What is the management for paracetamol (Acetaminophen) poisoning?

Management of Paracetamol (Acetaminophen) Poisoning

Administer N-acetylcysteine (NAC) immediately to all patients with acetaminophen levels above the treatment line on the Rumack-Matthew nomogram, or when hepatotoxicity is suspected, as this is the only proven antidote that reduces mortality and prevents liver failure. 1, 2

Initial Assessment and Risk Stratification

Immediate Actions Upon Presentation

• Obtain acetaminophen level at least 4 hours post-ingestion to plot on the Rumack-Matthew nomogram; levels drawn earlier than 4 hours are unreliable and may underestimate toxicity 2, 3
• Measure baseline liver function tests (AST, ALT), INR, creatinine, BUN, electrolytes, and blood glucose to assess for existing hepatotoxicity 2, 3
• Administer activated charcoal (1 g/kg orally) if patient presents within 4 hours of ingestion and can protect their airway; this should be given just prior to starting NAC 2, 4

Risk Assessment Using the Rumack-Matthew Nomogram

• Plot the acetaminophen concentration against time post-ingestion (valid only for 4-24 hours post-ingestion) to determine treatment need 2, 3
• Initiate NAC for any level at or above the "possible toxicity" line (the lower treatment line at 150 mg/L at 4 hours, declining to 18.8 mg/L at 24 hours) 2, 3
• The nomogram only applies to single acute ingestions with known timing; it cannot be used for repeated supratherapeutic ingestions or unknown time of ingestion 2, 5

N-Acetylcysteine Treatment Protocol

Standard Intravenous Dosing Regimen

The FDA-approved three-bag regimen consists of:

• Loading dose: 150 mg/kg in 200 mL diluent over 60 minutes 3
• Second dose: 50 mg/kg in 500 mL diluent over 4 hours 3
• Third dose: 100 mg/kg in 1000 mL diluent over 16 hours 3
• Total treatment duration: 21 hours with total dose of 300 mg/kg 3

Alternative two-bag regimen (newer, with fewer adverse reactions):

• 200 mg/kg over 4 hours, then 100 mg/kg over 16 hours; this protocol significantly reduces anaphylactoid reactions (odds ratio 0.23) and vomiting (odds ratio 0.37) compared to the traditional regimen 4, 6

Critical Timing Considerations

• NAC initiated within 8 hours of ingestion: 2.9% risk of severe hepatotoxicity 2
• NAC initiated within 10 hours: 6.1% risk of severe hepatotoxicity 2
• NAC initiated after 10 hours: 26.4% risk of severe hepatotoxicity 2
• Treatment remains beneficial even when started 15-24 hours post-ingestion, though efficacy is diminished; it should never be withheld as reported ingestion time may be inaccurate 3, 7

Special Clinical Scenarios Requiring Modified Management

Unknown Time of Ingestion

• Start NAC loading dose immediately without waiting for acetaminophen level 2, 3
• Obtain acetaminophen concentration to guide continuation of treatment 2, 3
• Continue full 21-hour course if level is detectable or if clinical evidence of toxicity exists 2

Patients Presenting with Established Hepatotoxicity

• Administer NAC to all patients with fulminant hepatic failure from acetaminophen, regardless of time since ingestion (Level B recommendation) 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
• Early NAC treatment (<10 hours) in fulminant hepatic failure: 100% survival without progression or dialysis 1
• Late NAC treatment (>10 hours) in fulminant hepatic failure: 37% mortality, 51% requiring dialysis 1

Repeated Supratherapeutic Ingestions (RSTI)

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

• Serum acetaminophen concentration ≥10 mg/mL 1, 2
• AST or ALT >50 IU/L 1, 2
• Total ingestion ≥10 g or 200 mg/kg (whichever is less) over 24 hours 8
• ≥6 g or 150 mg/kg per 24 hours for ≥48 hours 8

Critical distinction: In the Daly et al. study, no patient with normal AST at presentation developed hepatotoxicity despite mean dosing of 10.6 g/day, but 50% of these patients received NAC, confounding the results 1

Extended-Release Formulations

• Obtain second acetaminophen level 8-10 hours post-ingestion if the 4-hour level is below the treatment line 2, 3
• Treat with full NAC course if any level plots above the treatment line 2
• All ingestions ≥10 g or ≥200 mg/kg of modified-release paracetamol should receive full NAC course 4
• Massive ingestions (≥30 g or ≥500 mg/kg) require increased NAC doses 4

High-Risk Populations Requiring Lower Treatment Threshold

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

• Chronic alcohol consumption (documented severe hepatotoxicity with doses as low as 4-5 g/day; mortality rate 33% in alcoholics with doses 5-20 g/day) 1, 8
• Malnutrition or fasting states 3
• CYP2E1 enzyme-inducing drugs (e.g., isoniazid) 3
• Pre-existing liver disease 8

Massive Overdoses

• For acetaminophen concentrations more than double the nomogram line, increase NAC dosing 4
• Patients ingesting ≥30 g or ≥500 mg/kg require increased acetylcysteine doses 4

Monitoring During and After Treatment

Laboratory Monitoring Schedule

• Repeat AST, ALT, INR, and creatinine at completion of 21-hour NAC infusion 2, 3
• If transaminases are rising or INR is elevated, continue NAC at 100 mg/kg over 16 hours and repeat labs 2
• Discontinue NAC when acetaminophen is undetectable, AST/ALT are normal or declining, and INR <2.0 2

Adverse Reactions to NAC

• Anaphylactoid reactions occur in up to 15% of patients, particularly during the initial loading dose when concentrations are highest 6, 9
• Symptoms include hypotension, wheezing, shortness of breath, bronchospasm, flushing, and urticaria 3
• Management: temporarily stop infusion, administer antihistamines ± bronchodilators, then restart at slower rate 3
• The two-bag regimen significantly reduces these reactions compared to the traditional three-bag protocol 6

Common Pitfalls and Critical Caveats

Pitfall #1: Relying on Patient-Reported Dose

• The reported quantity ingested is often inaccurate and unreliable; always base treatment decisions on serum levels and clinical presentation, not history alone 3

Pitfall #2: Drawing Levels Too Early

• Acetaminophen levels obtained <4 hours post-ingestion are misleading and may not represent peak concentrations; wait until 4 hours or treat empirically 2, 3

Pitfall #3: Withholding Treatment in Late Presenters

• Never withhold NAC because the patient presents >24 hours post-ingestion; it still provides benefit in established hepatotoxicity and the reported time may be incorrect 3, 7

Pitfall #4: Misapplying the Nomogram

• The nomogram is invalid for repeated supratherapeutic ingestions, unknown time of ingestion, and extended-release formulations; these require different management algorithms 2, 5

Pitfall #5: Stopping NAC Prematurely in Hepatotoxicity

• Continue NAC beyond 21 hours if transaminases are still rising or INR remains elevated; some patients require days of treatment 2

Pitfall #6: Missing Therapeutic Dose Toxicity

• Even therapeutic doses of 4 g/day for 14 days can cause ALT elevations >3× normal in 31-41% of healthy adults 8
• Severe hepatotoxicity has occurred with doses as low as 3-4 g/day in susceptible individuals 8

Disposition and Follow-Up

• Patients with acetaminophen levels below the treatment line and normal liver function can be medically cleared after psychiatric evaluation if intentional ingestion 2
• Patients receiving NAC require hospital admission for the full treatment course and monitoring 2
• Patients with severe hepatotoxicity (AST >1000 IU/L) or coagulopathy require ICU-level care and early consultation with transplant hepatology 1
• Contact regional poison center (1-800-222-1222) or acetaminophen overdose hotline (1-800-525-6115) for complex cases 3