What is the definition and treatment of a paracetamol (acetaminophen) overdose in adults and children, including dosage and administration of N-acetylcysteine (NAC) therapy?

Paracetamol (Acetaminophen) Overdose: Definition and Treatment

Definition of Overdose

A paracetamol overdose is defined as a single acute ingestion of ≥150 mg/kg or ≥10 grams (whichever is less) in adults, or ≥200 mg/kg in children. 1

Acute Single Ingestion Thresholds

• Adults: Ingestions exceeding 10 grams in a 24-hour period are potentially toxic and require medical evaluation 1
• Children: Ingestions ≥150 mg/kg are considered potentially toxic 1
• High-risk populations (chronic alcohol use, pre-existing liver disease, enzyme-inducing drugs): Toxicity can occur at doses as low as 4-5 g/day 2, 1

Repeated Supratherapeutic Ingestion (RSTI)

• ≥10 grams or 200 mg/kg (whichever is less) over a single 24-hour period 1
• ≥6 grams or 150 mg/kg (whichever is less) per 24-hour period for ≥48 hours 1
• High-risk individuals: >4 grams or 100 mg/kg per day 1

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Treatment Algorithm

Step 1: Immediate Assessment (Within 4 Hours of Ingestion)

Administer activated charcoal 1 g/kg orally just prior to starting N-acetylcysteine (NAC) if the patient presents within 4 hours of ingestion. 2

• Most effective within 1-2 hours but may provide benefit up to 4 hours post-ingestion 2
• Ensure airway protection, especially with co-ingestions (e.g., sedatives, opioids) 2

Step 2: Obtain Serum Paracetamol Level

Draw serum paracetamol level at 4 hours post-ingestion (or immediately if presentation is >4 hours). 2

• Critical pitfall: Levels drawn before 4 hours are unreliable and must be repeated at 4 hours 2
• Plot the level on the Rumack-Matthew nomogram to determine hepatotoxicity risk 2
• The nomogram is only valid for single acute ingestions with known time of ingestion, drawn between 4-24 hours post-ingestion 2

Step 3: Initiate NAC Based on Risk Stratification

Start NAC immediately if the paracetamol level plots at or above the "possible toxicity" line on the Rumack-Matthew nomogram (≥150 mcg/mL at 4 hours or ≥50 mcg/mL at 12 hours). 2

Mandatory NAC Treatment Scenarios (Regardless of Nomogram):

• Any elevation in AST or ALT with suspected paracetamol ingestion 2
• Hepatic failure (AST/ALT >1,000 IU/L) with suspected paracetamol overdose, regardless of time since ingestion 2
• Detectable paracetamol levels with unknown time of ingestion 2
• Extended-release formulations: All ingestions ≥10 g or ≥200 mg/kg require full NAC course 3
• Massive overdoses: Ingestions ≥30 g or ≥500 mg/kg require increased NAC dosing 3
• Repeated supratherapeutic ingestions with serum paracetamol ≥10 mg/mL or AST/ALT >50 IU/L 2

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NAC Dosing Regimens

Intravenous NAC Protocol (Preferred in Most Settings)

The FDA-approved 21-hour three-bag IV regimen is the standard treatment in North America. 4

Standard IV Dosing:

1. Loading dose: 150 mg/kg in 200 mL diluent over 60 minutes (previously 15 minutes, but extended to reduce anaphylactoid reactions) 4
2. Second dose: 50 mg/kg in 500 mL diluent over 4 hours 4
3. Third dose: 100 mg/kg in 1000 mL diluent over 16 hours 4
4. Total dose: 300 mg/kg over 21 hours 4

Two-Bag Regimen (Australia/New Zealand):

• First dose: 200 mg/kg over 4 hours 3
• Second dose: 100 mg/kg over 16 hours 3
• This regimen has similar efficacy but significantly reduced adverse reactions compared to the three-bag regimen 3

Oral NAC Protocol (Alternative)

Oral NAC is equally effective as IV NAC and may be superior when treatment is delayed beyond 10 hours. 2

1. Loading dose: 140 mg/kg orally or via nasogastric tube 2
2. Maintenance dose: 70 mg/kg every 4 hours for 17 additional doses (total 72 hours) 2

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Critical Timing Considerations

NAC must be initiated within 8 hours of ingestion to maximize efficacy—this is the single most important factor in preventing hepatotoxicity. 2

Efficacy by Treatment Timing:

• Within 8 hours: 2.9% risk of severe hepatotoxicity 2
• Within 10 hours: 6.1% risk of severe hepatotoxicity 2
• 10-24 hours: 26.4% risk of severe hepatotoxicity 2
• >24 hours: Still beneficial but significantly less effective; NAC reduces mortality from 80% to 52% in fulminant hepatic failure 2

Critical pitfall: The Rumack-Matthew nomogram does NOT apply to patients presenting >24 hours after ingestion—treatment decisions must be based on paracetamol levels, liver function tests, and clinical presentation 2

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Special Scenarios Requiring Modified Management

Massive Overdose (High Paracetamol Concentrations)

For paracetamol levels more than double the nomogram line (>300 mcg/mL at 4 hours), increase NAC dosing with step-wise escalation. 5

• 300-line: Consider increased NAC dosing 5
• 450-line: Further increase in NAC doses 5
• 600-line: Maximum NAC dose escalation 5
• Extended-release formulations ≥30 g or ≥500 mg/kg require increased NAC doses 3

Extended-Release Formulations

Obtain serial paracetamol levels at 4 hours and again 4-6 hours later, as late increases in concentration may occur at 14 hours or beyond. 2

• All potentially toxic ingestions (≥10 g or ≥200 mg/kg) should receive a full NAC course 3

Repeated Supratherapeutic Ingestion (RSTI)

The Rumack-Matthew nomogram does NOT apply to RSTI—treatment is based on specific criteria. 4

Treatment Criteria for RSTI:

• Serum paracetamol ≥10 mg/mL 2
• AST or ALT >50 IU/L in high-risk patients 2
• ≥10 g or 200 mg/kg in any 24-hour period 2
• ≥6 g or 150 mg/kg per 24-hour period for ≥48 hours 2

High-Risk Populations

Chronic alcohol users, patients with pre-existing liver disease, malnourished patients, and those on enzyme-inducing drugs require a lower threshold for NAC treatment. 2, 1

• Treat even with paracetamol levels in the "non-toxic" range on the nomogram 2
• Maximum daily therapeutic dose should be limited to 2-3 grams in these patients 1
• Severe hepatotoxicity documented with doses as low as 4-5 g/day in chronic alcoholics 2

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Monitoring During Treatment

Essential Laboratory Tests:

• Baseline: Paracetamol level, AST, ALT, INR, creatinine, BUN, electrolytes 2, 6
• Repeat every 24 hours for at least 72 hours or until trending down 6
• Very high aminotransferases (AST/ALT >3,500 IU/L) are highly correlated with paracetamol poisoning even without clear overdose history 1

Criteria for Discontinuing NAC:

NAC can be discontinued when paracetamol level is undetectable AND liver function tests remain normal. 2

Red Flags That Mandate Continuing or Restarting NAC:

• Any elevation in AST or ALT above normal 2
• Rising transaminases 2
• Any coagulopathy (elevated INR) 2
• Detectable paracetamol level 2
• Clinical signs of hepatotoxicity 2

Extended NAC Treatment Required For:

• Delayed presentation (>24 hours post-ingestion) 2
• Extended-release formulations 2
• Repeated supratherapeutic ingestions 2
• Unknown time of ingestion with detectable levels 2
• Chronic alcohol use 2
• Massive overdose 4
• Concomitant ingestion of other substances 4
• Pre-existing liver disease 4

If paracetamol levels remain detectable or ALT/AST continue rising after the standard 21-hour protocol, continue NAC and contact a regional poison center (1-800-222-1222) or the acetaminophen overdose assistance line (1-800-525-6115). 4

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Critical Pitfalls to Avoid

1. Do not wait for paracetamol levels if presentation is >8 hours—start NAC immediately while awaiting results 2
2. Low or absent paracetamol levels do NOT rule out poisoning if ingestion was remote, occurred over several days, or timing is uncertain 2
3. Patients may have elevated transaminases despite "no risk" nomogram placement due to inaccurate history or increased susceptibility 2
4. Do not use the nomogram for RSTI, extended-release formulations, or presentations >24 hours 2
5. Combination products (e.g., paracetamol with opioids) significantly increase risk of unintentional overdose 1
6. Even therapeutic doses of 4 g/day for 14 days can cause ALT elevations >3× normal in 31-41% of healthy adults 1

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Severe Hepatotoxicity and Liver Failure

For patients with fulminant hepatic failure (AST/ALT >1,000 IU/L), administer NAC immediately regardless of time since ingestion—it reduces mortality from 80% to 52%. 2

Additional Benefits of NAC in Liver Failure:

• Reduces cerebral edema from 68% to 40% 2
• Reduces need for inotropic support from 80% to 48% 2
• Early treatment (<10 hours) results in 100% survival without progression or dialysis 2
• Late treatment (>10 hours) results in 37% mortality and 51% requiring dialysis 2

Disposition:

• Patients with AST >1,000 IU/L or coagulopathy require ICU-level care and early consultation with transplant hepatology 2
• Contact a liver transplant center immediately when there is any evidence of liver failure 2