What is the treatment for paracetamol (acetaminophen) poisoning?

Treatment of Paracetamol (Acetaminophen) Poisoning

Immediate Management: N-Acetylcysteine (NAC) is the Cornerstone

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

Critical Time Windows for NAC Efficacy

The effectiveness of NAC is dramatically time-dependent:

• 0-8 hours post-ingestion: Only 2.9% develop severe hepatotoxicity when treated within this window 1
• 8-10 hours: Risk increases to 6.1% 1
• 10-24 hours: Risk jumps to 26.4% 1
• Beyond 24 hours: NAC still provides benefit and reduces mortality, though efficacy is significantly diminished 1

Never withhold NAC even in late presentations (>24 hours), as it reduces mortality from 80% to 52% in fulminant hepatic failure regardless of time since ingestion. 1

Initial Assessment and Risk Stratification

Laboratory Evaluation (Obtain Immediately)

• Serum paracetamol level (must be drawn ≥4 hours post-ingestion for accurate nomogram interpretation) 2
• Liver function tests: AST, ALT, alkaline phosphatase, total bilirubin 3, 2
• Coagulation studies: INR/prothrombin time 3, 2
• Renal function: Creatinine, BUN 2
• Metabolic panel: Glucose, electrolytes, arterial lactate 3
• Arterial blood gas 3

Using the Rumack-Matthew Nomogram

The nomogram applies ONLY to single acute ingestions with known time of ingestion when levels are drawn 4-24 hours post-ingestion. 1, 2

• Plot the paracetamol concentration against time post-ingestion 1
• Treatment line: Starts at 150 mg/L (992 µmol/L) at 4 hours, extending to 24 hours with a half-life of 4 hours 4
• Treat all patients at or above the "possible toxicity" line 1, 2

Critical pitfall: The nomogram does NOT apply to repeated supratherapeutic ingestions, extended-release formulations, or presentations >24 hours post-ingestion 1

NAC Dosing Regimens

Intravenous Protocol (Preferred in Most Settings)

Two-bag regimen (current recommendation): 5

• First dose: 200 mg/kg in 5% dextrose over 4 hours
• Second dose: 100 mg/kg over 16 hours (total 20-hour protocol)

Traditional three-bag regimen: 1, 2

• Loading dose: 150 mg/kg over 15 minutes (or more slowly over 1-2 hours to reduce anaphylactoid reactions)
• Second dose: 50 mg/kg over 4 hours
• Third dose: 100 mg/kg over 16 hours (total 21-hour protocol)

Oral Protocol (Alternative)

• Loading dose: 140 mg/kg by mouth or nasogastric tube 1
• Maintenance: 70 mg/kg every 4 hours for 17 additional doses (total 72 hours) 1

The oral regimen may be superior when treatment is delayed and is as effective as IV NAC. 1

Activated Charcoal

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

• Most effective within 1-2 hours but may provide benefit up to 4 hours 1
• Ensure airway protection, especially with co-ingestions 1

Special Clinical Scenarios

Unknown Time of Ingestion

Start NAC loading dose immediately without waiting for laboratory results. 1, 2

• Obtain paracetamol level to guide continuation of therapy 2
• Treat if any detectable paracetamol level is present 1

Delayed Presentation (>24 Hours Post-Ingestion)

Administer NAC immediately based on clinical presentation and laboratory findings rather than nomogram placement. 1

• The nomogram is invalid in this timeframe 1
• Base treatment decisions on paracetamol levels, transaminases, and INR 1
• Continue NAC until transaminases are declining and INR normalizes 1

Established Hepatotoxicity or Fulminant Hepatic Failure

All patients with acute liver failure suspected to be from paracetamol must receive NAC immediately, regardless of time since ingestion (Level B recommendation). 1

• NAC reduces mortality from 80% to 52% 1
• Reduces cerebral edema from 68% to 40% 1
• Reduces need for inotropic support from 80% to 48% 1
• Contact liver transplant center immediately 3
• Requires ICU-level care 1, 3

Repeated Supratherapeutic Ingestions (RSTI)

Treat with NAC if: 1

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

The nomogram does not apply to RSTI—use clinical judgment and laboratory values. 1

Extended-Release Paracetamol

Obtain two paracetamol levels: 1, 2

• First at 4 hours post-ingestion
• Second at 8-10 hours post-ingestion

Treat with full NAC course if either level is at or above the treatment line. 2

Massive Overdoses

For paracetamol concentrations more than double the nomogram line, increase NAC dosing beyond standard protocol. 1, 5

• Consider step-wise increases at the 300-, 450-, and 600-lines on the nomogram 1
• Patients ingesting ≥30 g or ≥500 mg/kg should receive increased doses 5

High-Risk Populations (Lower Treatment Threshold)

Treat even with paracetamol levels in the "non-toxic" range for: 1

• Chronic alcohol consumption: Severe hepatotoxicity documented with doses as low as 4-5 g/day 1, 6
• Malnutrition or fasting states 1
• Pre-existing liver disease 6, 3
• CYP2E1 enzyme-inducing drugs (e.g., isoniazid) 2

Criteria for Stopping NAC

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

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

Red flags that mandate continuing or restarting NAC: 1

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

For delayed presentations, extended-release formulations, RSTI, or unknown timing, continue NAC beyond the standard protocol until criteria above are met. 1

Critical Warning Signs Requiring Immediate Escalation

Very high aminotransferases (AST/ALT >3,500 IU/L) are highly correlated with paracetamol poisoning even without clear overdose history. 6, 3

Immediate ICU transfer and transplant hepatology consultation if: 1, 3

• AST/ALT >1,000 IU/L
• Coagulopathy (elevated INR)
• Altered mental status or hepatic encephalopathy
• Hypoglycemia
• Elevated arterial lactate
• Renal dysfunction

Clinical Presentation Timeline

Understanding the temporal progression helps guide management:

• 0-24 hours: Nonspecific symptoms (nausea, vomiting, malaise); may be asymptomatic 3
• 24-72 hours: Liver enzymes begin rising; jaundice may appear; right upper quadrant tenderness variably present 3
• 72-96 hours: Maximum liver damage; AST/ALT potentially in thousands; coagulopathy develops 3

Early recognition is critical as liver damage may not be apparent until 24-72 hours post-ingestion. 3

Common Pitfalls to Avoid

• Do not wait for paracetamol levels if presentation is >8 hours post-ingestion—start NAC immediately 1, 2
• Low or absent paracetamol levels do not rule out poisoning if ingestion was remote or occurred over several days 1, 6
• Do not rely on patient-reported ingestion quantity—it is often inaccurate 2
• Do not use the nomogram for RSTI, extended-release formulations, or presentations >24 hours 1
• Even therapeutic doses (4 g/day for 14 days) can cause ALT elevations >3× normal in 31-41% of healthy adults 6