What is the recommended dose of N-acetyl cysteine (NAC) for acetaminophen overdose?

N-Acetylcysteine Dosing for Acetaminophen Overdose

For acetaminophen overdose, administer N-acetylcysteine (NAC) immediately using either the oral regimen (140 mg/kg loading dose, then 70 mg/kg every 4 hours for 17 doses) or the intravenous regimen (150 mg/kg over 15 minutes, then 50 mg/kg over 4 hours, then 100 mg/kg over 16 hours), with treatment initiated as soon as possible—ideally within 8 hours but still beneficial up to 24 hours or beyond. 1, 2, 3

Oral Dosing Regimen

The standard oral protocol consists of: 1, 3

• Loading dose: 140 mg/kg by mouth or nasogastric tube, diluted to 5% solution in diet cola or other diet soft drink 1, 3
• Maintenance doses: 70 mg/kg every 4 hours for 17 additional doses (total of 18 doses over 72 hours) 1, 3, 4
• If the patient vomits within 1 hour of any dose, repeat that dose 3
• For persistent vomiting, NAC may be administered via duodenal intubation 3

Intravenous Dosing Regimen

The standard IV protocol consists of: 1, 2, 5

• Loading dose: 150 mg/kg in 5% dextrose over 15 minutes 1, 2, 5
• Second dose: 50 mg/kg over 4 hours 1, 2, 5
• Third dose: 100 mg/kg over 16 hours (total 21-hour protocol) 1, 2, 5

The IV route is preferred when oral administration is precluded by active gastrointestinal bleeding, worsening mental status, or intractable vomiting. 1

Critical Timing Considerations

Treatment efficacy is highly time-dependent: 2, 5, 4

• 0-8 hours post-ingestion: Maximum hepatoprotection with only 2.9% developing severe hepatotoxicity when NAC started within 8 hours 5, 4
• 8-10 hours: Hepatotoxicity increases to 6.1% when treatment begins within 10 hours 2, 4
• 10-24 hours: Severe hepatotoxicity develops in 26.4% when therapy begins in this window 2, 4
• 16-24 hours: Among high-risk patients, 41% develop hepatotoxicity—still lower than untreated historical controls (58%) 5, 4
• Beyond 24 hours: NAC should still be administered as it remains beneficial in reducing hepatotoxicity and mortality even with delayed treatment 2, 5

Special Clinical Scenarios Requiring Immediate NAC

Administer NAC immediately in the following situations, regardless of timing or acetaminophen levels: 1, 2, 5

• Any case of acute liver failure where acetaminophen overdose is suspected or possible, even without confirmatory history 1, 2, 5
• Established hepatic failure thought to be due to acetaminophen, regardless of time since ingestion 1, 5
• Very high aminotransferases (AST/ALT >1,000 IU/L or "in the thousands"), which are highly correlated with acetaminophen poisoning 5, 6
• Chronic alcoholics or fasting patients, who may develop toxicity at lower doses and should receive NAC even if levels are below typical treatment thresholds 1, 2, 5

Extended or Modified Dosing Protocols

Certain situations mandate longer NAC courses beyond the standard protocol: 2, 5, 6

• Delayed presentation (>24 hours post-ingestion) 2, 5, 6
• Extended-release acetaminophen formulations 2, 5, 6
• Repeated supratherapeutic ingestions 2, 5, 6
• Unknown time of ingestion with detectable acetaminophen levels 2, 5, 6
• Any elevation in AST or ALT above normal 5, 6
• Rising transaminases or any coagulopathy 5, 6

For massive overdoses with acetaminophen concentrations above the "300-line" on the Rumack-Matthew nomogram, consider step-wise increases in NAC dosing at the 300-, 450-, and 600-lines. 7 This higher-dose approach may involve the 48-hour IV protocol using 140 mg/kg loading dose followed by 70 mg/kg every 4 hours for 12 doses, which has shown low rates of hepatotoxicity (18.1% overall, 3.4% when treated within 10 hours). 8

Adjunctive Measures

For patients presenting within 4 hours of ingestion, give activated charcoal (1 g/kg) just prior to starting NAC. 1, 6 However, if activated charcoal has already been administered, perform gastric lavage before giving NAC, as activated charcoal adsorbs NAC and may reduce its effectiveness. 3 Do not delay NAC administration while awaiting acetaminophen levels if there is strong suspicion of significant overdose. 5, 6

Adverse Effects and Management

Common adverse effects include: 1, 2

• Nausea and vomiting (<5% with IV, more common with oral) 2, 3
• Skin rash (<5%) 2
• Bronchospasm (1-2%) 2
• Rare urticaria or anaphylactoid reactions 1, 3

Allergic reactions may be successfully treated with discontinuation, antihistamines, and epinephrine for bronchospasm. 1 Treatment should not be discontinued unless allergic symptoms cannot be otherwise controlled. 3

Critical Pitfalls to Avoid

• Never withhold NAC while awaiting acetaminophen levels if overdose is suspected—administer immediately. 2, 5, 3
• Low or absent acetaminophen levels do NOT rule out acetaminophen poisoning if ingestion was remote or occurred over several days. 5, 6
• The Rumack-Matthew nomogram does NOT apply to patients presenting >24 hours after ingestion, repeated supratherapeutic ingestions, or extended-release formulations—treat based on clinical presentation and laboratory findings. 5, 6
• Do not stop NAC prematurely if any red flags develop: rising transaminases, coagulopathy, detectable acetaminophen, or clinical signs of hepatotoxicity. 5, 6

Monitoring During Treatment

Obtain baseline and serial laboratory studies: 1, 3

• Acetaminophen level (4-24 hours post-ingestion for nomogram use) 1, 6
• AST, ALT, bilirubin, prothrombin time/INR 1, 3
• Creatinine, BUN, electrolytes, glucose 1, 3
• Repeat liver function tests and coagulation studies daily if acetaminophen level is in the potentially toxic range 3