What is the dosing regimen for N-acetylcysteine (NAC) in cases of paracetamol intoxication?

N-Acetylcysteine Dosing for Paracetamol Intoxication

The standard intravenous NAC regimen consists of a loading dose of 150 mg/kg over 15 minutes, followed by 50 mg/kg over 4 hours, then 100 mg/kg over 16 hours (total 21-hour protocol), which should be initiated immediately when acetaminophen toxicity is suspected or confirmed. 1, 2

Standard IV Dosing Protocol

The FDA-approved three-phase intravenous regimen is:

• Loading dose: 150 mg/kg in 5% dextrose infused over 15 minutes 1, 2
• Second dose: 50 mg/kg over 4 hours 1, 2
• Third dose: 100 mg/kg over 16 hours 1, 2
• Total duration: 21 hours 1, 2

Alternative Oral Dosing Protocol

For oral administration when IV access is unavailable or impractical:

• Loading dose: 140 mg/kg by mouth or nasogastric tube, diluted to 5% solution 1, 2
• Maintenance dose: 70 mg/kg every 4 hours for 17 additional doses (total 72 hours) 1, 2

Timing-Based Treatment Algorithm

The critical window is 0-8 hours post-ingestion, where NAC provides maximal hepatoprotection with only 2.9% developing severe hepatotoxicity. 3, 1

Early Presentation (<8 hours)

• If acetaminophen level plots above the "possible toxicity" line on the Rumack-Matthew nomogram: initiate NAC immediately 1, 2
• If level is unavailable within 8 hours: start NAC immediately without waiting for results 1, 2
• Efficacy is highest when treatment begins within 8 hours, with severe hepatotoxicity developing in only 2.9% of patients 3, 1

Intermediate Presentation (8-24 hours)

• Start NAC immediately upon presentation 1, 2
• Efficacy diminishes progressively: severe hepatotoxicity develops in 6.1% when started within 10 hours, but rises to 26.4% when started after 10 hours 3, 1
• Among high-risk patients treated 16-24 hours post-ingestion, hepatotoxicity still develops in 41%—but this remains lower than untreated controls (58%) 1

Late Presentation (>24 hours)

• Administer NAC immediately regardless of time since ingestion if hepatotoxicity is suspected or confirmed 1, 2
• The Rumack-Matthew nomogram does NOT apply beyond 24 hours; base treatment decisions on acetaminophen levels, liver function tests, and clinical presentation 1
• NAC remains beneficial even with delayed treatment, though efficacy is significantly diminished 1

Modified Dosing Regimens (Alternative Protocols)

SNAP 12-Hour Regimen

A validated alternative showing similar efficacy with fewer adverse reactions:

• 100 mg/kg over 2 hours, then 200 mg/kg over 10 hours 4
• Hepatotoxicity rates were comparable (3.6% vs 4.3% with standard regimen) 4
• Significantly fewer anaphylactoid reactions (2.0% vs 11.0%) 4

Patient-Tailored Protocol

NAC can be discontinued when both criteria are met:

• Acetaminophen level <10 mg/L AND
• AST <40 IU/L 5, 6

This approach may shorten treatment duration without increasing hepatotoxicity risk, with no hepatotoxicity observed in patients treated <24 hours who met discontinuation criteria. 5, 6

Special Clinical Scenarios Requiring Immediate NAC

Established Hepatic Failure

• Administer NAC to all patients with fulminant hepatic failure from acetaminophen, regardless of time since ingestion (Level B recommendation) 1
• NAC reduces mortality from 80% to 52%, cerebral edema from 68% to 40%, and need for inotropic support from 80% to 48% 1
• Early NAC treatment (<10 hours) in fulminant hepatic failure results in 100% survival 1

Unknown Time of Ingestion

• Start NAC loading dose immediately 1, 2
• Obtain acetaminophen concentration to guide continued treatment 1, 2

Detectable Acetaminophen with Elevated Transaminases

• Initiate NAC immediately even if nomogram suggests "no risk" 1
• Very high aminotransferases (AST/ALT >3,500 IU/L) are highly correlated with acetaminophen poisoning and warrant NAC even with inadequate history 1

Repeated Supratherapeutic Ingestions

• Consider NAC if serum acetaminophen ≥10 mg/mL OR if AST or ALT >50 IU/L 1
• Nomogram does not apply; treat based on laboratory values 1

Extended-Release Acetaminophen

• Obtain second acetaminophen level 8-10 hours post-ingestion if initial 4-hour level is below treatment line 2
• If second value is at or above "possible" toxicity line, initiate NAC 2

High-Risk Populations Requiring Lower Treatment Threshold

Patients with chronic alcohol consumption, malnutrition, or CYP2E1 enzyme-inducing drugs (e.g., isoniazid) should be treated even with acetaminophen levels in the "non-toxic" range, as severe hepatotoxicity has been documented with doses as low as 4-5 g/day. 1, 2

Large Overdoses (>30g or >500 mg/kg)

Standard 300 mg/kg NAC regimen is effective in most patients with large overdoses; higher doses are NOT routinely required. 7

• For massive overdoses (≥40g) with levels >300 mg/L, consider modified regimen providing 400-500 mg/kg NAC over 21-22 hours 7
• However, impact on hepatic failure, transplantation, and mortality with higher doses remains unknown 7

Adjunctive Treatment

Administer activated charcoal (1 g/kg) just prior to starting NAC if patient presents within 4 hours of ingestion. 1

Duration of Treatment and Discontinuation Criteria

Standard Approach

Complete the full 21-hour IV protocol or 72-hour oral protocol 1, 2

Early Discontinuation (Carefully Selected Patients)

NAC can be stopped when ALL of the following are met:

• Acetaminophen level is undetectable 1
• AST and ALT remain normal 1
• No coagulopathy present 1
• Patient presented early (<8 hours) 1

If criteria are met at 12 hours, a 12-hour NAC course may be safe in carefully selected low-risk patients, but this requires careful consideration of risk factors. 1

Mandatory Extended Treatment

Continue NAC beyond standard protocol if:

• Delayed presentation (>24 hours post-ingestion) 1
• Extended-release acetaminophen 1
• Repeated supratherapeutic ingestions 1
• Unknown time of ingestion 1
• Any elevation in AST or ALT above normal 1
• Rising transaminases 1
• Any coagulopathy 1
• Detectable acetaminophen level 1

Hepatotoxicity Develops During Treatment

If AST/ALT >1000 IU/L develops, restart NAC immediately and continue until transaminases are declining and INR normalizes. 1

Critical Pitfalls and Caveats

• Never delay NAC while awaiting acetaminophen levels if presentation is >8 hours or if hepatotoxicity is suspected 1, 2
• Low or absent acetaminophen levels do NOT rule out acetaminophen poisoning if ingestion was remote or occurred over several days 1
• The nomogram may underestimate hepatotoxicity risk in chronic alcoholics, malnourished patients, or those on CYP2E1 inducers 2
• Patients may present with elevated transaminases despite "no risk" stratification due to inaccurate history or increased susceptibility 1
• Mortality risk correlates with treatment delay; both deaths in the Prescott study occurred with treatment delays of 17.8 and 24 hours 3

Monitoring During Treatment

Obtain and monitor:

• AST, ALT, bilirubin 1, 2
• INR, PT 1, 2
• Creatinine, BUN 2
• Blood glucose 2
• Electrolytes 2

Adverse Reactions Management

• Monitor for anaphylactoid reactions (nausea, vomiting, rash, bronchospasm) 1
• If allergic reaction occurs: discontinue infusion temporarily, administer antihistamines, then restart at slower rate 1
• SNAP regimen has significantly lower adverse reaction rate (2.0% vs 11.0%) 4