Role of Oral N-Acetylcysteine in Paracetamol Toxicity
Oral N-acetylcysteine (NAC) is a highly effective antidote for paracetamol overdose that should be administered at 140 mg/kg loading dose followed by 70 mg/kg every 4 hours for 17 doses (72-hour protocol), with treatment initiated as soon as possible and ideally within 8-10 hours of ingestion. 1, 2
Primary Indications for Oral NAC
Administer oral NAC when serum paracetamol levels plot in the possible or probable risk zones on the Rumack-Matthew nomogram (for patients presenting 4-24 hours post-ingestion). 1
Start NAC immediately for any patient presenting >24 hours after ingestion when the nomogram cannot be used, particularly if acetaminophen levels are detectable or liver transaminases are elevated. 1
Give NAC in acute liver failure cases where paracetamol ingestion is suspected or possible, even without confirmatory history, especially when very high aminotransferases (>3,500 IU/L) suggest paracetamol poisoning. 1
Oral vs Intravenous NAC: Route Selection
Both oral and intravenous NAC have equivalent efficacy in preventing hepatotoxicity, with meta-analysis showing similar rates of liver injury whether treated within 10 hours (3% vs 6%), late presentations 10-24 hours (30% vs 26%), or overall (16% vs 19%). 3
Oral NAC may preserve more hepatocytes than the 21-hour intravenous protocol according to mechanistic modeling, suggesting the oral 72-hour regimen provides superior hepatoprotection. 4
Intravenous NAC is preferred when oral administration is contraindicated: patients with coma, active vomiting, or when activated charcoal has been given (which may reduce oral NAC bioavailability). 5
Oral NAC has no absolute contraindications for treating paracetamol overdose per FDA labeling. 2
Critical Timing Considerations
The 0-8 hour window is critical: NAC initiated within 8 hours results in only 2.9% risk of severe hepatotoxicity. 6
Efficacy decreases progressively with delay: 6.1% hepatotoxicity risk when started within 10 hours, versus 26.4% when started 10-24 hours post-ingestion. 1, 6
NAC remains beneficial even after 24 hours: Among high-risk patients treated 16-24 hours post-ingestion, hepatotoxicity occurs in 41%—still lower than untreated controls (58%). 6
Treatment must be initiated within 24 hours of ingestion per FDA labeling, though benefit persists beyond this timeframe in established hepatotoxicity. 2
Oral NAC Dosing Protocol
Loading dose: 140 mg/kg orally or via nasogastric tube, diluted to 5% solution in juice or soft drink to mask the sulfur taste. 1, 6
Maintenance dosing: 70 mg/kg every 4 hours for 17 additional doses, totaling 72 hours of treatment. 1, 6
The full 72-hour oral course may be unnecessary in many cases, but provides superior protection compared to shorter intravenous protocols, particularly for delayed presentations or extended-release formulations. 4
Special Clinical Scenarios
High-risk patients require treatment at lower thresholds: Chronic alcohol users, fasting patients, or those on enzyme-inducing medications may develop toxicity at lower paracetamol levels and should receive NAC even below typical treatment thresholds. 1, 6
Repeated supratherapeutic ingestions (>4g per 24 hours): Treat with the standard 72-hour oral protocol if serum paracetamol ≥10 mg/mL or if AST/ALT >50 IU/L. 6
Extended-release paracetamol preparations: Use standard oral dosing but extend monitoring beyond 24 hours due to prolonged absorption. 1
Unknown time of ingestion with detectable paracetamol levels: Initiate oral NAC immediately without waiting for nomogram placement. 6
Activated Charcoal Considerations
Give activated charcoal (1 g/kg) just prior to starting NAC if patient presents within 4 hours of ingestion. 1, 6
Do not delay NAC administration even if activated charcoal has been given, though this creates a theoretical concern about reduced oral NAC bioavailability (favoring intravenous route in this scenario). 1, 5
Adverse Effects of Oral NAC
Nausea, vomiting, and diarrhea are the primary adverse effects of oral NAC administration. 5
Oral NAC avoids the anaphylactoid reactions (angioedema, bronchospasm, flushing, hypotension, rash) that occur in up to 10% of patients receiving intravenous NAC. 5
Treatment Discontinuation Criteria
Stop oral NAC when paracetamol level is undetectable AND liver function tests remain completely normal (no elevation in AST or ALT above normal range). 6
Continue or restart NAC immediately if: any transaminase elevation develops, rising AST/ALT trends, any coagulopathy appears, or detectable paracetamol persists. 6
For established hepatotoxicity (AST/ALT >1000 IU/L): Continue NAC until transaminases are declining and INR normalizes, as this reduces mortality from 80% to 52% regardless of time since ingestion. 6
Critical Pitfalls to Avoid
Never delay NAC while awaiting confirmatory paracetamol levels if there is strong clinical suspicion of significant overdose. 1
Do not rely on the Rumack-Matthew nomogram for presentations >24 hours post-ingestion—base treatment decisions on paracetamol levels, liver function tests, and clinical presentation. 6
Low or absent paracetamol levels do not rule out poisoning if ingestion was remote or occurred over several days. 6
Patients may develop hepatotoxicity despite "no risk" nomogram placement due to inaccurate history or increased susceptibility—maintain high clinical suspicion. 6