What is the evaluation and treatment approach for a patient with a possible acetaminophen (Tylenol) overdose, particularly within the past 24 hours, with or without a history of liver disease?

Evaluation and Treatment of Acetaminophen (Tylenol) Overdose

Immediate Assessment and Risk Stratification

For suspected acetaminophen overdose, immediately obtain a serum acetaminophen level at 4 hours post-ingestion (or as soon as possible if >4 hours), liver function tests (AST, ALT), prothrombin time/INR, and start N-acetylcysteine (NAC) without delay if the ingestion is potentially toxic or the timing is uncertain. 1, 2

Critical Initial History Elements

Obtain the following specific information immediately:

• Exact timing of ingestion (single acute vs. repeated supratherapeutic) 3
• Total dose ingested (in grams and mg/kg) 3
• Formulation type (immediate-release vs. extended-release) 1, 3
• Intent (intentional self-harm requires immediate ED referral regardless of dose) 3
• Risk factors for increased susceptibility: chronic alcohol use, prolonged fasting, malnutrition, or enzyme-inducing drugs 1, 3
• Co-ingestions that may affect management 3

Laboratory Assessment

Draw serum acetaminophen level at 4-24 hours post-ingestion to plot on the Rumack-Matthew nomogram 4, 1. If timing is unknown or patient presents >24 hours, the nomogram does NOT apply—base treatment decisions on acetaminophen levels, transaminases, and clinical presentation 1, 2.

Obtain baseline:

• AST and ALT (severe hepatotoxicity defined as >1,000 IU/L) 1
• Prothrombin time/INR 1
• Creatinine (acute renal failure occurs in <2% of poisonings but 10% of severe cases) 5

Treatment Algorithm Based on Presentation Timing

Presentation Within 4 Hours of Ingestion

Administer activated charcoal 1 g/kg orally just prior to starting NAC if the patient can protect their airway and a potentially toxic dose was ingested 1, 6. Activated charcoal is most effective within 1-2 hours but may provide benefit up to 4 hours post-ingestion 1.

Do not delay NAC while giving activated charcoal—administer NAC immediately after charcoal 6.

Presentation 4-24 Hours Post-Ingestion (Known Time)

Use the Rumack-Matthew nomogram to guide treatment 4, 1, 2:

• Plot the 4-hour (or later) acetaminophen level on the nomogram 4, 1
• Start NAC immediately if the level plots at or above the "possible toxicity" line 4, 1
• Do NOT give NAC if the level plots below the treatment line (Level B recommendation) 4

Critical timing considerations:

• Within 8 hours: Only 2.9% develop severe hepatotoxicity with NAC 1, 6
• 8-10 hours: 6.1% develop severe hepatotoxicity 1
• 10-24 hours: 26.4% develop severe hepatotoxicity 1
• After 24 hours: Efficacy diminishes but NAC still reduces mortality and should never be withheld 1

Presentation >24 Hours Post-Ingestion or Unknown Time

The Rumack-Matthew nomogram does NOT apply 1, 2. Start NAC immediately without waiting for laboratory confirmation if overdose is suspected 1.

Treatment decisions based on:

• Any detectable acetaminophen level → treat with NAC 1
• Elevated transaminases (AST or ALT >50 IU/L) → treat with NAC 1
• Clinical signs of hepatotoxicity → treat with NAC 1

Repeated Supratherapeutic Ingestion (RSI)

The nomogram does NOT apply to RSI 1, 2, 3. Treat with NAC if any of the following:

• ≥10 g or 200 mg/kg (whichever is less) in any 24-hour period 1, 3
• ≥6 g or 150 mg/kg (whichever is less) per day for ≥48 hours 1, 3
• Serum acetaminophen ≥10 mg/mL 1
• AST or ALT >50 IU/L 1

For high-risk patients (chronic alcohol use, fasting, enzyme-inducing drugs): treat if >4 g or 100 mg/kg per day 3.

N-Acetylcysteine (NAC) Dosing Regimens

Intravenous Protocol (21-Hour Regimen)

Loading dose: 150 mg/kg in 200 mL 5% dextrose over 15 minutes 1, 6, 2

Second dose: 50 mg/kg in 500 mL 5% dextrose over 4 hours 1, 6, 2

Third dose: 100 mg/kg in 1000 mL 5% dextrose over 16 hours 1, 6, 2

Total duration: 21 hours (total dose 300 mg/kg) 2

Oral Protocol (72-Hour Regimen)

Loading dose: 140 mg/kg orally or via nasogastric tube 1, 6

Maintenance: 70 mg/kg every 4 hours for 17 additional doses (total 72 hours) 1, 6

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

Special Clinical Scenarios Requiring Extended or Modified NAC Treatment

Acute Liver Failure

Administer NAC immediately to ALL patients with acute liver failure from acetaminophen, regardless of time since ingestion (Level B recommendation) 4, 1, 6.

NAC reduces mortality from 80% to 52%, cerebral edema from 68% to 40%, and need for inotropic support from 80% to 48% 1.

Continue NAC until transaminases are declining and INR normalizes 1. Contact liver transplant center immediately 1.

Extended-Release Formulations

Obtain serial acetaminophen levels (may show late increases at 14 hours or beyond) 1. Continue NAC beyond standard protocol and monitor for prolonged absorption 1, 6.

Massive Overdose

Consider increased NAC dosing beyond standard protocol for ingestions plotting at the 300-, 450-, or 600-lines on the nomogram 1.

Chronic Alcohol Users

Treat with NAC even if acetaminophen levels are in the "non-toxic" range on the nomogram—severe hepatotoxicity documented with doses as low as 4-5 g/day 1.

Criteria for Discontinuing NAC

NAC can be discontinued when ALL of the following are met 1:

• Acetaminophen level is undetectable 1
• AST and ALT are normal 1
• No coagulopathy 1
• Patient is asymptomatic 1

Do NOT stop NAC or restart immediately if 1:

• Any elevation in AST or ALT above normal
• Rising transaminases
• Any coagulopathy (elevated INR)
• Detectable acetaminophen level
• Clinical signs of hepatotoxicity

Certain scenarios mandate longer NAC courses despite undetectable acetaminophen: delayed presentation (>24 hours), extended-release formulations, repeated supratherapeutic ingestions, unknown time of ingestion, or chronic alcohol use 1, 6.

Management of NAC Hypersensitivity Reactions

Anaphylactoid reactions occur most commonly during the loading dose 2, 7. Symptoms include rash, urticaria, facial flushing, pruritus, wheezing, shortness of breath, bronchospasm, or hypotension 2.

If serious reaction occurs 2:

1. Immediately discontinue NAC infusion
2. Administer antihistamines (diphenhydramine)
3. Treat bronchospasm if present
4. Restart NAC at slower infusion rate after symptoms resolve

NAC infusion may be carefully restarted after treatment of hypersensitivity 2.

Critical Pitfalls and Caveats

Common Errors to Avoid

• Do not wait for acetaminophen levels if >8 hours post-ingestion or timing is uncertain—start NAC immediately 1, 2
• Low or absent acetaminophen levels do NOT rule out acetaminophen poisoning if ingestion was remote or occurred over several days 1
• Do not rely on nomogram for presentations >24 hours, RSI, or extended-release formulations 1, 2
• Patients may present with elevated transaminases despite "no risk" nomogram placement due to inaccurate history or increased susceptibility 1
• Even therapeutic doses (4 g/day for 14 days) can cause ALT elevations >3× normal in 31-41% of healthy adults 1
• Very high aminotransferases (AST/ALT >3,500 IU/L) are highly correlated with acetaminophen poisoning—treat with NAC even without confirmatory history 1, 6

High-Risk Populations Requiring Lower Treatment Threshold

Chronic alcohol users: Treat even with "non-toxic" levels—hepatotoxicity threshold as low as 4 g/day 1, 3

Fasting/malnourished patients: Glutathione-depleted, increased susceptibility 3, 5

Patients on enzyme-inducing drugs: Anticonvulsants increase toxic metabolite formation 3, 5

Disposition Considerations

Admit to ICU if 1:

• AST or ALT >1,000 IU/L
• Any coagulopathy
• Signs of hepatic encephalopathy
• Acute renal failure

All patients with intentional self-harm require psychiatric evaluation regardless of acetaminophen dose 3.