What is the treatment for suspected paracetamol (Acetaminophen) toxicity?

Treatment of Paracetamol (Acetaminophen) Toxicity

Administer N-acetylcysteine (NAC) immediately to all patients with suspected or confirmed paracetamol overdose when serum levels plot above the treatment line on the Rumack-Matthew nomogram, or when hepatotoxicity is present, or when timing is unknown—ideally within 8 hours of ingestion to maximize efficacy. 1

Initial Assessment and Immediate Interventions

Within 4 Hours of Presentation

• Give activated charcoal (1 g/kg orally in a slurry) just prior to starting NAC if the patient presents within 4 hours of ingestion 1, 2
• Activated charcoal is most effective within 1-2 hours but may provide benefit up to 4 hours post-ingestion 1
• Ensure airway protection is adequate, especially with co-ingestions (e.g., sedatives, alcohol) 1

Essential Laboratory Testing

Draw the following immediately upon presentation 2:

• Serum paracetamol concentration (must be drawn at least 4 hours post-ingestion for acute overdose) 2
• AST, ALT, bilirubin 2
• INR (international normalized ratio) 2
• Creatinine, BUN 2
• Blood glucose and electrolytes 2

Critical pitfall: Paracetamol levels drawn before 4 hours post-ingestion are unreliable and may underestimate peak concentrations 2

Risk Stratification Using the Rumack-Matthew Nomogram

When to Use the Nomogram

The nomogram applies only to 1, 2:

• Single acute ingestions of immediate-release paracetamol
• Known time of ingestion
• Paracetamol level drawn 4-24 hours post-ingestion

Treatment Decision Algorithm Based on Nomogram

• If paracetamol concentration plots at or above the "possible toxicity" line (150 mg/L at 4 hours in the US; 100 mg/L at 4 hours in the UK): Start NAC immediately 1, 2, 3
• If concentration plots below the line but timing is uncertain or level was drawn <4 hours: Start NAC immediately 2
• If concentration is below the line and timing is reliable: NAC may not be needed, but monitor closely 1

Important caveat: The nomogram may underestimate hepatotoxicity risk in patients with chronic alcoholism, malnutrition, or those taking CYP2E1-inducing drugs (e.g., isoniazid)—consider treating these patients even with "non-toxic" levels 2, 1

When the Nomogram Does NOT Apply

Start NAC immediately without waiting for nomogram assessment in 1, 2:

• Unknown time of ingestion with detectable paracetamol level 1
• Presentation >24 hours post-ingestion 1
• Extended-release paracetamol formulations 1, 4
• Repeated supratherapeutic ingestions 1
• Any evidence of hepatotoxicity (elevated AST/ALT) 1
• Acute liver failure with suspected paracetamol etiology 1

NAC Dosing Regimens

Standard Intravenous Protocol (21-Hour Regimen)

1, 2:

• Loading dose: 150 mg/kg in 5% dextrose over 15 minutes (or over 1-2 hours to reduce anaphylactoid reactions)
• Second dose: 50 mg/kg over 4 hours
• Third dose: 100 mg/kg over 16 hours

Modified UK Protocol (SNAP - Scottish and Newcastle Anti-emetic Pretreatment)

3:

• Loading dose: 100 mg/kg over 2 hours
• Maintenance: 200 mg/kg over 10 hours
• This regimen has comparable efficacy with significantly reduced adverse reactions 3, 4

Oral NAC Protocol (72-Hour Regimen)

1:

• Loading dose: 140 mg/kg orally or via nasogastric tube (diluted to 5% solution)
• Maintenance: 70 mg/kg every 4 hours for 17 additional doses (total 72 hours)
• The oral regimen is as effective as IV and may be superior when treatment is delayed 1

Special Clinical Scenarios Requiring Modified Management

Massive Overdose (Very High Paracetamol Levels)

• If paracetamol concentration is more than double the nomogram treatment line: Increase NAC dosing 4
• For ingestions ≥30 g or ≥500 mg/kg: Use increased acetylcysteine doses 4

Extended-Release Paracetamol

• All potentially toxic ingestions (≥10 g or ≥200 mg/kg, whichever is less) should receive a full course of NAC 4
• Draw a second paracetamol level 8-10 hours post-ingestion if the 4-hour level is below the treatment line 2

Repeated Supratherapeutic Ingestions

• Start NAC if serum paracetamol ≥10 mg/mL OR if AST or ALT >50 IU/L 1
• The nomogram cannot be used for these cases 1

Established Hepatotoxicity or Acute Liver Failure

• Administer NAC immediately regardless of time since ingestion (Level B recommendation) 1
• NAC reduces mortality from 80% to 52% in fulminant hepatic failure 1
• NAC reduces cerebral edema from 68% to 40% and need for inotropic support from 80% to 48% 1
• Early NAC (<10 hours) in fulminant hepatic failure results in 100% survival 1
• Late NAC (>10 hours) results in 37% mortality but should still be given 1

Chronic Alcohol Users

• Treat with NAC even with levels in the "non-toxic" range 1
• Severe hepatotoxicity documented with doses as low as 4-5 g/day in alcoholics 5, 1

Cirrhotic Patients

• Start NAC immediately with any suspected overdose 6
• Use a lower treatment threshold as cirrhotics have increased susceptibility 6
• Continue NAC beyond 21 hours if transaminases remain elevated or rising 6

Timing and Efficacy of NAC Treatment

Critical Time Windows

The relationship between treatment delay and hepatotoxicity risk 1:

• 0-8 hours: 2.9% risk of severe hepatotoxicity with NAC
• Within 10 hours: 6.1% risk of severe hepatotoxicity
• 10-24 hours: 26.4% risk of severe hepatotoxicity
• 16-24 hours: 41% risk in high-risk patients (still better than 58% without treatment)

Key principle: Efficacy diminishes progressively after 8 hours, but NAC should never be withheld even in late presentations as it still provides benefit and reduces mortality 1, 2

Late Presentations (>24 Hours Post-Ingestion)

• Start NAC immediately without waiting for laboratory confirmation 1
• The nomogram does NOT apply—base treatment decisions on paracetamol levels, liver function tests, and clinical presentation 1
• Continue NAC until transaminases are declining and INR normalizes 1

Duration of NAC Treatment and Stopping Criteria

Standard Stopping Criteria (After 21-Hour Protocol)

NAC can be discontinued when ALL of the following are met 1:

• Paracetamol level is undetectable
• AST and ALT are normal (not just "improving"—must be normal)
• INR is normal
• Patient is asymptomatic

Mandatory Extended Treatment Beyond 21 Hours

Continue NAC if ANY of the following are present 1:

• AST or ALT remains elevated or rising
• INR remains elevated
• Detectable paracetamol level persists
• Delayed presentation (>24 hours post-ingestion)
• Extended-release formulation
• Repeated supratherapeutic ingestions
• Unknown time of ingestion
• Chronic alcohol use

When Hepatotoxicity Develops (AST/ALT >1000 IU/L)

• Restart NAC immediately if previously stopped, or continue indefinitely 1
• Continue until transaminases are declining and INR normalizes 1
• Mortality reduction from 80% to 52% regardless of time since ingestion 1

Monitoring and Supportive Care

Laboratory Monitoring During Treatment

• Repeat AST, ALT, INR, creatinine every 12-24 hours 2
• Monitor for signs of hepatic failure: coagulopathy, encephalopathy, hypoglycemia 1

Patients Requiring ICU-Level Care

Transfer to ICU and contact liver transplant center immediately if 1:

• AST/ALT >1000 IU/L (severe hepatotoxicity)
• Any coagulopathy (elevated INR)
• Hepatic encephalopathy
• Renal failure
• Metabolic derangements

Managing NAC Adverse Reactions

• Anaphylactoid reactions (nausea, vomiting, flushing, bronchospasm) occur most commonly during the loading dose 3, 7
• Slow the infusion rate or temporarily stop NAC, treat symptoms, then resume at slower rate 3
• Newer regimens with slower loading doses (over 1-2 hours instead of 15 minutes) significantly reduce adverse reactions 3, 4

Critical Pitfalls to Avoid

1. Never rely solely on reported ingestion amount—it is often inaccurate 2
2. Low or absent paracetamol levels do NOT rule out toxicity if ingestion was remote or occurred over several days 1
3. Do not use the nomogram for repeated supratherapeutic ingestions, extended-release formulations, or presentations >24 hours 1, 2
4. Do not wait for laboratory results if presentation is >8 hours post-ingestion or timing is unknown—start NAC immediately 2
5. Very high transaminases (AST/ALT >3500 IU/L) are highly correlated with paracetamol poisoning—start NAC even with inadequate history 1
6. Patients may develop hepatotoxicity despite "no risk" nomogram placement due to inaccurate history or increased susceptibility 1
7. Never stop NAC at 21 hours if any abnormality persists (elevated transaminases, INR, or detectable paracetamol) 1