Sepsis Syndrome

Section: Critical care Curriculum: Curriculum, page 30, Curriculum, page 46

Definitions

• Sepsis
  • Clinical syndrome of organ dysfunction due to a dysregulated host immune response
    • Sepsis 3 guideline state diagnosed in the setting of suspected or confirmed infection with a SOFA of 2 or more or a qSOFA score of 2 or more
• Septic Shock
  • Definition
    • Sepsis with cellular, circulatory and metabolic abnormalities
    • High risk of mortality
  • Clinical
    • Satisfy criteria of sepsis
      • Requirement of vasopressor to maintain MAP of >/= 65 despite adequate fluid resuscitation
      • Lactate >2mmol/L
• SIRS
  • Nonspecific Inflammatory response - may represent a normal or dysregulated response to infection or injury
    • 2/4 of:
      • HR >90
      • Temp <36 or >38
      • RR >20 or PaCO2>32mmHg
      • WBC <4, >12 or >10% bands
• SOFA
  • Assessment of organ dysfunction by scoring derangement of clinical and biochemical parameters as representative features of organ function
    • Brain - GCS
    • Heart - BP and pressor requirement
    • Lungs - PaO2:FiO2
    • Kidney - creatinine
    • Haematology - platelets
    • Liver - bilirubin
• qSOFA
  • Rapid bedside assessment to identify early sepsis or those at high risk of developing sepsis
    • ⅔ indicates high risk and prompts screening of SOFA score
      • GCS 14 or less
      • SBP <100
      • RR >22
• Sepsis 6
  • 3 in - IVF, IV abx, oxygen
  • 3 out - urine output, blood culture and lactate
• MODS
  • Progressive organ dysfunction involving 2 or more organs
  • Homeostasis unable to be maintained without intervention

Inflammatory cascade

1. Initiation phase

• Stimulus:
  • Infection (bacteria, viruses, fungi).
  • Tissue injury (trauma, ischemia, toxins).
  • Immune reactions (allergies, autoimmune conditions)
• Activation of Innate immune cells
  • Mainly macrophages - recognise and bind microbial parts or injured tissue
    • Host immune cells have pattern recognition receptors - PRR
      • Pathogen associated molecular patterns (PAMPs) on pathogenic toxins, pathogenic DNA etc
      • Danger associated molecular patterns (DAMPs) on injured tissues E.g heat shock protein
• Release of proinflammatory mediators
  • Cytokines - TNF alpha, Interferon- gama, IL-1, IL- 6, IL-8
  • Prostaglandins and leukotrienes - Amplify inflammation.
  • Histamine (from mast cells): Increases vascular permeability and vasodilation.

2. Amplification phase

• Vascular Phase
  • Vasodilation: Increased blood flow (hyperemia) leads to redness and warmth.
  • Increased Vascular Permeability: Leakage of protein-rich fluid (exudate) into the interstitial space causes swelling (edema).
  • Stasis: Slowing of blood flow in capillaries facilitates leukocyte recruitment.
• Cellular Phase
  • Leukocyte Recruitment: Margination, adhesion, transmigration and chemotaxis
  • Leukocyte Activation: Neutrophils and macrophages become activated, enhancing their ability to phagocytose pathogens and secrete inflammatory mediators (e.g., IL-1, IL-6, TNF-α)
• Systemic effects
  • Fever - IL-1, TNF-alpha
  • Stress hormones - cytokines
  • RAAS system
  • Activation of Complement cascade
  • Bone marrow response - increased WBC
  • Acute phase reactants - CRP, fibrinogen amyloid A
  • Metabolic - hyperglycaemia and insulin resistance

3. Resolution

• CARS - compensatory anti-inflammatory response
• Inflammation subsides after the threat is neutralized:
  • Anti-inflammatory mediators (e.g., IL-4, IL-10, TGF-β) dampen the immune response.
• Repair processes (angiogenesis, fibroblast activity) restore tissue integrity

4. Transition to Sepsis/MODS

• Proinflammatory mediators exceed the boundaries of the local environment
  • Concepts → malignant intravascular inflammation
    • Malignant - uncontrolled, unregulated and self sustaining
    • Intravascular - haematogenous mediator spread
    • Inflammatory - exaggerated normal inflammatory response
• This is due to:
  • Endothelial damage and dysfunction
    • Increased vascular permeability, edema, and impaired blood flow.
    • Leads to fluid loss and decreased oxygen delivery
  • Microcirculatory Dysfunction
    • Inflammatory mediators disrupt the balance between oxygen delivery and consumption.
    • Leads to tissue ischemia, hypoxia, and cellular injury.
  • Cellular Energy Failure
    • Mitochondrial dysfunction impairs ATP production, leading to cellular apoptosis or necrosis.
  • Inflammation and proinflammatory factors
    • Cause direct damage to tissue
• This leads to
  • Progressive Organ Failure
    • Initial damage to one organ increases the risk of dysfunction in others through systemic effects

Organ Effects of Sepsis

Cardiovascular

• Hypotension
  • Vasodilatation e.g. NO
    • Vasoactive mediators cause widespread dilatation
    • Attempt to improve metabolic autoregulation
      • Makes tissue perfusion easier
    • Impaired ADH
    • Redistribution of intravascular fluid
      • Increased endothelial permeability
      • Reduced arterial vascular tone

Lung

• Pulmonary oedema → ARDS
  • Interstitial and alveolar oedema
    • Endothelial injury (pulmonary vessels)
    • Increased vascular permeability
  • Neutrophils trapped in lung microcirculation
    • Amplifies inflammation
  • Causes VQ mismatch → hypoxaemia and hypoxia

GIT

• Loss of barrier function → bacterial translocation (PV and lymphatic)
  • Amplifies septic response
•  Gastroparesis to ileus to bowel ischaemia and GI bleeding

Liver

• Failure of the reticulendothelial system
  • Reduce ability to clear endotoxins and pathogenic products
  • Spills into systemic circulation
• Shock liver/Hepatic ischaemia
  • Acute and LFT deterioration with elevated INR.
  • Transaminases, ALP and bilirubin are markers of hepatic injury
  • Synthetic function - measured by INR, albumin and bilirubin.
• Non-shock liver
  • Milder form which usually resolves as MODS resolves
  • Treatment for both is to avoid hepatotoxins

Kidney

• AKI
  • RIFLE
    • Risk - 1.5x baseline creatinine rise. Urine output < 0.5mls/kg/6 hours.
    • Injury - 2x baseline creatinine rise. Urine output < 0.5mls/kg/12 hours.
    • Failure - 3x baseline creatinine rise. Urine output < 0.5mls/kg/24 hours.
    • Loss of renal function - persistent failure for 4 weeks.
    • ESRD - Renal failure at 3 months.
• ATN
• Hypoperfusion and hypoxia

CNS

• GCS should be measured
  • Failure to treat results in brain death - occurs due increased intracranial pressure resulting in decreased cerebral perfusion pressure.
• Encephalopathy

Endocrine

• Relative adrenal insufficiency occurs commonly
• Glucocorticoids should be given to patients who demonstrate refractory shock (> 1 hour)

Hematological

• Anaemia is caused by anaemia of inflammation or anaemia of chronic disease
  • Likely occurs due to decreased iron availability - which may be a defense mechanism
  • Restricted transfusion practices should be used (Hb < 70 or <80 for patients with CAD)
• Thrombocytopenia is common
  • Can be mild (100-150), moderate (50-100), or severe (<50)
  • Should give platelets if < 10
  • If needing surgery - give platelets if < 50

CRISP algorithm

Goal directed therapy

• Supportive (advanced organ and system support)

CV support

• Indications
  • MAP <60mmHg
  • Reduced SBP from baseline resulting in end organ dysfunction from hypoperfusion
• Principles/Considerations
  • Need to replaced IV volume prior to commencement
    • 2-3L of IVF prior
  • Given centrally - rapid delivery, less chance of extravasation
    • Except Metaraminol can be given peripherally
  • Monitor in ICU
• Drugs
  • Metaraminol
    • Alpha agonist
    • Vascoconstriction
  • NA
    • Alpha 1 and 2
    • Potent vasoconstriction
  • Adrenaline
    • Adrenergic receptor stimulation
    • Vasoconstriction
    • Inotropic
    • Chronotropic
  • Dopamine
    • Dopaminergic, alpha 1 and beta 1 adrenergic R
    • Renal vasodilation
  • Vasopressin = only vasoconstriction
• Complications
  • Hypoperfusion
    • Excess vasoconstriction (high SVR)
    • Poor perfusion to non preferential areas
    • Mesenteric hypoperfusion - poor healing of anastomosis
  • Arrhythmia
    • Tachy, AF
  • Myocardial ischaemia
    • Increased myocardial oxygen consumption
  • Local effects
    • Extravasation - local VC and skin necrosis
      • Inject local phentolamine to reduce risks if it occurs

Respiratory support

• Ventilator
• ETT
• Tracheostomy

Renal support

• Dialysis (continuous renal replacement therapy or CRRT)
• Indications
  • A: Acid-base issues
    • Metabolic acidosis refractory to medical therapy
  • E: Electrolyte disturbances
    • Hyperkalaemia refractory to medical therapy
  • I: Intoxication (Toxins)
    • Intoxication amenable to dialysis - e.g lithium
  • O: Overload (Fluid overload)
    • Diuretic resistant pulmonary oedema
  • U: Uremia
    • Uraemia and complications
• Complications
  • Vascular access related
    • Bleeding
    • Vessel thrombosis/fistula probs
    • Infection
    • Air embolism
  • Non vascular
    • Hypotension
    • Haemorrhage
    • Hyperkalaemia
    • Seizures