What are the diagnosis and management of acetaminophen (N-acetylcysteine) toxicity in a patient with suspected overdose?

Acetaminophen Toxicity: Diagnosis and Management

Immediate Diagnostic Assessment

For any suspected acetaminophen overdose, immediately obtain a serum acetaminophen level (drawn at least 4 hours post-ingestion), AST, ALT, INR, creatinine, BUN, and electrolytes—and start N-acetylcysteine (NAC) without delay if the ingestion time is unknown, the level cannot be obtained within 8 hours, or there is any clinical evidence of hepatotoxicity. 1, 2

Critical History Elements

• Timing of ingestion: Essential for nomogram use (only valid 4-24 hours post-ingestion) 1, 2
• Quantity ingested: Though often unreliable—do not rely on patient-reported dose alone 1, 2
• Ingestion pattern: Single acute vs. repeated supratherapeutic vs. extended-release formulation 1, 3
• Risk factors: Chronic alcohol use, malnutrition, fasting, enzyme-inducing drugs (significantly lower toxicity threshold) 1, 2
• Intent: Self-harm or malicious administration mandates immediate ED referral regardless of dose 4

Laboratory Interpretation

• Acetaminophen level: Must be drawn ≥4 hours post-ingestion; earlier levels are misleading 1, 2
• Severe hepatotoxicity: Defined as AST or ALT >1,000 IU/L 1
• Very high transaminases (>3,500 IU/L): Highly correlated with acetaminophen poisoning even without confirmatory history 1
• Low or absent acetaminophen levels do NOT rule out toxicity if ingestion was remote or occurred over several days 1

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Risk Stratification Using the Rumack-Matthew Nomogram

Use the nomogram ONLY for single acute ingestions with known time of ingestion when the level is drawn 4-24 hours post-ingestion. 1, 2

When the Nomogram Applies

• Plot acetaminophen concentration against time post-ingestion 1
• Treat with NAC if level plots at or above the "possible toxicity" line (150 mcg/mL at 4 hours or 37.5 mcg/mL at 12 hours) 1, 5
• Three risk zones: probable risk, possible risk, and no risk 1

When the Nomogram Does NOT Apply

The nomogram cannot be used and NAC should be started immediately in: 1, 2

• Unknown time of ingestion 1, 6
• Presentation >24 hours post-ingestion 1
• Extended-release formulations (prolonged absorption with potential late peaks at 14+ hours) 1, 6
• Repeated supratherapeutic ingestions 1, 6
• Established hepatotoxicity (elevated transaminases) 1

Special Populations Requiring Lower Treatment Threshold

Chronic alcohol users, malnourished patients, and those on CYP2E1-inducing drugs should be treated even with levels in the "non-toxic" range, as severe hepatotoxicity can occur with doses as low as 4 g/day. 1, 5, 2

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N-Acetylcysteine (NAC) Treatment Protocol

Start NAC immediately without waiting for laboratory confirmation in any patient with suspected significant acetaminophen overdose—treatment delay directly correlates with mortality. 1, 6, 5

Timing Is Critical

• 0-8 hours post-ingestion: Maximal protection—only 2.9% develop severe hepatotoxicity 1, 6, 7
• 8-10 hours: Efficacy begins to diminish—6.1% develop severe hepatotoxicity 1, 7
• 10-24 hours: Significantly reduced efficacy—26.4% develop severe hepatotoxicity 1, 7
• 16-24 hours: Among high-risk patients, 41% develop hepatotoxicity (still better than untreated controls at 58%) 1
• >24 hours: NAC should still be administered—it remains beneficial and reduces mortality even with delayed treatment 1, 6

Standard IV NAC Dosing (21-Hour Protocol)

1, 6, 5, 2

1. Loading dose: 150 mg/kg IV over 15 minutes
2. Second dose: 50 mg/kg IV over 4 hours
3. Third dose: 100 mg/kg IV over 16 hours

Alternative Oral NAC Dosing (72-Hour Protocol)

1, 7

1. Loading dose: 140 mg/kg orally or via nasogastric tube
2. Maintenance: 70 mg/kg every 4 hours for 17 additional doses

The 72-hour oral regimen is as effective as the 20-hour IV regimen and may be superior when treatment is delayed. 7

Activated Charcoal Adjunct

Give activated charcoal (1 g/kg orally) just prior to starting NAC if the patient presents within 4 hours of ingestion, provided the airway is protected. 1, 6, 5 Activated charcoal is most effective within 1-2 hours but may provide benefit up to 4 hours post-ingestion. 1

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Special Clinical Scenarios Requiring Mandatory NAC

Acute Liver Failure

All patients with hepatic failure thought to be due to acetaminophen must receive NAC immediately, regardless of time since ingestion—this reduces mortality from 80% to 52%, cerebral edema from 68% to 40%, and need for inotropic support from 80% to 48%. 1, 6

Repeated Supratherapeutic Ingestions

Treat with NAC if: 1, 4

• ≥10 g or 200 mg/kg (whichever is less) during a single 24-hour period, OR
• ≥6 g or 150 mg/kg (whichever is less) per 24-hour period for ≥48 hours, OR
• Serum acetaminophen ≥10 mg/mL, OR
• AST or ALT >50 IU/L with any detectable acetaminophen level

Extended-Release Formulations

Serial acetaminophen levels should be obtained as late increases may occur at 14 hours or beyond; continue NAC beyond the standard protocol if levels remain detectable. 1, 6

Pre-Existing Liver Disease

Patients with chronic liver disease have significantly increased susceptibility and should be treated even with levels in the "non-toxic" range—maximum safe daily dose is only 2-3 grams (vs. 4 grams in healthy adults). 5

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Criteria for Extending NAC Beyond Standard Protocol

Continue NAC beyond 21 hours if ANY of the following persist after completion: 1, 5

• Detectable acetaminophen level
• Rising AST or ALT
• Any elevation in AST or ALT above normal
• Elevated INR or any coagulopathy
• Delayed presentation (>24 hours post-ingestion)
• Massive overdose (>30 g or 500 mg/kg)
• Extended-release formulation
• Repeated supratherapeutic ingestions
• Unknown time of ingestion with detectable levels
• Pre-existing liver disease
• Chronic alcohol use

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Criteria for Safely Discontinuing NAC

NAC can be discontinued when acetaminophen level is undetectable AND liver function tests remain completely normal. 1 In carefully selected low-risk patients with normal labs at presentation and 12 hours, a 12-hour NAC course may be safe, but this requires careful consideration. 1

Red Flags That Mandate Continuing or Restarting NAC

1

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

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Disposition and Monitoring

ICU-Level Care Required For

1, 5

• Severe hepatotoxicity (AST or ALT >1,000 IU/L)
• Any coagulopathy (elevated INR)
• Encephalopathy
• Renal failure
• Metabolic derangements

Immediate Liver Transplant Consultation

Contact a liver transplant center immediately when there is any evidence of liver failure—patients with severe hepatotoxicity or coagulopathy require early transplant hepatology consultation. 1, 5

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Critical Pitfalls to Avoid

• Do not wait for acetaminophen levels if presentation is delayed or timing uncertain—start NAC immediately 1, 5
• Do not rely on patient-reported dose—history is often inaccurate 1, 2
• Do not withhold NAC in late presentations—it still provides benefit even >24 hours post-ingestion 1, 6
• Do not use the nomogram for presentations >24 hours, extended-release formulations, or repeated supratherapeutic ingestions 1
• Do not assume low/absent acetaminophen levels rule out toxicity if ingestion was remote 1
• Patients may have elevated transaminases despite "no risk" nomogram placement due to inaccurate history or increased susceptibility 1
• Do not delay NAC while awaiting activated charcoal 5

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NAC Adverse Effects

Anaphylactoid reactions (not true anaphylaxis) usually occur during the loading dose and are easily managed by: 8

• Discontinuing the NAC infusion
• Administering antihistamines
• Restarting the loading dose at a slower infusion rate