When should N-acetylcysteine (NAC) be started for acetaminophen overdose?

When to Start NAC for Acetaminophen Overdose

Start N-acetylcysteine (NAC) immediately for any patient with suspected or confirmed acetaminophen overdose when the serum level plots above the "possible toxicity" line on the Rumack-Matthew nomogram, or when the time of ingestion is unknown, or when hepatotoxicity is already present—ideally within 8 hours of ingestion to maximize efficacy. 1, 2

Timing-Based Treatment Algorithm

Presentation Within 8 Hours of Known Ingestion Time

• If acetaminophen level is available and plots above the "possible toxicity" line (the lower dotted line on the Rumack-Matthew nomogram at 4-24 hours post-ingestion): Start NAC immediately 1, 3
• If acetaminophen level plots below the "possible toxicity" line and sample was drawn ≥4 hours post-ingestion: Do not administer NAC, as hepatotoxicity risk is minimal 3
• If level is unavailable or sample drawn <4 hours post-ingestion: Start NAC loading dose immediately and obtain level to guide continued treatment 3
• Give activated charcoal (1 g/kg) just prior to starting NAC if patient presents within 4 hours of ingestion 1

The critical window is 0-8 hours post-ingestion, where NAC provides maximal hepatoprotection with only 2.9% developing severe hepatotoxicity when treated within 8 hours 1, 2. There is no difference in outcome whether NAC is started 0-4 hours versus 4-8 hours after ingestion, but efficacy decreases substantially after 8 hours. 4

Presentation 8-24 Hours After Known Ingestion

• Start NAC loading dose immediately upon presentation, before waiting for laboratory results 3, 2
• Obtain acetaminophen level to confirm need for continued treatment 3
• Efficacy diminishes progressively after 8 hours: severe hepatotoxicity develops in 26.4% when treatment begins 10-24 hours post-ingestion, compared to 6.1% when started within 10 hours 1, 4
• Among high-risk patients treated 16-24 hours after ingestion, hepatotoxicity still develops in 41%—but this remains lower than untreated historical controls (58%) 1, 2

Presentation >24 Hours or Unknown Time of Ingestion

• Start NAC immediately without waiting for confirmatory testing 2, 3
• The Rumack-Matthew nomogram does NOT apply to patients presenting >24 hours after ingestion 2
• Base treatment decisions on: detectable acetaminophen levels, elevated aminotransferases (AST/ALT), or clinical evidence of hepatotoxicity 1
• NAC should still be administered even 48 hours or more after ingestion, as it may still provide benefit and does not worsen the patient's condition 1

Special Clinical Scenarios Requiring Immediate NAC

Established Hepatotoxicity or 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) 1, 2
• Start NAC in any case of acute liver failure where acetaminophen overdose is suspected or possible, even with inadequate history 1
• 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 1

Repeated Supratherapeutic Ingestions

• Administer NAC if serum acetaminophen concentration is ≥10 mg/mL OR if aminotransferases are elevated (AST or ALT >50 IU/L) 2
• The nomogram cannot be used for repeated doses over time 1
• These patients require individualized assessment based on acetaminophen levels and liver function tests 1, 2

Extended-Release Acetaminophen

• If initial level at 4 hours post-ingestion is below the possible toxicity line, obtain a second sample 8-10 hours after ingestion 3
• If the second value is at or above the "possible toxicity" line, start NAC immediately 3

High-Risk Populations

• Chronic alcoholics, malnourished patients, or those on CYP2E1-inducing drugs (e.g., isoniazid) should be treated even if acetaminophen levels are in the "non-toxic" range, as the nomogram may underestimate hepatotoxicity risk 3, 2
• Severe liver injury can occur with doses as low as 3-4 g/day in susceptible patients 1

NAC Dosing Regimens

Intravenous Protocol (FDA-approved)

• Loading dose: 150 mg/kg in 5% dextrose over 15 minutes 1, 3
• Second dose: 50 mg/kg over 4 hours 1, 3
• Third dose: 100 mg/kg over 16 hours (total 21-hour protocol) 1, 3

Oral Protocol

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

The oral protocol may be superior to the 21-hour IV protocol in preserving hepatocytes, particularly when treatment is delayed 5, 4. However, IV administration is necessary when oral route is precluded by gastrointestinal bleeding, worsening mental status, or intractable vomiting 1.

Critical Pitfalls and Caveats

• Never delay NAC while waiting for acetaminophen levels if the patient presents >8 hours post-ingestion or has unknown timing 2, 3
• Low or absent acetaminophen levels do NOT rule out acetaminophen poisoning if ingestion was remote or occurred over several days 1
• Patients may present with elevated transaminases despite being stratified as "no risk" on the nomogram due to inaccurate history or increased susceptibility—consider alternative causes but treat if acetaminophen remains suspected 1, 2
• The 21-hour IV NAC infusion is often too short for optimal hepatoprotection, while the full 72-hour oral course may be unnecessary in some cases 5
• No deaths occurred among patients treated with NAC within 16 hours of ingestion in the largest prospective study 4