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To Ενδοθήλιο στη Σήψη
Σ. Ορφανός
Β’ Κλινική Εντατικής Θεραπείας Π.Γ.Ν. ΑΤΤΙΚΟΝ
Sepsis: An Urgent Healthcare Challenge More than 1400 people lose their lives to severe sepsis every day.
Definitions (ACCP/SCCM, 1991)
• Systemic Inflamatory Response Syndrome (SIRS): The systemic inflammatory response to a variety of severe clinical insults (For example, infection).
• Sepsis: The systemic inflammatory response to infection.
Relationship Between Sepsis and SIRS
TRAUMA
BURNS
PANCREATITIS
SEPSIS SIRS INFECTION SEPSIS
BACTEREMIA
Severe Sepsis
• Major cause of morbidity and mortality worldwide. • Leading cause of death in noncoronary ICU. • 11th leading cause of death overall.
• More than 750,000 cases of severe sepsis
in US annually.
Definitions (ACCP/SCCM):
• Multiple Organ Dysfunction Syndrome (MODS): The presence of altered organ function in an acutely ill patient such that homeostasis cannot be maintained without intervention.
Stages In the Development of SIRS (Bone, 1996)
• Stage 1. In response to injury / infection, the local environment produces cytokines.
• Stage 2. Small amounts of cytokines are released into the circulation: • Recruitment of inflammatory cells. • Acute Phase Response. • Normally kept in check by endogenous anti-inflammatory
mediators (IL-10, PGE2, Antibodies, Cytokine receptor antagonists).
Stages In the Development of SIRS
• Stage 3. Failure to control inflammatory cascade: • Loss of capillary integrity. • Stimulation of Nitric Oxide Production. • Maldistribution of microvascular blood flow.
• Organ injury and dysfunction.
Challenge of SIRS/MOF
• Gap between Pathophysiology and Diagnosis
• Gap between Mechanisms and Treatment
• Gap between Basic Science and Clinical Implementation
• Nonlinear Behavior => Complexity
High-risk vs
Low-risk
Sepsis is like pornography. It’s hard to define but you know it when you see it.
Clear vs
Unclear
Courtesy of Pr. J.D. Catravas
Courtesy of Pr. J.D. Catravas
Copyright ©2007 American Heart Association
Aird, W. C. Circ Res 2007;100:174-190
Copyright ©2007 American Heart Association
Aird, W. C. Circ Res 2007;100:174-190
ECs in the heart
Copyright ©2007 American Heart Association
ECs in the lung
Copyright ©2007 American Heart Association
ECs in the lung
Copyright ©2007 American Heart Association
Aird, W. C. Circ Res 2007;100:174-190
ECs in the lung
Intensive Care Med 2004; 30:1702
Anti-adhesive, anti-coagulant, fibrinolytic NO, PGI2, AT II,
TxA2, ET-1
O2, CO2
Alveolus
RBC PMN
Plt
Lymphatic drainage
caveolae Aquaporins
Vascular tone
Permeability
Gas exchange VSMC
Vessel
EC
Maniatis et al. Vascul Pharmacol 2008
NF-κB
TNF-α IL-1
LPS
Vascular
Endothelium
Neutrophil
Monocyte
TLR chemokines
eNOS ECE COX-1
NO PGI2
ET-1
smooth muscle
relaxation
constriction
Vasodilation Vasoconstriction
LPS LPS
TxA2
adhesion molecules ACE
ANG II BK
B2
ROS
LBP
iNOS
PGI2
ONOO-
COX-2 ECE
ET-1 NO
ROS
TxA2
hypoxia
LPS
Intensive Care Med 2004; 30:1702
Mediators of Septic Response
Pro-inflammatory Mediators
• Bacterial Endotoxin • TNF-α • Interleukin-1 • Interleukin-6 • Interleukin-8 • Platelet Activating Factor (PAF) • Interferon-Gamma • Prostaglandins • Leukotrienes • Nitric Oxide
Anti-inflammatory Mediators
• Interleukin-10 • PGE2 • Protein C • Interleukin-6 • Interleukin-4 • Interleukin-12 • Lipoxins • GM-CSF • TGF • IL-1RA
Pathophysiology of Sepsis-Induced Organ Injury
• Multiple Organ Dysfunction (MODS) and Multiple Organ Failure (MOF) result from diffuse cell injury / death resulting in compromised organ function.
• Mechanisms of cell injury / death: • Cellular Necrosis (ischemic injury). • Apoptosis. • Leukocyte-mediated tissue injury. • Cytopathic Hypoxia
Pathophysiology of Sepsis-Induced Ischemic Organ Injury
• Cytokine production leads to massive production of endogenous vasodilators.
• Structural changes in the endothelium result in extravasation of intravascular fluid into interstitium and subsequent tissue edema.
• Plugging of select microvascular beds with neutrophils, fibrin aggregates, and microthrombi impair microvascular perfusion.
• Organ-specific vasoconstriction.
Infection
Microbial Products (endotoxin)
Cellular Responses
Oxidases Platelet
Activation Kinins
Complement
Coagulopathy/DIC Vascular/Organ System Injury
Multi-Organ Failure
Death
Coagulation Activation
Cytokines TNF, IL-1, IL-6
Pathogenesis of Severe Sepsis:
Pathogenesis of Vasodilation in Sepsis
• Loss of Sympathetic Responsiveness: • Down-regulation of adrenergic receptor number and
sensitivity, possible altered signal transduction.
• Vasodilatory
• Endotoxin has direct vasodilatory effects.
• Increased Nitric Oxide Production. • Inflammatory Mediators.
NF-κB
TNF-α IL-1
LPS
Vascular
Endothelium
Neutrophil
Monocyte
TLR chemokines
eNOS ECE COX-1
NO PGI2
ET-1
smooth muscle
relaxation
constriction
Vasodilation Vasoconstriction
LPS LPS
TxA2
adhesion molecules ACE
ANG II BK
B2
ROS
LBP
iNOS
PGI2
ONOO-
COX-2 ECE
ET-1 NO
ROS
TxA2
hypoxia
LPS
Intensive Care Med 2004; 30:1702
Endothelial Leukocyte Interactions in Sepsis • Endothelial cell expression of Selectins and CAMs is
upregulated in Sepsis due to inflammatory activation. • Selectins bind carbohydrate ligands on the surfaces
of PMN’s.
• ICAM bind Integrins on the surfaces of PMN’s.
• The Selectins initiate a weak bond between the PMN and the endothelial cell causing PMN’s to tumble along the vessel wall.
Pathogenesis of Endothelial Cell Dysfunction in Sepsis
• Binding of leukocytes to ICAM leads to transmigration of PMN’s into interstitium.
• Transmigration disrupts normal cell-cell adhesions resulting in increased vascular permeability and tissue edema.
• Vascular permeability is also increased by several types of inflammatory cytokines.
Pulmonary Endothelium
Macrophage
Neutrophil Lumen
IL-1 TNF-α
LPS
LPS
rolling
transmigration
IL-1
IL-1
TNF-α
prothrombotic
TNF-α
infection
PAF cytokines TxA2
NO, PGI2 t-PA
growth factors
L-selectin
E & P-selectins ET-1 L-selectin CD11/CD18
ICAM-1
adhesion β2-integrins
antithrombotic
ROS Proteases
ET-1
chemokines
IL-1
PSGL-1 capture
PECAM-1
Intensive Care Med 2004; 30:1702
Leukocyte-Mediated Tissue Injury
• Transmigration and release of elastase and other degradative enzymes can disrupt normal cell-cell connections and normal tissue architecture required for organ function.
• Reactive oxygen species cause direct cellular DNA and membrane damage and induce apoptosis.
NF-κΒ
PMN-PLT complex
ROS
Mediators
Myosin
Actin cytoskeletal contraction
Adhesion molecules
iNOS
RhoA
MLCK
Ca2+ AT I AT II
Ο2-
ΝΟ
-ΟΝΟΟ
Gap junction
P-selectin ACE
HSP-90
Ca2+
TNF-α
AJ disassembly
Fyn
Fluid, PMN
Maniatis & Orfanos Curr Opin Crit Care 2008
Apoptosis in Sepsis
• A physiologic process of homeostatically-regulated programmed cell death to eliminate dysfunctional or excessive cells.
• A number of inflammatory cytokines, NO, low tissue perfusion, oxidative injury, LPS, and glucocorticoids all are known to increase apoptosis in endothelial and parenchymal cells.
• Levels of circulating sfas (circulating apoptotic receptor) and nuclear matrix protein (general cell death marker) are both elevated in MODS.
Microvascular Plugging in Sepsis • Decreased red cell deformability in inflammatory states.
• Microvascular sequestration of activated leukocytes and platelets.
• Sepsis is a Procoagulant State.
• The extrinsic pathway may be activated in sepsis by
upregulation of Tissue Factor on monocytes or endothelial cells.
• Fibrinolysis appears to be inhibited in sepsis by upregulation of
Plasminogen Activator Inhibitor. • A variety of pathways result in reduced Protein C activity in
sepsis.
PMN adhesion , AT II, TxA2, ET-1
O2, CO2
Alveolar edema
RBC
PMN
Plt-PMN complex
Lymphatic drainage
caveolae Aquaporins
vasoconstriction
Clotting
Hyaline membrane
Cytokines Proteolytic
enzymes Thromboxane A2
Increased permeability
Hypoxemia EC
VSMC
Maniatis et al. Vascul Pharmacol 2008
Therapy For Sepsis
Experimental Therapies in Sepsis • Modulation of Host Response
• Targeting Endotoxin
• Anti-endotoxin monoclonal antibody failed to reduce mortality in gram negative sepsis.
• Neutralizing TNF • Excellent animal data. • Large clinical trials of anti-TNF monoclonal
antibodies showed a very small reduction in mortality (3.5%).
Experimental Therapies in Sepsis • Modulation of Host Response
• IL-1 Antagonism
• Three randomized trials: Only 5% mortality improvement.
• PAF-degrading enzyme • Great phase II trial. • Phase III trial stopped due to no demonstrable efficacy.
• NO Antagonist (LNMA)
• Increased mortality (? Pulmonary Hypertension).
Experimental Therapies in Sepsis • Modulation of Host Response
• Antithrombin III
• No therapeutic effect. • Subset of patients with effect when concomitant heparin
not given.
• Activated Protein C (Drotrecogin alpha / Xigris) • Statistically significant 6% reduction in mortality. • Well-conducted multicenter trial (PROWESS). • FDA-approved for use in reduction of mortality in severe
sepsis (sepsis with organ failure).
NF-κΒ
APC
Adhesion molecules
iNOS
Apoptosis
Barrier protection
PC PAR-1
TM
Thrombin Neutrophil
Endothelial Cell
EPCR
Actin cytoskeleton
Orfanos et al. 2008 Yearbook Intensive Care & Emergency Med
PULMONARY METABOLISM STUDIES in
Humans
NF-κB
TNF-α IL-1
LPS
Vascular
Endothelium
Neutrophil
Monocyte
TLR chemokines
eNOS ECE COX-1
NO PGI2
ET-1
smooth muscle
relaxation
constriction
Vasodilation Vasoconstriction
LPS LPS
TxA2
adhesion molecules ACE
ANG II BK
B2
ROS
LBP
iNOS
PGI2
ONOO-
COX-2 ECE
ET-1 NO
ROS
TxA2
hypoxia
LPS
Intensive Care Med 2004; 30:1702
Assessing Pulmonary Endothelial Angiotensin Converting Enzyme Activity
In Vivo • Pulmonary Capillary Endothelium Bound Angiotensin Converting Enzyme
(PCEB-ACE) is homogeneously expressed on the luminal endothelial surface area (ectoenzyme)
• Due to its location, PCEB-ACE is directly accessible to blood-borne substrates and inhibitors; its activity may be assessed by means of indicator-dilution techniques
• PCEB-ACE activity has been shown to be a sensitive and quantifiable index of pulmonary endothelial function in both animals and humans, in health and disease
THE BASIC PRINCIPLE 3H-Benzoyl-Phe-Ala-Pro
ACE 3H-Benzoyl-Phe
LIS = 2.7
LIS = 1.7
Circulation 2000; 102:2011
Circulation 2000; 102:2011
Circulation 2000; 102:2011
Circulation 2000; 102:2011
SUBJECTS & METHODS
Applying indicator-dilution type techniques, we estimated PCEB-ACE activity in nineteen (19) suffering from septic ALI/ARDS.
All patients were on severe sepsis-septic shock Patients were subsequently divided in survivors (N=9;
28-day survival) and non-survivors (N=10). Both groups were balanced for sex and age
survivors non-survivors0.00
0.40
0.80
1.20
subs
trat
e hy
drol
ysis
(v)
0
10
20
30
40
50
subs
trat
e %
met
abol
ism
v % M
*
*
survivors non-survivors0
60
120
180
240
300
PaO
2/FiO
2 (m
mH
g)
0
1
2
3
4
Lung
Inju
ry S
core
PaO2/FiO2 LIS
survivors non-survivors0
10
20
30
40
50
APA
CH
E II
scor
e
0
6
12
18
24
SOFA
sco
re
APACHE II SOFA
*
Acknowledgements
• E. Psevdi A. Kotanidou • I. Mavrommati N. Maniatis • C. Glynos • P. Kaltsas • I. Korovesi • Ch. Athanasiou • K. Kaziani • O. Livaditi
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