Inflammatory Response:
Current Concepts
Edward R. Sherwood, M.D., Ph.D.
Department of Anesthesiology
The University of Texas Medical Branch
Shriners Hospital for Children
Galveston Burns Unit
Galveston, Texas
Inflammation
• A protective response that removes sources of
injury and facilitates tissue repair
• Uncontrolled or inappropriate inflammation can
cause injury
• Inflammation-associated injuries during the
perioperative period and the ICU
–
–
–
–
–
–
Thrombosis (myocardial infarction, stroke)
Acute lung injury, ARDS
Metabolic disturbances (hyperglycemia)
Hemodynamic dysfunction (hypotension)
End organ dysfunction (renal, hepatic insufficiency)
Pain
Classification of Inflammation
• Acute inflammation
– Occurs over hours, days or weeks
– Characterized by vasodilation, fluid exudation and
neutrophil infiltration
– Caused by acute trauma, surgery, acute infection
• Chronic Inflammation
– Occurs over weeks, months or years
– Characterized by vasodilation, fluid exudation and
mononuclear cell (lymphocyte/monocyte)
infiltrates.
– Presence of concomitant repair (fibrosis)
– Rheumatoid arthritis, atherosclerosis,
inflammatory bowel disease
Acute Inflammation
• Initiation
– Increased vascular caliber and flow
– Increased vascular permeability
• fluid exudation and edema formation
– Leukocyte infiltration (mainly neutrophils)
• Amplification
– mediated by soluble and cellular factors
• Resolution
– mediated by removal of source, antiinflammatory cytokines, cholinergic nervous
system and apoptosis
Initiation of Acute Inflammation
• Increased Vascular Diameter and Flow
– Arteriolar dilation and opening of new capillary
beds
– Functional importance
• Delivers soluble mediators and leukocytes to site of
injury
• Promotes transvascular fluid flux
– Clinical signs
• Erythema and warmth
– Pathology
• Systemic vasodilation, low systemic vascular
resistance, hypotension
Mediators of Increased Vascular
Diameter and Flow
Nitric Oxide (NO)
Vascular smooth muscle relaxation and vasodilation
Calcium influx
and eNOS
activation
Macrophage
NO
NO
eNOS
Endothelial
stimulation
Microbe
Endothelium
iNOS
Activation
stimulus
Cytotoxicity
Vasodilatory Prostaglandins
Membrane
Phospholipids
Arachidonic
Acid
Phospholipases
PGG2
Cyclooxygenase
(COX-1, COX-2)
PGI2
PGH2
PGD2
PGE2
PGF2
Initiation of Acute Inflammation
• Transvascular Fluid Flux
– Increased hydrostatic pressure causes net outflow of
fluid from vascular compartment
– Increased vascular permeability (to water, solute and
protein)
• Formation of endothelial gaps
• Formation of transcytoplasmic channels
• Direct or leukocyte-mediated endothelial injury
– Functional importance
• Delivers soluble mediators (antibodies, acute phase proteins) to
site of injury
– Clinical signs
• Edema formation
– Pathology
• ARDS, interstitial edema
Burn Shock
• Edema formation
– Increased vascular permeability
• Solutes
• Electrolytes
• Colloids
– Decreased plasma oncotic pressure
(hypoproteinemia)
• Intravascular hypovolemia
• Increased systemic vascular resistance
• Tissue hypoperfusion, metabolic acidosis
Burn Shock: Edema Formation
From Demling R, J Burn Care Rehab 26:207, 2005
Clinical Ramifications of
Transvascular Fluid Flux
Clinical Ramifications of
Transvascular Fluid Flux
Mediators of Increased
Vascular Permeability
•
•
•
•
Histamine
Bradykinin
Substance P
Leukotrienes
Membrane
Phospholipids
Arachidonic
Acid
Phospholipases
LTB4 chemotaxis
5-HPETE
5- Lipoxygenase
LTA4
LTC4 Increase
LTD4 vascular
LTE4 permeability
Initiation of Acute Inflammation
• Leukocyte (neutrophil) Infiltration
– Process
• Margination
• Rolling
• Adhesion
• Transmigration
• Chemotaxis
– Functional importance
• Phagocytosis, removal of bacteria and debris
– Pathology
• Acute lung injury, ischemia-reperfusion injury
Neutrophil Adhesion and
Chemotaxis
Rolling 1
Adherance 2
Transmigration
Lectins
 integrins
ICAM-1
Endothelium
E-selectin
P-selectin
PECAM
Apoptosis 6
Chemotaxis: 4
Phagocytosis
5
Chemokines
Bacterial products
LTB4
Adapted from Seely et al, Crit Care 7:291-307, 2003
3
Ischemia-Reperfusion Injury
2
3
4
5
1
6
Adapted from Shernan, Anesthesiology Clinics of North America 21:2003
Interactions Between
Inflammation and Coagulation
Macrophage/
Monocyte
(-)
TNF
IL-1
Endothelial
Cell
Tissue Factor
VIIa
Tissue Factor
Pathway Inhibitor(-)
Binds TF-VIIa
Complex
Degradation
of Va and VIIIa
VIIIa IXa
Xa
+
Va
Anti-Thrombin
III
Thrombin
Binds Thrombin
Intrinsic
Pathway
Activated
Protein C
Fibrin clot
Macrophage/
Monocyte
Activation
Role of Complement in Systemic
Inflammation
Adapted from Rittirsch et al, Nat Rev Immunol 8:776, 2008
Potential Thrombotic Complications Associated
with Perioperative Inflammation
• Myocardial Infarction
– Inflammation is associated with increased risk of
plaque rupture and acute coronary syndromes
• Koenig et al, Arthersler Thromb Vasc Biol 27:15, 2006
– Risk of post-operative MI associated with SNPs in
IL-6, ICAM-1,CRP and E-selectin genes
• Podgoreanu et al, Circulation 114:I275, 2006
• Stroke
– Risk of post-operative stroke in cardiac surgery
patients associated with SNPs in IL-6 and CRP
genes
• Grocott et al, Stroke 36:1854, 2005
Systemic Effects of Inflammation
Edema
Pain
Erythema
Cachexia,
Fever
Myocardial
depression
Edema
Adapted from Abbas et al, Cellular and Molecular Immunology, 2001
Metabolic
Dysfunction
The Systemic Inflammatory Response
Syndrome (SIRS) and Sepsis
Sepsis and SIRS
• Tachycardia
• Tachypnea
• Leukocytosis or
leukopenia
• Fever or hypothermia
Severe Sepsis/SIRS
• Hemodynamic alterations
– Hypotension, decreased SVR
• Tissue Hypoperfusion or
impaired oxygen utilization
– Lactic acidosis
• Organ Dysfunction
– Renal failure, mental status
changes, thrombocytopenia,
ARDS,coagulopathy
• Metabolic dysfunction
– Hyperglycemia
Bone et al, Crit Care Med 20, 1992; Bone et al Chest 101, 1992
Levy et al, Crit Care Med 31, 2003
Current Treatment of Severe
SIRS/Septic Shock
• Cardiopulmonary/Organ-specific Support
–
–
–
–
Goal directed fluid resuscitation
Inotropic support
Mechanical ventilation
Treat metabolic, coagulation and end organ
dysfunction
• Remove infection/sources of inflammation
– Antibiotics
– Drain Abscess
– Excise Necrotic/Inflamed Tissue
Potential Anti-inflammatory
Treatment Approaches
• Block/remove inflammatory
mediators
• Inhibit inflammatory response
• Reduce cellular injury
• Inhibit coagulation cascade
Anti-inflammatory Therapy of Sepsis:
Block Mediators
TNF-MAb
sTNFr
TNF-MAb
IL-1ra
IL-1ra
PAFra
TNF-MAb
Anti-bradykinin
sTNFr
ibuprofen
TNF-MAb
PAFra
0.5 0.67
1 1.5
Odds ratio
injury
2
benefit
Adapted from Natanson et al, Crit Care Med 1998
Anti-inflammatory Therapy of Sepsis
• Hemofiltration
• Complement antagonism
– C1 inhibitor (blocks classical/lectin pathways)
• Anti-adhesion molecule
– Selectins, ICAM-1
• Blockade of Nitric Oxide
– iNOS inhibition, NO scavenging
• Phosphodiesterase inhibitors
– Pentoxifylline, milrinone
• Anti-oxidants
– Selenium, N-acetylcysteine, Vit. C and E
Steroids in Septic Shock
High dose
(30 mg/kg
prednisone)
Short term
(1-3 days)
steroids
Cronin et al, Crit Care Med 1995
Steroids in Septic Shock
• Patients in septic shock with low adrenal reserve (corticotropin stimulation
test) showed improved survival when treated with replacement
corticosteroids
Annane et al, JAMA 288:862, 2002
• Replacement dose steroids may only have benefit in septic patients with
vasopressor-refractory hypotension (CORTICUS), Z. Thomas, Ann
Pharmacother 41:1456, 2007
• ‘Intravenous corticosteroids (hydrocortisone 200–300 mg/day, for seven
days in three or four divided doses or by continuous infusion) are
suggested in patients with septic shock whose blood pressure is poorly
responsive to fluid replacement and vasopressor therapy.’ Surviving Sepsis
Campaign, Crit Care Med 36:296, 2008
Biology of Activated Protein C
Normal
Proteolysis of factors Va and VIIIa
Profibrinolysis
Activated protein C
inhibit
Cytokine
Production
Sepsis
Inflammation
Consumption of
Protein C
Protein C
Fibrin clot
Formation
Cytokine
Production
induce
Tissue
factor
Thrombosis
Tissue
factor
Adapted from Kumar et al, Robbins Textbook of Pathology
Fibrin clot
Formation
Treatment of Severe Sepsis
with Activated Protein C
Activated protein C
75.3%
placebo
69.2%
Bernard et al NEJM 2001
• Mortality due to all
causes significantly
improved in patients
treated with
activated protein C
(APC)
• 1 life saved for
every 16 patients
treated with APC
• Decreased IL-6 and
D Dimer levels in
APC-treated
patients
Treatment of Severe Sepsis
with Activated Protein C
From Vincent et al, Crit Care 10:R274, 2006
Treatment of Patients with Severe Sepsis
and at Lower Risk of Mortality with
Activated Protein C
Single organ
failure
or Apache II
score
less than 25
From Abraham et al, NEJM 353:1332, 2005
Efficacy of Activated Protein C in Patients with
Severe Sepsis and Elevated Troponin Levels
Normal Troponin
Elevated Troponin
From John et al, Int Care Med 33:212, 2007
APC suggested in adult patients with septic shock, organ failure and high
risk of death without contraindications. Surviving Sepsis Campaign, Crit
Care Med 36:296, 2008
The Autonomic Nervous
System and Inflammation
From: Czura and Tracey J Int Med 257:156, 2005; Metz and Tracey Nat Immunol 6:756, 2005
Pavlov et al Crit Care Med 35:1139, 2007
Summary
• Our understanding of inflammation at the cellular
and molecular levels has advanced significantly
during the last 20 years
• These advances have not yet translated into
widespread clinical benefit in management of
acute inflammatory processes although promising
results with newer approaches have been
obtained in some settings (e.g. Activated Protein
C for severe sepsis)