What is the management of paracetamol (Acetaminophen) toxicity?

Management of Paracetamol (Acetaminophen) Toxicity

N-acetylcysteine (NAC) should be administered to patients with possible or probable risk for hepatotoxicity as determined by the Rumack-Matthew nomogram, ideally within 8-10 hours post-ingestion to reduce mortality and severe hepatotoxicity. 1, 2

Initial Assessment and Risk Stratification

• Obtain a plasma or serum acetaminophen concentration at least 4 hours after ingestion to accurately assess potential toxicity 3
• Use the Rumack-Matthew nomogram to determine risk of hepatotoxicity for acute single ingestions with known time of ingestion within 24 hours 1, 2
• Assess liver function tests (AST, ALT, bilirubin), coagulation parameters (INR), and renal function (creatinine, BUN) 3
• If time of ingestion is unknown or patient presents >24 hours after ingestion, administer NAC immediately and obtain acetaminophen concentration to determine need for continued treatment 3

Treatment Algorithm Based on Clinical Scenario

1. Acute Single Ingestion with Known Time (<24 hours)

• If acetaminophen level plots above the "possible toxicity" line (treatment line) on the Rumack-Matthew nomogram:

  • Administer NAC immediately 1, 2
  • Early administration (within 8 hours) results in minimal hepatotoxicity (2.9% incidence) 1
  • Delayed administration (>10 hours) results in significantly higher hepatotoxicity (26.4% incidence) 1

• If acetaminophen level plots below the treatment line:

  • NAC is not indicated 1
  • Risk of severe hepatotoxicity is minimal (only 1 of 297 patients developed toxicity in studies) 1

2. Late Presentation (>24 hours) or Unknown Time of Ingestion

• Administer NAC immediately without waiting for acetaminophen levels 2, 3
• Continue NAC treatment for a total of three doses over 21 hours 3
• If hepatotoxicity is already present (elevated transaminases), continue NAC until clinical improvement 1

3. Patients with Hepatotoxicity or Hepatic Failure

• Administer NAC to patients with hepatic failure thought to be due to acetaminophen (Level B recommendation) 1
• Administer NAC to patients with hepatotoxicity and suspected or known acetaminophen overdose, including repeated supratherapeutic ingestions (Level C recommendation) 1
• NAC has been shown to reduce disease progression in patients with fulminant hepatic failure due to acetaminophen 1

4. Repeated Supratherapeutic Ingestion (RSTI)

• For patients ≥6 years who have ingested:
  • ≥10 g or ≥200 mg/kg (whichever is less) over a single 24-hour period, or
  • ≥6 g or ≥150 mg/kg (whichever is less) per 24-hour period for ≥48 hours
  • Refer to emergency department and administer NAC 4, 2
• The Rumack-Matthew nomogram does not apply to RSTI cases 3, 4

NAC Administration Protocols

Intravenous Administration (preferred in most settings)

• Loading dose: 150 mg/kg in 5% dextrose over 15 minutes
• Second dose: 50 mg/kg over 4 hours
• Third dose: 100 mg/kg over 16 hours
• Total dose: 300 mg/kg over 21 hours 2, 3

Oral Administration

• Loading dose: 140 mg/kg
• Maintenance dose: 70 mg/kg every 4 hours for 17 doses 2

Special Considerations and Pitfalls

• Patients at increased risk for acetaminophen toxicity may develop hepatotoxicity at lower doses and should receive NAC even with acetaminophen levels below the typical treatment threshold 2:

  • Chronic alcoholics
  • Fasting patients
  • Patients on enzyme-inducing medications (e.g., isoniazid)

• For massive overdoses (≥30 g or ≥500 mg/kg), consider increased doses of NAC beyond the standard protocol 5

• Monitor for anaphylactoid reactions during NAC administration, particularly during the loading dose. If reactions occur:

  • Temporarily discontinue the infusion
  • Administer antihistamines
  • Restart the loading dose at a slower infusion rate 6

• For extended-release acetaminophen formulations, if the 4-hour level is below the possible toxicity line, obtain a second sample at 8-10 hours post-ingestion 3

• Very high aminotransferases are highly correlated with acetaminophen poisoning and should prompt consideration of NAC even without confirmatory history 2

• NAC is most effective when administered within 8-10 hours of ingestion, but should not be withheld even if presentation is delayed, as it may still provide benefit 1, 3