Key Facts

Sepsis is one of the leading causes of death worldwide and in the UK. Early recognition using structured screening tools (NEWS2) and prompt delivery of the Sepsis Six bundle significantly reduces mortality. The 2016 Sepsis-3 definitions replaced the older SIRS criteria.

Epidemiology

• ~250,000 cases per year in the UK; ~48,000 deaths annually
• Incidence increasing due to ageing population, immunosuppression, antimicrobial resistance
• In-hospital mortality: 15–20% for sepsis, 40–50% for septic shock
• Leading cause of preventable death in hospitals
• Disproportionately affects extremes of age, immunocompromised, and those with chronic disease

Aetiology

Common sources:

• Respiratory (~40%): pneumonia
• Urinary (~20%): UTI, pyelonephritis
• Abdominal (~15%): peritonitis, cholangitis, appendicitis
• Skin/soft tissue (~10%): cellulitis, necrotising fasciitis
• Line-related (~5%): central venous catheter infections
• Other: endocarditis, meningitis, bone/joint infections

Common organisms:

• Gram-positive: S. aureus, S. pneumoniae, Enterococcus
• Gram-negative: E. coli, Klebsiella, Pseudomonas
• Fungi: Candida (especially in ICU, immunocompromised)

Pathophysiology

• Infection triggers innate immune response → pattern recognition receptors (TLRs) detect PAMPs
• Cytokine storm: TNF-α, IL-1, IL-6 → systemic inflammation
• Endothelial dysfunction → increased vascular permeability → distributive shock
• Coagulation activation → microvascular thrombosis → DIC
• Mitochondrial dysfunction → impaired cellular oxygen utilisation
• Organ dysfunction: AKI, ARDS, hepatic dysfunction, encephalopathy, myocardial depression

Typical Presentation

• Fever (>38°C) or hypothermia (<36°C)
• Tachycardia (HR >90)
• Tachypnoea (RR >20)
• Altered mental state (new confusion — very sensitive early sign)
• Hypotension (SBP <90 or MAP <65)

Source-Specific Features

• Respiratory: cough, dyspnoea, pleuritic chest pain, consolidation
• Urinary: dysuria, frequency, loin pain
• Abdominal: pain, tenderness, rigidity, absent bowel sounds
• Skin: erythema, warmth, fluctuance, crepitus (necrotising fasciitis)
• CNS: headache, neck stiffness, photophobia, non-blanching rash

Red Flags (NICE NG51 high-risk criteria)

• SBP ≤90 mmHg (or drop >40 from baseline)
• Heart rate >130
• Respiratory rate ≥25
• Lactate >2 mmol/L
• New need for oxygen to maintain SpO2 >92%
• Non-blanching rash, mottled/ashen/cyanotic skin
• Not passed urine in 18 hours (or <0.5 ml/kg/hr)
• Recent chemotherapy

Bedside

• NEWS2 score: calculate and escalate appropriately
• Blood glucose: hypoglycaemia or hyperglycaemia
• VBG/ABG: pH, lactate (most important prognostic marker), bicarbonate
• Urinalysis: MSU if urinary source suspected
• ECG: exclude MI, new arrhythmia

Bloods

• Blood cultures: minimum 2 sets (peripheral ± line) BEFORE antibiotics
• FBC: leucocytosis or leucopenia, thrombocytopenia
• U&Es: AKI
• LFTs: hepatic dysfunction
• CRP/procalcitonin: inflammation markers
• Lactate: >2 mmol/L indicates tissue hypoperfusion; >4 mmol/L associated with >40% mortality
• Coagulation screen: DIC (prolonged PT/APTT, low fibrinogen, raised D-dimer)
• Blood gas: metabolic acidosis

Imaging

• CXR: pneumonia, ARDS
• CT abdomen/pelvis: intra-abdominal source (abscess, perforation, cholangitis)
• CT head: if CNS source suspected
• Echocardiography: if endocarditis suspected or to assess cardiac function in shock

Special Tests

• Lumbar puncture: if meningitis suspected (after CT if raised ICP signs)
• Joint aspiration: if septic arthritis suspected
• Procalcitonin: may guide antibiotic duration (PRORATA, SAPS trials)

Non-pharmacological

• Sepsis Six bundle (complete within 1 hour):
  1. Give high-flow oxygen (target SpO2 94–98%)
  2. Take blood cultures
  3. Give IV antibiotics
  4. Give IV fluids
  5. Measure lactate
  6. Measure urine output (catheterise)

Pharmacological

Antibiotics (within 1 hour — NICE NG51):

• Empirical: piperacillin-tazobactam 4.5g IV TDS (or per local antimicrobial guidelines)
• If penicillin allergy: meropenem 1g IV TDS
• Unknown source with septic shock: add gentamicin 5mg/kg IV
• Suspected MRSA: add vancomycin 15–20 mg/kg IV BD
• Suspected meningitis: ceftriaxone 2g IV BD
• Review at 48–72 hours: narrow spectrum based on cultures (antimicrobial stewardship)

IV fluid resuscitation:

• 500ml 0.9% NaCl bolus over 15 min
• Repeat up to 30 ml/kg in first 3 hours if hypotensive/lactate elevated
• Reassess fluid status after each bolus (avoid fluid overload)

Vasopressors (if MAP <65 despite fluids):

• Noradrenaline: first-line vasopressor (0.05–0.5 mcg/kg/min) — requires ICU/critical care setting
• Vasopressin: 0.03 units/min as adjunct to noradrenaline
• Hydrocortisone 50mg QDS IV: for refractory septic shock (ADRENAL, APROCCHSS trials support use)

Landmark trials:

• PROCESS, ARISE, ProMISe: early goal-directed therapy no better than usual care
• ADRENAL/APROCCHSS: hydrocortisone in septic shock — faster shock reversal, possible mortality benefit
• Surviving Sepsis Campaign 2021: updated international guidelines

Surgical/Interventional

• Source control: drain abscesses, remove infected devices, debride necrotic tissue — within 6–12 hours
• Central venous access: for vasopressors, monitoring
• Arterial line: for continuous BP monitoring in shock

Referral Criteria

• ICU/critical care: septic shock, multi-organ failure, need for vasopressors/ventilation
• Surgical team: if source requires operative intervention
• Microbiology/infectious diseases: complex infections, unusual organisms, persistent bacteraemia

• Overall sepsis mortality: 15–20%
• Septic shock mortality: 40–50%
• Each hour delay in antibiotics increases mortality by ~4–8%
• Lactate >4 mmol/L: ~40% mortality
• 1-year mortality after sepsis: ~40% (including post-discharge deaths)
• Long-term sequelae: cognitive impairment, PTSD, chronic fatigue, functional decline in ~50% of survivors
• Re-hospitalisation rate within 90 days: ~40%
• Compliance with Sepsis Six bundle reduces mortality by ~20%

Sepsis-3 Definitions

Sepsis Six Bundle (Within 1 Hour)

NEWS2 Escalation