Inflammatory Response: Current Concepts

1
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

2
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

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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

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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, anti-inflammatory
  cytokines, cholinergic nervous system and
  apoptosis

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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

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Mediators of Increased Vascular Diameter and Flow
Nitric Oxide (NO)
Vasodilatory Prostaglandins
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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

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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

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Burn Shock Edema Formation
From Demling R, J Burn Care Rehab 26207, 2005
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Clinical Ramifications of Transvascular Fluid Flux
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Clinical Ramifications of Transvascular Fluid Flux
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Mediators of Increased Vascular Permeability

• Histamine
• Bradykinin
• Substance P
• Leukotrienes

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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

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Neutrophil Adhesion and Chemotaxis
1
Rolling
2
Adherance
3
Transmigration
Lectins
? integrins
ICAM-1
Endothelium
E-selectin P-selectin
PECAM
6
Apoptosis
4
Chemotaxis Chemokines Bacterial products LTB4
5
Phagocytosis
Adapted from Seely et al, Crit Care 7291-307,
2003
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Ischemia-Reperfusion Injury
2
3
4
5
6
1
Adapted from Shernan, Anesthesiology Clinics of
North America 212003
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Interactions Between Inflammation and Coagulation
Endothelial Cell
Macrophage/ Monocyte
TNF?
IL-1
Activated Protein C
Intrinsic Pathway
(-)
Tissue Factor
Degradation of Va and VIIIa
VIIa
Tissue Factor Pathway Inhibitor
(-)
VIIIa
IXa
Xa
Binds TF-VIIa Complex

Fibrin clot
Va
Anti-Thrombin III
Macrophage/ Monocyte Activation
Thrombin
Binds Thrombin
17
Role of Complement in Systemic Inflammation
Adapted from Rittirsch et al, Nat Rev Immunol
8776, 2008
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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 2715,
  2006
• Risk of post-operative MI associated with SNPs in
  IL-6, ICAM-1,CRP and E-selectin genes
• Podgoreanu et al, Circulation 114I275, 2006
• Stroke
• Risk of post-operative stroke in cardiac surgery
  patients associated with SNPs in IL-6 and CRP
  genes
• Grocott et al, Stroke 361854, 2005

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Systemic Effects of Inflammation
Myocardial depression
Cachexia, Fever
Edema Pain Erythema
Edema
Metabolic Dysfunction
Adapted from Abbas et al, Cellular and Molecular
Immunology, 2001
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The Systemic Inflammatory Response Syndrome
(SIRS) and Sepsis

• 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

• Sepsis and SIRS
• Tachycardia
• Tachypnea
• Leukocytosis or leukopenia
• Fever or hypothermia

Bone et al, Crit Care Med 20, 1992 Bone et al
Chest 101, 1992 Levy et al, Crit Care Med 31, 2003
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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

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Potential Anti-inflammatory Treatment Approaches

• Block/remove inflammatory mediators
• Inhibit inflammatory response
• Reduce cellular injury
• Inhibit coagulation cascade

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Anti-inflammatory Therapy of SepsisBlock
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 2
Odds ratio
benefit
injury
Adapted from Natanson et al, Crit Care Med 1998
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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

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Steroids in Septic Shock
High dose (30 mg/kg prednisone) Short term (1-3
days) steroids
Cronin et al, Crit Care Med 1995
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Steroids in Septic Shock

• Patients in septic shock with low adrenal reserve
  (corticotropin stimulation test) showed improved
  survival when treated with replacement
  corticosteroids
• Replacement dose steroids may only have benefit
  in septic patients with vasopressor-refractory
  hypotension (CORTICUS), Z. Thomas, Ann
  Pharmacother 411456, 2007
• Intravenous corticosteroids (hydrocortisone
  200300 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 36296, 2008

Annane et al, JAMA 288862, 2002
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Biology of Activated Protein C
Normal
Sepsis
Proteolysis of factors Va and VIIIa Profibrinolysi
s Activated protein C Protein C
Inflammation
Thrombosis
Consumption of Protein C
inhibit
Cytokine Production
Fibrin clot Formation
Fibrin clot Formation
Cytokine Production
induce
Tissue factor
Tissue factor
Adapted from Kumar et al, Robbins Textbook of
Pathology
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Treatment of Severe Sepsis with Activated Protein
C

• 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

Activated protein C
75.3
placebo
69.2
Bernard et al NEJM 2001
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Treatment of Severe Sepsis with Activated Protein
C
From Vincent et al, Crit Care 10R274, 2006
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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 3531332, 2005
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Efficacy of Activated Protein C in Patients with
Severe Sepsis and Elevated Troponin Levels
Elevated Troponin
Normal Troponin
From John et al, Int Care Med 33212, 2007
APC suggested in adult patients with septic
shock, organ failure and high risk of death
without contraindications. Surviving Sepsis
Campaign, Crit Care Med 36296, 2008
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The Autonomic Nervous System and Inflammation
From Czura and Tracey J Int Med 257156, 2005
Metz and Tracey Nat Immunol 6756, 2005 Pavlov et
al Crit Care Med 351139, 2007
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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)