What is the treatment for a paracetamol (acetaminophen) overdose?

Treatment of Paracetamol (Acetaminophen) Overdose

Immediately administer N-acetylcysteine (NAC) to any patient with suspected or confirmed paracetamol overdose when serum levels plot above the treatment line on the Rumack-Matthew nomogram, or when hepatotoxicity is present, or when timing is uncertain—ideally within 8 hours of ingestion to maximize survival and prevent liver failure. 1

Initial Management Within 4 Hours of Ingestion

• Give activated charcoal (1 g/kg orally) just prior to starting NAC if the patient presents within 4 hours of ingestion, as this significantly reduces paracetamol absorption and lowers subsequent serum concentrations 1, 2
• Activated charcoal administered within 4 hours reduces paracetamol concentrations by approximately 40% (paracetamol ratio 1.4 vs 2.2 without charcoal) and decreases hepatotoxicity risk 2
• Ensure airway protection is adequate before administering activated charcoal, particularly with co-ingestions of sedating substances 1

Risk Stratification Using the Rumack-Matthew Nomogram

• Draw serum paracetamol concentration between 4-24 hours post-ingestion and plot on the Rumack-Matthew nomogram to determine treatment need 1
• The nomogram uses a treatment line at 150 mg/L at 4 hours (or 50 mg/L at 12 hours) to identify patients requiring NAC 1, 3
• Start NAC immediately for any patient plotting at or above the "possible toxicity" line—do not wait for repeat levels 1
• The nomogram is ONLY valid for single acute ingestions with known timing; it does NOT apply to repeated supratherapeutic ingestions, extended-release formulations, or presentations >24 hours post-ingestion 1

NAC Dosing Regimens

Intravenous Protocol (Preferred in Most Settings)

• Loading dose: 150 mg/kg in 5% dextrose over 15 minutes 1
• Second dose: 50 mg/kg over 4 hours 1
• Third dose: 100 mg/kg over 16 hours (total 21-hour protocol) 1
• The newer two-bag regimen (200 mg/kg over 4 hours, then 100 mg/kg over 16 hours) has similar efficacy with significantly fewer adverse reactions 4

Oral Protocol (Alternative)

• Loading dose: 140 mg/kg orally or via nasogastric tube (diluted to 5% solution) 1
• Maintenance: 70 mg/kg every 4 hours for 17 additional doses (total 72-hour protocol) 1
• The 72-hour oral regimen is as effective as the 20-hour IV regimen and may be superior when treatment is delayed 1

Critical Timing Considerations

• Treatment within 8 hours results in only 2.9% developing severe hepatotoxicity—this is the golden window 1, 5
• Efficacy diminishes progressively: 6.1% hepatotoxicity when treated within 10 hours, and 26.4% when treated 10-24 hours post-ingestion 1
• Never withhold NAC based on timing alone—even late presentations (>24 hours) benefit significantly, with mortality reduction from 80% to 52% in fulminant hepatic failure 1

Special Clinical Scenarios Requiring Immediate NAC

Established Hepatotoxicity or Liver Failure

• Administer NAC to ALL patients with hepatic failure thought to be due to paracetamol, regardless of time since ingestion (Level B recommendation) 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 1

Unknown Time of Ingestion

• Start NAC immediately for any patient with detectable paracetamol levels and unknown timing 1
• Base treatment decisions on paracetamol levels and liver function tests rather than the nomogram 1

Repeated Supratherapeutic Ingestions (RSTI)

• Treat with NAC if serum paracetamol ≥10 mg/mL OR if AST or ALT >50 IU/L 1
• Consider NAC for ingestions of ≥10 g or 200 mg/kg (whichever is less) in a single 24-hour period 1
• Also treat if ≥6 g or 150 mg/kg per 24-hour period for ≥48 hours 1

Extended-Release Formulations

• All potentially toxic modified-release paracetamol ingestions (≥10 g or ≥200 mg/kg) should receive a full course of NAC 4
• Obtain serial paracetamol levels due to prolonged absorption 1

Massive Overdoses (≥40 g)

• For paracetamol concentrations more than double the nomogram line, increase NAC dosing 1, 4
• Most commonly double the third bag dose (100 to 200 mg/kg over 16 hours) 2
• Increased acetylcysteine dosing in massive overdoses reduces hepatotoxicity risk by 73% (OR 0.27) 2

High-Risk Populations Requiring Lower Treatment Threshold

• Chronic alcohol users should be treated with NAC even with levels in the "non-toxic" range, as severe hepatotoxicity occurs with doses as low as 4-5 g/day 1
• Patients with pre-existing liver disease require more conservative treatment thresholds 3
• Consider treating at lower nomogram levels for patients taking enzyme-inducing drugs 1

Monitoring and Laboratory Assessment

• Obtain baseline liver function tests (AST, ALT), prothrombin time/INR, and serum paracetamol level 1
• Repeat liver function tests at 12-24 hours to assess for developing hepatotoxicity 1
• Very high aminotransferases (AST/ALT >3,500 IU/L) are highly correlated with paracetamol poisoning even without clear overdose history 1

Criteria for Stopping NAC

• NAC can be discontinued when paracetamol level is undetectable AND liver function tests remain completely normal 1
• Do NOT stop NAC if any of the following are present: any elevation in AST or ALT above normal, rising transaminases, any coagulopathy, detectable paracetamol level, or clinical signs of hepatotoxicity 1
• Certain scenarios mandate longer NAC courses: delayed presentation (>24 hours), extended-release formulations, repeated supratherapeutic ingestions, unknown timing with detectable levels, or chronic alcohol use 1

Management of NAC Adverse Reactions

• Anaphylactoid reactions (hypotension, wheezing, bronchospasm) typically occur during the loading dose 5, 6
• If reactions occur: stop the infusion, administer antihistamines, then restart at a slower rate 6
• The two-bag regimen significantly reduces adverse reactions compared to the traditional three-bag protocol 4

Disposition and Transplant Considerations

• Patients with severe hepatotoxicity (AST >1000 IU/L) or coagulopathy require ICU-level care and immediate transplant hepatology consultation 1
• Contact a liver transplant center immediately when there is any evidence of liver failure 1
• Monitor for complications including encephalopathy, coagulopathy, renal failure, and metabolic derangements 1

Critical Pitfalls to Avoid

• Low or absent paracetamol levels do NOT rule out paracetamol poisoning if ingestion was remote or occurred over several days 1
• Patients may present with elevated transaminases despite being stratified as "no risk" on the nomogram due to inaccurate history or increased susceptibility 1
• The nomogram is invalid for presentations >24 hours post-ingestion—base treatment on paracetamol levels and liver function tests instead 1
• Failing to recognize paracetamol in combination products (opioids, cold medicines) leads to unintentional overdose 3
• Never delay NAC while waiting for laboratory results in suspected overdose—start empirically and adjust based on results 1