What is the treatment for acetaminophen (N-Acetylcysteine (NAC)) overdose?

Treatment of Acetaminophen Overdose with N-Acetylcysteine (NAC)

N-acetylcysteine is the antidote of choice for acetaminophen overdose and must be administered immediately when indicated, with the intravenous protocol (150 mg/kg loading dose over 15 minutes, followed by 50 mg/kg over 4 hours, then 100 mg/kg over 16 hours) or oral protocol (140 mg/kg loading dose, then 70 mg/kg every 4 hours for 17 doses) both being effective, though the oral 72-hour regimen may be superior when treatment is delayed beyond 10 hours. 1, 2, 3

Initial Assessment and Decision to Treat

For Acute Single Ingestions with Known Timing (<24 hours)

• If presenting within 4 hours of ingestion: Administer activated charcoal (1 g/kg) just prior to starting NAC, then obtain acetaminophen level at 4 hours post-ingestion to plot on the Rumack-Matthew nomogram 1, 2

• If acetaminophen level plots above the "possible toxicity" line on the Rumack-Matthew nomogram: Start NAC immediately 1, 4

• If presenting 4-8 hours post-ingestion with known toxic ingestion (>7g or >100 mg/kg): Start NAC immediately without waiting for levels, as this represents a potentially hepatotoxic dose 4

• If presenting 8-24 hours post-ingestion: Administer NAC loading dose immediately, then obtain acetaminophen level to guide continued treatment 2

For Unknown Time of Ingestion or Delayed Presentation (>24 hours)

• If time of ingestion is unknown but acetaminophen is detectable: Start NAC immediately and continue for full treatment course, as the Rumack-Matthew nomogram does not apply 1, 2

• If presenting >24 hours after ingestion: Administer NAC immediately based on acetaminophen levels and liver function tests rather than nomogram placement 4

• If acetaminophen level is undetectable but AST/ALT are elevated (>50 IU/L) with suspected acetaminophen exposure: Start NAC immediately, as low or absent levels do not rule out acetaminophen poisoning when ingestion was remote 1, 4

For Special Clinical Scenarios

• Repeated supratherapeutic ingestions (>4g per 24 hours): Treat with NAC if serum acetaminophen ≥10 mg/mL OR if AST or ALT >50 IU/L, as the nomogram does not apply to this scenario 5, 4

• Extended-release acetaminophen preparations: Treat with standard NAC protocol but extend monitoring due to prolonged absorption 5, 1

• Fulminant hepatic failure from acetaminophen: Administer NAC regardless of time since ingestion, as it reduces mortality from 80% to 52%, cerebral edema from 68% to 40%, and need for inotropic support from 80% to 48% 5, 4

NAC Dosing Protocols

Intravenous Protocol (21-hour regimen)

• Loading dose: 150 mg/kg in 5% dextrose over 15 minutes 1, 2
• Second dose: 50 mg/kg over 4 hours 1, 2
• Third dose: 100 mg/kg over 16 hours 1, 2
• Total duration: 21 hours with total dose of 300 mg/kg 2

Oral Protocol (72-hour regimen)

• Loading dose: 140 mg/kg by mouth or nasogastric tube diluted to 5% solution 1, 3
• Maintenance doses: 70 mg/kg every 4 hours for 17 additional doses 1, 3
• Total duration: 72 hours 3

Comparative Efficacy

• The oral 72-hour protocol may be superior to the 21-hour IV protocol when treatment is delayed beyond 10 hours, as modeling studies suggest the 21-hour infusion is often too short while the full 72-hour oral course provides better hepatocyte preservation 6, 3

• Both protocols are equally effective when started within 8 hours of ingestion, with severe hepatotoxicity developing in only 2.9% of at-risk patients 3

Timing and Efficacy

Critical Time Windows

• 0-8 hours post-ingestion: Maximum efficacy with only 2.9% developing severe hepatotoxicity when NAC started in this window 4, 3

• 8-10 hours post-ingestion: Efficacy begins to decline, with 6.1% developing severe hepatotoxicity when treatment started within 10 hours 4, 3

• 10-24 hours post-ingestion: Significantly reduced efficacy with 26.4% developing severe hepatotoxicity, but still beneficial compared to no treatment 4, 3

• 16-24 hours post-ingestion: Among high-risk patients, 41% develop hepatotoxicity—still lower than untreated historical controls (58%) 4, 3

• >24 hours post-ingestion: NAC remains beneficial and should still be administered, particularly in patients with established hepatotoxicity or hepatic failure 5, 4

Duration of Treatment and Stopping Criteria

Standard Duration

• For IV protocol: Complete the full 21-hour course unless criteria for early discontinuation are met 2

• For oral protocol: Continue for 72 hours or until acetaminophen is undetectable and liver function tests remain normal 3

Early Discontinuation Criteria (Use with Caution)

• NAC may be discontinued when: Acetaminophen level is undetectable AND AST/ALT remain normal AND no clinical signs of hepatotoxicity 4, 7

• A 12-hour course may be safe in carefully selected low-risk patients with normal labs at presentation and 12 hours, but this requires careful risk assessment 4

Mandatory Extended Treatment Scenarios

• Continue NAC beyond standard protocols for: Delayed presentation (>24 hours), extended-release acetaminophen, repeated supratherapeutic ingestions, unknown time of ingestion with detectable levels, any elevation in AST/ALT above normal, chronic alcohol use, or rising transaminases 4

• If hepatotoxicity develops (AST/ALT >1000 IU/L): Continue NAC until transaminases are declining and INR normalizes 4

High-Risk Populations Requiring Lower Treatment Threshold

• Chronic alcohol users: Treat with NAC even with levels in the "non-toxic" range, as severe hepatotoxicity can occur with doses as low as 4-5 g/day 4

• Fasting patients: May develop toxicity at lower doses and should have a lower threshold for NAC initiation 8

• Patients with chronic liver disease or malnutrition: Consider NAC treatment even when levels are below typical treatment thresholds 8

Critical Pitfalls and Caveats

• Do not delay NAC administration while awaiting confirmatory acetaminophen levels if there is strong suspicion of significant overdose 1

• The Rumack-Matthew nomogram underestimates risk for patients presenting within 8 hours and should not be used to withhold treatment when clinical suspicion is high 6

• Normal transaminases in the ED do not exclude risk of developing toxicity in the subsequent hours, particularly with delayed presentations 5

• Very high aminotransferases (AST/ALT >3,500 IU/L) are highly correlated with acetaminophen poisoning and should prompt NAC treatment even without confirmatory history 1

• Activated charcoal does not interfere with NAC administration and should not delay NAC initiation 1

Adverse Reactions and Management

• Hypersensitivity reactions occur in approximately 14% of patients receiving IV NAC, consisting mostly of transient skin erythema or mild urticaria during the loading dose 9

• If serious hypersensitivity reaction occurs: Immediately discontinue infusion, treat the reaction, then carefully restart NAC after symptoms resolve, as the benefits outweigh risks 2

Disposition

• Patients with severe hepatotoxicity (AST >1000 IU/L) or coagulopathy require ICU-level care and early consultation with transplant hepatology 4