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, anti-

inflammatory 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

NO

Endothelial stimulation

Endothelium

Microbe

Macrophage

Activation stimulus

Calcium influxand eNOS activation

Cytotoxicity

NO

eNOS

iNOS

MembranePhospholipids

ArachidonicAcid

PGG2 PGH2 PGD2

PGE2

PGF2

PGI2

Cyclooxygenase(COX-1, COX-2)

Phospholipases

Vasodilatory Prostaglandins

• 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

Initiation of Acute Inflammation

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

MembranePhospholipids

ArachidonicAcid

5-HPETE LTA4

5- LipoxygenasePhospholipases

LTC4

LTD4

LTE4

LTB4 chemotaxis

Increasevascular permeability

• Leukocyte (neutrophil) Infiltration– Process

• Margination• Rolling• Adhesion• Transmigration• Chemotaxis

– Functional importance• Phagocytosis, removal of bacteria and debris

– Pathology• Acute lung injury, ischemia-reperfusion injury

Initiation of Acute Inflammation

Neutrophil Adhesion and Chemotaxis

Adapted from Seely et al, Crit Care 7:291-307, 2003

Rolling 1

Adherance 2

Transmigration 3

Chemotaxis:Chemokines

Bacterial productsLTB4

4

Phagocytosis5

Apoptosis 6

E-selectinP-selectin

Lectins integrinsICAM-1

PECAM

Endothelium

Ischemia-Reperfusion Injury

Adapted from Shernan, Anesthesiology Clinics of North America 21:2003

1

2

3

4

5

6

Interactions Between Inflammation and Coagulation

Macrophage/Monocyte

Endothelial Cell

Tissue Factor

TNFIL-1

VIIIa IXa

Va

Xa

Thrombin

Fibrin clot

Activated Protein C

Macrophage/MonocyteActivation

(-)

(-)

Degradation of Va and VIIIa

Anti-ThrombinIII

Intrinsic Pathway

+

VIIaTissue FactorPathway InhibitorBinds TF-VIIaComplex

Binds Thrombin

Role of Complement in Systemic Inflammation

Adapted from Rittirsch et al, Nat Rev Immunol 8:776, 2008

• 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

Potential Thrombotic Complications Associated with Perioperative Inflammation

Systemic Effects of Inflammation

EdemaPainErythema

Adapted from Abbas et al, Cellular and Molecular Immunology, 2001

Myocardialdepression

MetabolicDysfunction

Cachexia,Fever

Edema

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, 1992Levy 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

Adapted from Natanson et al, Crit Care Med 1998

TNF-MAb

TNF-MAb

TNF-MAb

TNF-MAb

sTNFr

sTNFr

IL-1ra

IL-1ra

PAFra

PAFra

Anti-bradykinin

ibuprofen

0.5 0.67 1 1.5 2 Odds ratio

benefitinjury

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

Cronin et al, Crit Care Med 1995

High dose (30 mg/kg

prednisone)Short term(1-3 days)steroids

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 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

Annane et al, JAMA 288:862, 2002

Biology of Activated Protein C

Cytokine Production

inhibit

induce

Fibrin clot Formation

Cytokine Production Fibrin clot

Formation

Inflammation Thrombosis

Normal Sepsis

Tissue factor

Tissue factor

Proteolysis of factors Va and VIIIaProfibrinolysis

Activated protein C Protein C

Adapted from Kumar et al, Robbins Textbook of Pathology

Consumption ofProtein C

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

69.2%

75.3%

Bernard et al NEJM 2001

placebo

Activated protein C

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

From Abraham et al, NEJM 353:1332, 2005

Single organ failure

or Apache II score

less than 25

Efficacy of Activated Protein C in Patients with Severe Sepsis and Elevated Troponin Levels

Elevated TroponinNormal 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, 2005Pavlov 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)