What is the treatment for paracetamol (acetaminophen) toxicity?

Treatment of Paracetamol (Acetaminophen) Toxicity

Immediate Management: Start NAC Without Delay

Administer N-acetylcysteine (NAC) immediately to any patient with suspected or confirmed paracetamol overdose if ≤24 hours have elapsed from ingestion, without waiting for laboratory confirmation. 1, 2

Initial Actions (Within First Hour)

• Give activated charcoal (1 g/kg orally) just prior to starting NAC if the patient presents within 4 hours of ingestion 1, 2

  • Most effective within 1-2 hours but may provide benefit up to 4 hours post-ingestion 1
  • If activated charcoal was already given, perform gastric lavage before NAC administration, as charcoal adsorbs NAC and reduces its effectiveness 2

• Draw blood immediately for: 1, 2

  • Paracetamol level (must be drawn ≥4 hours post-ingestion for nomogram use)
  • AST, ALT, bilirubin, prothrombin time/INR
  • Creatinine, BUN, electrolytes, blood glucose

NAC Dosing Regimens

Intravenous Protocol (Preferred - Two-Bag Regimen)

The modern two-bag IV regimen has similar efficacy but significantly fewer adverse reactions compared to older protocols: 3

• Loading dose: 200 mg/kg in 5% dextrose over 4 hours 3
• Maintenance dose: 100 mg/kg over 16 hours 3
• Total treatment duration: 20 hours (can be extended based on clinical criteria) 1, 3

Oral Protocol (Alternative)

• Loading dose: 140 mg/kg orally or via nasogastric tube, diluted to 5% solution 2
• Maintenance dose: 70 mg/kg every 4 hours for 17 additional doses (total 72 hours) 1, 2
• If vomiting occurs within 1 hour of any dose, repeat that dose immediately 2
• For persistent vomiting, administer via duodenal intubation 2

Risk Stratification Using the Rumack-Matthew Nomogram

Use the nomogram ONLY for single acute ingestions with known time of ingestion when paracetamol level is drawn 4-24 hours post-ingestion: 1

• Plot the paracetamol concentration on the nomogram 1
• Treat with NAC if the level plots at or above the "possible toxicity" line (the lower treatment line, 25% below the original "probable toxicity" line) 1, 4
• The nomogram does NOT apply to: 1
  • Presentations >24 hours post-ingestion
  • Extended-release formulations
  • Repeated supratherapeutic ingestions
  • Unknown time of ingestion

Critical Time-Dependent Efficacy

NAC effectiveness is dramatically time-dependent, making early treatment essential: 1

• 0-8 hours: Only 2.9% develop severe hepatotoxicity when treated within 8 hours 1, 5
• 8-10 hours: 6.1% develop severe hepatotoxicity 1, 5
• 10-24 hours: 26.4% develop severe hepatotoxicity 1
• >24 hours: Still administer NAC—it reduces mortality even with delayed treatment 1

Special Clinical Scenarios Requiring Immediate NAC (Regardless of Nomogram)

Established Hepatotoxicity or Liver Failure

Administer NAC immediately to all patients with hepatic failure or hepatotoxicity from paracetamol, regardless of time since ingestion: 1, 5

• NAC reduces mortality from 80% to 52% in fulminant hepatic failure 1, 5
• NAC reduces cerebral edema from 68% to 40% 1
• Early NAC (<10 hours) in fulminant hepatic failure results in 100% survival 1, 5
• Late NAC (>10 hours) still reduces mortality to 37% compared to no treatment 1, 5

Repeated Supratherapeutic Ingestions

Treat with NAC if any of the following criteria are met: 1

• ≥10 g or 200 mg/kg (whichever is less) during a single 24-hour period 1
• ≥6 g or 150 mg/kg (whichever is less) per 24-hour period for ≥48 hours 1
• Serum paracetamol ≥10 mg/mL 1
• AST or ALT >50 IU/L with any detectable paracetamol level 1

High-Risk Populations (Lower Treatment Threshold)

Treat with NAC even with levels in the "non-toxic" range for: 1, 5

• Chronic alcohol users: Severe hepatotoxicity documented with doses as low as 4-5 g/day 1, 5
• Cirrhotic patients: Increased susceptibility to hepatotoxicity even at therapeutic doses 5
• Patients taking enzyme-inducing drugs (e.g., anticonvulsants, rifampin) 1
• Malnourished or fasting patients 4

Extended-Release Formulations

All potentially toxic modified-release paracetamol ingestions (≥10 g or ≥200 mg/kg, whichever is less) should receive a full course of NAC: 3

• Patients ingesting ≥30 g or ≥500 mg/kg should receive increased doses of acetylcysteine 3
• Extended-release formulations require individualized treatment due to prolonged absorption 1

Massive Overdoses

For massive overdoses with paracetamol concentrations more than double the nomogram line, increase the NAC dose: 3

• Standard two-bag regimen may be insufficient 3
• Consider step-wise dose increases at the 300-, 450-, and 600-lines on the nomogram 1

Unknown Time of Ingestion

If time of ingestion is unknown but paracetamol is detectable, start NAC immediately: 1

• Draw paracetamol level immediately and repeat in 4 hours 2
• Continue NAC until levels are undetectable and liver function remains normal 1

When to Extend NAC Beyond Standard Protocol

Continue NAC beyond the standard 20-21 hour protocol if ANY of the following are present: 1, 5

• AST or ALT remains elevated or rising 1, 5
• INR remains elevated 1, 5
• Detectable paracetamol level persists 1, 5
• Delayed presentation (>24 hours post-ingestion) 1, 5
• Extended-release formulation 1
• Repeated supratherapeutic ingestions 1
• Unknown time of ingestion 1

Continue NAC until transaminases are declining and INR normalizes in patients with established hepatotoxicity 1

When NAC Can Be Safely Discontinued

NAC can be discontinued when ALL of the following criteria are met: 1

• Paracetamol level is undetectable 1
• AST and ALT are normal (not just "improving"—must be normal) 1
• INR is normal 1
• No clinical signs of hepatotoxicity 1
• Known time of ingestion with appropriate treatment window 1

A shortened 12-hour course may be considered ONLY in carefully selected low-risk patients with normal labs at presentation and 12 hours, but this requires careful risk assessment 1

Critical Red Flags Requiring ICU Care and Transplant Consultation

Contact a liver transplant center immediately and provide ICU-level care if: 1

• AST or ALT >1,000 IU/L (severe hepatotoxicity) 1
• AST or ALT >3,500 IU/L (highly correlated with paracetamol poisoning) 1
• Any coagulopathy (INR >1.5) 1, 2
• Evidence of hepatic encephalopathy 1
• Acute liver failure (elevated bilirubin, INR, and transaminases "in the thousands") 1

Supportive Care

Provide the following supportive measures: 2

• Maintain fluid and electrolyte balance based on clinical evaluation 2
• Treat hypoglycemia if present 2
• Administer vitamin K1 if prothrombin time ratio exceeds 1.5 2
• Give fresh frozen plasma if prothrombin time ratio exceeds 3.0 2
• Avoid diuretics and forced diuresis 2
• Monitor for complications: encephalopathy, coagulopathy, renal failure, metabolic derangements 1, 6

Common Pitfalls and Caveats

Avoid these critical errors: 1

• Never delay NAC while waiting for paracetamol levels—start immediately if overdose is suspected and ≤24 hours have elapsed 1, 2
• Low or absent paracetamol levels do NOT rule out paracetamol poisoning if ingestion was remote or occurred over several days 1
• The nomogram may underestimate risk in cirrhotic patients, chronic alcohol users, and other high-risk populations—use a lower threshold for treatment 1, 5
• Patients may present with elevated transaminases despite "no risk" nomogram placement due to inaccurate history or increased susceptibility 1
• Do not stop NAC prematurely—verify ALL discontinuation criteria are met, not just undetectable paracetamol 1
• Monitor renal function closely—acute renal failure from acute tubular necrosis can occur and may require hemodialysis 6