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

N-Acetylcysteine (NAC) Regimen for Acetaminophen Overdose

For acetaminophen overdose, administer NAC using either the 21-hour intravenous protocol (150 mg/kg over 15 minutes, then 50 mg/kg over 4 hours, then 100 mg/kg over 16 hours) or the 72-hour oral protocol (140 mg/kg loading dose, then 70 mg/kg every 4 hours for 17 doses), with the IV route preferred when oral administration is precluded by altered mental status, gastrointestinal bleeding, or vomiting. 1, 2

Route Selection Algorithm

Choose intravenous NAC when:

• Patient has altered mental status or worsening encephalopathy 1
• Active gastrointestinal bleeding is present 1
• Persistent vomiting prevents oral administration 1
• Patient presents with established hepatic failure 1, 2

Choose oral NAC when:

• Patient can tolerate oral/nasogastric administration 1
• No contraindications to enteral route exist 1

Intravenous NAC Protocol (21-Hour Regimen)

Loading dose: 150 mg/kg in 5% dextrose infused over 15 minutes 1, 2, 3

Second dose: 50 mg/kg infused over 4 hours 1, 2, 3

Third dose: 100 mg/kg infused over 16 hours (completing 21-hour total duration) 1, 2, 3

Managing IV NAC Adverse Reactions

Anaphylactoid reactions (most common adverse effect with IV route) should be managed by discontinuing the infusion temporarily, administering antihistamines, and using epinephrine for bronchospasm 1, 4

Oral NAC 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 (total 72 hours of therapy) 1, 3

Managing Oral NAC Side Effects

Common side effects include nausea and vomiting (most frequent with oral route), with rare urticaria or bronchospasm 1, 4

Timing-Based Treatment Imperatives

Initiate NAC within 8 hours of ingestion to achieve maximal hepatoprotection—only 2.9% of patients develop severe hepatotoxicity when treated this early 2

Treatment between 8-10 hours post-ingestion results in 6.1% severe hepatotoxicity rate 2

Treatment after 10 hours post-ingestion results in 26.4% severe hepatotoxicity rate, but NAC still provides significant benefit compared to no treatment 2

Treatment initiated 16-24 hours post-ingestion in high-risk patients results in 41% hepatotoxicity rate, which remains lower than untreated historical controls at 58% 2

Special Clinical Scenarios Requiring Immediate NAC

Acute Liver Failure from Acetaminophen

Administer NAC immediately regardless of time since ingestion when hepatic failure is present—this reduces mortality from 80% to 52%, cerebral edema from 68% to 40%, and need for inotropic support from 80% to 48% 1, 2, 3

Unknown Time of Ingestion

Start NAC immediately without waiting for laboratory confirmation when acetaminophen overdose is suspected but timing cannot be determined 1, 2, 3

Any detectable acetaminophen level with unknown ingestion time warrants NAC treatment 1, 2

Repeated Supratherapeutic Ingestions

Administer NAC when serum acetaminophen ≥10 mg/mL or when AST/ALT >50 IU/L in patients with repeated ingestions over time 2

The Rumack-Matthew nomogram does not apply to repeated supratherapeutic ingestions—base treatment decisions on acetaminophen levels and liver function tests 1, 2

Extended-Release Acetaminophen

Treat with standard NAC protocol but extend monitoring due to prolonged absorption kinetics 1, 3

High-Risk Populations

Chronic alcohol users should receive NAC even with levels in the "non-toxic" range on the nomogram, as severe hepatotoxicity can occur with doses as low as 4-5 g/day in this population 2

Fasting patients have altered acetaminophen metabolism and should have a lower threshold for NAC treatment 1, 3

Adjunctive Treatment

Administer activated charcoal (1 g/kg) just prior to starting NAC if patient presents within 4 hours of ingestion 1, 2, 3

Do not delay NAC administration while giving or after giving activated charcoal 3

Duration of Treatment Considerations

Standard Duration

Complete the full 21-hour IV protocol or 72-hour oral protocol for most patients 1, 3

Criteria for Early Discontinuation (Carefully Selected Cases Only)

NAC may be discontinued when ALL of the following are met:

• Acetaminophen level is undetectable 2
• AST and ALT remain completely normal 2
• No coagulopathy present 2
• Patient presented early (<24 hours) with known single acute ingestion 2

Scenarios Mandating Extended Treatment Beyond Standard Protocol

Continue NAC beyond standard duration when:

• Delayed presentation (>24 hours post-ingestion) 2
• Extended-release formulation involved 2, 3
• Repeated supratherapeutic ingestions 2
• Unknown time of ingestion with detectable levels 2
• Any elevation in AST or ALT above normal 2
• Rising transaminases during treatment 2
• Chronic alcohol use 2
• Massive overdose (consider increased dosing) 2

Continue NAC until transaminases are declining and INR normalizes when hepatotoxicity has developed (AST/ALT >1000 IU/L) 2

Critical Pitfalls to Avoid

Never withhold NAC based solely on low or undetectable acetaminophen levels if ingestion was remote or occurred over several days—very high aminotransferases (AST/ALT >3500 IU/L) are highly correlated with acetaminophen poisoning even without detectable drug levels 2

Do not use the Rumack-Matthew nomogram for presentations >24 hours post-ingestion—base treatment decisions on acetaminophen levels, liver function tests, and clinical presentation 2

Never delay NAC while awaiting confirmatory levels when there is strong clinical suspicion of significant overdose 3

Recognize that normal transaminases in the emergency department do not exclude evolving toxicity—patients may develop hepatotoxicity in subsequent hours 1

Contact a liver transplant center immediately when any evidence of liver failure exists, as patients with severe hepatotoxicity (AST >1000 IU/L) or coagulopathy require ICU-level care and early transplant hepatology consultation 2