Paracetamol Overdose

Paracetamol (acetaminophen) toxicity results from saturation of the normal glucuronidation and sulfation conjugation pathways at supratherapeutic doses, forcing a greater proportion of the drug through the cytochrome P450 pathway.

This generates NAPQI, a highly reactive metabolite that is normally detoxified by conjugation with glutathione.

In overdose, hepatic glutathione stores become depleted, allowing NAPQI to accumulate and cause centrilobular hepatocyte necrosis.

Toxicity is dose dependent, with a single ingestion above roughly 150 mg/kg (or a lower threshold in malnourished, alcohol dependent, or enzyme induced patients) generally considered potentially serious.

Presentation is classically divided into four phases:

• 0 to 24 hours: often asymptomatic, or mild nausea, vomiting, and malaise. This early deceptive well appearance is a key reason overdose is dangerous, patients and even clinicians can underestimate severity.
• 24 to 72 hours: right upper quadrant pain and tenderness develop as hepatic injury evolves; transaminases begin rising, sometimes dramatically.
• 72 to 96 hours: peak hepatotoxicity, with jaundice, coagulopathy, encephalopathy, and, in severe cases, progression to fulminant liver failure and acute kidney injury.
• 4 days to 2 weeks: resolution in survivors, with complete histological recovery typical if the patient survives the acute insult.

A paracetamol level should be measured in every suspected overdose, ideally at or after 4 hours post ingestion (levels before this are unreliable due to ongoing absorption), and plotted against the treatment nomogram to determine whether treatment is indicated.

• Timing matters enormously: staggered ingestion, unknown timing, or presentation more than 8 hours after a significant single ingestion changes the approach, since waiting for a 4 hour level in these situations risks missing the treatment window.
• LFTs, INR, U&E and creatinine, venous blood gas, and glucose should be checked in all significant ingestions, and repeated serially to track evolving hepatic and renal injury.
• A baseline paracetamol level plus LFTs should be checked in any patient presenting more than 8 hours post ingestion, or with an unclear history, given the risk of delayed presentation with established injury.

Differentials for the presenting complaint (nausea, abdominal pain) are broad, but the diagnosis here is rarely in doubt once a history of ingestion is obtained or suspected; the key clinical task is accurate risk stratification rather than differential diagnosis.

N-acetylcysteine (NAC) is the antidote, working by replenishing glutathione stores and providing an alternative substrate for NAPQI conjugation. It is highly effective when started early, ideally within 8 hours of ingestion, with efficacy declining progressively thereafter, though it should still be given even at late presentation given ongoing benefit and low risk of harm.

• NAC is given as a weight based intravenous infusion. The traditional regimen is a loading dose of 150 mg/kg in 200 mL of 5% dextrose over 60 minutes, then 50 mg/kg in 500 mL over 4 hours, then 100 mg/kg in 1000 mL over 16 hours, a total of 300 mg/kg over 21 hours. Simplified two bag regimens delivering the same 300 mg/kg total dose over a shorter or differently divided course are now standard practice in many centres, chosen for lower anaphylactoid reaction rates; follow the specific regimen and infusion durations set out in local or national protocol.
• Anaphylactoid reactions (flushing, urticaria, bronchospasm, hypotension) are common, particularly with the first infusion, and are managed by slowing or briefly pausing the infusion and giving antihistamines, rather than stopping NAC altogether given how effective and necessary it is.
• Activated charcoal (50 g) is considered if presentation is within 1 to 2 hours of a significant ingestion, and the patient is able to protect their airway.
• Staggered or unknown timing ingestions, or those with any uncertainty, should generally be treated with NAC pending levels and clinical assessment, given the low risk of the antidote itself versus the high risk of missing significant toxicity.
• Severe hepatotoxicity progressing toward liver failure requires transfer to a specialist liver unit, with King's College criteria used to guide transplant listing decisions.

Referral: poison control or toxicology service for any significant or uncertain ingestion; hepatology or a specialist liver unit urgently for evolving hepatotoxicity, coagulopathy, or encephalopathy.