What is the treatment for paracetamol (acetaminophen) poisoning?

Treatment of Paracetamol (Acetaminophen) Poisoning

Immediately administer N-acetylcysteine (NAC) to all patients with paracetamol levels above the treatment line on the Rumack-Matthew nomogram or when hepatotoxicity is suspected, as NAC is the only proven antidote that reduces mortality and prevents liver failure. 1

Initial Management and Decontamination

• Administer activated charcoal (1 g/kg orally) within 4 hours of ingestion if the patient presents early with known or suspected paracetamol overdose, ideally within 1-2 hours but potentially beneficial up to 4 hours post-ingestion. 1

• Give activated charcoal just prior to starting NAC therapy to maximize benefit while ensuring airway protection is adequate, particularly in cases of co-ingestion with sedating substances. 1

Risk Assessment Using the Rumack-Matthew Nomogram

• Obtain a serum paracetamol concentration at least 4 hours post-ingestion (concentrations drawn earlier than 4 hours are unreliable and may not represent peak levels). 2

• Plot the paracetamol level on the Rumack-Matthew nomogram to determine treatment need:

  • Treatment line starts at 150 mg/L (992 µmol/L) at 4 hours in the United States, Australia, and New Zealand. 3
  • The UK previously used 200 mg/L at 4 hours but lowered it to 100 mg/L in 2012, though this increases treatment burden. 3

• The nomogram only applies to single acute ingestions with known timing within 24 hours—it does NOT apply to repeated supratherapeutic ingestions, extended-release formulations, or presentations beyond 24 hours. 1, 2

NAC Treatment Protocol

Standard Dosing Regimen

• Total NAC dose is 300 mg/kg given intravenously over 21 hours in three divided doses:

  • Loading dose: 150 mg/kg over 15-60 minutes (newer protocols use 2 hours to reduce adverse reactions)
  • Second dose: 50 mg/kg over 4 hours
  • Third dose: 100 mg/kg over 16 hours 2

• Alternative two-bag regimen (Scottish and Newcastle protocol): 100 mg/kg over 2 hours, then 200 mg/kg over 10 hours, which has comparable efficacy with significantly reduced adverse reactions. 4

• NAC must be diluted prior to administration as it is hyperosmolar (2600 mOsmol/L); use sterile water, 0.45% sodium chloride, or 5% dextrose. 2

Critical Timing Considerations

• NAC initiated within 8 hours of ingestion carries only 2.9% risk of severe hepatotoxicity, compared to 6.1% when started within 10 hours and 26.4% when started after 10 hours. 1

• The 0-8 hour window is the critical treatment interval for maximal protection; efficacy diminishes progressively after 8 hours but treatment should never be withheld even in late presentations. 2, 3

Special Clinical Scenarios Requiring Immediate NAC

Unknown Time of Ingestion

• Administer NAC loading dose immediately without waiting for laboratory results if the time of ingestion is unknown but paracetamol overdose is suspected. 2

• Obtain paracetamol concentration after starting treatment to determine need for continuation. 1, 2

Presentations Beyond 8 Hours

• Start NAC immediately if the patient presents more than 8 hours post-ingestion, regardless of paracetamol level availability. 1, 2

• Between 10-24 hours, severe hepatotoxicity develops in 26.4% of at-risk patients, but this is still lower than untreated historical controls (58%). 1

• NAC remains beneficial even beyond 24 hours and should be administered to reduce hepatotoxicity and mortality, though efficacy is significantly diminished compared to early treatment. 1

Established Hepatotoxicity or Fulminant Hepatic Failure

• All patients with fulminant hepatic failure from paracetamol must receive NAC regardless of time since ingestion (Level B recommendation from the American College of Emergency Physicians). 1

• NAC reduces mortality from 80% to 52%, cerebral edema from 68% to 40%, and need for inotropic support from 80% to 48% in fulminant hepatic failure. 1

• Early NAC treatment (<10 hours) in fulminant hepatic failure results in 100% survival, while late treatment (>10 hours) results in 37% mortality. 1

• Patients with hepatotoxicity (elevated transaminases) and suspected paracetamol overdose should receive NAC, including cases of repeated supratherapeutic ingestion where timing cannot be determined by nomogram. 1

Repeated Supratherapeutic Ingestions (RSTI)

• The Rumack-Matthew nomogram does NOT apply to RSTI—treatment decisions must be based on paracetamol levels and liver function tests. 2, 4

• Administer NAC if serum paracetamol concentration is ≥10 mg/mL OR if aminotransferases are elevated (AST or ALT >50 IU/L). 1

• Obtain paracetamol concentration and liver function tests to guide treatment rather than relying on nomogram placement. 2, 4

Extended-Release Paracetamol Overdose

• All potentially toxic modified-release ingestions (≥10 g or ≥200 mg/kg, whichever is less) should receive a full course of NAC. 4

• If the 4-hour paracetamol level is below the treatment line, obtain a second sample at 8-10 hours post-ingestion; if this second value is at or above the treatment line, administer NAC. 2

• Patients ingesting ≥30 g or ≥500 mg/kg should receive increased doses of NAC. 4

Massive Overdoses

• Massive overdoses resulting in paracetamol concentrations more than double the nomogram line require increased doses of NAC. 4

• The standard 300 mg/kg total dose may be insufficient for very large ingestions. 4

High-Risk Populations

• Patients with chronic alcohol consumption should be treated with NAC even with levels in the "non-toxic" range due to documented severe hepatotoxicity with doses as low as 4-5 g/day. 1

• Consider treating patients with malnutrition or CYP2E1 enzyme-inducing drugs (e.g., isoniazid) even if paracetamol concentrations are below the treatment line, as the nomogram may underestimate hepatotoxicity risk. 2

Monitoring and Laboratory Assessment

• Obtain baseline and serial measurements of AST, ALT, bilirubin, INR, creatinine, BUN, blood glucose, and electrolytes to monitor hepatic and renal function. 2

• Patients with very high aminotransferase levels should be suspected of paracetamol toxicity even without clear overdose history. 5

• Patients with severe hepatotoxicity (AST >1000 IU/L) or coagulopathy require ICU-level care and early consultation with transplant hepatology. 1

Common Pitfalls and Caveats

• Never rely solely on patient-reported ingestion quantity—the history is often inaccurate and unreliable for guiding therapy. 2

• Patients may develop elevated hepatic transaminases despite being stratified as "no risk" on the nomogram due to inaccurate history or increased susceptibility. 1

• Do not withhold NAC while waiting for laboratory results if the acetaminophen concentration cannot be obtained within 8 hours or if there is clinical evidence of toxicity. 2

• The reported time of ingestion may be incorrect, so err on the side of treatment initiation when uncertain. 2

• For presentations >24 hours, treatment decisions must be based on paracetamol levels and liver function tests, NOT nomogram placement. 1

Adverse Reactions to NAC

• NAC infusion may cause hypersensitivity reactions including hypotension, wheezing, shortness of breath, bronchospasm, rash, urticaria, facial flushing, and pruritus. 2

• If serious hypersensitivity occurs, immediately discontinue the infusion and initiate appropriate treatment; NAC may be carefully restarted after treating the reaction. 2

• Slower loading dose administration (over 2 hours rather than 15 minutes) significantly reduces adverse reactions. 3, 4

Pregnancy Considerations

• Paracetamol overdose during pregnancy should be treated with NAC according to regular protocols to prevent maternal and potentially fetal toxicity. 6

• Unless severe maternal toxicity develops, paracetamol overdose does not appear to increase risk for adverse pregnancy outcomes. 6