;
• Hydrocortisone and Fludrocortisone for Septic Shock
– JAMA 2002; 288:862-71; Corticus (unpublished data)
• Remove septic focus and source control asap
• Feed early and enterally if possible
• Provide DVT prophylaxis and elevate the head of the bed
The next 24 hr. - Conservative fluid strategy
Furosemide
UOP < 0.5 ml/kg/h & MAP < 60
CVP or PAOP low Low flow by exam or CI <2.5
KIDNEY
CVP < 4
Favors
PAOP < 8
Dry
LUNG
Or the Liberal fluid strategy ?
Fluids
FiO2 > 0.7 CI > 4.5
Wet
Favors
LUNG CVP 10-14 Perfused
PAOP 14-18 KIDNEY
(organs)
FACTT trial-favors dry
lung (NEJM 2006:354:2564)
Intensive Insulin Therapy in Critically Ill Patients
Van den Berghe et al. Intensive Insulin in Critically Ill Patients. NEJM 2001;345:1359
All
patients
If in ICU>3 days
(Van den Berghe et al.
NEJM 2006;354:449)
rh Activated Protein C in severe sepsis (PROWESS)
100
Bernard et al. NEJM 2001; 344:699
Percent Survivors
90
Drotrecogin Alfa (activated)
(N=850)
80
Placebo
(N=840)
70
p=0.006 (stratified log-rank test)
0
0 7 14 21 28
Days from Start of Infusion to Death
The ADDRESS trial – rhAPC in severe sepsis at
low risk of death (NEJM 2005;353:1332)
Placebo did better the rhAPC
even when APACHE 2 > 24
Additional clinical trials with rhAPC: ENHANCE (no placebo); ADDRESS
low risk of death study; Xpress trial (rhAPC+/-heparin); RESOLVE trial
placebo-controlled trial in pediatrics
Activated Protein C - Mechanisms of Activity
Co agulation Neutrophil
C ascade
X Adhesion
PAI-1
TAFI
X
VIIIa M onocyte
X Increased F ibrinolysis Activation
2 X
Va X 11 3
Prothrom bin
PC
Th rom bin 4
4
Th rom bin aPC P EPCR
PAR S CD1/
Th ro m b om od ulin MH C
Fibrin/Platelets
A PC
Receptor
Cell activation Anti-apoptotic
Effect of Treatment With
Low Doses of
Hydrocortisone and
Fludrocortisone on
Mortality in Patients With
Septic Shock
But: the Corticus trial
(n=600)
Significantly improved NS ?Worse outcome in responders
recovery for septic shock
but no improvement in
overall survival (the
primary endpoint)
(Annane et al. JAMA 2002; 288:862)
Therapy for severe sepsis/septic shock in 2007
Standard care for sepsis Consider for sepsis
• Early goal directed therapy • Intensive insulin-
• Rapidly culture and treat euglycemia (if feasible)
for likely pathogens • rhAPC (? Another trial)
• Source control • Stress dose steroids (low
risk, low cost ?efficacy)
• Optimize supportive care • Hemoperfusion,
and monitoring diafiltration columns (?
• Fluids, nutrition, DVT and Needs to be studied)
aspiration prevention • Participate in clinical trials-
still lots of room for
improvement
Current overall mortality 25-35% severe sepsis- 40-45% for
septic shock managed in the ICU
MKSAP questions: #1
• 30 yo man with no significant PMH presents with a 1 day hx of
increasing pain in right leg 2 days after a splinter was removed from
his rt thigh. Initial exam is unremarkable other than marked thigh
tenderness. Lab studies in ER normal expect CT scan evidence FB
in thigh with some stranding and edema rt thigh. He now develops
acute deterioration BP 60/0 and renal and hepatic insufficiency.
• The most appropriate empiric antibiotic choice at this point is ?:
– 1) Nafcillin and aztreonam
– 2) Nafcillin and clindamycin
– 3) Nafcillin and piperacillin-tazabactam
– 4) Vancomycin and clindamycin
– 5) Piperacillin-tazabactam and gentamicin
• Correct answer is 4
MKSAP questions: #2
• 15 yo boy with no significant PMH presents with swelling and pain
after abrading his arm in a high school football game. He rapidly
develops fever, confusion, and orthostatic hypotension. Initial exam
shows marked erthyema, edema tenderness in the right arm and an
area of pale gray skin suggestive of dermal necrosis. Lab studies
show multisystem dysfunction and blood cultures are positive for
gram-positive cocci in chains.
• Which of the following prophylactic agents should be offered to the
household contacts ?:
– 1) oral Penicillin V (PCN)
– 2) IM benzathine PCN
– 3) Throat cultures followed by oral PCN
– 4) Throat cultures followed by clindamycin
– 5) No prophylaxis indicated
• Correct answer is 5
MKSAP questions: #3
• 35 yo man presents to the ER with acute onset fever, dyspnea, nausea,
vomiting, malaise, watery sputum with occasional hemoptysis. He
works as a veterinarian at a local zoo. His mother, with whom he lives,
died of an unknown type of pneumonia 4 days earlier.The USA has
just issued a code red terrorism risk in the past 7 days. Exam shows
fever, tachypnea, tachycardia and mild hypotension. Physical exam
and radiographic findings confirm a dense right sided consolidation
without any significant hilar lymphadenopathy. Therapy with
ceftriaxone and clarithromycin is not effective and the patient dies
from septic shock, DIC and respiratory failure. The laboratory calls to
report the blood cultures are now positive for an unidentified gram-
negative rod.
• The most likely bacterial pathogen is ?:
– 1) Yersinia pestis
– 2) Bacillus anthracis
– 3) Haemophilus influenzae
– 4) Francisella tularensis
– 5) Coxiella burnetti
• Correct answer is 1
