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Pathogenesis of sepsis Flashcards

1
Q

What is sepsis (general)

A

Sepsis is defined as SIRS in response to an infectious process

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2
Q

Systemic Inflammatory Response Syndrome (SIRS)

A

Fever - >38 degrees or <36 degrees

Tachypnoea - > 20 rpm or PaCO2 <32mmHG

Tachycardia - >90bpm

Leucocytosis/leucopenia - >12000 ul^-1 or <4000 ul^-1

> or equal to 2 out of 4 required

  • Infection (proven or probable)
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3
Q

Problems with SIRS criteria

A

Too sensitive - may represent a healthy response to infective process

Too non-specific - many SIRS patients have non-infective process

  • ‘Infection’ (proven or probable) - too nebulous. Patients with sepsis easily missed
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4
Q

Sepsis 3 criteria

A
  • Organ dysfunction
  • Dysregulated host response
  • Infection
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5
Q

Immunopathology of sepsis - the endotoxin paradigm

A

Sepsis begins with wide-spread recognition of generic microbial elements (eg lipopolysaccharide)

  • gram negative LPS binding protein (endotoxin)
  • CD14
  • Toll like receptors (monocyte/macrophage, endothelium) - tLR4
  • Receptor associated kinases
  • Regulation of cytokine gene transcription
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6
Q

Pathophysiology of sepsis

A

Pro-inflammatory cytokines

  • Increase in vascular permeability
  • Decrease in vascular resistance
  • Decrease in cardiac contractility
  • Fever, diarrhoea
  • Metabolic changes (insulin resistance, protein catabolism)
  • increase in neutrophil migration, adhesion
  • Increase in coagulation
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7
Q

Cardiovascular changes in sepsis

A

Early distributive shock(warm peipheries) - peripheral vasodilatation

Then hypovolaemic shock(cold peropheries) - capillary leak, peripheral and pulmonary oedema, low filling pressure(fluid responsive)

Late cardiogenic shock(cold peripheries) - cardiac myocyte suppression, high filling pressure (not fluid responsive)

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8
Q

Coagulation response in sepsis

A

Coagulation homeostasis disrupted early and profoundly in sepsis

  • Platelet activation
  • Activation of coagulation cascades
  • Down-regulation of anticoagulant mediators
  • Consumption of coagulation factors
  • Coagulation and inflammation closely linked

Coagulation factors –> pro-inflammatory activity
Anticoagulation factors –> anti-inflammatory activity

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9
Q

Coagulopathy in sepsis

A

Intrinsic ‘contact activation’ pathway
Loss of endothelial integrity –> VIII –> thrombin –> fibrin clot

Extrinsic ‘tissue factor’ pathway
Monocyte –> IL1, TNF-alpha –> TF-VII–. Thrombin –> fibrin clot

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10
Q

What is consumption coagulopathy (disseminated intravascular coagulation)

A
  • Acquired disturbance of blood clotting leading to an increased turnover of coagulation factors and platelets by which the production sites are being exhausted
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11
Q

Metabolic changes in sepsis

A
  • Protein catabolism
  • Insulin resistance
  • Decrease in tissue oxygen uptake (altered mitochondrial function)
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12
Q

What do circulatory changes, coagulation and metabolic changes in sepsis lead to

A

Tissue hypoxia –> lactic acidosis

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13
Q

Other examples of PAMPS in sepsis

A
  • Lipopeptides
  • Peptidoglycans
  • Flagellin
  • Microbial DNA/RNA
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14
Q

Other examples of PRRs in sepsis

A
  • TLRs1-11
  • CD14
  • NOD1 and 2
  • Beta integrins
  • Mannose binding lectin
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15
Q

Sepsis aetiology

A
  1. Constantly changes
    - 1980s predominantly gram negative
    - 1990s-2000s emergence of gram positives
    - 2010s emergence of yeasts, re-emergence of gram negatives
  2. Varies geographically
    e. g. case mix
  3. Major changes in paediatrics with vaccination - disappearance of meningococcus, hemophilus, pneumococcus
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16
Q

Gram positive sepsis

A 
Gram positive bacteria - no LPS 
Activation of innate immune processes 
- peptidoglycans 
- lipotechoic acid 
In vitro less potent than LPS 
But same fundamental mchanisms apply
17
Q

Superantigen exotoxins

A
  • Staph aureus
  • Strep pyogenes

Specific form of sepsis ‘toxic shock syndrome’

18
Q

Presentation of toxic shock syndrome

A
  • Fever
  • Confusion, diarrhiea
  • Generalised erythema
  • Fulminant hypotension
  • Renal failure
  • 5% mortality
  • Desquamation of palms and soles
  • S.aureus producing toxic shock syndrome toxin - 1 (TSST-1)
19
Q

S.aureus toxic shock

A

New strains of S. aureus (TSST-1)

  • Tampon shock still seen occasionally
  • Burns patients - high rates of S. aureus
  • ICU - especially neonatal ICU
  • Nasal and surgical packs
20
Q

Streptococcal toxic shock syndrome

A

S. pyogenes (group A streptococcus)

- Following deep seated S. pyogenes infections (necrotising fascitis, myositis, septic arthritis etc)

21
Q

Strep toxic shock syndrome mortality rate

A

20-50%

22
Q

Immunopathogenesis of toxic shock

A

Protein exotoxins of certain bacteria
Function immunologically as superantigens

Antigens - trigger T cell responses in tiny proportions of resting T cells

Superantigens - trigger T cell responses in up to 20% of all resting T cells

23
Q

Features of superantigen responses

A
  • Not restricted by antigen specificity of cells

- Big

24
Q

Conventional antigen presentation vs superantigen presentation

A

Conventional - 1/10^5 T cells activated. CD4 T cells

Superantigen - Up to 1/5 T cells activated CD4 and CD8 T cells

  • IL2, IFNgamma - T cell
  • TNFalpha, IL1beta - APC
25
Q

Superantigen vs endotoxin mediated sepsis

A

Fundamental mechanisms different
- Initiated by T cell vs APC activation

Superantigen and endotoxin may act synergistically in clinical sepsis

Final end-points very similar

  • Cytokine mediated
  • Cellular damage, organ damage
  • Death
26
Q

What is SOFA score

A

The sequential organ failure assessment score (SOFA score), previously known as the sepsis-related organ failure assessment score, is used to track a person’s status during the stay in an intensive care unit

27
Q

Life-threatening organ-dysfunction SOFA score

A
  • Increase in SOFA of 2 or more from baseline
28
Q

What does SOFA assess

A
  • Assesses function of 6 organ systems
  • Really designed for iCU-pronostication
  • Outside ICU the qSOFA
  • > 1 of tachypnoea: >22 GCS <15 SBP <100
29
Q

Sepsis red flags

A

Responds only to voice or pain/unresponsive
Acute confusional state
Systolic BP < 90 mmHg for drop > 40 from normal
Heart rate > 130 per min
Respiratory rate > 25 per min
Needs oxygen to keep SpO2>92%
Non-blanching rash, mottled/ashen/cyanotic
Not passed urine in last 18h/UP<0.5ml/kg/hr
Lactate > 2 mmol/l
Recent chemotherapy

(RASHRNNNLR) :(

30
Q

Indicators of clinical concern for sepsis

A
  • Hypotensive systolic <90mmHg
  • Altered mental state
  • Tachypnoea RR>25 per min (or new need for 40% oxygen or more to maintain sats more than 92%)
  • Not passed urine in previous 18 hrs or for catheterised patients passed less than 0.5ml/kg of urine per hr
  • Lactate > 2 mmol/L
  • Non-blanching rash/cyanotic
  • Tachycardia >130 bpm

If one of these indicators of clinical concern are identified, then start sepsis 6 immediately

31
Q

Sepsis 6

A
  • O2
  • Antibiotics
  • Fluids
  • Blood cultures
  • Lactate
  • Urine output
32
Q

Right initial antibiotic treatment of sepsis

A
  • Empiric broad-spectrum therapy with one or more antimicrobials…to cover all likely pathogens…as soon as possible (<1 hr)
33
Q

Impact of time to effective antibiotic therapy

A
  • Subsequent studies suggest that 1 hr time really applies to septic shock and esp patients on vasopressors
  • Very little evidence that delays <3-6 hrs matter
  • Large(>2600 pts) RCT of pre-hospital vs post triage antibiotics for sepsis - no survival benefit
34
Q

Impact of in vitro antibiotic susceptibility

A
  • No negative impact on outcome
35
Q

CRP - sepsis

A
  • Synthesised by hepatocytes
  • Regulated by IL6
  • Following stimulus - peak 48hrs, t1/2 19 hrs, clearance constant in renal disease
  • Minimal genetic variation
  • Production impaired in severe liver disease
36
Q

Potential uses of biomarkers

A
  • Excluding sepsis
  • Monitoring response
  • Identifying focus
  • Identifying likely pathogen
  • Predicting onset of sepsis/shock
  • Predicting outcome
  • Targeting interventions

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