What is the recommended dose of N-acetylcysteine (NAC) for a patient with acute hepatic dysfunction likely due to acetaminophen overdose?

NAC Dosing for Acute Hepatic Dysfunction from Acetaminophen Overdose

For acute hepatic dysfunction from acetaminophen overdose, administer IV N-acetylcysteine at 150 mg/kg over 15 minutes, followed by 50 mg/kg over 4 hours, then 100 mg/kg over 16 hours (total 21-hour protocol), and continue beyond 21 hours if acetaminophen remains detectable or transaminases continue rising. 1, 2, 3

Standard IV NAC Protocol

The FDA-approved intravenous regimen consists of three sequential doses totaling 300 mg/kg over 21 hours 3:

• 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 1, 3

Alternatively, oral NAC can be administered as 140 mg/kg loading dose followed by 70 mg/kg every 4 hours for 17 doses (72-hour protocol), though IV is preferred in established hepatic failure 1, 2.

Critical Management in Established Hepatic Failure

When hepatic failure is already present, NAC must be administered immediately regardless of time since ingestion, as it reduces mortality from 80% to 52%. 1, 2 This represents a Level B recommendation from the American College of Emergency Physicians 2.

Key benefits in fulminant hepatic failure include 2:

• Mortality reduction from 80% to 52%
• Cerebral edema reduction from 68% to 40%
• Decreased need for inotropic support from 80% to 48%

Extended Treatment Beyond 21 Hours

Do not stop NAC at 21 hours if any of the following are present 2, 3:

• Detectable acetaminophen levels
• Rising or elevated transaminases (AST/ALT)
• Elevated INR or coagulopathy
• Clinical signs of hepatotoxicity

The FDA label explicitly states: "If acetaminophen levels are still detectable, or if the ALT/AST are still increasing or the INR remains elevated; dosing should be continued" 3. In massive overdoses or with co-ingestions, the standard 21-hour protocol is often insufficient 1, 4, 5.

For continued therapy, contact poison control (1-800-222-1222) or the acetaminophen overdose assistance line (1-800-525-6115) for dosing guidance 3.

Monitoring Requirements

Throughout treatment, monitor 2, 3:

• Acetaminophen levels (repeat if initially elevated)
• AST/ALT (check after each dosing phase)
• INR/PT (coagulation status)
• Creatinine and BUN (renal function)
• Electrolytes and blood glucose

Very high aminotransferases (AST/ALT >3,500 IU/L) are highly correlated with acetaminophen poisoning and should prompt NAC treatment even without confirmatory history. 2

Special Considerations for Acute Liver Failure

In patients presenting with established acute liver failure 1, 2:

• Initiate NAC immediately without waiting for confirmatory acetaminophen levels
• Low or absent acetaminophen levels do NOT rule out acetaminophen poisoning if ingestion was remote
• Contact liver transplant center immediately for any evidence of liver failure
• ICU-level care required for severe hepatotoxicity (AST >1,000 IU/L) or coagulopathy

High-Risk Populations Requiring Lower Treatment Threshold

Patients with chronic alcohol use should receive NAC even with acetaminophen levels in the "non-toxic" range, as severe hepatotoxicity can occur with doses as low as 4 g/day in alcoholics 2. Other high-risk groups include fasting patients and those on enzyme-inducing drugs 2.

Common Pitfalls

• Never delay NAC while awaiting confirmatory levels if there is strong suspicion of significant overdose 2
• The Rumack-Matthew nomogram does NOT apply to patients presenting >24 hours after ingestion or with repeated supratherapeutic ingestions 2
• Standard 21-hour protocols may be inadequate in massive overdoses (initial levels >400 mg/L), combination product ingestions, or extended-release formulations 4, 5
• Activated charcoal can be given just prior to NAC if patient presents within 4 hours, but should not delay NAC administration 2

Oral vs. IV NAC Efficacy

While both routes are effective, modeling studies suggest the 72-hour oral protocol may preserve more hepatocytes than the 21-hour IV protocol, particularly in delayed presentations 6. However, IV NAC is preferred in established hepatic failure due to concerns about absorption and the need for reliable delivery 1.