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 overdose when the serum level plots 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, 2

Initial Assessment and Immediate Actions

Within 4 Hours of Presentation

• Administer activated charcoal (1 g/kg orally) just prior to starting NAC if the patient presents within 4 hours of ingestion and can protect their airway 1, 2
• Activated charcoal is most effective within 1-2 hours but may provide benefit up to 4 hours post-ingestion 1

Critical Laboratory Testing

• Draw serum paracetamol concentration at least 4 hours post-ingestion for acute overdose—levels obtained earlier than 4 hours may be misleading and not represent peak concentrations 1, 2
• Obtain baseline liver function tests (AST, ALT), INR, bilirubin, creatinine, BUN, glucose, and electrolytes immediately 1, 2

Risk Stratification Using the Rumack-Matthew Nomogram

When to Use the Nomogram

The nomogram applies only to single acute ingestions with known time of ingestion when the paracetamol level is drawn 4-24 hours post-ingestion 1, 2, 3

Treatment Thresholds

• Start NAC if the paracetamol concentration plots at or above the "possible toxicity" line (the lower treatment line on the nomogram) 1, 2, 3
• The nomogram categorizes patients into probable risk, possible risk, and no risk based on concentration and timing 1

Critical Nomogram Limitations

• The nomogram does NOT apply to: repeated supratherapeutic ingestions, extended-release formulations, presentations >24 hours post-ingestion, or unknown time of ingestion 1, 2, 3
• The nomogram may underestimate risk in high-risk populations: chronic alcohol users, malnourished patients, or those on CYP2E1-inducing drugs (e.g., isoniazid)—treat these patients even with levels in the "non-toxic" range 1, 2, 4

NAC Dosing Regimens

Intravenous Protocol (21-Hour Regimen)

• Loading dose: 150 mg/kg in 5% dextrose over 15 minutes 1, 2
• Second dose: 50 mg/kg over 4 hours 1, 2
• Third dose: 100 mg/kg over 16 hours (total 300 mg/kg over 21 hours) 1, 2
• NAC must be diluted prior to IV administration as it is hyperosmolar (2600 mOsmol/L)—use sterile water, 0.45% sodium chloride, or 5% dextrose 2

Oral Protocol (72-Hour Regimen)

• 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

Recent Protocol Update

• Two-bag acetylcysteine regimen (200 mg/kg over 4 hours, then 100 mg/kg over 16 hours) has similar efficacy but significantly reduced adverse reactions compared to the traditional three-bag regimen 3

Timing-Based Treatment Algorithm

0-8 Hours Post-Ingestion (Critical Window)

• NAC provides maximal hepatoprotection with only 2.9% developing severe hepatotoxicity when treated within 8 hours 1, 4
• If the patient presents <8 hours with known timing and known paracetamol level, use the nomogram to guide treatment 1, 2
• If the level cannot be obtained within 8 hours or there is clinical evidence of toxicity, start NAC immediately without waiting 2

8-10 Hours Post-Ingestion

• Efficacy diminishes but remains substantial: 6.1% develop severe hepatotoxicity when treated within 10 hours 1, 4
• Administer loading dose immediately and obtain paracetamol level to determine need for continued treatment 2

10-24 Hours Post-Ingestion

• Efficacy is significantly reduced: 26.4% develop severe hepatotoxicity when treatment begins in this window 1, 4
• Among high-risk patients treated 16-24 hours after ingestion, hepatotoxicity develops in 41%—still lower than untreated controls (58%) 1, 4
• Start NAC immediately regardless of reduced efficacy 1, 2, 5

>24 Hours Post-Ingestion

• The nomogram does NOT apply—treatment decisions must be based on paracetamol levels, liver function tests, and clinical presentation 1
• Administer NAC immediately without waiting for laboratory confirmation 1
• NAC should still be administered as it remains beneficial in reducing hepatotoxicity and mortality even with delayed treatment 1, 5

Special Clinical Scenarios Requiring Immediate NAC

Established Hepatic Failure

• Administer NAC to all patients with hepatic failure thought to be due to paracetamol, 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, 6
• Early NAC treatment (<10 hours) in fulminant hepatic failure results in 100% survival without progression or dialysis 1, 6
• Late NAC treatment (>10 hours) in fulminant hepatic failure results in 37% mortality and 51% requiring dialysis 1, 6

Unknown Time of Ingestion

• Start NAC loading dose immediately if paracetamol is detectable and timing is unknown 1, 2
• Obtain paracetamol concentration to determine need for continued treatment 1, 2

Hepatotoxicity Already Present

• Start NAC immediately if hepatotoxicity is present (elevated transaminases) with suspected or known paracetamol overdose, including repeated supratherapeutic ingestions 1, 2
• Continue NAC until transaminases are declining and INR normalizes 1

Extended-Release Paracetamol

• All potentially toxic modified release ingestions (≥10 g or ≥200 mg/kg, whichever is less) should receive a full course of NAC 1, 3
• If the paracetamol concentration at 4 hours post-ingestion is below the possible toxicity line, obtain a second sample 8-10 hours after ingestion 2
• If the second value is at or above the "possible" toxicity line, administer NAC 2

Repeated Supratherapeutic Ingestions

• The nomogram does NOT apply to repeated supratherapeutic ingestions 1, 2, 3
• Treat with NAC if ≥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 1
• Treat if serum paracetamol ≥10 mg/mL or if AST or ALT >50 IU/L 1

Massive Overdoses

• Massive paracetamol overdoses resulting in concentrations more than double the nomogram line should be managed with increased doses of NAC 1, 3
• Patients ingesting ≥30 g or ≥500 mg/kg should receive increased doses of NAC 3

High-Risk Populations Requiring Lower Treatment Threshold

Chronic Alcohol Users

• Treat with NAC even with paracetamol levels in the "non-toxic" range as severe hepatotoxicity can occur with doses as low as 4-5 g/day in chronic alcohol users 1, 6, 2
• The nomogram may underestimate risk in this population 1, 2

Cirrhotic Patients

• Administer NAC immediately to all cirrhotic patients with suspected or confirmed paracetamol overdose as they have increased susceptibility to hepatotoxicity even at therapeutic doses 6
• The nomogram may underestimate risk in cirrhotic patients 6
• Continue NAC beyond 21 hours if AST/ALT remains elevated or rising, INR remains elevated, detectable paracetamol persists, or if delayed presentation 6

Other High-Risk Groups

• Malnourished patients 2
• Patients on CYP2E1-inducing drugs (e.g., isoniazid) 1, 2
• Consider lower treatment threshold for these populations 1

Criteria for Discontinuing NAC

Standard Protocol Completion

• NAC can be discontinued when paracetamol level is undetectable AND liver function tests remain normal 1
• Verify that AST and ALT are not elevated above normal 1

Scenarios Requiring Extended Treatment Beyond 21 Hours

Continue NAC beyond the standard protocol if: 1, 6

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

Red Flags Mandating Continuation or Restart

• Do not stop or immediately restart NAC if: any elevation in AST or ALT above normal, rising transaminases, any coagulopathy, detectable paracetamol level, or clinical signs of hepatotoxicity 1
• If hepatotoxicity develops (AST/ALT >1000 IU/L), restart NAC immediately and continue until transaminases are declining and INR normalizes 1

Critical Care and Transplant Considerations

ICU-Level Care Indications

• Patients with severe hepatotoxicity (AST >1000 IU/L) or coagulopathy require ICU-level care and early consultation with transplant hepatology 1, 6
• Monitor for complications of acute liver failure: encephalopathy, coagulopathy, renal failure, and metabolic derangements 6

Transplant Evaluation

• Contact a liver transplant center immediately when there is any evidence of liver failure 6
• Very high aminotransferases (AST/ALT >3500 IU/L) are highly correlated with paracetamol poisoning and should prompt aggressive treatment 1

Common Pitfalls and Caveats

Diagnostic Pitfalls

• Low or absent paracetamol levels do NOT rule out paracetamol poisoning if ingestion was remote or occurred over several days 1, 6
• Patients may present with elevated transaminases despite being stratified as "no risk" on the nomogram due to inaccurate history or increased susceptibility 1
• The reported history of quantity ingested is often inaccurate and is not a reliable guide to therapy 2

Treatment Pitfalls

• Never withhold NAC based on timing alone—it should not be withheld even in late presentations as it still provides benefit and does not worsen the patient's condition 1, 2, 7, 5
• A 7g ingestion represents a potentially hepatotoxic dose and warrants treatment regardless of nomogram placement in most clinical scenarios 1
• For patients weighing <70 kg, a 7g ingestion represents >100 mg/kg, placing them at higher risk 1

Adverse Reactions

• Hypersensitivity reactions can occur during NAC infusion: observe patients during and after infusion for hypotension, wheezing, shortness of breath, and bronchospasm 2
• If a serious reaction occurs, immediately discontinue infusion and initiate appropriate treatment 2
• NAC infusion may be carefully restarted after treatment of hypersensitivity 2
• The most common adverse reactions (>2%) are rash, urticaria/facial flushing, and pruritus 2

Fluid Management

• Total volume administered should be reduced for patients weighing <40 kg and those requiring fluid restriction 2