At what serum paracetamol (acetaminophen) concentration and time after ingestion should N‑acetylcysteine be initiated?

Paracetamol Level and NAC Initiation Threshold

N-acetylcysteine (NAC) should be initiated when the serum paracetamol concentration, drawn between 4 and 24 hours post-ingestion, plots at or above the "possible toxicity" treatment line on the Rumack-Matthew nomogram (150 mg/L at 4 hours or 50 mg/L at 12 hours). 1

Critical Timing for Serum Level Measurement

• Draw the serum paracetamol level at 4 hours post-ingestion or as soon as possible thereafter if the patient presents within the 4-24 hour window 1, 2
• Levels drawn before 4 hours are unreliable and must be repeated at 4 hours, as early concentrations cannot accurately predict hepatotoxicity risk 1, 3
• The nomogram is only valid for levels drawn between 4 and 24 hours after a single acute ingestion 1

Common Pitfall: Pre-4-Hour Levels

Obtaining paracetamol concentrations before 4 hours occurs in 62% of early presentations but leads to inappropriate treatment decisions—patients are more likely to receive unnecessary NAC (29% vs 17%) and less likely to have properly timed levels obtained (59% vs 93% get a 4-hour level) 3. Never use pre-4-hour levels to guide NAC decisions.

The Rumack-Matthew Nomogram Treatment Thresholds

• "Possible toxicity" treatment line: 150 mg/L (993 μmol/L) at 4 hours, declining to 50 mg/L at 12 hours 1, 4
• High-risk threshold: Concentrations above 300 mg/L (1,985 μmol/L) at 4 hours indicate very high risk despite early treatment 5
• Any level plotting at or above the treatment line mandates immediate NAC administration 1, 6

When to Start NAC Without Waiting for Levels

Start NAC immediately in these scenarios, without waiting for laboratory confirmation: 1

• Unknown time of ingestion with any detectable paracetamol level 1
• Delayed presentation >24 hours with suspected overdose (nomogram does not apply) 1
• Any evidence of hepatotoxicity (AST/ALT >50 IU/L) with suspected paracetamol ingestion 1, 4
• Established acute liver failure with suspected paracetamol etiology (AST/ALT >1,000 IU/L, elevated INR) 1, 6
• Stated ingestion ≥10 g or 200 mg/kg (whichever is lower) in adults, even before levels return 1, 2

Special Scenarios Requiring Modified Thresholds

Repeated Supratherapeutic Ingestion (RSTI)

The nomogram does not apply to repeated ingestions. Treat with NAC if: 1, 2

• ≥10 g or 200 mg/kg (whichever is less) in any 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 at any time, OR
• AST or ALT >50 IU/L with any detectable paracetamol

High-Risk Populations Requiring Lower Treatment Threshold

Treat with NAC even if levels fall below the standard treatment line in: 1, 4

• Chronic alcohol users (severe hepatotoxicity documented with doses as low as 4-5 g/day) 1, 4
• Malnourished or fasting patients (depleted glutathione stores) 4
• Patients on enzyme-inducing drugs (anticonvulsants, rifampin) 6
• Pre-existing liver disease (lower toxicity threshold) 4

For these patients, consider NAC if ingestion exceeds >4 g or 100 mg/kg per day 1, 2

Extended-Release Formulations

• Obtain serial paracetamol levels at 4 hours and again 4-6 hours later (14 hours post-ingestion) 1, 4
• Late increases in concentration can occur beyond 14 hours 4, 7
• Start NAC if any level plots above the treatment line 1

Critical Time Windows and Hepatotoxicity Risk

The efficacy of NAC is time-dependent: 1

• 0-8 hours: Only 2.9% develop severe hepatotoxicity when treated 1
• 8-10 hours: 6.1% develop severe hepatotoxicity 1
• 10-24 hours: 26.4% develop severe hepatotoxicity 1
• >24 hours: Still beneficial (reduces mortality from 80% to 52% in fulminant hepatic failure) but significantly less effective 1, 6

All 11 deaths in the landmark Smilkstein cohort occurred in patients who received NAC more than 10 hours after ingestion 1, emphasizing the critical importance of the 8-10 hour window.

Algorithm for NAC Initiation

1. Establish time of ingestion (if possible) 1, 2
2. If <4 hours post-ingestion:
   • Do NOT draw paracetamol level yet 1, 3
   • Consider activated charcoal if <2 hours post-ingestion 2
   • Draw level at exactly 4 hours 1
3. If 4-24 hours post-ingestion:
   • Draw stat paracetamol level immediately 1
   • Plot on Rumack-Matthew nomogram 1
   • Start NAC if at or above treatment line 1
4. If >24 hours post-ingestion:
   • Nomogram does NOT apply 1
   • Draw paracetamol level AND liver function tests (AST, ALT, INR) 1
   • Start NAC immediately if: detectable paracetamol OR elevated transaminases OR suspected significant ingestion 1
5. If unknown time:
   • Draw paracetamol level and LFTs immediately 1
   • Start NAC if any detectable paracetamol level 1

Key Caveats

• Low or absent paracetamol levels do NOT rule out toxicity if ingestion was remote, occurred over several days, or timing is uncertain 1, 4
• Patients may develop hepatotoxicity despite being stratified as "no risk" on the nomogram due to inaccurate history or increased susceptibility 1
• Very high aminotransferases (AST/ALT >3,500 IU/L) are highly correlated with paracetamol poisoning and should prompt NAC treatment even without clear overdose history 1, 4
• For combination products containing other medications, absorption kinetics may be altered—consider serial levels 7