What is the treatment for acetaminophen (Tylenol) ingestion toxicity?

Treatment of Acetaminophen (Tylenol) Overdose

Administer N-acetylcysteine (NAC) immediately to any patient with suspected or confirmed acetaminophen overdose—ideally within 8 hours of ingestion—as this is the only proven antidote that prevents liver failure and reduces mortality. 1

Immediate Initial Management

First Steps (Within Minutes of Presentation)

• Start NAC immediately without waiting for laboratory results if ≤24 hours have elapsed since ingestion, regardless of the reported amount ingested 2
• Administer activated charcoal (1 g/kg orally) just prior to starting NAC if the patient presents within 4 hours of ingestion 1, 2
• Draw blood for acetaminophen level (must be drawn ≥4 hours post-ingestion to be interpretable), baseline AST, ALT, bilirubin, PT/INR, creatinine, BUN, glucose, and electrolytes 2

Critical pitfall: Do not delay NAC while waiting for acetaminophen levels—treatment efficacy is time-dependent and diminishes rapidly after 8 hours 1, 2

NAC Dosing Regimens

Intravenous Protocol (21-hour regimen)

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

Oral Protocol (72-hour regimen)

• Loading dose: 140 mg/kg by mouth or nasogastric tube, diluted to 5% solution 1, 2
• Maintenance doses: 70 mg/kg every 4 hours for 17 additional doses (total 72 hours) 1, 2
• If the patient vomits within 1 hour of oral administration, repeat that dose 2

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

Risk Stratification Using the Rumack-Matthew Nomogram

When to Use the Nomogram

• Only applies to: Single acute ingestions with known time of ingestion, when acetaminophen level is drawn 4-24 hours post-ingestion 3, 1
• Plot the acetaminophen concentration against time since ingestion 1
• Treat if the level plots at or above the "possible toxicity" line (the lower treatment line) 1, 2

When the Nomogram CANNOT Be Used

The nomogram is invalid and treatment decisions must be based on clinical judgment, acetaminophen levels, and liver function tests in these scenarios:

• Delayed presentation (>24 hours after ingestion) 3, 1
• Unknown time of ingestion 3, 1
• Extended-release acetaminophen formulations 3, 4
• Repeated supratherapeutic ingestions (multiple doses over >8 hours) 3, 1
• Ingestion occurred over multiple hours 3

For extended-release formulations, obtain at least two acetaminophen levels 4-6 hours apart, as absorption may continue beyond 8 hours and initial levels may be falsely reassuring 4

Timing and Efficacy: The Critical 8-Hour Window

Treatment Efficacy by Time to NAC Initiation

• 0-8 hours: Only 2.9% develop severe hepatotoxicity 1
• 8-10 hours: 6.1% develop severe hepatotoxicity 1
• 10-24 hours: 26.4% develop severe hepatotoxicity 1
• 16-24 hours: Among high-risk patients, 41% develop hepatotoxicity (still better than 58% in untreated historical controls) 1

NAC should never be withheld even in late presentations (>24 hours), as it still provides benefit and reduces mortality regardless of time since ingestion 1

Special Clinical Scenarios Requiring Immediate NAC

Mandatory NAC Treatment (Regardless of Nomogram or Timing)

• Acute liver failure with suspected acetaminophen overdose: Administer NAC immediately, even with inadequate history—reduces mortality from 80% to 52% 1
• Any elevation in AST or ALT above normal with suspected acetaminophen exposure 1
• Detectable acetaminophen level with unknown time of ingestion 1
• Very high aminotransferases (AST/ALT >3,500 IU/L): Highly correlated with acetaminophen poisoning even when history is lacking 1

Repeated Supratherapeutic Ingestions

These represent therapeutic misadventures rather than suicide attempts and require ED referral if: 3, 5

• ≥10 g or 200 mg/kg (whichever is less) during a single 24-hour period, OR 3, 5
• ≥6 g or 150 mg/kg (whichever is less) per 24-hour period for ≥48 hours 3, 5
• For high-risk patients (chronic alcohol use, isoniazid, prolonged fasting): ≥4 g or 100 mg/kg (whichever is less) per day 3, 5

Treat with NAC if serum acetaminophen ≥10 mg/mL OR if AST or ALT >50 IU/L 1

High-Risk Populations Requiring Lower Treatment Threshold

• Chronic alcohol users: 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
• Patients taking enzyme-inducing drugs (anticonvulsants) or glutathione-depleting conditions (starvation, fasting) 6

When to Stop NAC Therapy

Standard Stopping Criteria (All Must Be Met)

• Acetaminophen level is undetectable 1
• AST and ALT remain normal (no elevation above normal) 1
• No coagulopathy (normal INR) 1
• Patient presented early and received timely treatment 1

A 12-hour NAC course may be safe in carefully selected low-risk patients with normal labs at presentation and 12 hours, but this requires careful consideration 1

Scenarios Requiring Extended NAC Treatment (Beyond Standard Protocol)

Continue NAC beyond the standard protocol in these situations: 1

• Delayed presentation (>24 hours post-ingestion)
• Extended-release acetaminophen
• Repeated supratherapeutic ingestions
• Unknown time of ingestion with detectable levels
• Chronic alcohol use
• Any elevation in AST or ALT
• Rising transaminases
• Any coagulopathy

Red Flags: When to Restart or Continue NAC

NAC must be restarted immediately or continued if: 1

• Any elevation in AST or ALT above normal
• Rising transaminases (even if initially normal)
• Any coagulopathy develops
• Detectable acetaminophen level persists
• Clinical signs of hepatotoxicity appear

If severe hepatotoxicity develops (AST/ALT >1,000 IU/L), restart NAC immediately and continue until transaminases are declining and INR normalizes 1

Disposition and Monitoring

ICU-Level Care Required For:

• Severe hepatotoxicity (AST >1,000 IU/L) 1
• Any coagulopathy 1
• Acute liver failure (encephalopathy, elevated bilirubin and INR) 1, 6
• Contact liver transplant center immediately when there is any evidence of liver failure 1

Daily Monitoring (If Acetaminophen Level in Toxic Range)

• AST, ALT, bilirubin, PT/INR 2
• Creatinine, BUN (acute renal failure occurs in <2% of all overdoses but 10% of severe poisonings) 6
• Glucose, electrolytes 2

Common Pitfalls to Avoid

• Do not wait for acetaminophen levels before starting NAC—treatment must begin immediately if ≤24 hours since ingestion 2
• Do not rely on patient-reported ingestion amount—history is often inaccurate 2
• Do not use a single 4-hour level for extended-release formulations—obtain serial levels 4
• Do not stop NAC prematurely—any transaminase elevation mandates continuation 1
• Low or absent acetaminophen levels do NOT rule out toxicity if ingestion was remote or occurred over several days 1
• Patients may present with elevated transaminases despite "no risk" nomogram placement due to inaccurate history or increased susceptibility 1