What is the recommended dosage of N-acetylcysteine (NAC)?

N-Acetylcysteine Dosing for Acetaminophen Overdose

For acetaminophen overdose, administer N-acetylcysteine (NAC) using either the oral regimen (140 mg/kg loading dose followed by 70 mg/kg every 4 hours for 17 doses over 72 hours) or the intravenous regimen (150 mg/kg over 15 minutes, then 50 mg/kg over 4 hours, then 100 mg/kg over 16 hours), with the choice based on clinical presentation and patient tolerance. 1, 2

Standard Dosing Regimens

Oral NAC Protocol

• Loading dose: 140 mg/kg orally or via nasogastric tube, diluted to 5% solution 1, 2
• Maintenance doses: 70 mg/kg every 4 hours for 17 additional doses (total 72 hours) 1, 3
• This 72-hour oral regimen is as effective as the 20-hour IV regimen and may be superior when treatment is delayed 3

Intravenous NAC Protocol

• Loading dose: 150 mg/kg in 5% dextrose over 15 minutes 1, 2
• Second dose: 50 mg/kg over 4 hours 1, 2
• Third dose: 100 mg/kg over 16 hours (total 21-hour protocol) 1, 2

Timing-Based Treatment Algorithm

Early Presentation (0-8 hours post-ingestion)

• Start NAC immediately if acetaminophen level plots above the treatment line on the Rumack-Matthew nomogram 2
• Treatment within 8 hours results in only 2.9% developing severe hepatotoxicity 4, 5
• No difference in outcome whether NAC is started 0-4 hours versus 4-8 hours after ingestion 3

Intermediate Presentation (8-24 hours post-ingestion)

• Efficacy decreases progressively: 6.1% severe hepatotoxicity when treated within 10 hours, 26.4% when treated 10-24 hours 4, 3
• Among high-risk patients treated 16-24 hours after ingestion, 41% develop hepatotoxicity—still lower than untreated controls (58%) 2, 3
• NAC remains indicated and beneficial throughout this window 3

Late Presentation (>24 hours post-ingestion)

• The Rumack-Matthew nomogram does NOT apply beyond 24 hours 2
• Administer NAC immediately based on acetaminophen levels, liver function tests, and clinical presentation rather than nomogram placement 2
• NAC still provides benefit in reducing hepatotoxicity and mortality even with delayed treatment 2

Special Clinical Scenarios Requiring Modified Dosing

Massive Overdose (Very High Acetaminophen Levels)

• For acetaminophen concentrations above the "300-line" on the nomogram, consider step-wise increases in NAC dosing 6
• Further dose increases may be warranted at the 450-line and 600-line 6
• This represents an emerging area where standard dosing may be insufficient 6

Established Hepatic Failure

• Administer IV NAC regardless of time since ingestion (Level B recommendation) 1, 2
• NAC reduces mortality from 80% to 52%, cerebral edema from 68% to 40%, and need for inotropic support from 80% to 48% 2
• Continue NAC until transaminases are declining and INR normalizes 2

Extended-Release Acetaminophen

• Use standard dosing regimen, but monitoring may need to be extended 1
• Absorption is prolonged, requiring longer observation and potentially extended NAC therapy 1

Repeated Supratherapeutic Ingestions

• Standard 72-hour oral protocol commonly applied 1
• Treat if ≥10 g or 200 mg/kg (whichever is less) during a single 24-hour period 2
• Treat if ≥6 g or 150 mg/kg (whichever is less) per 24-hour period for ≥48 hours 2

High-Risk Populations (Chronic Alcohol Use, Fasting, Liver Disease)

• Treat even if acetaminophen levels are below typical treatment threshold 1, 2
• These patients may develop toxicity at lower doses 1
• Consider lower threshold for extended treatment 2

Duration of Treatment Considerations

Standard Duration

• Complete the full 72-hour oral protocol or 21-hour IV protocol for most patients 1, 3

Criteria for Early Discontinuation (Carefully Selected Cases Only)

• Acetaminophen level is undetectable AND liver function tests remain completely normal 2
• Any elevation in AST or ALT above normal mandates continuing NAC 2
• If criteria are met at 12 hours, a shortened course may be safe in low-risk patients, but this requires careful consideration 2

Mandatory Extended Treatment Beyond Standard Protocol

• Delayed presentation (>24 hours post-ingestion) 2
• Extended-release acetaminophen formulations 2
• Repeated supratherapeutic ingestions 2
• Unknown time of ingestion with detectable acetaminophen levels 2
• Any elevation in AST or ALT above normal 2
• Chronic alcohol use 2

Critical Red Flags Requiring Immediate NAC Restart

• Any elevation in AST or ALT above normal 2
• Rising transaminases 2
• Any coagulopathy 2
• Detectable acetaminophen level 2
• Clinical signs of hepatotoxicity 2

Important Clinical Pitfalls

Do Not Delay NAC for These Reasons:

• Do not wait for confirmatory acetaminophen levels if there is strong suspicion of significant overdose 1
• Do not delay NAC even if activated charcoal has been given 1
• Activated charcoal (1 g/kg) may be given just prior to starting NAC if patient presents within 4 hours, but NAC should not be delayed 1, 2

Common Dosing Errors to Avoid:

• The FDA-labeled 3-step IV regimen is complex and produces frequent medication errors 7
• Loading dose errors are most common, particularly rate-related and dose-related errors 7
• Ensure proper dilution and infusion rates to minimize adverse effects 7

When Low or Absent Acetaminophen Levels Are Misleading:

• Low or absent levels do NOT rule out acetaminophen poisoning if ingestion was remote or occurred over several days 2, 5
• Very high aminotransferases (AST/ALT >3,500 IU/L) are highly correlated with acetaminophen poisoning and should prompt NAC treatment even without clear history 2, 5

Comparison of Oral vs. Intravenous Routes

• The 72-hour oral regimen is as effective as the 20-hour IV regimen 3
• Oral NAC may be superior when treatment is delayed 3
• IV route preferred when: oral route not tolerated, patient cannot protect airway, fulminant hepatic failure present, or rapid treatment initiation needed 1
• Oral route offers increased tolerability and reduced hospital stay in appropriate patients 8