Sepsis/SIRS

Definition

• Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection
  • SEPSIS 3 (2016) defines organ dysfunction as an acute change in total SOFA score of two or more points consequent to infection
  • This was found to have superior predictive value than SIRS score alone (only 0.74 vs 0.64 though, so SIRS score does retain some validity)
• Septic shock - a subset of sepsis in which underlying circulatory and cellular/metabolic abnormalities are profound enough to substantially increase mortality

Risk factors

• Extremes of age
• Indwelling devices/breach of skin integrity
• IVDU
• ICU/HDU
• Immunosuppression
• Surgery in past 6/52

Pathophysiology:

Normal response to infection

• • Host response initiated when innate immune cells (especially macrophages) recognise and to microbial components
    • Pattern-recognition receptors (PRRs) on the surface of immune cells recognise and bind to microbial pathogen-associated molecular patterns (PAMPs) or endogenous danger signals
      • PRRs include toll-like receptors (TLRs) and others
    • Neutrophils begin to defend against pathogens - phagocytosis, secretion of antimicrobial peptides, and the release of neutrophil extracellular traps (NETs)
    • Signalling cascade developed via the activation of cytosolic nuclear factor-kb (NF-kb), which leads to activation of genes involved in host inflammatory response such as TNF-a, IL-1, IL-6, chemokines, vascular adhesion molecule-1, and nitric oxide
    • Polymorphonuclear leucocytes become activated and aggregate at site of infection, causing warmth and erythema due to local vasodilation and hyperaemia
    • Pro-coagulant status causes micro-thrombosis
    • Some anti-inflammatory mediators balance this activation
    • If the inflammatory process is balanced, haemostasis is restored, leading to tissue repair and healing

Transition to sepsis

• • Sepsis occurs when the release of pro-inflammatory mediators exceeds the boundaries of the local environment, leading to a more generalised response (can also occur without sepsis, as SIRS). This can also be characterised as malignant intra-vascular inflammation
  • It is unclear why this happens, but likely multifactorial
    • Direct effects of invading micro-organisms and their toxins
    • Release of large quantities of pro-inflammatory mediators - mainly IL-1 and TNF-a
    • Complement activation
    • Possible genetic susceptibility
    • Loss or reduction of Compensatory Anti-inflammatory Response Syndrome (CARS) which includes factors like IL-4 and 10
  • Excessive and prolonged activation of these pathways probably contributes to the development of multiple organ dysfunction
  • Leads to vasodilation, enhanced capillary leak and eventually myocardial depression

Systemic effects of sepsis

• • Organ dysfunction
    • Circulation - hypotension due to diffuse vasodilation - distributive shock, largely mediated by NO and prostacyclin
    • Lung - endothelial injury leads to pulmonary oedema and ARDS
    • GIT - depressed function allowing translocation
    • Liver dysfunction
    • Kidney - pre-renal injury, including ATN
    • CNS - often fails before other organs - encephalopathy
  • Multiple organ dysfunction syndrome (MODS) - see below
  • Tissue ischaemia - due to derangements in metabolic autoregulation, and also endothelial injury
  • Cytopathic injury
  • Cell death pathways activated
  • Immunosuppression
  • Activation of coagulation system and vascular endothelium - DIC

Diagnosis:

New criteria

• • qSOFA (recommended by CCrISP, and was initially thought to be a good way of approximating SOFA score by Sepsis 3, but the data to back up that use has been highly conflicted, and it is probably less useful than first thought) - Breathing, BP, Brain
    • Two or more of:
      • RR >22
      • SBP<100
      • Altered mentation
  • SOFA - Sequential Organ Failure Assessment score - more complicated points calculator, up to 4 points in each category, best for ICU patients
    • Respiratory failure
    • Platelet level
    • Bilirubin
    • BP/vasopressors
    • GCS
    • Creatinine
  • Septic shock - patients who, after adequate fluid resuscitation and antibiotics, meet the following criteria:
    • Persistent lactate >2
    • Vasopressors required to maintain MAP >65
    • 40% risk of mortality in this group, compared to 10% in those who do not

Old criteria:

• • SIRS (no longer recommended for clinical use by sepsis 3 - think of it as an appropriate, regulated non-specific response to infection):
    • Two or more of:
      • Temp >38 or <36
      • HR >90
      • RR>20
      • WCC >12 or <4
      • Acutely altered mental state
      • BGL > 6.6 in absence of diabetes
  • Sepsis = SIRS + documented source of infection
    • Alternative definition from CCrISP is of 'a life-threatening organ dysfunction caused by a dysregulated host response to infection'
  • Severe sepsis = SIRS + altered organ perfusion (no longer a clinically useful definition according to CCrISP)
    • CVS (lactate > 1.2)
    • Pa02/Fi02 < 30 or Pa02 < 9.3kPa
    • Urine output < 120ml over 4 hours
    • GCS < 15 acutely
  • Septic shock: infection plus
    • Definition 1:
      • Vasopressors to maintain MAP >65, and
      • Lactate >2
    • Associated with 40% mortality

MODS

• • Progressive organ dysfunction in an acutely ill patient, such that homeostasis cannot be maintained without intervention.
  • Primary - organ dysfunction is directly attributable to the insult itself
  • Secondary - organ dysfunction is a consequence of the host's response
  • Typically lungs, liver and kidneys affected most
  • Early MODS (<3 days) is usually inadequate fluid resuscitation. Late MODS is usually infection.
  • Treatment is via generalised approach
    • Resuscitate
    • Treat infections
    • Maintain tissue oxygenation
    • Debride devitalised tissue
    • Early enteral nutrition
    • Early mobilisation

Approach when seeing a patient with possible sepsis on ward/ED:

• CCrISP ABCD
• Use qSOFA to evaluate for organ dysfunction
• Intervene as below
• Consider ICU if goal-directed resuscitation is required
• Identify likely source of sepsis
  • Chest
  • Abdomen
  • CNS - headache/neck stiffness
  • Lines - >48 hours old or being used for TPN
  • Urinary

Intervention

• Within one hour - the Sepsis Six: (three in, three out)
  • High-flow oxygen
  • IV Abx
  • IVF - be aggressive if patient is hypotensive and there isn't a contraindication - bolus of 20mL/kg, or 30mL/kg if lactate >4
  • BCs
  • Hb, lactate
  • Hourly UO
• Within three hours:
  • If persistent hypotension or increased lactate, apply goal-directed resuscitation
  • Consider need for escalation of monitoring and level of care
• Within six hours:
  • Apply vasopressors for hypotension that does not respond to initial fluid, aiming MAP>65
  • Reassess volume status and tissue perfusion and document findings
  • Remeasure lactate if it was initially elevated
• Definitive control:
  • Septic screen - CXR, urine, stool, sputum, review and culture all lines

Follow-up:

• Consider and anticipate risk of multi-organ failure:
  • ARDS - respiratory support almost always needed, usually mechanical ventilation. Vague clinical picture, so suspicion is needed, and escalation for critical care input.
  • Cardiovascular failure
    • Loss of peripheral vascular tone
    • Loss of circulating volume
    • Myocardial depression secondary to cytokines
  • Renal failure
    • Often established early on during hypotension
  • Gut
  • Brain
  • Clotting system
    • Thrombocytopaenia
    • Coagulopathies
  • Liver