Paracetamol Toxicity Summary

Referral Criteria

  • Self-harm context (any dose)
  • Symptomatic patients
  • Ingested ≥75 mg/kg in 1 hour
  • Uncertain timing + dose ≥75 mg/kg

Time Windows

  • Irreversible damage after 8-12 hours
  • Blood levels at 4+ hours post-ingestion
  • NAC most effective within 8 hours
  • Liver failure peaks at 3-4 days

Key Investigations

  • Paracetamol level (4+ hours)
  • LFTs (ALT most sensitive)
  • INR/coagulation
  • U&Es, bicarbonate
  • Glucose, FBC

NAC Indications

  • Level above treatment line (4-24h)
  • Detectable level >24h + abnormal LFTs
  • Staggered overdose + detectable level
  • Clinical liver injury signs

21-hour NAC Regimen

  • Bag 1: 150 mg/kg over 1h (200mL)
  • Bag 2: 50 mg/kg over 4h (500mL)
  • Bag 3: 100 mg/kg over 16h (1000mL)
  • Total: 300 mg/kg over 21h

Adverse Reactions

  • Anaphylactoid reactions (30%)
  • Stop infusion temporarily
  • Antihistamines, bronchodilators
  • Restart at slower rate
  • NOT a contraindication

King's College Criteria

  • pH < 7.30
  • INR > 6.5
  • Creatinine > 300 µmol/L
  • Grade III/IV encephalopathy
  • ± Lactate > 3.5 mmol/L

Paracetamol Toxicity

Comprehensive guide to pathophysiology, assessment, and management of paracetamol overdose

Pathophysiology

Paracetamol is usually conjugated in the liver to inactive substances. A small amount is metabolised by the cytochrome P450 system producing a toxic metabolite N-acetyl-p-benzoquinoneimine (NAPQI), which is then inactivated by conjugation with glutathione.

Normal Metabolism

  • Major pathway: Conjugation to inactive metabolites
  • Minor pathway: CYP450 to NAPQI
  • NAPQI detoxified by glutathione

Overdose Mechanism

  • Conjugation pathway saturated
  • Increased CYP450 metabolism
  • Glutathione depletion
  • NAPQI accumulation → hepatic necrosis

Referral Criteria

All patients who meet any of the following criteria should be referred to hospital for medical assessment:

Mandatory Referral

  • Patients who have ingested paracetamol in the context of self-harm (irrespective of reported dose)
  • Symptomatic patients
  • Patients who have ingested 75 mg/kg or more paracetamol over a period of one hour or less
  • Patients where the time of ingestion is uncertain but the dose ingested is 75 mg/kg or more

Dose Calculation

  • Calculate ingested dose in mg/kg to determine significance
  • Disregard any additional kilos in excess of 110 kg
  • If pregnant, enter pre-pregnancy, not actual weight
  • All paracetamol ingestions ≥ 75 mg/kg/24hrs are significant

Clinical Features

Early (0-24 hours)

  • Common: nausea and vomiting
  • Rarely: coma and severe metabolic acidosis (levels >700 mg/L)
  • 12-36 hours: abdominal pain

Intermediate (24-72 hours)

  • Features of hepatic necrosis
  • Right subcostal pain and tenderness
  • Nausea, vomiting, jaundice
  • Acute kidney injury
  • Hepatic encephalopathy

Late (2-4 days)

  • Loin pain, haematuria, proteinuria (AKI)
  • Clotting abnormalities → bleeding risk
  • Peak liver failure at 3-4 days

Initial Assessment Algorithm

Step 1: Timing and Dose Assessment

1. If ingestion ≤ 1 h ago AND dose ≥ 150 mg/kg:

  • Consider administration of single dose activated charcoal (50 g for adults; 1 g/kg body weight for children)
  • Delay blood sampling until 4 h post-ingestion
  • After 4 h, obtain venous blood sample and await results

2. If single ingestion > 1 h but < 4 h ago:

  • Delay blood sampling until 4 h post-ingestion
  • After 4 h, obtain venous blood sample and await results

3. If single ingestion ≥ 4 h but < 8 h ago:

  • And it will be possible to act on blood results within 8 h: Immediately obtain venous blood sample and await results
  • And it will NOT be possible to act within 8 h AND dose ≥ 150 mg/kg: Immediately start NAC and obtain venous blood sample
Step 2: Later Presentations

4. If single ingestion 8 - 24 h ago:

  • Dose < 150 mg/kg and asymptomatic: Immediately obtain venous blood sample and await results
  • Dose ≥ 150 mg/kg or symptomatic: Immediately start NAC and obtain venous blood sample

5. If single ingestion > 24 h ago:

  • Dose < 150 mg/kg and asymptomatic: Immediately obtain venous blood sample and await results
  • Dose ≥ 150 mg/kg or symptomatic: Immediately start NAC and obtain venous blood sample

6. If ingestion is staggered:

  • Immediately start NAC and obtain venous blood sample
  • Delay blood sampling to ensure 4 h has passed since last ingestion if necessary

Required Blood Tests

  • Plasma paracetamol level
  • U&Es, bicarbonate
  • Glucose
  • LFTs (ALT most sensitive)
  • INR and FBC

N-Acetylcysteine (NAC) Treatment

NAC Treatment Required If:

Indications for NAC

  • 4-24h after single ingestion, paracetamol level is on or above treatment line
  • >24h after single ingestion, paracetamol detectable + ALT abnormal or INR >1.3
  • >4h after last ingestion in staggered overdose, paracetamol detectable
  • Biochemical evidence of acute liver injury (ALT ↑) even if level below treatment line

Note: The level of detection of paracetamol is 10 mg/L. Patients with chronically elevated ALT may not require NAC if stable - discuss with NPIS.

Standard 21-hour NAC Regimen

Infusion NAC Dose Infusion Fluid Duration
1 150 mg/kg 200 mL 1 hour
2 50 mg/kg 500 mL 4 hours
3 100 mg/kg 1000 mL 16 hours

Preparation: N-Acetylcysteine ampoules contain 2 g NAC in 10 mL (200 mg/mL). Total dose = 300 mg/kg over 21 hours.

Monitoring and Discontinuation

End of Infusion Assessment

  • Re-check INR, creatinine, ALT at end of 21h infusion
  • Check paracetamol level only if large overdose
  • In severe toxicity: check lactate, venous pH/bicarbonate

NAC Can Be Stopped If:

  • INR ≤ 1.3 AND ALT normal
  • OR ALT < 2x ULN AND not doubled from admission

Continue NAC If ANY:

  • ALT > 2x ULN
  • ALT doubled AND above ULN
  • INR > 1.3 AND ALT above ULN
  • INR risen by ≥0.5 from admission

Modified 12-hour NAC Regimen (SNAP)

The Scottish and Newcastle Acetylcysteine Protocol (SNAP) regimen for IV acetylcysteine is not licensed or endorsed by the MHRA. It should only be used after discussion with a senior clinician.

Infusion NAC Dose Infusion Fluid Duration
1 100 mg/kg (max 11g) 200 mL 2 hours
2 200 mg/kg (max 22g) 1000 mL 10 hours

Discharge Criteria (SNAP): INR ≤1.3 AND ALT normal AND paracetamol <10 mg/L AND no liver damage symptoms.

NAC Adverse Reactions

Anaphylactoid Reactions

  • Occur in up to 30% of patients
  • Usually during first infusion
  • More common in: women, asthma/atopy, family allergies, low paracetamol levels

Clinical Features

  • Nausea, vomiting
  • Flushing, urticarial rash
  • Angioedema
  • Tachycardia, hypotension
  • Bronchospasm, shock

Management of Reactions

Reaction Management Protocol
  1. Stop infusion temporarily
  2. Chlorphenamine 10 mg IV if needed
  3. Nebulised salbutamol 5 mg if bronchospasm
  4. RESTART NAC once reaction settled
  5. Consider slower infusion rate (first bag over 2h)

Important: Previous reaction is NOT a contraindication to NAC. Consider pre-treatment with chlorphenamine, ranitidine, and salbutamol. SNAP regimen reduces reaction risk.

Liver Transplant Referral

King's College Criteria (KCC) predict poor prognosis and guide liver transplant referral decisions.

King's College Criteria

Major Criteria

  • Arterial pH < 7.30
  • INR > 6.5 (PT > 100 sec)
  • Creatinine > 3.4 mg/dL (300 µmol/L)
  • Grade III or IV hepatic encephalopathy

Additional Poor Prognostic Factors

  • Lactate > 3.5 mmol/L after fluid resuscitation (<4h)
  • Lactate > 3 mmol/L after full fluid resuscitation (12h)
  • Phosphate > 3.75 mg/dL (1.2 mmol/L) at 48-96h

Patients meeting KCC criteria have high mortality without liver transplantation. Urgent hepatology consultation required.

Special Considerations

Enhanced Elimination

  • Consider in levels >700 mg/L with coma and ↑ lactate
  • Intermittent hemodialysis preferred
  • Continuous renal replacement if HD unavailable
  • Double NAC dose if on renal replacement therapy

High-Risk Patients

  • Chronic alcohol use
  • Malnourished patients
  • Enzyme-inducing drugs (e.g., anticonvulsants)
  • Consider treatment line adjustment