What is the recommended N-acetylcysteine (NAC) infusion protocol for acetaminophen overdose?

NAC Infusion Protocol for Acetaminophen Overdose

The standard intravenous NAC protocol consists of a 150 mg/kg loading dose over 15 minutes, followed by 50 mg/kg over 4 hours, then 100 mg/kg over 16 hours (total 21-hour protocol), though the oral regimen (140 mg/kg loading dose, then 70 mg/kg every 4 hours for 17 doses over 72 hours) may be superior when treatment is delayed. 1, 2, 3

Intravenous Protocol (Standard 21-Hour Regimen)

Loading Dose:

• 150 mg/kg in 5% dextrose over 15 minutes 1, 2, 3
• Must be diluted in sterile water for injection, 0.45% sodium chloride, or 5% dextrose prior to administration because NAC is hyperosmolar (2600 mOsmol/L) 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 duration: 21 hours 1, 3

Oral Protocol (72-Hour Regimen)

Loading Dose:

• 140 mg/kg by mouth or nasogastric tube, diluted to 5% solution 1, 2

Maintenance Doses:

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

Critical Timing Considerations

Initiate NAC immediately when:

• Acetaminophen level plots above the "possible toxicity" line on the Rumack-Matthew nomogram 1, 2, 3
• Time of ingestion is unknown with detectable acetaminophen levels 1, 2
• Hepatotoxicity is already present (elevated AST/ALT) 1, 2
• Acute liver failure is suspected from acetaminophen, regardless of time since ingestion 1, 2

The efficacy of NAC is time-dependent:

• Within 8 hours: 2.9% risk of severe hepatotoxicity 1
• Within 10 hours: 6.1% risk of severe hepatotoxicity 1
• After 10 hours: 26.4% risk of severe hepatotoxicity 1
• Between 16-24 hours: 41% risk in high-risk patients 1

When to Extend Treatment Beyond Standard Protocol

Continue NAC beyond 21 hours (IV) or 72 hours (oral) when: 1, 3

• Acetaminophen levels remain detectable 1, 3
• AST/ALT continue rising 1, 3
• INR remains elevated 1, 3
• Delayed presentation (>24 hours post-ingestion) 1, 2
• Extended-release acetaminophen formulation 1, 2
• Repeated supratherapeutic ingestions 1, 3
• Massive overdose or concomitant ingestion of other substances 3
• Pre-existing liver disease 3

When NAC Can Be Discontinued Early

NAC may be stopped when ALL of the following criteria are met: 1

• Acetaminophen level is undetectable 1
• AST and ALT are normal or declining 1
• INR is normal 1
• No clinical signs of hepatotoxicity 1

Important caveat: Some evidence suggests the 21-hour IV protocol is often too short, while the full 72-hour oral course may be unnecessary in low-risk patients 4, 5, 6. The oral protocol or an IV protocol with identical dosing may be superior to the standard 21-hour IV regimen 4.

Adjunctive Measures

Activated charcoal:

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

Special Populations Requiring Modified Approach

High-risk patients (chronic alcoholics, fasting patients, enzyme-inducing drugs):

• Treat with NAC even if acetaminophen levels are below typical treatment threshold 1, 2
• Severe hepatotoxicity can occur with doses as low as 4-5 g/day in alcoholics 1

Repeated supratherapeutic ingestions:

• Treat if serum acetaminophen ≥10 mg/mL OR if AST or ALT >50 IU/L 1
• Contact poison control center (1-800-222-1222) for dosing guidance 3

Critical Pitfalls to Avoid

• Never delay NAC while awaiting confirmatory acetaminophen levels if there is strong suspicion of significant overdose 2
• The Rumack-Matthew nomogram does NOT apply to patients presenting >24 hours after ingestion, repeated supratherapeutic ingestions, or extended-release formulations 1
• Low or absent acetaminophen levels do NOT rule out acetaminophen poisoning if ingestion was remote or occurred over several days 1
• Do not stop NAC prematurely in patients with any elevation in AST/ALT, rising transaminases, coagulopathy, or detectable acetaminophen 1

Monitoring During Treatment

Check the following throughout NAC therapy: 3

• Hepatic function tests (AST, ALT, alkaline phosphatase, bilirubin) 3
• Renal function (creatinine, BUN) 3
• Coagulation parameters (INR, PT) 3
• Electrolytes and fluid balance 3

After completion of standard protocol:

• Recheck acetaminophen level, ALT/AST, and INR 3
• If any remain abnormal, continue NAC and contact poison control center for guidance 3

Established Hepatic Failure

For patients with acetaminophen-induced acute liver failure:

• Administer NAC regardless of time since ingestion (Level B recommendation) 1, 2
• NAC reduces mortality from 80% to 52% 1
• NAC reduces cerebral edema from 68% to 40% 1
• Requires ICU-level care and early transplant hepatology consultation 1