What is the dosage and usage of N-acetylcysteine (NAC) in clinical scenarios?

N-Acetylcysteine (NAC) Dosage and Clinical Usage

Primary Indication: Acetaminophen Overdose

Administer NAC immediately when acetaminophen overdose is known or suspected, ideally within 8-10 hours of ingestion, but treatment remains beneficial and should never be withheld even up to 24 hours or beyond. 1, 2

Standard Dosing Protocols

Intravenous Regimen (21-hour protocol):

• Loading dose: 150 mg/kg in 5% dextrose over 15 minutes 2, 3
• Second dose: 50 mg/kg over 4 hours 2, 3
• Third dose: 100 mg/kg over 16 hours 2, 3

Oral Regimen (72-hour protocol):

• Loading dose: 140 mg/kg by mouth or nasogastric tube 1, 2
• Maintenance: 70 mg/kg every 4 hours for 17 additional doses 1, 2
• The 72-hour oral regimen is as effective as the 20-hour IV regimen and may be superior when treatment is delayed 4

Treatment Decision Algorithm

Initiate NAC immediately if ANY of the following:

• Acetaminophen levels plot in possible or probable risk zones on Rumack-Matthew nomogram (drawn 4-24 hours post-ingestion) 1, 2
• Unknown time of ingestion with detectable acetaminophen levels 2, 3
• Presentation >24 hours after ingestion with elevated transaminases 2, 3
• Suspected acute liver failure where acetaminophen ingestion is possible, even without confirmatory history 2, 3
• Very high aminotransferases (AST/ALT >3,500 IU/L) which are highly correlated with acetaminophen poisoning 3

Timing and Efficacy

Critical time windows for treatment efficacy:

• 0-8 hours: Only 2.9% develop severe hepatotoxicity 3, 4
• 8-10 hours: 6.1% develop severe hepatotoxicity 1, 4
• 10-24 hours: 26.4% develop severe hepatotoxicity 3, 4
• 16-24 hours (high-risk patients): 41% develop hepatotoxicity (still lower than 58% in untreated controls) 3, 4

Do not delay NAC while awaiting confirmatory acetaminophen levels if there is strong suspicion of significant overdose. 2

High-Risk Populations Requiring Lower Treatment Threshold

Treat with NAC even at lower acetaminophen levels or in "non-toxic" range for:

• Chronic alcoholics (severe hepatotoxicity documented with doses as low as 4-5 g/day) 3
• Fasting or malnourished patients 1
• Patients taking enzyme-inducing drugs 3
• Cirrhotic patients, particularly those malnourished or actively drinking 1

Special Clinical Scenarios

Extended-Release Acetaminophen

• Standard dosing regimen applies, but monitoring and treatment may need extension due to prolonged absorption 2, 3

Repeated Supratherapeutic Ingestions

• Treat with NAC if ≥10 g or 200 mg/kg (whichever is less) during a single 24-hour period 3
• Or ≥6 g or 150 mg/kg (whichever is less) per 24-hour period for ≥48 hours 3
• Treat if serum acetaminophen ≥10 mg/mL or AST/ALT >50 IU/L 3

Established Hepatic Failure

• Administer IV NAC regardless of time since ingestion 2, 3
• Reduces mortality from 80% to 52% 3
• Reduces cerebral edema from 68% to 40% 3
• Reduces need for inotropic support from 80% to 48% 3

Secondary Indication: Acute Liver Failure

Acetaminophen-Associated Acute Liver Failure

NAC is strongly recommended for all patients with acetaminophen-associated acute liver failure, with demonstrated mortality reduction (relative risk 0.65,95% CI 0.43-0.99). 1

Non-Acetaminophen Acute Liver Failure

• Consider NAC administration, especially when cause is indeterminate 1
• Improves transplant-free survival (41% vs 30%, OR 1.61, P=0.01) 1
• Improves overall survival (76% vs 59%, OR 2.30, P<0.0001) 1

Discontinuation Criteria

NAC can be discontinued when ALL of the following are met:

• Acetaminophen level is undetectable 3
• AST and ALT remain normal (no elevation above normal) 3
• No coagulopathy present 3
• Patient is clinically well 3

Continue or restart NAC immediately if:

• Any elevation in AST or ALT above normal 3
• Rising transaminases 3
• Any coagulopathy develops 3
• Detectable acetaminophen level persists 3
• Clinical signs of hepatotoxicity 3

Mandatory full 72-hour protocol or longer required for:

• Delayed presentation (>24 hours post-ingestion) 3
• Extended-release acetaminophen formulations 3
• Repeated supratherapeutic ingestions 3
• Unknown time of ingestion with detectable levels 3
• Chronic alcohol use 3

Adjunctive Therapy

Activated charcoal (1 g/kg orally) should be given just prior to starting NAC if patient presents within 4 hours of ingestion. 2, 3

• Most effective within 1-2 hours but may have benefit up to 4 hours 3
• Do not delay NAC administration even if activated charcoal has been given 2
• Charcoal may adsorb up to 96% of oral NAC, but this should not prevent NAC administration 5

Adverse Effects

Overall incidence of adverse effects is low:

• Nausea/vomiting: <5% 1
• Skin rash: <5% 1
• Bronchospasm: 1-2% 1
• Anaphylactoid reactions (with IV administration): up to 10% of patients, occurring 15-60 minutes into infusion 6
• Reactions include angioedema, bronchospasm, flushing, hypotension, tachycardia 6

Critical Pitfalls to Avoid

• Do not rely solely on the Rumack-Matthew nomogram for patients presenting >24 hours after ingestion - base decisions on acetaminophen levels, liver function tests, and clinical presentation 3
• Low or absent acetaminophen levels do NOT rule out acetaminophen poisoning if ingestion was remote or occurred over several days 3
• Never withhold NAC in late presentations - it provides benefit even beyond 24 hours, particularly in established hepatic failure 2, 3
• Do not stop NAC prematurely - verify all discontinuation criteria are met before stopping therapy 3

Respiratory/Mucolytic Use (Non-Overdose)

For mucolytic therapy via nebulization:

• Face mask/mouthpiece/tracheostomy: 3-5 mL of 20% solution 3-4 times daily 7
• Direct instillation: 1-2 mL as often as every hour 7
• Tracheostomy care: 1-2 mL every 1-4 hours 7
• Use glass, plastic, aluminum, or stainless steel equipment (avoid iron, copper, rubber) 7