What is the recommended dosing regimen for N-acetylcysteine (NAC) in acetaminophen overdose?

N-Acetylcysteine Dosing for Acetaminophen Overdose

For acute acetaminophen overdose, administer NAC using either the FDA-approved 21-hour intravenous protocol (150 mg/kg over 15 minutes, then 50 mg/kg over 4 hours, then 100 mg/kg over 16 hours) or the 72-hour oral protocol (140 mg/kg loading dose, then 70 mg/kg every 4 hours for 17 doses), with the oral regimen providing superior hepatoprotection when feasible. 1, 2

Intravenous Dosing Protocol (FDA-Approved 21-Hour Regimen)

The standard IV protocol delivers a total of 300 mg/kg over 21 hours in three sequential phases 1:

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

Critical preparation requirement: NAC must be diluted in sterile water for injection, 0.45% sodium chloride, or 5% dextrose prior to IV administration because the undiluted solution is hyperosmolar (2600 mOsmol/L) 1.

Oral Dosing Protocol (72-Hour Regimen)

The oral protocol is preferred when the patient can tolerate oral/nasogastric administration 2:

• Loading dose: 140 mg/kg by mouth or nasogastric tube, diluted to 5% solution 2, 3
• Maintenance doses: 70 mg/kg every 4 hours for 17 additional doses (total 72 hours) 2, 3

Important consideration: Modeling studies suggest the oral protocol preserves more hepatocytes than the 21-hour IV protocol, making it the superior choice when gastrointestinal administration is feasible 4. However, oral administration may be precluded by active GI bleeding, worsening mental status, or severe nausea 2.

When to Initiate NAC Treatment

Timing-Based Algorithm

Start NAC immediately without waiting for confirmatory levels if: 3, 5

• Acetaminophen level plots above the "possible toxicity" line on the Rumack-Matthew nomogram (drawn 4-24 hours post-ingestion) 2, 5
• Time of ingestion is unknown 3, 5
• Hepatotoxicity is already present (elevated transaminases) 2
• Presentation is >24 hours post-ingestion (nomogram does not apply) 2, 3
• Acute liver failure with suspected acetaminophen involvement, even without confirmatory history 2, 3

Critical window: NAC provides maximal benefit when started within 8 hours of ingestion (2.9% severe hepatotoxicity rate), with efficacy declining progressively thereafter: 6.1% when started within 10 hours, 26.4% when started 10-24 hours, and 41% when started 16-24 hours post-ingestion 2, 5.

High-Risk Populations Requiring Lower Treatment Threshold

Administer NAC even with levels in the "non-toxic" range for 2, 3:

• Chronic alcohol consumers (documented severe hepatotoxicity with doses as low as 4-5 g/day) 5
• Fasting patients 2, 3
• Patients on enzyme-inducing medications 2

Extended Treatment Beyond Standard Protocols

When to Continue NAC Beyond 21 Hours (IV) or 72 Hours (Oral)

Continue NAC infusion if, after completing the standard protocol: 1

• Acetaminophen levels remain detectable 1
• ALT/AST continue rising 1
• INR remains elevated 1

Special scenarios requiring extended treatment: 1

• Suspected massive overdose 1
• Concomitant ingestion of other substances 1
• Preexisting liver disease 1

Action required: Contact regional poison center (1-800-222-1222) or the special health professional assistance line (1-800-525-6115) for dosing guidance when extending treatment 1.

Special Clinical Scenarios

Repeated Supratherapeutic Ingestions (RSI)

The Rumack-Matthew nomogram does NOT apply to RSI 1. Instead, base treatment decisions on 1:

• Serum acetaminophen concentration 1
• Hepatic function tests (AST, ALT, bilirubin, INR) 1
• Renal function (creatinine, BUN) 1

Treatment threshold: Consider NAC if serum acetaminophen ≥10 mg/mL or if AST/ALT >50 IU/L 5.

Acute Liver Failure

Administer NAC to all patients with hepatic failure thought to be due to acetaminophen, regardless of time since ingestion (Level B recommendation) 2, 5. NAC reduces mortality from 80% to 52%, cerebral edema from 68% to 40%, and need for inotropic support from 80% to 48% in fulminant hepatic failure 5.

Presentation >24 Hours Post-Ingestion

NAC should still be administered when patients present beyond 24 hours, as it provides benefit in reducing hepatotoxicity and mortality even with delayed treatment 3, 5. The nomogram cannot be used for risk stratification in these cases; base treatment on acetaminophen levels, liver function tests, and clinical presentation 3, 5.

Adjunctive Therapy

Activated charcoal: Give 1 g/kg orally just prior to starting NAC if the patient presents within 4 hours of ingestion 2, 3, 5. Do not delay NAC administration even if activated charcoal has been given 3.

Alternative Dosing Regimens (Research Evidence)

While not FDA-approved, research supports alternative protocols that may be considered in specific circumstances:

• 48-hour IV protocol: 140 mg/kg loading dose followed by 70 mg/kg every 4 hours for 12 doses showed an 18.1% overall hepatotoxicity rate and only 3.4% when treated within 10 hours 6
• Shortened oral protocol: Discontinuing NAC when acetaminophen is undetectable and transaminases remain normal (typically 24-36 hours) showed similar outcomes to the full 72-hour course 7
• 12-hour protocol for low-risk patients: 250 mg/kg over 12 hours for patients with normal ALT, creatinine, and acetaminophen <20 mg/L at 12 hours showed no hepatic injury in a controlled trial 8

However, the FDA-approved protocols remain the standard of care 1.

Monitoring During Treatment

Check the following throughout NAC therapy 2, 1:

• Hepatic function: AST, ALT, alkaline phosphatase, total bilirubin 2, 1
• Renal function: creatinine, BUN 2, 1
• Coagulation: INR, PT 2, 1
• Electrolytes: sodium, potassium, chloride, bicarbonate, calcium, magnesium, phosphate 2
• Glucose 2, 1

Critical Pitfalls to Avoid

• Do not delay NAC while awaiting confirmatory acetaminophen levels if there is strong suspicion of significant overdose 3, 5
• Low or absent acetaminophen levels do NOT rule out acetaminophen poisoning if ingestion was remote or occurred over several days 5
• The 21-hour IV protocol is often too short for massive overdoses or patients with preexisting liver disease—be prepared to extend treatment 1, 4
• Very high aminotransferases (AST/ALT >3,500 IU/L) are highly correlated with acetaminophen poisoning and should prompt NAC treatment even when history is lacking 5
• Use caution in asthmatic patients—one patient with asthma died from bronchospasm after IV NAC; monitor closely and be prepared to treat hypersensitivity reactions 1