What is the treatment for acetaminophen (N-acetylpaminophenol) ingestion and what is the toxic dose?

Treatment of Acetaminophen Ingestion and Toxic Dose

Administer N-acetylcysteine (NAC) immediately for any patient with suspected acetaminophen overdose when serum levels plot above the "possible toxicity" line on the Rumack-Matthew nomogram, when time of ingestion is unknown, or when hepatotoxicity is already present—ideally within 8 hours of ingestion to maximize efficacy and prevent severe liver injury. 1, 2

Toxic Dose Thresholds

Acute Single Ingestion:

• Adults and children ≥6 years: 10 g or 200 mg/kg (whichever is lower) represents a potentially hepatotoxic dose requiring emergency evaluation 1, 3
• Children <6 years: 200 mg/kg or more requires emergency evaluation 3
• Most cases of acute liver failure involve ingestions exceeding 10 g/day, though severe injury can rarely occur with doses as low as 3-4 g/day 4, 5

Repeated Supratherapeutic Ingestion (RSTI):

• Children <6 years: Refer to emergency department if ingested 200 mg/kg or more over 24 hours, OR 150 mg/kg or more per 24 hours for 48 hours, OR 100 mg/kg or more per 24 hours for 72+ hours 3
• Patients ≥6 years: Refer if ingested ≥10 g or 200 mg/kg (whichever is less) over 24 hours, OR ≥6 g or 150 mg/kg (whichever is less) per 24 hours for 48+ hours 3
• High-risk patients (chronic alcohol use, malnutrition, CYP2E1 inducers): Consider treatment threshold of >4 g or 100 mg/kg per day 3

Initial Assessment and Risk Stratification

Laboratory Testing:

• Obtain acetaminophen level at least 4 hours post-ingestion (earlier levels are unreliable as they may not represent peak concentrations) 2
• Obtain AST, ALT, bilirubin, INR, creatinine, BUN, glucose, and electrolytes 2

Using the Rumack-Matthew Nomogram:

• Plot acetaminophen concentration drawn 4-24 hours post-ingestion to determine hepatotoxicity risk 1
• The nomogram categorizes patients into probable risk, possible risk, and no risk 1
• Critical caveat: The nomogram may underestimate risk in patients with chronic alcoholism, malnutrition, or CYP2E1 enzyme-inducing drugs (e.g., isoniazid)—treat these patients even if levels are in the "nontoxic" range 2
• The nomogram does NOT apply to repeated supratherapeutic ingestions, extended-release formulations, or presentations >24 hours post-ingestion 1, 3

Treatment Algorithm Based on Clinical Scenario

Scenario 1: Known Time of Ingestion, Presenting <8 Hours, Level Available

• If acetaminophen level plots at or above the "possible toxicity" line: Start NAC immediately 1, 2
• If level is below the line: No NAC needed, but monitor for symptoms 1
• Consider activated charcoal (1 g/kg) if presenting within 4 hours of ingestion, given just prior to starting NAC 1, 2

Scenario 2: Unknown Time of Ingestion

• Administer NAC loading dose immediately without waiting for laboratory results 2
• Obtain acetaminophen concentration to determine need for continued treatment 2

Scenario 3: Presenting >8 Hours Post-Ingestion

• Administer NAC loading dose immediately 2
• Obtain acetaminophen level to guide continued treatment 2
• Treatment between 10-24 hours post-ingestion is associated with 26.4% risk of severe hepatotoxicity (vs. 6.1% when started within 10 hours) 1

Scenario 4: Acetaminophen Level Unavailable Within 8 Hours OR Clinical Evidence of Toxicity

• Administer NAC loading dose immediately and continue full 21-hour protocol 2

Scenario 5: Extended-Release Acetaminophen

• If 4-hour level is below toxicity line, obtain second level at 8-10 hours post-ingestion 2
• If second value is at or above "possible toxicity" line, start NAC 2

Scenario 6: Repeated Supratherapeutic Ingestion

• Treat with NAC if serum acetaminophen ≥10 mg/mL OR if AST or ALT >50 IU/L 1
• The Rumack-Matthew nomogram does not apply to this scenario 1, 3

Scenario 7: Established Hepatotoxicity or Fulminant Hepatic Failure

• Administer NAC immediately regardless of time since ingestion 1, 2
• NAC reduces mortality from 80% to 52%, cerebral edema from 68% to 40%, and need for inotropic support from 80% to 48% in fulminant hepatic failure 1
• Early NAC treatment (<10 hours) in fulminant hepatic failure results in 100% survival 1

NAC Dosing Regimens

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 dose: 300 mg/kg over 21 hours 2

Oral Protocol (72-hour regimen):

• Loading dose: 140 mg/kg by mouth or nasogastric tube diluted to 5% solution 1
• Maintenance: 70 mg/kg every 4 hours for 17 additional doses 1
• The 72-hour oral regimen is as effective as the 20-hour IV regimen and may be superior when treatment is delayed 1

Important: Acetylcysteine is hyperosmolar (2600 mOsmol/L) and must be diluted in sterile water, 0.45% sodium chloride, or 5% dextrose prior to IV administration 2

Criteria for Discontinuing NAC

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

• Acetaminophen level is undetectable 1
• AST and ALT remain normal (no elevation above normal) 1
• INR is normal 1
• Patient is asymptomatic 1

Extend NAC beyond 21 hours if:

• Delayed presentation (>24 hours post-ingestion) 1
• Extended-release acetaminophen ingestion 1
• Repeated supratherapeutic ingestions 1
• Unknown time of ingestion with detectable acetaminophen 1
• Any elevation in AST or ALT above normal 1
• Rising transaminases 1
• Any coagulopathy 1
• Detectable acetaminophen level 1

If hepatotoxicity develops (AST/ALT >1000 IU/L):

• Continue NAC until transaminases are declining and INR normalizes 1
• Consider ICU-level care and early transplant hepatology consultation 1

Critical Timing Considerations

The critical window is 0-8 hours post-ingestion:

• NAC within 8 hours: Only 2.9% develop severe hepatotoxicity 1, 2
• NAC within 10 hours: 6.1% develop severe hepatotoxicity 1
• NAC after 10 hours: 26.4% develop severe hepatotoxicity 1
• Efficacy diminishes progressively after 8 hours, but NAC should never be withheld as the reported time may be incorrect 2

Special High-Risk Populations

Chronic alcohol users:

• Treat with NAC even with levels in the "non-toxic" range 1
• Documented severe hepatotoxicity with doses as low as 4-5 g/day 1
• The nomogram may underestimate hepatotoxicity risk 2

Other high-risk groups requiring lower treatment threshold:

• Malnutrition 2
• CYP2E1 enzyme-inducing drugs (e.g., isoniazid) 2

Common Pitfalls and Caveats

• The reported history of quantity ingested is often inaccurate and not a reliable guide to therapy—always obtain objective acetaminophen levels 2
• Patients may present with elevated transaminases despite being stratified as "no risk" on the nomogram due to inaccurate history or increased susceptibility 1
• Low or absent acetaminophen levels do NOT rule out poisoning if ingestion was remote or occurred over several days 1
• Very high aminotransferases (AST/ALT >3,500 IU/L) are highly correlated with acetaminophen poisoning and should prompt NAC treatment even when history is lacking 1
• Activated charcoal is most effective within 1-2 hours but may have benefit up to 4 hours post-ingestion 1
• Do not delay NAC while waiting for activated charcoal or laboratory results if clinical suspicion is high 1, 2

Management of NAC Hypersensitivity Reactions

• Anaphylactoid reactions (hypotension, wheezing, shortness of breath, bronchospasm) can occur, usually during loading doses 2, 6
• Immediately discontinue NAC infusion if serious reaction occurs 2
• Treat with antihistamines 6
• NAC can be carefully restarted at a slower infusion rate after treatment of hypersensitivity 2, 6