What is the recommended treatment for a patient suspected of acetaminophen overdose, particularly with regards to N-Acetylcysteine (NAC)?

N-Acetylcysteine (NAC) for Acetaminophen Overdose

Administer NAC immediately to any patient with suspected or confirmed acetaminophen overdose—do not wait for laboratory confirmation if clinical suspicion exists, as treatment efficacy is critically time-dependent with severe hepatotoxicity developing in only 2.9% when started within 8 hours versus 26.4% when delayed beyond 10 hours. 1

Immediate Treatment Protocol

Start NAC immediately if any of the following apply:

• Suspected acetaminophen overdose within 24 hours of ingestion, regardless of serum level availability 2
• Acetaminophen level plots above the "possible toxicity" line on Rumack-Matthew nomogram (drawn 4-24 hours post-ingestion) 1, 3
• Unknown time of ingestion with detectable acetaminophen level 1
• Any evidence of hepatotoxicity (AST/ALT >50 IU/L) with suspected acetaminophen exposure 1
• Acute liver failure where acetaminophen is suspected, even without confirmatory history 1, 3

NAC Dosing Regimens

Intravenous Protocol (21-hour standard):

• Loading dose: 150 mg/kg in 5% dextrose over 15 minutes 1, 3
• Second dose: 50 mg/kg over 4 hours 1, 3
• Third dose: 100 mg/kg over 16 hours 1, 3

Oral Protocol (72-hour standard):

• Loading dose: 140 mg/kg diluted to 5% solution 1, 2
• Maintenance: 70 mg/kg every 4 hours for 17 additional doses 1, 2
• Dilute 20% solution with diet cola or diet soft drink to 5% concentration 2

The 72-hour oral regimen is as effective as the 20-hour IV regimen and may be superior when treatment is delayed beyond 8 hours. 1, 4

Critical Timing Considerations

Treatment efficacy decreases dramatically with delay:

• 0-8 hours: 2.9% develop severe hepatotoxicity—maximal protection window 1, 4
• 8-10 hours: 6.1% develop severe hepatotoxicity 1, 4
• 10-24 hours: 26.4% develop severe hepatotoxicity 1, 4
• 16-24 hours: 41% develop hepatotoxicity (still better than 58% in untreated historical controls) 1, 4

Even when started beyond 24 hours, NAC reduces mortality from 80% to 52% in established liver failure—never withhold treatment based on timing alone. 1

Adjunctive Measures

Activated charcoal (1 g/kg) should be given just prior to starting NAC if patient presents within 4 hours of ingestion. 1, 3 Do not delay NAC administration if charcoal has already been given, as charcoal may reduce NAC absorption but treatment should not be postponed 3, 2

When to Continue NAC Beyond Standard Protocol

Extend NAC treatment in these scenarios:

• Delayed presentation (>24 hours post-ingestion) 1
• Extended-release acetaminophen formulations 1, 3
• Repeated supratherapeutic ingestions 1
• Unknown time of ingestion with detectable levels 1
• Any elevation in AST/ALT above normal 1
• Rising transaminases despite treatment 1
• Chronic alcohol use (lower threshold for toxicity) 1

Discontinuation Criteria

NAC can be stopped when ALL of the following are met:

• Acetaminophen level undetectable 1
• AST and ALT remain normal (not just "stable"—must be normal) 1
• No coagulopathy (normal INR) 1
• Patient is at least 24 hours from ingestion 1

If hepatotoxicity develops (AST/ALT >1000 IU/L), continue NAC until transaminases are declining and INR normalizes. 1

Special Populations Requiring Lower Treatment Threshold

Chronic alcohol users: Treat with NAC even with levels in the "non-toxic" range on nomogram, as severe hepatotoxicity can occur with doses as low as 4 g/day in this population 1, 3

Repeated supratherapeutic ingestions: Treat if serum acetaminophen ≥10 mg/mL OR if AST/ALT >50 IU/L, regardless of nomogram placement 1

Critical Red Flags Requiring ICU Care and Transplant Consultation

Contact liver transplant center immediately if any of these develop:

• AST/ALT >1000 IU/L (severe hepatotoxicity threshold) 1, 5
• Coagulopathy (INR >1.5) 5
• Hepatic encephalopathy (altered mental status, confusion) 5
• Rising bilirubin with elevated INR 5

Patients with severe hepatotoxicity have 50% transplant-free survival, improving to 71% with NAC treatment. 1

Common Pitfalls to Avoid

Do not wait for 4-hour acetaminophen level if ingestion occurred within 24 hours—start NAC immediately. 2 The level can guide continuation decisions but should never delay initiation 1

Do not rely on the Rumack-Matthew nomogram for: repeated supratherapeutic ingestions, presentations >24 hours post-ingestion, extended-release formulations, or unknown time of ingestion 1

Low or absent acetaminophen levels do NOT rule out toxicity if ingestion was remote or occurred over several days 1, 5

Do not stop NAC prematurely based on "low" levels—continue until all discontinuation criteria are met 5

Patients may develop hepatotoxicity despite "no risk" nomogram placement due to inaccurate history or increased susceptibility 1

Adverse Effects

The most common adverse effects are anaphylactic reactions and cutaneous reactions with IV administration, and gastrointestinal effects with oral administration 6. If the patient vomits oral NAC within 1 hour, repeat that dose 2. For persistent vomiting, consider duodenal intubation or switch to IV route 2