What is the approach to managing a paracetamol (acetaminophen) overdose?

Management of Paracetamol (Acetaminophen) Overdose

Immediately administer N-acetylcysteine (NAC) to any patient with suspected or confirmed paracetamol overdose when serum levels plot above the treatment line on the Rumack-Matthew nomogram, when timing is unknown, or when hepatotoxicity is already present—ideally within 8 hours of ingestion to maximize survival and prevent liver failure. 1, 2

Initial Assessment and Risk Stratification

Immediate Actions Upon Presentation

• Obtain critical history: Determine the exact time of ingestion, quantity ingested, whether it was immediate-release or extended-release formulation, and identify any co-ingestions 1, 3
• Recognize that patient-reported ingestion amounts are often inaccurate and should not guide treatment decisions alone 3
• Draw baseline laboratories immediately: AST, ALT, INR, creatinine, BUN, electrolytes, and blood glucose 3
• Obtain serum paracetamol concentration at least 4 hours post-ingestion (levels drawn earlier than 4 hours are unreliable and may underestimate peak concentrations) 3

Activated Charcoal Administration

• Give activated charcoal 1 g/kg orally within 4 hours of ingestion, just prior to starting NAC 1, 2
• Activated charcoal is most effective within 1-2 hours but may provide benefit up to 4 hours post-ingestion 2
• Do not delay NAC administration even if activated charcoal has been given 1
• Ensure adequate airway protection, especially with co-ingestions (e.g., sedatives, alcohol) 2

Treatment Decision Algorithm Based on Presentation Timing

Presentation Within 8 Hours of Known Ingestion Time

This is the critical window for maximal hepatoprotection—only 2.9% develop severe hepatotoxicity when NAC is started within 8 hours 1, 2

• If paracetamol level is available and plots above the treatment line on the Rumack-Matthew nomogram: Start NAC immediately 1, 3
• If paracetamol level plots below the treatment line: NAC is generally not required unless risk factors are present (chronic alcohol use, malnutrition, fasting, CYP2E1-inducing drugs) 1, 3
• If paracetamol level is unavailable or delayed: Start NAC immediately and continue for full 21-hour protocol 3

Presentation 8-24 Hours Post-Ingestion

Efficacy diminishes progressively after 8 hours: severe hepatotoxicity develops in 26.4% when treatment begins 10-24 hours post-ingestion, compared to 6.1% when started within 10 hours 1, 2

• Start NAC loading dose immediately upon presentation—do not wait for laboratory results 1
• Obtain paracetamol level to guide continuation of therapy 3
• Even with delayed treatment (16-24 hours), hepatotoxicity occurs in 41% versus 58% in untreated historical controls, demonstrating continued benefit 1

Presentation Beyond 24 Hours Post-Ingestion

The Rumack-Matthew nomogram does NOT apply to patients presenting >24 hours after ingestion 1, 2

• Administer NAC immediately based on clinical presentation and laboratory evidence, not nomogram placement 1, 3
• Treatment decisions must be based on: detectable paracetamol levels, elevated transaminases (AST/ALT), and clinical signs of hepatotoxicity 1, 2
• NAC remains beneficial in reducing hepatotoxicity and mortality even with delayed treatment beyond 24 hours 1

Unknown Time of Ingestion

• Start NAC loading dose immediately 3
• Obtain paracetamol concentration to determine need for continued treatment 3
• If paracetamol is detectable at any level with unknown timing, complete the full NAC protocol 1, 2

NAC Dosing Regimens

Intravenous Protocol (Preferred in Most Guidelines)

The two-bag regimen has similar efficacy but significantly reduced adverse reactions compared to the traditional three-bag regimen 4

Standard 21-Hour Three-Bag Regimen:

• Loading dose: 150 mg/kg in 200 mL 5% dextrose over 15 minutes 1, 3
• Second dose: 50 mg/kg in 500 mL 5% dextrose over 4 hours 1, 3
• Third dose: 100 mg/kg in 1000 mL 5% dextrose over 16 hours 1, 3

Alternative Two-Bag Regimen (Reduced Adverse Events):

• First bag: 200 mg/kg over 4 hours 4
• Second bag: 100 mg/kg over 16 hours 4

Oral Protocol (72-Hour Regimen)

• Loading dose: 140 mg/kg orally or via nasogastric tube, diluted to 5% solution 1, 3
• Maintenance: 70 mg/kg every 4 hours for 17 additional doses (total 72 hours) 1, 3
• 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 Modified Management

Massive Overdose (>30g or >500 mg/kg)

• Increase NAC dosing beyond standard protocol for massive overdoses 1, 4
• Modified release paracetamol ingestions ≥30g or ≥500 mg/kg require increased doses of NAC 4
• One case report documented survival after 60g ingestion (1200 mg/kg) with 3-day modified NAC regimen 5

Extended-Release Formulations

• All potentially toxic modified-release paracetamol ingestions (≥10g or ≥200 mg/kg, whichever is less) should receive a full course of NAC 4
• Standard dosing regimen applies, though monitoring may need to be extended due to prolonged absorption 1
• Obtain serial paracetamol levels at 4 hours and again at 8-12 hours to detect delayed peaks 1

Repeated Supratherapeutic Ingestions (RSTI)

The nomogram cannot be used for RSTI—treatment decisions are based on total dose and laboratory evidence 1, 2

• Start NAC if serum paracetamol concentration is ≥10 mg/mL OR if AST or ALT >50 IU/L 2
• For adults: repeated ingestions totaling ≥10g or 200 mg/kg (whichever is less) over 24 hours require evaluation 6
• Severe hepatotoxicity documented with doses as low as 4-5 g/day when taken repeatedly, particularly in chronic alcoholics 6
• Apply the full 72-hour protocol commonly, as timing cannot be determined by nomogram 1

Acute Liver Failure

Administer NAC to all patients with hepatic failure thought to be due to paracetamol, regardless of time since ingestion 1, 2

• NAC reduces mortality from 80% to 52%, cerebral edema from 68% to 40%, and need for inotropic support from 80% to 48% in fulminant hepatic failure 1
• Very high aminotransferases (AST/ALT >3,500 IU/L) are highly correlated with paracetamol poisoning and should prompt NAC treatment even when history is lacking 1
• Early NAC treatment (<10 hours) in fulminant hepatic failure results in 100% survival 1
• Late NAC treatment (>10 hours) results in 37% mortality and 51% requiring dialysis 1

High-Risk Populations (Lower Treatment Threshold)

Patients with chronic alcohol consumption, malnutrition, fasting, or taking CYP2E1-inducing drugs should be treated with NAC even with levels in the "non-toxic" range 1, 3

• Multiple case series demonstrate severe hepatotoxicity and mortality (20-33%) in chronic alcoholics taking 2.5-16.5 g/day (median 6.4 g/day) 6
• Even therapeutic doses of 4 g/day for 14 days caused ALT elevations >3 times normal in 31-41% of healthy adults 6
• The nomogram may underestimate hepatotoxicity risk in these populations 3

Criteria for Discontinuing NAC Therapy

Standard Stopping Criteria (Must Meet ALL):

• Acetaminophen level is undetectable 1
• AST and ALT remain normal (no elevation above upper limit of normal) 1
• INR is normal 1
• Patient is asymptomatic 1

Scenarios Mandating Extended Treatment Beyond 21 Hours:

• Delayed presentation (>24 hours post-ingestion) 1
• Extended-release paracetamol formulations 1
• Repeated supratherapeutic ingestions 1
• Unknown time of ingestion with detectable paracetamol 1
• Any elevation in AST or ALT above normal 1
• Rising transaminases 1
• Any coagulopathy (INR >1.3) 1
• Chronic alcohol use (lower threshold for extended treatment) 1

When to Restart NAC:

If hepatotoxicity develops (AST/ALT >1000 IU/L), restart NAC immediately and continue until transaminases are declining and INR normalizes 1

Critical Pitfalls and Caveats

Common Errors to Avoid:

• Never rely solely on patient-reported ingestion amount—it is often inaccurate 3
• Do not use the Rumack-Matthew nomogram for presentations >24 hours, RSTI, or extended-release formulations 1, 2
• Low or absent paracetamol levels do NOT rule out paracetamol poisoning if ingestion was remote or occurred over several days 1
• Normal admission ALT has high negative predictive value (98-100%) but elevated ALT has poor positive predictive value (14-23%) for predicting severe hepatotoxicity 7
• Do not delay NAC while awaiting confirmatory paracetamol levels if there is strong suspicion of significant overdose 1

Pregnancy Considerations:

• Paracetamol overdose during pregnancy should be treated with NAC according to regular protocols to prevent maternal and potentially fetal toxicity 8
• Unless severe maternal toxicity develops, paracetamol overdose does not appear to increase risk for adverse pregnancy outcome 8

Pediatric Considerations:

• Test liver enzymes if a child has received >75 mg/kg/day of paracetamol for >24 hours during febrile illness, and treat with NAC when transaminases are elevated 8
• Most trials excluded children, so evidence pertains primarily to adults 9

Disposition and Monitoring

• Patients with severe hepatotoxicity (AST >1000 IU/L) or coagulopathy require ICU-level care and early consultation with transplant hepatology 1
• Monitor AST, ALT, INR, creatinine, and clinical status every 12-24 hours during NAC therapy 3
• Patients with normal admission ALT and undetectable paracetamol at 4 hours have very low risk (NPV 98-100%) and may be suitable for early discharge after completing NAC 7