Should N-acetylcysteine (NAC) be administered for a patient with a paracetamol (acetaminophen) overdose of 6 grams?

Should NAC Be Given for 6g Paracetamol Overdose?

Yes, N-acetylcysteine (NAC) should be administered for a 6-gram paracetamol overdose, as this represents a potentially hepatotoxic dose that warrants treatment regardless of nomogram placement in most clinical scenarios. 1

Risk Assessment for 6-Gram Ingestion

A 6-gram ingestion meets the threshold for potential hepatotoxicity and requires immediate evaluation:

• For patients weighing >60 kg: This represents approximately 100 mg/kg, placing them at risk for hepatotoxicity 1
• **For patients weighing <60 kg**: This represents >100 mg/kg, placing them at even higher risk 1
• Paracetamol is a dose-related toxin, with severe liver injury possible at doses as low as 3-4 g/day in susceptible individuals, though acute liver failure typically occurs with ingestions exceeding 10 g/day 1

Treatment Algorithm Based on Presentation Time

If Presenting Within 4 Hours of Ingestion:

• Administer activated charcoal (1 g/kg) just prior to starting NAC to reduce paracetamol absorption 1, 2
• Draw serum paracetamol level at 4 hours post-ingestion (or as soon as the 4-hour mark is reached) 1
• Start NAC immediately without waiting for the 4-hour level if there is any delay in obtaining laboratory results or if clinical suspicion is high 1, 2
• Use the Rumack-Matthew nomogram once the 4-hour level is available to guide continuation of therapy 1, 3

If Presenting 4-8 Hours Post-Ingestion:

• Draw serum paracetamol level immediately 1
• Plot the level on the Rumack-Matthew nomogram 1, 3
• If the level plots above the "possible toxicity" line, continue NAC for the full 21-hour protocol 1, 3
• If the level plots below the treatment line but the patient has risk factors (chronic alcohol use, fasting, enzyme-inducing drugs), strongly consider treating anyway as these patients can develop hepatotoxicity at lower doses 1, 3

If Presenting 8-24 Hours Post-Ingestion:

• Administer NAC loading dose immediately without waiting for laboratory results 1, 2
• Obtain serum paracetamol level, AST, ALT, and INR urgently 1
• Continue full NAC protocol regardless of nomogram placement, as efficacy diminishes significantly after 8 hours but treatment still provides substantial benefit 1, 4
• Severe hepatotoxicity develops in 26.4% of at-risk patients when NAC is started 10-24 hours post-ingestion, compared to only 6.1% when started within 10 hours 1, 4

If Presenting >24 Hours Post-Ingestion:

• The Rumack-Matthew nomogram does NOT apply 1
• Administer NAC immediately based on clinical presentation, paracetamol levels, and liver function tests 1, 3
• Treatment decisions must be based on acetaminophen levels and evidence of hepatotoxicity (elevated transaminases) rather than nomogram placement 1

NAC Dosing Regimen

Intravenous Protocol (FDA-approved): 2

• 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 duration: 21 hours (300 mg/kg total)

Oral Protocol (alternative): 1, 3

• Loading dose: 140 mg/kg by mouth or nasogastric tube
• Maintenance: 70 mg/kg every 4 hours for 17 additional doses
• Total duration: 72 hours

The 72-hour oral regimen is as effective as the 20-hour IV regimen and may be superior when treatment is delayed 4

Critical Timing Considerations

The critical window is 0-8 hours post-ingestion, where NAC provides maximal hepatoprotection with only 2.9% developing severe hepatotoxicity when treated within 8 hours 1

Efficacy by treatment initiation time: 1, 4

• Within 8 hours: 2.9% risk of severe hepatotoxicity
• Within 10 hours: 6.1% risk of severe hepatotoxicity
• 10-24 hours: 26.4% risk of severe hepatotoxicity
• 16-24 hours (high-risk patients): 41% risk of hepatotoxicity (still better than 58% in untreated historical controls)

Special Populations Requiring Lower Treatment Threshold

Chronic alcohol users should be treated with NAC even with paracetamol levels in the "non-toxic" range on the nomogram, as severe hepatotoxicity has been documented with doses as low as 4-5 g/day in this population 1, 3

Other high-risk groups requiring lower treatment threshold: 1, 3

• Patients taking enzyme-inducing drugs (anticonvulsants, rifampin)
• Fasting or malnourished patients
• Patients with chronic liver disease

Critical Pitfalls to Avoid

Do not delay NAC administration while awaiting laboratory confirmation if there is strong suspicion of significant overdose 1, 2

Do not rely solely on patient-reported ingestion amount, as history may be unreliable—always obtain serum paracetamol levels 1

Do not stop NAC prematurely if any of the following are present: 1

• Detectable paracetamol level
• Any elevation in AST or ALT above normal
• Rising transaminases
• Any coagulopathy
• Unknown time of ingestion

For a 6-gram ingestion specifically, err on the side of treatment, as this dose exceeds the threshold for repeated supratherapeutic ingestion criteria (≥6 g per 24-hour period) and approaches the acute toxic threshold 3