N-Acetylcysteine in Paracetamol Poisoning
N-acetylcysteine (NAC) is the only proven antidote for paracetamol poisoning and must be administered immediately when overdose is suspected—ideally within 8 hours of ingestion—to prevent hepatotoxicity and death. 1, 2
Critical Timing: The 8-Hour Window
The efficacy of NAC is dramatically time-dependent, creating distinct treatment windows:
- Within 8 hours: Only 2.9% develop severe hepatotoxicity—this represents near-complete protection 1, 2
- 8-10 hours: Severe hepatotoxicity increases to 6.1% 1, 2
- 10-24 hours: Severe hepatotoxicity jumps to 26.4% 1, 2
- After 24 hours: NAC still provides benefit and reduces mortality, though efficacy is significantly diminished 2, 3
NAC should never be withheld regardless of presentation time—even in established hepatic failure, it reduces mortality from 80% to 52% 1, 2
When to Administer NAC: Decision Algorithm
Immediate Treatment Required (Do Not Wait for Labs):
- Serum paracetamol level plots above the treatment line on the Rumack-Matthew nomogram (drawn 4-24 hours post-ingestion) 1, 2
- Unknown time of ingestion with detectable paracetamol levels 1, 2
- Established hepatic failure with suspected paracetamol ingestion, even without confirmatory history 1, 2
- Very high aminotransferases (AST/ALT >3,500 IU/L), which are highly correlated with paracetamol poisoning 1
- Any elevation in AST or ALT with suspected overdose 2
Special High-Risk Populations (Lower Treatment Threshold):
- Chronic alcohol users: Treat even with levels in the "non-toxic" range—severe hepatotoxicity documented with doses as low as 4-5 g/day 1, 2
- Prolonged fasting or malnutrition 1
- Enzyme-inducing drugs 2
NAC Dosing Regimens
Intravenous Protocol (21-hour regimen):
- Loading dose: 150 mg/kg in 5% dextrose over 15 minutes 1, 3
- Second dose: 50 mg/kg over 4 hours 1
- Third dose: 100 mg/kg over 16 hours 1
Oral Protocol (72-hour regimen):
- Loading dose: 140 mg/kg orally or via nasogastric tube 1
- Maintenance: 70 mg/kg every 4 hours for 17 additional doses 1
The oral 72-hour protocol may be superior to the 21-hour IV regimen when treatment is delayed, as modeling studies suggest the 21-hour infusion is often too short 2, 4
Adjunctive Management
- Activated charcoal (1 g/kg) should be given just prior to starting NAC if patient presents within 4 hours of ingestion 1, 2
- Do not delay NAC even if activated charcoal has been given 1
Special Clinical Scenarios Requiring Extended Treatment
Continue NAC beyond standard protocol for:
- Delayed presentation (>24 hours post-ingestion) 2
- Extended-release paracetamol formulations (prolonged absorption requires extended monitoring) 1, 2
- Repeated supratherapeutic ingestions 1, 2
- Unknown time of ingestion with detectable levels 2
- Any elevation in transaminases 2
When to Stop NAC
NAC can be discontinued only when ALL of the following criteria are met:
- Paracetamol level is undetectable 2
- AST and ALT remain completely normal (no elevation above normal) 2
- No coagulopathy 2
- No clinical signs of hepatotoxicity 2
Critical Red Flags—Continue or Restart NAC Immediately:
- Any elevation in AST or ALT above normal 2
- Rising transaminases 2
- Any coagulopathy 2
- Detectable paracetamol level 2
Critical Pitfalls to Avoid
- The Rumack-Matthew nomogram does NOT apply to presentations >24 hours post-ingestion, repeated supratherapeutic ingestions, or extended-release formulations 2
- Low or absent paracetamol levels do NOT rule out poisoning if ingestion was remote or occurred over several days 2
- Never delay NAC while awaiting confirmatory levels if there is strong suspicion of significant overdose 1
- Extended-release formulations may show late increases in serum paracetamol at 14 hours or beyond—obtain serial levels 2
Severe Hepatotoxicity Management
For patients with AST/ALT >1,000 IU/L or coagulopathy:
- Restart or continue NAC immediately 2
- Require ICU-level care 2
- Contact liver transplant center immediately 2
- Continue NAC until transaminases are declining and INR normalizes 2