What is the treatment for acetaminophen (N-acetylpaminophenol) ingestion?

Treatment for Acetaminophen Ingestion

Immediately administer N-acetylcysteine (NAC) as the primary antidote for acetaminophen overdose, ideally within 8 hours of ingestion to maximize hepatoprotection, with treatment decisions guided by the Rumack-Matthew nomogram for acute ingestions with known timing, or empirically for unknown timing or established hepatotoxicity. 1, 2

Initial Assessment and Decontamination

Activated Charcoal Administration

• Give activated charcoal (1 g/kg orally) just prior to starting NAC if the patient presents within 4 hours of ingestion 1, 3
• Activated charcoal is most effective within 1-2 hours but may provide benefit up to 4 hours post-ingestion 1
• Do not delay NAC administration while giving activated charcoal—both can be administered together 3
• Ensure adequate airway protection, especially with co-ingestions (e.g., sedatives, alcohol) 1

Laboratory Assessment

• Obtain acetaminophen level at least 4 hours post-ingestion (earlier levels are unreliable and may not reflect peak concentrations) 2
• Measure AST, ALT, bilirubin, INR, creatinine, BUN, blood glucose, and electrolytes 2
• Obtain prothrombin time to assess for developing hepatotoxicity 1

NAC Treatment Algorithm Based on Clinical Scenario

Scenario 1: Known Time of Ingestion <8 Hours + Acetaminophen Level Available

• Plot the acetaminophen concentration on the Rumack-Matthew nomogram 1, 2
• Start NAC if the level plots at or above the "possible toxicity" line (lower treatment line) 1, 2
• The nomogram stratifies patients into probable risk, possible risk, and no risk categories 1
• Critical caveat: The nomogram may underestimate risk in chronic alcoholics, malnourished patients, or those on CYP2E1 inducers (e.g., isoniazid)—treat these patients even with "non-toxic" levels 1, 2

Scenario 2: Known Time of Ingestion >8 Hours

• Administer NAC loading dose immediately without waiting for laboratory results 1, 2
• Obtain acetaminophen level to guide continuation of treatment 2
• Efficacy diminishes progressively after 8 hours: severe hepatotoxicity develops in 2.9% when treated within 8 hours, 6.1% within 10 hours, and 26.4% after 10 hours 1

Scenario 3: Unknown Time of Ingestion

• Start NAC loading dose immediately 3, 2
• Obtain acetaminophen level to determine need for continued treatment 3, 2
• If acetaminophen is detectable, continue full NAC protocol 1

Scenario 4: Acetaminophen Level Unavailable or Uninterpretable Within 8 Hours

• Administer NAC loading dose immediately and continue for full 21-hour protocol (3 doses) 2
• Do not delay treatment waiting for laboratory confirmation 3, 2

Scenario 5: Clinical Evidence of Hepatotoxicity (Any Elevation in AST/ALT)

• Start NAC immediately regardless of acetaminophen level or time since ingestion 1, 3
• Continue NAC until transaminases are declining and INR normalizes 1
• For fulminant hepatic failure, NAC reduces mortality from 80% to 52%, cerebral edema from 68% to 40%, and need for inotropic support from 80% to 48% 1

Scenario 6: Repeated Supratherapeutic Ingestions (RSI)

• The Rumack-Matthew nomogram does NOT apply to RSI 2
• Start NAC if acetaminophen level ≥10 mg/mL OR if AST or ALT >50 IU/L 1
• Obtain acetaminophen concentration and liver function tests to guide treatment 2

Scenario 7: Extended-Release Acetaminophen

• Obtain initial acetaminophen level at 4 hours post-ingestion 2
• If below the "possible toxicity" line, obtain a second level at 8-10 hours post-ingestion 2
• Start NAC if the second value is at or above the "possible toxicity" line 2

NAC Dosing Regimens

Intravenous Protocol (21-Hour Regimen)

• Loading dose: 150 mg/kg in 5% dextrose over 15 minutes 1, 3, 2
• Second dose: 50 mg/kg over 4 hours 1, 3, 2
• Third dose: 100 mg/kg over 16 hours 1, 3, 2
• Total dose: 300 mg/kg over 21 hours 2
• NAC is hyperosmolar (2600 mOsmol/L) and must be diluted in sterile water, 0.45% sodium chloride, or 5% dextrose prior to administration 2

Oral Protocol (72-Hour Regimen)

• Loading dose: 140 mg/kg orally or via nasogastric tube, diluted to 5% solution 1, 3
• Maintenance: 70 mg/kg every 4 hours for 17 additional doses (total 72 hours) 1, 3
• The 72-hour oral regimen is as effective as the 20-hour IV regimen and may be superior when treatment is delayed 1

Duration of NAC Treatment and Stopping Criteria

Standard Duration

• Continue NAC for the full 21-hour IV protocol or 72-hour oral protocol 1, 2

Early Discontinuation Criteria (Use with Extreme Caution)

• NAC may be discontinued at 21 hours if ALL of the following are met: 1
  • Acetaminophen level is undetectable
  • AST and ALT are normal (not just "improving")
  • INR is normal
  • Patient is asymptomatic

Mandatory Extended Treatment Beyond Standard Protocol

Continue NAC beyond 21 hours in these scenarios: 1

• Delayed presentation (>24 hours post-ingestion)
• Extended-release acetaminophen formulation
• Repeated supratherapeutic ingestions
• Unknown time of ingestion with detectable acetaminophen
• Any elevation in AST or ALT above normal
• Rising transaminases
• Any coagulopathy (elevated INR)
• Chronic alcohol use (lower threshold for extended treatment)

Treatment for Established Hepatotoxicity

• If AST/ALT >1000 IU/L, continue NAC until transaminases are declining and INR normalizes 1
• Patients with severe hepatotoxicity or coagulopathy require ICU-level care and early transplant hepatology consultation 1

Treatment Beyond 24 Hours Post-Ingestion

• NAC should still be administered to patients presenting >24 hours after ingestion 1, 3
• The Rumack-Matthew nomogram does NOT apply to presentations >24 hours—base treatment decisions on acetaminophen levels and liver function tests 1
• Between 16-24 hours, hepatotoxicity occurs in 41% of high-risk patients when treatment begins in this window, compared to 58% in untreated historical controls 1
• For established hepatic failure from acetaminophen, administer NAC regardless of time since ingestion 1, 3

Special Populations and Considerations

High-Risk Patients Requiring Lower Treatment Threshold

• Chronic alcohol consumers: 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 1, 2
• Malnourished patients 2
• Patients on CYP2E1 enzyme-inducing drugs (e.g., isoniazid) 2

Massive Overdoses (>500 mg/kg or 4-Hour Levels ~6000 μmol/L)

• Standard NAC protocol applies, but consider adjuvant therapies 4
• In massive overdoses with refractory shock, metabolic acidosis, and multiorgan dysfunction, consider fomepizole and hemodialysis in addition to NAC 4

Adverse Effects and Management

Anaphylactoid Reactions

• Monitor for nausea, vomiting, skin rash (<5%), urticaria, facial flushing, pruritus, and transient bronchospasm (1-2%) 5, 2
• Anaphylactoid reactions typically occur during the loading dose 6
• If a serious hypersensitivity reaction occurs: immediately discontinue the infusion, treat with antihistamines, and restart at a slower infusion rate 2, 6

Fluid Overload

• Reduce total volume for patients <40 kg or those requiring fluid restriction 2

Critical Pitfalls to Avoid

• Do not rely on reported history of quantity ingested—it is often inaccurate 2
• Do not obtain acetaminophen levels before 4 hours post-ingestion—they may be misleadingly low 2
• Do not delay NAC while awaiting confirmatory levels if there is strong suspicion of significant overdose 3, 2
• Low or absent acetaminophen levels do NOT rule out acetaminophen poisoning if ingestion was remote or occurred over several days 1
• Patients may present with elevated transaminases despite "no risk" stratification on the nomogram due to inaccurate history or increased susceptibility 1
• The nomogram only applies to acute single ingestions with known timing—do not use for RSI, extended-release formulations, or presentations >24 hours 1, 2