What is the treatment for paracetamol (acetaminophen) poisoning?

Treatment of Paracetamol (Acetaminophen) Poisoning

Immediately administer N-acetylcysteine (NAC) to any patient with suspected or confirmed paracetamol poisoning when the serum level plots above the "possible toxicity" line on the Rumack-Matthew nomogram, or when timing is unknown, or when hepatotoxicity is already present—ideally within 8 hours of ingestion to maximize efficacy. 1

Initial Emergency Management

Gastrointestinal Decontamination

• Administer activated charcoal (1 g/kg orally) if the patient presents within 4 hours of ingestion, given 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. 1
• Ensure airway protection is adequate, especially with co-ingestions (e.g., sedatives, alcohol). 1

Immediate Laboratory Assessment

Obtain the following tests urgently to guide treatment and monitor for complications: 1, 3

• Serum paracetamol concentration (must be drawn at least 4 hours post-ingestion for accurate interpretation)
• AST, ALT, alkaline phosphatase, total bilirubin
• Prothrombin time/INR
• Creatinine and BUN
• Blood glucose
• Arterial blood gas and lactate
• Complete blood count
• Electrolytes

Critical caveat: 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
• Known time of ingestion
• Immediate-release formulations
• Levels drawn 4-24 hours post-ingestion

When the Nomogram Does NOT Apply

Do not use the nomogram for: 1, 2

• Repeated supratherapeutic ingestions
• Unknown time of ingestion
• Extended-release formulations
• Presentations >24 hours post-ingestion
• Established hepatotoxicity (elevated transaminases)

Interpreting the Nomogram

• Levels at or above the "possible toxicity" line (150 treatment line): Start NAC immediately 1, 2
• Levels below the line: Generally do not require NAC, but consider risk factors (see below)
• The nomogram may underestimate risk in chronic alcoholics, malnourished patients, or those taking CYP2E1-inducing drugs (e.g., isoniazid). 2

N-Acetylcysteine (NAC) Treatment Protocol

Standard IV Dosing Regimen (21-Hour Protocol)

The FDA-approved three-bag regimen: 1, 2

1. Loading dose: 150 mg/kg IV over 15 minutes (in 200 mL D5W)
2. Second dose: 50 mg/kg IV over 4 hours (in 500 mL D5W)
3. Third dose: 100 mg/kg IV over 16 hours (in 1000 mL D5W)

Total dose: 300 mg/kg over 21 hours 2

Alternative Oral Dosing Regimen (72-Hour Protocol)

• Loading dose: 140 mg/kg orally or via nasogastric tube (diluted to 5% solution) 1
• Maintenance: 70 mg/kg every 4 hours for 17 additional doses (total 72 hours) 1
• The 72-hour oral regimen is as effective as the 20-hour IV regimen and may be superior when treatment is delayed. 1

Critical Timing Considerations

The efficacy of NAC is directly related to how quickly it is started: 1, 3

• Within 8 hours: Only 2.9% develop severe hepatotoxicity
• Within 10 hours: 6.1% develop severe hepatotoxicity
• 10-24 hours: 26.4% develop severe hepatotoxicity
• 16-24 hours: 41% develop hepatotoxicity (high-risk patients)
• >24 hours: Still beneficial but significantly reduced efficacy

Even with delayed presentation beyond 24 hours, NAC should never be withheld as it still reduces mortality and hepatotoxicity. 1, 4

Special Clinical Scenarios Requiring Immediate NAC

Unknown Time of Ingestion

• Start NAC loading dose immediately without waiting for laboratory results. 2
• Obtain paracetamol level and liver function tests to guide continuation of therapy. 1
• If paracetamol level is detectable, continue full NAC course. 1

Established Hepatotoxicity or Acute Liver Failure

Administer NAC immediately to all patients with hepatic failure from paracetamol, regardless of time since ingestion (Level B recommendation). 1

NAC benefits in fulminant hepatic failure: 1

• Reduces mortality from 80% to 52%
• Reduces cerebral edema from 68% to 40%
• Reduces need for inotropic support from 80% to 48%
• Early treatment (<10 hours) results in 100% survival
• Late treatment (>10 hours) results in 37% mortality

Extended-Release Formulations

• Obtain a second paracetamol level 8-10 hours post-ingestion if the 4-hour level is below the treatment line. 1, 2
• If the second level is at or above the treatment line, start NAC immediately. 2
• All potentially toxic ingestions (≥10 g or ≥200 mg/kg) should receive a full NAC course. 5

Repeated Supratherapeutic Ingestions (RSTI)

Treat with NAC if any of the following criteria are met: 1

• Serum paracetamol ≥10 mg/mL (≥66 μmol/L)
• AST or ALT >50 IU/L
• Ingestion of ≥10 g or 200 mg/kg (whichever is less) in a single 24-hour period
• Ingestion of ≥6 g or 150 mg/kg (whichever is less) per 24-hour period for ≥48 hours

The nomogram does NOT apply to RSTI cases—treatment decisions are based on paracetamol levels and liver function tests. 1, 2

High-Risk Populations Requiring Lower Treatment Threshold

Treat with NAC even with levels in the "non-toxic" range for: 1, 3

• Chronic alcohol consumption (severe hepatotoxicity documented with doses as low as 4-5 g/day)
• Malnutrition or fasting states
• Pre-existing liver disease
• Patients taking CYP2E1-inducing drugs (isoniazid, phenytoin, carbamazepine)

Massive Overdoses

For ingestions resulting in paracetamol concentrations more than double the nomogram line: 1, 5

• Consider increased NAC dosing beyond the standard protocol
• Patients ingesting ≥30 g or ≥500 mg/kg should receive increased doses of NAC 5

When to Continue or Extend NAC Beyond 21 Hours

Criteria for Stopping NAC After Standard Protocol

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

• Paracetamol level is undetectable
• AST and ALT are normal or declining
• INR is normal
• Patient is asymptomatic

Mandatory Extended Treatment Scenarios

Continue NAC beyond 21 hours if any of the following are present: 1

• Detectable paracetamol level
• Any elevation in AST or ALT above normal
• Rising transaminases
• Any coagulopathy (elevated INR)
• Delayed presentation (>24 hours post-ingestion)
• Extended-release formulation
• Repeated supratherapeutic ingestions
• Unknown time of ingestion
• Clinical signs of hepatotoxicity

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

Monitoring During and After Treatment

During NAC Infusion

• Monitor for hypersensitivity reactions (rash, urticaria, bronchospasm, hypotension). 2
• If serious reaction occurs, temporarily stop infusion, treat reaction, then carefully restart at slower rate. 2
• Most reactions occur during the loading dose when concentrations are highest. 6

Laboratory Monitoring Schedule

• Repeat AST, ALT, INR, creatinine at 12-24 hours after starting NAC 1
• If abnormal, continue monitoring every 12-24 hours until improving
• Monitor for complications: encephalopathy, coagulopathy, renal failure, hypoglycemia, metabolic acidosis 3

Critical Warning Signs Requiring ICU Care

Immediately consult transplant hepatology and transfer to ICU if: 1, 3

• AST/ALT >1000 IU/L (severe hepatotoxicity)
• INR >1.5 (coagulopathy)
• Altered mental status or hepatic encephalopathy
• Elevated arterial lactate
• Renal dysfunction
• Hypoglycemia

Very high aminotransferases (AST/ALT >3500 IU/L) are highly specific for paracetamol poisoning and should raise suspicion even without clear overdose history. 3, 7

Common Pitfalls and How to Avoid Them

Pitfall #1: Waiting for Laboratory Results Before Starting NAC

Solution: If presentation is >8 hours post-ingestion, unknown timing, or clinical suspicion of hepatotoxicity, start NAC immediately without waiting for levels. 1, 2

Pitfall #2: Relying on Patient History of Ingested Amount

Solution: The reported quantity is often inaccurate—always obtain serum paracetamol level and use the nomogram for risk stratification. 2

Pitfall #3: Drawing Paracetamol Level Too Early

Solution: Levels drawn <4 hours post-ingestion are unreliable and may underestimate peak concentrations. Wait until at least 4 hours or start NAC empirically. 2

Pitfall #4: Using the Nomogram for Inappropriate Cases

Solution: Remember the nomogram only applies to single acute ingestions with known timing. Do not use for RSTI, extended-release, unknown timing, or late presentations. 1, 2

Pitfall #5: Stopping NAC Prematurely

Solution: Do not stop NAC if paracetamol is still detectable, transaminases are elevated or rising, or INR is abnormal. 1

Pitfall #6: Missing Low or Absent Paracetamol Levels in Late Presentations

Solution: Low or absent paracetamol levels do NOT rule out paracetamol poisoning if ingestion was remote or occurred over several days. Treat based on clinical presentation and liver function tests. 1, 7

Pitfall #7: Undertreating High-Risk Populations

Solution: Use a lower threshold for NAC treatment in chronic alcoholics, malnourished patients, and those on enzyme-inducing drugs—even "non-toxic" levels may cause severe hepatotoxicity. 1, 3, 2

Pitfall #8: Delayed Recognition of Acute Liver Failure

Solution: Patients may feel relatively well despite severe biochemical liver injury. Monitor closely for encephalopathy, coagulopathy, and metabolic derangements. Early transplant consultation is critical. 1, 3

Disposition and Follow-Up

• Patients with normal paracetamol levels below the treatment line and normal liver function: Can be medically cleared after psychiatric evaluation if intentional overdose 1
• Patients receiving NAC with normal labs at completion: Repeat labs before discharge to ensure no delayed hepatotoxicity 1
• Patients with any hepatotoxicity: Require admission and continued monitoring until transaminases are declining 1
• Patients with severe hepatotoxicity or liver failure: Require ICU admission and immediate transplant hepatology consultation 1, 3