What is the dosing regimen for intravenous (IV) N-acetyl cysteine (NAC) in the treatment of acetaminophen overdose?

Intravenous N-Acetylcysteine Dosing for Acetaminophen Overdose

Administer IV N-acetylcysteine using the standard 21-hour three-bag protocol: 150 mg/kg loading dose over 15 minutes, followed by 50 mg/kg over 4 hours, then 100 mg/kg over 16 hours. 1, 2, 3

Standard IV NAC Dosing Protocol

The FDA-approved regimen delivers a total of 300 mg/kg over 21 hours in three sequential doses 3:

• Loading dose: 150 mg/kg diluted in 200 mL of diluent, infused over 15 minutes 1, 3
• Second dose: 50 mg/kg diluted in 500 mL of diluent, infused over 4 hours 1, 3
• Third dose: 100 mg/kg diluted in 1000 mL of diluent, infused over 16 hours 1, 3

Critical Preparation Requirements

NAC must be diluted before IV administration because the concentrate is hyperosmolar (2600 mOsmol/L). 3 Use sterile water for injection, 0.45% sodium chloride (half-normal saline), or 5% dextrose in water as diluent 3. The diluted solution can be stored for 24 hours at room temperature, but discard any unused portion from previously opened vials 3.

Timing-Based Treatment Decisions

• Start NAC immediately if acetaminophen level plots above the "possible toxicity" line on the Rumack-Matthew nomogram, ideally within 8 hours of ingestion 1, 2
• When initiated within 8 hours, severe hepatotoxicity develops in only 2.9% of at-risk patients 1, 4
• Efficacy decreases with delay: 6.1% hepatotoxicity when started within 10 hours, versus 26.4% when started 10-24 hours post-ingestion 1, 4
• Even when treatment begins 16-24 hours after ingestion, NAC still reduces hepatotoxicity to 41% compared to 58% in untreated historical controls 1

When to Extend Treatment Beyond 21 Hours

Continue NAC beyond the standard protocol if any of the following are present after completing the third dose: 1, 3

• Detectable acetaminophen levels 1, 3
• Rising AST or ALT 1, 3
• Elevated INR 1, 3
• Massive overdose (acetaminophen concentration above the "300-line" on the nomogram) 1, 5
• Concomitant ingestion of other substances 3
• Extended-release acetaminophen formulation 1, 2
• Pre-existing liver disease 3

For massive overdoses, consider step-wise increases in NAC dosing at the 300-, 450-, and 600-lines on the nomogram 1, 5. Contact a regional poison center (1-800-222-1222) or the acetaminophen overdose assistance line (1-800-525-6115) for guidance on extended dosing 3.

Special Clinical Scenarios Requiring Immediate NAC

Administer NAC regardless of time since ingestion in these situations: 1, 2

• Established hepatic failure from acetaminophen (reduces mortality from 80% to 52%) 1
• Acute liver failure where acetaminophen overdose is suspected, even without confirmatory history 1, 2
• Very high aminotransferases (AST/ALT >3,500 IU/L), which strongly correlate with acetaminophen poisoning 1
• Unknown time of ingestion with detectable acetaminophen levels 1, 2
• Repeated supratherapeutic ingestions (>4g per 24 hours) with acetaminophen ≥10 mg/mL or AST/ALT >50 IU/L 1

Managing Hypersensitivity Reactions

Acute hypersensitivity reactions occur in approximately 14% of patients, most commonly during the loading dose. 3 These typically manifest as transient skin flushing, erythema, or mild urticaria 30-60 minutes after starting the infusion 3:

• Mild reactions (flushing/erythema only): Often resolve spontaneously despite continued infusion 3
• More severe reactions (rash, hypotension, wheezing, shortness of breath): Temporarily interrupt the infusion and administer antihistamines 3
• Severe hypersensitivity: Immediately stop NAC and initiate appropriate treatment 3
• Use extreme caution in patients with asthma (one fatal bronchospasm case reported); monitor closely throughout therapy 3

Comparison: IV vs. Oral NAC

The 72-hour oral regimen (140 mg/kg loading dose, then 70 mg/kg every 4 hours for 17 doses) is equally effective as the 20-hour IV regimen and may be superior when treatment is delayed 1, 4. However, IV administration is preferred when 6, 4:

• Patient cannot tolerate oral medication due to vomiting
• Altered mental status or airway protection concerns
• Fulminant hepatic failure is present
• Rapid administration is critical

Critical Pitfalls to Avoid

• Never delay NAC while awaiting confirmatory acetaminophen levels if overdose is strongly suspected 2
• The Rumack-Matthew nomogram does NOT apply to presentations >24 hours post-ingestion or repeated supratherapeutic ingestions 1
• Low or undetectable acetaminophen levels do NOT rule out poisoning if ingestion was remote or occurred over several days 1
• Do not stop NAC at 21 hours if any red flags are present (detectable acetaminophen, rising transaminases, elevated INR, or clinical hepatotoxicity) 1, 3
• Activated charcoal (1 g/kg) can be given just prior to starting NAC if patient presents within 4 hours, but never delay NAC administration 1, 2