What is the role of N-acetyl cysteine (NAC) in treating acetaminophen poisoning?

N-Acetylcysteine in Acetaminophen Poisoning

N-acetylcysteine (NAC) should be administered immediately to all patients with known or suspected acetaminophen overdose when serum levels plot above the treatment line on the Rumack-Matthew nomogram, or when hepatotoxicity is present—ideally within 8 hours of ingestion to maximize efficacy, but it remains beneficial and should never be withheld even in late presentations beyond 24 hours. 1, 2, 3

Immediate Treatment Indications

NAC must be started immediately in the following scenarios:

• Acetaminophen levels plotting in the "possible" or "probable" risk zones on the Rumack-Matthew nomogram (drawn 4-24 hours post-ingestion) 1, 2, 3
• Any established hepatic failure from acetaminophen, regardless of time since ingestion—this reduces mortality from 80% to 52% 1, 3
• Acute liver failure with suspected acetaminophen ingestion, even without confirmatory history, particularly when aminotransferases exceed 3,500 IU/L 2, 3
• Unknown time of ingestion with detectable acetaminophen levels 2, 3
• Extended-release acetaminophen or repeated supratherapeutic ingestions (>4g per 24 hours) 2, 3

Critical Timing and Efficacy

The effectiveness of NAC is highly time-dependent, but treatment should never be delayed or withheld:

• Within 8 hours: Only 2.9% develop severe hepatotoxicity—this is the optimal window 3, 4
• Within 10 hours: 6.1% develop severe hepatotoxicity 1, 3
• 10-24 hours: 26.4% develop severe hepatotoxicity, but this is still significantly better than no treatment 1, 3
• Beyond 24 hours: NAC still provides mortality benefit and should be administered immediately, particularly in established liver failure 1, 3, 5

The Rumack-Matthew nomogram does NOT apply to patients presenting >24 hours after ingestion—treatment decisions must be based on acetaminophen levels, liver function tests, and clinical presentation. 3

Standard Dosing Regimens

Intravenous Protocol (21-hour standard):

• 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 1, 2

Oral Protocol (72-hour):

• 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

Note: A 12-hour abbreviated IV regimen (100 mg/kg over 2 hours, then 200 mg/kg over 10 hours) has demonstrated similar efficacy with fewer adverse reactions (2.0% vs 11.0% requiring antihistamines), though the standard 21-hour protocol remains most widely recommended. 6

High-Risk Populations Requiring Lower Treatment Threshold

Certain patients develop toxicity at lower acetaminophen doses and warrant NAC even with levels below typical treatment thresholds:

• Chronic alcoholics: Can develop severe hepatotoxicity with doses as low as 4-5 g/day 1, 3
• Fasting or malnourished patients: Have depleted glutathione stores 1
• Patients on enzyme-inducing drugs: Increased production of toxic metabolite NAPQI 3, 5
• Cirrhotic patients: Particularly those actively drinking or malnourished 1

For these patients, treat with NAC if serum acetaminophen ≥10 mg/mL or if AST/ALT >50 IU/L. 3

Adjunctive Measures

• Activated charcoal (1 g/kg) should be given just prior to starting NAC if the patient presents within 4 hours of ingestion 2, 3
• Do not delay NAC while awaiting acetaminophen levels if there is strong clinical suspicion 2
• Activated charcoal does not interfere with NAC administration—give both when indicated 2

When to Continue or Extend NAC Beyond Standard Protocol

NAC should be continued beyond the standard 21-hour IV or 72-hour oral protocol in these situations:

• Any elevation in AST or ALT above normal 3
• Rising transaminases or any coagulopathy 3
• Detectable acetaminophen level at completion of standard protocol 3
• Delayed presentation (>24 hours post-ingestion) 2, 3
• Extended-release formulations with prolonged absorption 2, 3
• Repeated supratherapeutic ingestions where timing cannot be determined 2, 3

If hepatotoxicity develops (AST/ALT >1000 IU/L), continue NAC until transaminases are declining and INR normalizes. 3

Critical Pitfalls to Avoid

• Low or absent acetaminophen levels do NOT rule out poisoning if ingestion was remote or occurred over several days 3
• Never withhold NAC in late presentations—even after 24 hours, it reduces mortality in established liver failure 1, 3
• Do not rely solely on nomogram placement—patients may develop hepatotoxicity despite "no risk" stratification due to inaccurate history or increased susceptibility 3
• Patients with severe hepatotoxicity (AST >1000 IU/L) or coagulopathy require ICU-level care and immediate transplant hepatology consultation 3

Adverse Effects

NAC is generally well-tolerated with low adverse effect rates:

• Nausea/vomiting: <5% 1
• Skin rash: <5% 1
• Bronchospasm: 1-2% 1
• Anaphylactoid reactions: More common with IV route, managed with antihistamines and slowing infusion rate 4, 6

Mechanism of Action

NAC protects the liver by maintaining or restoring hepatic glutathione levels, or by acting as an alternate substrate for conjugation with the toxic metabolite N-acetyl-p-benzoquinone imine (NAPQI), thereby preventing cellular necrosis. 5, 7