What is the administration protocol for N-acetylcysteine (NAC) in a patient with acetaminophen (paracetamol) overdose?

N-Acetylcysteine Administration for Acetaminophen Overdose

N-acetylcysteine (NAC) should be administered intravenously using a 3-bag protocol: 150 mg/kg over 15 minutes, then 50 mg/kg over 4 hours, then 100 mg/kg over 16 hours (total 21 hours), and treatment should be initiated immediately without waiting for acetaminophen levels if overdose is suspected. 1, 2, 3

Immediate Initiation Criteria

Start NAC immediately in the following scenarios without waiting for laboratory confirmation:

• Any suspected or confirmed acetaminophen overdose, regardless of serum levels or time since ingestion 1
• Presentation within 24 hours of suspected overdose 1
• Unknown time of ingestion with detectable acetaminophen levels 1, 2
• Established acute liver failure with suspected acetaminophen toxicity 1, 2
• Very high aminotransferases (AST/ALT >3,500 IU/L) even without confirmatory history 1, 4

The critical principle: never delay NAC while awaiting acetaminophen levels if overdose is suspected. 1, 2

Intravenous Dosing Protocol (Preferred Route)

Standard 3-Bag Regimen:

Loading dose: 150 mg/kg in 5% dextrose over 15 minutes 1, 2, 3

Second dose: 50 mg/kg over 4 hours 1, 2, 3

Third dose: 100 mg/kg over 16 hours 1, 2, 3

Total treatment time: 21 hours 1, 3

Critical Preparation Requirements:

• NAC is hyperosmolar (2600 mOsmol/L) and must be diluted in sterile water, 0.45% sodium chloride, or 5% dextrose prior to IV administration 3
• Adjust osmolarity to physiologically safe levels (generally not less than 150 mOsmol/L in pediatric patients) 3
• Visually inspect for particulate matter; color ranges from colorless to slight pink/purple (does not affect quality) 3

Oral Dosing Protocol (Alternative)

Loading dose: 140 mg/kg orally or via nasogastric tube, diluted to 5% solution 1, 4

Maintenance: 70 mg/kg every 4 hours for 17 additional doses (total 72 hours) 1, 2

The oral protocol may be superior to the 21-hour IV protocol when treatment is delayed, as it provides longer NAC exposure. 5, 6 However, the IV route is preferred in clinical practice due to better tolerability and compliance. 6

Timing-Based Treatment Algorithm

Presentation 0-8 Hours Post-Ingestion:

• This is the critical window for maximal hepatoprotection 2, 4
• Only 2.9% develop severe hepatotoxicity when treated within 8 hours 2, 4
• If acetaminophen level available and drawn ≥4 hours post-ingestion: use Rumack-Matthew nomogram 2, 4, 3
• If level plots above "possible toxicity" line: initiate NAC 2, 4
• If time unknown or level drawn <4 hours: start NAC immediately and obtain repeat level 2, 3

Presentation 8-24 Hours Post-Ingestion:

• Start NAC immediately without waiting for levels 1, 2
• Efficacy diminishes but remains beneficial: 6.1% severe hepatotoxicity if treated within 10 hours, 26.4% if treated 10-24 hours 2, 4
• Obtain acetaminophen level to guide continuation of therapy 2, 3

Presentation >24 Hours Post-Ingestion:

• Start NAC immediately—the Rumack-Matthew nomogram does NOT apply 2, 4
• NAC still reduces mortality even with late treatment (from 80% to 52% in fulminant hepatic failure) 1, 2, 4
• Base treatment decisions on acetaminophen levels, liver function tests, and clinical presentation 2, 4

Extended Treatment Beyond 21 Hours

Continue NAC beyond the standard 21-hour protocol in these scenarios:

• Delayed presentation (>24 hours post-ingestion) 2, 4
• Extended-release acetaminophen formulations 1, 2, 4
• Repeated supratherapeutic ingestions 1, 2, 4
• Unknown time of ingestion with detectable acetaminophen levels 1, 4
• Massive overdose (>500 mg/kg or 4-hour equivalent concentrations ~6000 μmol/L) 3, 7
• Any elevation in AST or ALT above normal 4
• Rising transaminases or elevated INR 4, 3
• Detectable acetaminophen level after 21 hours 4, 3
• Chronic alcohol use (lower threshold for hepatotoxicity) 2, 4

Check acetaminophen levels, ALT/AST, and INR after the last maintenance dose to determine if continuation is needed. 3

Special Clinical Scenarios

Repeated Supratherapeutic Ingestion (RSI):

• The Rumack-Matthew nomogram does not apply 3
• Obtain acetaminophen concentration, AST, ALT, bilirubin, INR, creatinine, BUN, glucose, and electrolytes 3
• Treat with NAC if: serum acetaminophen ≥10 mg/mL OR AST/ALT >50 IU/L 4
• Contact poison control (1-800-222-1222) for dosing guidance 3

Acute Liver Failure:

• Administer NAC regardless of time since ingestion 1, 2, 4
• Mortality reduction from 80% to 52% 2, 4
• Cerebral edema reduction from 68% to 40% 4
• Contact liver transplant center immediately 4

Massive Overdose:

• Consider adjuvant therapies: fomepizole and hemodialysis in addition to NAC 7
• May require increased NAC dosing beyond standard protocol 4
• Contact poison control for assistance (1-800-525-6115) 3

Adjunctive Management

Activated charcoal: Give 1 g/kg orally within 4 hours of ingestion, just prior to starting NAC 2, 4

• Most effective within 1-2 hours but may benefit up to 4 hours 4
• Do not delay NAC administration even if activated charcoal given 2

Discontinuation Criteria

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

• Acetaminophen level is undetectable 4
• AST and ALT remain normal (no elevation above normal) 4
• INR is normal 4
• No clinical signs of hepatotoxicity 4

If any red flags develop, continue or restart NAC immediately: rising transaminases, any coagulopathy, detectable acetaminophen level, or clinical hepatotoxicity. 4

Critical Pitfalls to Avoid

• Never delay NAC while awaiting acetaminophen levels if overdose is suspected 1, 2
• Low or absent acetaminophen levels do NOT rule out poisoning if ingestion was remote or occurred over several days 1, 4
• The Rumack-Matthew nomogram is invalid for presentations >24 hours, repeated supratherapeutic ingestions, extended-release formulations, or unknown time of ingestion 2, 4, 3
• Chronic alcohol users require treatment even with levels in the "non-toxic" range (hepatotoxicity can occur with doses as low as 4 g/day) 4
• The 21-hour IV protocol may be too short in many cases—monitor for need to extend treatment 4, 3, 5

Adverse Effects Monitoring

• Hypersensitivity reactions (anaphylactoid): most common with IV route, especially during loading dose 3, 6
• If serious reaction occurs: immediately discontinue infusion, treat reaction, then carefully restart at slower rate 3
• Gastrointestinal effects (nausea, vomiting): more common with oral route 6