What is the treatment for paracetamol (acetaminophen) overdose using N-acetylcysteine (NAC)?

N-Acetylcysteine (NAC) for Paracetamol Overdose

Administer NAC immediately to all patients with paracetamol overdose who plot in the possible or probable risk zones on the Rumack-Matthew nomogram, ideally within 8 hours of ingestion to prevent hepatotoxicity and mortality. 1, 2

Indications for NAC Treatment

Acute Single Ingestion (Known Time)

• Administer NAC when serum paracetamol levels plot above the treatment line on the Rumack-Matthew nomogram (measured 4-24 hours post-ingestion) 1, 2
• The nomogram includes a "possible risk" zone 25% below the original line to account for assay measurement errors 1
• Level B Recommendation: Administer NAC to all patients with hepatic failure thought to be due to paracetamol 1

Special Clinical Scenarios Requiring NAC

• Unknown or unreliable ingestion time with detectable paracetamol levels: Treat with NAC and check aminotransferases to guide management 1, 2
• Repeated supratherapeutic ingestions (>4g per 24 hours): Administer NAC if paracetamol level ≥10 mg/mL OR aminotransferases (AST/ALT) >50 IU/L 1, 2, 3
• Extended-release preparations: Use standard NAC protocol but extend monitoring due to prolonged absorption 1, 2
• Presentation >24 hours post-ingestion: Administer NAC based on elevated aminotransferases or clinical hepatotoxicity, as nomogram cannot be used 1, 2
• Acute liver failure with suspected paracetamol ingestion: Give NAC even without confirmatory history, especially if very high aminotransferases present 2

Dosing Regimens

Standard Intravenous Protocol (21-hour regimen)

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

Alternative SNAP 12-hour Regimen

• 100 mg/kg IV over 2 hours, then 200 mg/kg IV over 10 hours (total 300 mg/kg over 12 hours) 4
• This regimen demonstrates similar efficacy with significantly fewer adverse reactions (2.0% vs 11.0% requiring antihistamine treatment) 4
• No difference in hepatotoxicity rates (3.6% vs 4.3%) or liver synthetic dysfunction compared to standard 21-hour protocol 4

Oral Protocol

• Loading dose: 140 mg/kg orally 5, 2
• Maintenance: 70 mg/kg orally every 4 hours for 17 additional doses 5, 2

Critical Timing Considerations

The efficacy of NAC is highly time-dependent, with outcomes directly tied to treatment delay:

• <8 hours: Virtually complete protection against liver damage (mean maximum ALT 27 IU/L); hepatotoxicity rate 2.9% 1, 6
• <10 hours: Hepatotoxicity rate 6.1%; no paracetamol-related mortality 1, 6
• 10-16 hours: Hepatotoxicity rate increases to 29% in high-risk patients 1
• 16-24 hours: Hepatotoxicity rate rises to 62% in high-risk patients 1
• >15 hours: Treatment efficacy diminishes substantially 6
• 12-24 hours: NAC still provides benefit and prevents further liver damage, reducing hepatotoxicity from expected 90% to 35% 7

No deaths occurred among patients treated within 24 hours of ingestion 1

High-Risk Populations

Patients at increased risk for toxicity at lower paracetamol doses include:

• Chronic alcohol users 2
• Fasting or malnourished patients 5, 2
• Patients on CYP2E1-inducing medications 2

These patients should receive NAC even if paracetamol levels fall below typical treatment thresholds 2

Management of Established Hepatotoxicity

• Hepatotoxicity without hepatic failure (ALT 50-1000 IU/L): Administer NAC; 15% progress to severe hepatotoxicity 1
• Fulminant hepatic failure: NAC reduces mortality by 28% (from 80% to 52%), decreases cerebral edema, and reduces need for inotropic support 1
• Continue NAC in patients with established liver injury regardless of time since ingestion 1

Large Overdoses (>30g or >500 mg/kg)

• Standard 300 mg/kg NAC regimen is effective in most patients with large overdoses 8
• For massive overdoses (>40g) with paracetamol concentrations >300 mg/L, consider modified regimen providing 400-500 mg/kg NAC over 21-22 hours, though impact on mortality is unknown 8

Critical Pitfalls to Avoid

• Never delay NAC while awaiting confirmatory paracetamol levels if strong suspicion exists 2
• Do not withhold NAC if activated charcoal has been given; charcoal may be administered within 4 hours of presentation but should not delay NAC 2
• Do not rely solely on normal aminotransferases in the ED to exclude toxicity risk, as levels may rise over subsequent hours 1
• Beware of patients with "no risk" by nomogram who have elevated aminotransferases—consider inaccurate history, increased susceptibility, or alternative causes of hepatic injury 1

Adverse Reactions

• Anaphylactoid reactions occur in approximately 11% with standard regimen, 2% with SNAP regimen 4
• Treat reactions with antihistamines; do not discontinue NAC 4
• Fatal overdose from 10-fold dosing error (160g instead of 16g) has been reported, causing widespread urticaria, hypotension, and death 3

Special Populations

Pregnancy

• NAC and paracetamol both cross the placenta 3
• Delaying treatment increases risk of maternal and fetal morbidity and mortality—treat immediately 3
• No adverse fetal effects observed in animal studies at doses equivalent to human dosing 3

Lactation

• NAC is nearly completely cleared 30 hours after administration 3
• Breastfeeding women may pump and discard milk for 30 hours post-treatment 3

Renal/Hepatic Impairment

• Hemodialysis removes some NAC but does not contraindicate treatment 3
• Hepatic impairment increases NAC half-life by 80% and AUC by 1.6-fold, but changes are not clinically significant 3

Administration Considerations

• No dietary restrictions or contraindications during NAC treatment 5
• Both oral and intravenous routes are effective 5, 2
• Intravenous route preferred for patients with vomiting, altered mental status, or inability to tolerate oral medication 2