What are the criteria for a paracetamol (acetaminophen) overdose?

Paracetamol Overdose Criteria

Paracetamol overdose is defined as an acute single ingestion of ≥150 mg/kg or ≥10 grams (whichever is less), or repeated supratherapeutic ingestions of ≥10 grams or 200 mg/kg (whichever is less) in a 24-hour period, or ≥6 grams or 150 mg/kg per day for ≥48 hours. 1, 2

Acute Single Ingestion Criteria

For immediate-release formulations:

• Potentially toxic dose: ≥150 mg/kg or ≥10 grams (whichever is less) 1, 2, 3
• High-risk threshold: A 7g ingestion represents a potentially hepatotoxic dose that warrants treatment regardless of nomogram placement in most clinical scenarios 1
• **For patients <70 kg:** A 7g ingestion represents >100 mg/kg, placing them at higher risk 1

Documented severe toxicity range:

• Severe hepatotoxicity and mortality have been documented with ingestions ranging from 10-65 grams 4
• Mean dose causing severe hepatotoxicity in intentional overdose was 23 g/day 4
• One case report documented survival after a massive 60-gram ingestion (1200 mg/kg) 4

Repeated Supratherapeutic Ingestion (RSTI) Criteria

Standard-risk patients:

• ≥10 grams or 200 mg/kg (whichever is less) during a single 24-hour period 1, 2
• ≥6 grams or 150 mg/kg (whichever is less) per 24-hour period for ≥48 hours 1, 2

High-risk patients (chronic alcohol use, malnutrition, enzyme-inducing drugs):

• 4 grams or 100 mg/kg per day 2

• Severe hepatotoxicity documented with doses as low as 4-5 g/day in chronic alcoholics 1, 2, 4
• Multiple case series demonstrate 20-33% mortality in chronic alcoholics taking 2.5-16.5 g/day (median 6.4 g/day) 4

Modified-Release Formulations

All potentially toxic modified-release paracetamol ingestions require different criteria:

• ≥10 grams or ≥200 mg/kg (whichever is less) should receive a full course of N-acetylcysteine 5
• Patients ingesting ≥30 grams or ≥500 mg/kg should receive increased doses of acetylcysteine 5
• Extended-release formulations have prolonged absorption requiring individualized treatment 1

Risk Assessment Using the Rumack-Matthew Nomogram

The nomogram applies ONLY to:

• Single acute immediate-release ingestions 1, 3
• Known time of ingestion 1, 3
• Acetaminophen level drawn 4-24 hours post-ingestion 1, 3

Treatment thresholds on nomogram:

• Levels above 200 mcg/mL at 4 hours or 50 mcg/mL at 12 hours indicate potential hepatotoxicity 2
• Levels at or above the "possible toxicity" line (dotted line) require NAC treatment 1, 3

Critical limitations of the nomogram:

• Does NOT apply to presentations >24 hours post-ingestion 1
• Does NOT apply to repeated supratherapeutic ingestions 1
• Does NOT apply to extended-release formulations 1
• May underestimate risk in chronic alcoholics, malnourished patients, or those on CYP2E1-inducing drugs 3

Laboratory Criteria Indicating Toxicity

Highly suggestive of paracetamol poisoning:

• AST/ALT >3,500 IU/L are highly correlated with acetaminophen poisoning even without clear overdose history 1, 2, 4
• AST/ALT potentially reaching thousands of units per liter at 72-96 hours post-ingestion 4

Treatment thresholds for RSTI:

• Serum acetaminophen ≥10 mg/mL 1
• AST or ALT >50 IU/L in patients with suspected repeated supratherapeutic ingestion 1

Special Clinical Scenarios Requiring Treatment

Treat with NAC regardless of dose criteria when:

• Hepatic failure thought to be due to acetaminophen (regardless of time since ingestion) 1
• Hepatotoxicity with suspected or known overdose, including RSTI 1
• Detectable acetaminophen levels with unknown time of ingestion 1
• Clinical evidence of acetaminophen toxicity 3
• Acetaminophen concentration cannot be obtained within 8 hours of ingestion 3

Common Pitfalls and Caveats

Critical diagnostic errors to avoid:

• Low or absent acetaminophen levels do NOT rule out poisoning if ingestion was remote or occurred over several days 1, 2
• Patients may present with elevated transaminases despite being stratified as "no risk" on nomogram due to inaccurate history or increased susceptibility 1
• Even therapeutic doses of 4 g/day for 14 days can cause ALT elevations >3 times normal in 31-41% of healthy adults 2
• Combination products containing acetaminophen significantly increase risk of unintentional overdose 2
• Staggered overdose pattern and delayed presentation beyond 24 hours are independently associated with adverse outcomes and increased mortality 6
• Consider screening all patients with intentional overdose or altered mental status for acetaminophen, as 0.9% had detectable levels despite negative history 7