Sepsis and Septic Shock

Question 1

What is sepsis?

Answer 1

Life-threatening organ dysfunction caused by dysregulated host response to infection

Question 2

What is septic shock?

Answer 2

Clinical construct of sepsis with persisting hypotension requiring vasopressors to maintain MAP >65mmHg and having serum lactate of >2mmol/L despite adequate volume resuscitation

Question 3

How is organ dysfunction identified in sepsis?

Answer 3

Organ dysfunction identified as acute change in total SOFA score >2

Question 4

What is sepsis caused by?

Answer 4

Is a systemic illness caused by microbial invasion of normally sterile parts of the body

Question 5

Describe the traditional model of sepsis?

Answer 5

Question 6

What is qSOFA used for?

Answer 6

To identify if a patient is likely to require ICU or die in hospital

Score of 2 or more indicates greater risk of poor outcome

Question 7

What does qSOFA look at?

Answer 7

• Hypotension systolic BP <100mmHg
• Altered mental state
• Tachypnea RR >22/min

Question 8

What is survival in septic shock based on?

Answer 8

Survival in septic shock is based on antimicrobial delay:

• Each hour delay increases mortality by 7.6%

Remember “time is life”

Question 9

What are some of the bodies defences against sepsis?

Answer 9

• Physical barrier
  
  • Skin, mucosa, epithelial lining
• Innate immune system
  
  • IgA in gastrointestinal tract, dendritic cells, macrophages
• Adaptive immune system
  
  • Lymphocytes, immunoglobulins

Question 10

Describe the pathophysiology of sepsis?

Answer 10

• Uncontrolled inflammatory response
• Features consistent with immunosuppression
  
  • Loss of delayed hypersensitivity
  • Inability to clear infection
  • Predisposition to nosocomial infection
• Probably change of the sepsis syndrome over time
  
  • Initially, increase in inflammatory markers
  • Later, shift towards an anti-inflammatory immunosuppressive phase

Question 11

What are the 3 phases of pathogenesis of sepsis?

Answer 11

1. Release of bacterial toxins
   
   1. Bacterial invasion into body tissues source of dangerous toxins
   2. May or may not be neutralised by existing immune system
   3. Commonly released toxins
      
      1. Gram negative
         
         1. Lipopolysaccharide (LPS)
      2. Gram positive
         
         1. Microbial-associated molecular pattern (MAMP)
            
            1. Lipoteichoic acid
            2. Murmyl dipeptides
         2. Superantigens
            
            1. Staphylococcal toxic shock syndrome toxin (TSST)
            2. Streptococcal exotoxins
2. Release of mediators
   
   1. Effects due to endotoxin release
      
      1. LPS needs an LPS-binding protein to bind to macrophages
      2. LTA do not need such proteins
   2. Effects due to exotoxin release
      
      1. Pro-inflammatory response
      2. Small amounts of superantigens cause a large amount of mediators to be secreted causing cascade effect
   3. Mediator role on sepsis
   4. Two types of mediators can be released
      
      1. Pro-inflammatory mediators – cause inflammatory response that characterises sepsis
      2. Compensatory anti-inflammatory reaction – can cause immunoparalysis
3. Effects of specific excessive mediators
   
   1. Pro-inflammatory mediators
      
      1. Promote endothelial cell – leukocyte adhesion
      2. Release of arachidonic acid metabolites
      3. Complement activation
      4. Vasodilation of blood vessels by NO
      5. Increase coagulation by release of tissue factors and membrane coagulants
      6. Cause hyperthermia
   2. Anti-inflammatory mediators
      
      1. Inhibit TNF alpha
      2. Augment acute phase reaction
      3. Inhibit activation of coagulation system
      4. Provide negative feedback mechanism to pro-inflammatory mediators
   3. Balance between pro and anti-inflammatory mediators determines outcome
      
      1. Pro-inflammatory stronger causes septic shock with multiorgan failure and death

Anti-inflammatory stronger causes immunoparalysis with uncontrolled infection and multiorgan failure

Question 12

What are commonly released toxins that cause sepsis?

Answer 12

1. Gram negative
   
   1. Lipopolysaccharide (LPS)
2. Gram positive
   
   1. Microbial-associated molecular pattern (MAMP)
      
      1. Lipoteichoic acid
      2. Murmyl dipeptides
   2. Superantigens
      
      1. Staphylococcal toxic shock syndrome toxin (TSST)
      2. Streptococcal exotoxins

Question 13

What are examples of superantigens that can cause sepsis?

Answer 13

1. Staphylococcal toxic shock syndrome toxin (TSST)
2. Streptococcal exotoxins

Question 14

What are the 2 types of mediators that can be released in the pathogenesis of sepsis?

Answer 14

1. Pro-inflammatory mediators – cause inflammatory response that characterises sepsis
2. Compensatory anti-inflammatory reaction – can cause immunoparalysis

Question 15

What do pro-inflammatory mediators cause in relation to sepsis?

Answer 15

Cause inflammatory response that characterises sepsis

Question 16

What do anti-inflammatory mediators cause in relation to sepsis?

Answer 16

Can cause immunoparalysis

Question 17

What are the specific effects of pro-inflammatory mediators?

Answer 17

1. Promote endothelial cell – leukocyte adhesion
2. Release of arachidonic acid metabolites
3. Complement activation
4. Vasodilation of blood vessels by NO
5. Increase coagulation by release of tissue factors and membrane coagulants
6. Cause hyperthermia

Question 18

What are the specific effects of anti-inflammatory mediators?

Answer 18

1. Inhibit TNF alpha
2. Augment acute phase reaction
3. Inhibit activation of coagulation system
4. Provide negative feedback mechanism to pro-inflammatory mediators

Question 19

Balance of pro and anti-inflammatory markers determines outcome of sepsis, what does pro-inflammatory being stronger cause?

Answer 19

1. Pro-inflammatory stronger causes septic shock with multiorgan failure and death

Question 20

Balance of pro and anti-inflammatory markers determines outcome of sepsis, what does anti-inflammatory being stronger cause?

Answer 20

1. Anti-inflammatory stronger causes immunoparalysis with uncontrolled infection and multiorgan failure

Question 21

What are toxins use endotoxin release?

Answer 21

LPS, lipopolysaccharide (needs an LPS-binding protein to bind to macrophages)

LTA, lipoteichoic acid (does not need such a protein)

Question 22

Which of LPS and LTA needs a binding protein before binding to macrophage?

Answer 22

LPS

Question 23

A common gram negative toxin with endotoxin release is?

Answer 23

LPS

Question 24

A common gram positive toxin with endotoxin release is?

Answer 24

LTA

Question 25

What toxins have exotoxin release?

Answer 25

Superantigens

Question 26

What are some examples of pro-inflammatory markers?

Question 27

What are some examples of anti-inflammatory markers?

Question 28

What do the clinical features of sepsis depend on?

Answer 28

* Host * Organism * Environment

Question 29

What are some signs of organ dysfunction?

Answer 29

Question 30

What are some general features of sepsis?

Answer 30

* Fever * Presenting as chills, rigors, flushes, cold sweats, night sweats etc * Hypothermia * Especially in elderly and young children (remember the immunosuppressed) * Tachycardia * Tachypnoea * Altered mental state * Especially in elderly * Hyperglycaemia in absence of diabetes

Question 31

What are some diagnostic markers of sepsis?

Answer 31

* Inflammatory * Leucocytosis (WCC \> 12,000/ml) * Leucopenia (WCC \< 4,000/ml) * Normal WCC with greater than 10% immature forms * High CRP * High procalcitonin * Haemodynamic * Arterial hypotension (systolic \<90mmHg or MAP \<70mmHg) * SvO₂ \>70% * Organ dysfunction * Arterial hypoxaemia (PaO₂/FiO₂ \< 50mmHg) * Oliguria (\<0.5ml/kg/h) * Creatinine increase compared to baseline * Coagulation abnormalities (PT \>1.5 or APTT \>60s) * Ileus * Thrombocytopenia (\<150,000/ml) * Hyperbilirubinaemia * Tissue perforation * High lactate * Skin mottling and reduced capillary perfusion

Question 32

What are some effects of the host on sepsis?

Answer 32

* Age * Co-morbidities * Immunosuppression * Acquired such as HIV/AIDS * Drug induced such as steroids, chemotherapy agents, biologics * Congenital * Previous surgery * Such as splenectomy

Question 33

What are some effects of the organism on sepsis?

Answer 33

* Gram positive vs gram negative * Virulence factors * Such as MRSA, toxin secretion etc * Bioburden

Question 34

What are some effects of the environment on sepsis?

Answer 34

* Occupation * Travel * Hospitalisation

Question 35

In general, what is the process for recognising and managing sepsis?

Answer 35

1. Recognise clinical presentation of sepsis 2. Identify source of infection 3. Treat with antibiotics, fluids and oxygen

Question 36

What is the sepsis 6 used for management of sepsis?

Answer 36

* Give 3 * Blood cultures * Blood lactate * Marker of hypoperfusion/severe sepsis/poorer prognosis * Measure urine output * Low urine output is marker of renal dysfunction * Take 3 * Oxygen aim sats 94-98% * IV antibiotics * IV fluid challenge * 30ml/kg

Question 37

When should you consider HDU referal?

Answer 37

* Low BP responsive to fluids * Lactate \>2 despite fluid resuscitation * Elevated creatinine * Oliguria * Liver dysfunction, Bil, PT, Plt * Bilateral infiltrates, hypoxaemia

Question 38

When should you consider ITU?

Answer 38

* Septic shock * Multi-organ failure * Requires sedation, intubation and ventilation