Pathogenesis of sepsis Flashcards
What is sepsis (general)
Sepsis is defined as SIRS in response to an infectious process
Systemic Inflammatory Response Syndrome (SIRS)
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)
Problems with SIRS criteria
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
Sepsis 3 criteria
- Organ dysfunction
- Dysregulated host response
- Infection
Immunopathology of sepsis - the endotoxin paradigm
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
Pathophysiology of sepsis
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
Cardiovascular changes in sepsis
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)
Coagulation response in sepsis
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
Coagulopathy in sepsis
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
What is consumption coagulopathy (disseminated intravascular coagulation)
- Acquired disturbance of blood clotting leading to an increased turnover of coagulation factors and platelets by which the production sites are being exhausted
Metabolic changes in sepsis
- Protein catabolism
- Insulin resistance
- Decrease in tissue oxygen uptake (altered mitochondrial function)
What do circulatory changes, coagulation and metabolic changes in sepsis lead to
Tissue hypoxia –> lactic acidosis
Other examples of PAMPS in sepsis
- Lipopeptides
- Peptidoglycans
- Flagellin
- Microbial DNA/RNA
Other examples of PRRs in sepsis
- TLRs1-11
- CD14
- NOD1 and 2
- Beta integrins
- Mannose binding lectin
Sepsis aetiology
- Constantly changes
- 1980s predominantly gram negative
- 1990s-2000s emergence of gram positives
- 2010s emergence of yeasts, re-emergence of gram negatives - Varies geographically
e. g. case mix - Major changes in paediatrics with vaccination - disappearance of meningococcus, hemophilus, pneumococcus
Gram positive sepsis
Gram positive bacteria - no LPS Activation of innate immune processes - peptidoglycans - lipotechoic acid In vitro less potent than LPS But same fundamental mchanisms apply
Superantigen exotoxins
- Staph aureus
- Strep pyogenes
Specific form of sepsis ‘toxic shock syndrome’
Presentation of toxic shock syndrome
- 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)
S.aureus toxic shock
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
Streptococcal toxic shock syndrome
S. pyogenes (group A streptococcus)
- Following deep seated S. pyogenes infections (necrotising fascitis, myositis, septic arthritis etc)
Strep toxic shock syndrome mortality rate
20-50%
Immunopathogenesis of toxic shock
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
Features of superantigen responses
- Not restricted by antigen specificity of cells
- Big
Conventional antigen presentation vs superantigen presentation
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
Superantigen vs endotoxin mediated sepsis
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
What is SOFA score
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
Life-threatening organ-dysfunction SOFA score
- Increase in SOFA of 2 or more from baseline
What does SOFA assess
- Assesses function of 6 organ systems
- Really designed for iCU-pronostication
- Outside ICU the qSOFA
- > 1 of tachypnoea: >22 GCS <15 SBP <100
Sepsis red flags
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) :(
Indicators of clinical concern for sepsis
- 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
Sepsis 6
- O2
- Antibiotics
- Fluids
- Blood cultures
- Lactate
- Urine output
Right initial antibiotic treatment of sepsis
- Empiric broad-spectrum therapy with one or more antimicrobials…to cover all likely pathogens…as soon as possible (<1 hr)
Impact of time to effective antibiotic therapy
- 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
Impact of in vitro antibiotic susceptibility
- No negative impact on outcome
CRP - sepsis
- 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
Potential uses of biomarkers
- Excluding sepsis
- Monitoring response
- Identifying focus
- Identifying likely pathogen
- Predicting onset of sepsis/shock
- Predicting outcome
- Targeting interventions
