admittomedicine

acetaminophen (paracetamol)

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acetaminophen (paracetamol)

pathophysiology

  • Metabolism: Most is conjugated (glucuronidation/sulfation). Small amount metabolised by CYP2E1 to NAPQI (toxic).
  • Toxicity: NAPQI is normally neutralised by Glutathione. In overdose, glutathione is depleted NAPQI causes hepatocyte necrosis.

clinical presentation

  • Stage I (0–24h): Asymptomatic or non-specific symptoms (nausea, vomiting, pallor, diaphoresis, lethargy).
  • Stage II (24–72h): RUQ pain/tenderness, hepatomegaly. Rising ALT/AST, bilirubin, and INR. Oliguria.
  • Stage III (72–96h): Peak Toxicity. Jaundice, confusion (hepatic encephalopathy), marked AST/ALT elevation (> 1000 IU/L), coagulopathy, hypoglycaemia, lactic acidosis, renal failure.
  • Stage IV (4d–2w): Recovery phase (hepatic regeneration) or progression to fulminant hepatic failure/death.

risk assessment

  • Toxic Dose (Acute): > 200 mg/kg or > 10 g (adults).
    • Note: Toxicity possible > 150 mg/kg or 7.5 g.
  • High-Risk Ingestion: > 30 g OR level above the “High Risk” nomogram line.
  • Risk Factors: Chronic alcohol use, malnutrition, CYP2E1 inducers (isoniazid, anticonvulsants).

investigations

  • Acetaminophen Level:
    • Draw 4 hours post-ingestion (levels before 4h cannot be plotted).
    • Extended Release: Check at 4h. If < treatment line but > 10 mg/L (66 µmol/L), recheck 4–6h later.
  • Labs: Lytes, Urea, Cr, AST, ALT, INR, Glucose, VBG (Lactate).

management

1. decontamination

  • Activated Charcoal: 1 g/kg (max 50–100 g).
  • Indication: Presentation within 4 hours of significant ingestion.
    • May consider > 4h for massive ingestions, extended-release, or co-ingestants delaying absorption (opioids/anticholinergics).

2. n-acetylcysteine (nac)

Indications:

  • Acute (< 24h): Level above Rumack-Matthew Nomogram treatment line (starts at 150 mg/L or ~1000 µmol/L at 4h).
  • Repeated/Unknown Time: Treat if APAP > 10 mg/L (66 µmol/L) OR ALT elevated.
  • Presentation > 24h: Evidence of liver injury or detectable APAP.

Dosing (20–21 Hour IV Protocol):

  1. Loading: 150 mg/kg in 200 mL D5W over 60 min.
  2. Maintenance 1: 50 mg/kg in 500 mL D5W over 4 hours.
  3. Maintenance 2: 100 mg/kg in 1000 mL D5W over 16 hours.
  • Total: 300 mg/kg over 21 hours.
  • Adverse Events: Flushing/urticaria (give antihistamine, slow rate). Anaphylaxis (stop, treat).

3. stopping criteria

Do not stop NAC solely based on time. Continue specific maintenance rate (e.g., 6.25 mg/kg/hr) until:

  1. INR < 1.3 (or normal).
  2. ALT < 100 U/L (or clearly declining).
  3. Acetaminophen undetectable (< 10 mg/L or < 66 µmol/L).
  4. Patient is clinically well.

4. enhanced elimination

Haemodialysis Indications:

  • Massive Levels: > 900 mg/L (~6000 µmol/L) AND altered mental status or metabolic acidosis.
  • Severe Acidosis: pH < 7.30 despite resuscitation.
  • Renal Failure: With elevated levels.

5. liver transplantation

King’s College Criteria:

  • Arterial pH < 7.3 (after fluid resuscitation).
  • OR all three of:
    1. INR > 6.5
    2. Creatinine > 300 mol/L
    3. Encephalopathy (Grade III/IV)

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