Infection 5: Sepsis

Question 1

Define sepsis

Answer 1

2016 Sepsis 3 criteria “life-threatening organ dysfunction caused by a dysregulated host response to infection”

Question 2

Give 3 Take 3

Answer 2

Give O2, fluids, Abx

Take culture, urine output, lactate

Question 3

Outline the pathophysiology of sepsis

Answer 3

• ↑Vascular permeability
• ↑Coagulation
• ↓Vascular resistance
• ↑Neutrophil
  migration, adhesion
• Fever
  Diarrhoea
• Metabolic changes
  Insulin resistance
  Protein catabolism

Question 4

What are the cardiovascular changes that occur in sepsis?

Answer 4

1. Early distributive shock (warm peripheries)
   Peripheral vasodilatation
2. Then hypovolaemic shock (cold peripheries)
   Capillary leak, peripheral and pulmonary oedema
   Low filling pressure (fluid responsive)
3. Late cardiogenic shock (cold peripheries)
   Cardiac myocyte suppression
   High filling pressure (not fluid responsive)

Question 5

Describe the coagulation response in sepsis

Answer 5

• Platelet activation
• Activation of coagulation cascades
• Down-regulation of anticoagulant mediators
• Consumption of coagulation factors= microvascular coagulopathy
• Coagulation and inflammation closely linked
  [Coagulation factors – pro-inflammatory activity
  Anticoagulation factors – anti-inflammatory activity]

Question 6

What metabolic changes occur in sepsis?

Answer 6

• Protein catabolism
• Insulin resistance
• ↓Tissue oxygen uptake (altered mitochondrial function)
• Circulatory changes- tissue hypoxia- lactic acidosis

Question 7

Describe the endotoxin paradigm

Answer 7

• Sepsis begins with wide-spread recognition of generic microbial elements (e.g. lipopolysaccharide)
• Gram negative LPS (endotoxin)
• Recognised by TLR4
• Monocyte/macrophage lineage responses
• Proinflammatory state
  Triggers clinical features of sepsis

Question 8

How does gram positive sepsis differ to gram negative sepis?

Answer 8

No LPS

S. aureus- Superantigen exotoxins- Toxic Shock syndrome Toxin -1 (TSST-1)

S pyogenes

These superantigen toxins trigger T cell responses in resting T cells

Question 9

Outline the immunopathogenesis of toxic shock

Answer 9

• Protein exotoxins of certain bacteria
• Function immunologically as superantigens

1. Antigens: trigger T cell responses in tiny proportions of resting T cells
2. Superantigens: trigger T cell responses in up to 20% of all resting T cells
3. Superantigen responses are:
   Not restricted by antigen specificity of cells
   Big

Question 10

What is the difference between superantigen and endotoxin mediated sepsis?

Answer 10

• Fundamental mechanisms different

Endotoxin= APC activation
Superantigen= Initiated by T cell 

• Superantigens and endotoxin may act synergistically in clinical sepsis
  Up to 50,000x augmented responses
• Final end-points very similar
  • Cytokine mediated
  • Cellular damage,
  • Organ damage
  • Death