N-Acetylcysteine Infusion Dosing
Acetaminophen Overdose: Standard IV Protocol
For acute acetaminophen overdose, administer IV N-acetylcysteine using the three-bag regimen: 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). 1, 2
Standard Dosing Algorithm
- Loading dose: 150 mg/kg in 5% dextrose infused 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
Alternative Oral Protocol
- Loading dose: 140 mg/kg by mouth or nasogastric tube diluted to 5% solution 1, 3
- Maintenance: 70 mg/kg every 4 hours for 17 additional doses (total 72 hours) 1, 3
The oral protocol preserves more hepatocytes than the 21-hour IV protocol and may be superior when treatment is delayed 4. However, the 72-hour oral course is often unnecessarily long 4.
Massive Overdose: Escalated Dosing
For acetaminophen concentrations plotting above the "300-line" on the Rumack-Matthew nomogram, increase NAC dosing in a stepwise fashion. 2, 5
- 300-line threshold: First dose escalation 5
- 450-line threshold: Second dose escalation 5
- 600-line threshold: Third dose escalation 5
This approach addresses the higher hepatotoxicity rates observed with massive overdoses 5.
Weight-Based Dosing Considerations
Use actual body weight for NAC dosing calculations, even in patients weighing >100 kg—do not cap the dose at a maximum weight cutoff. 6
Clinicians routinely dose NAC based on actual weight rather than maximum weight limits, with median dosing of 140 mg/kg orally and 150 mg/kg IV in patients >100 kg 6. Adverse events in this population are relatively common but not serious 6.
Timing and Efficacy
Initiate NAC immediately within 8 hours of ingestion for maximal hepatoprotection—severe hepatotoxicity develops in only 2.9% when treated within 8 hours versus 26.4% when treated after 10 hours. 1, 2, 3
Time-Dependent Outcomes
- 0-8 hours: 2.9% severe hepatotoxicity 1, 3
- Within 10 hours: 6.1% severe hepatotoxicity 1, 2
- 10-24 hours: 26.4% severe hepatotoxicity 1, 2
- 16-24 hours: 41% hepatotoxicity in high-risk patients 2
Late Presentation (>24 Hours)
Administer NAC regardless of time since ingestion if acetaminophen overdose is suspected—mortality reduces from 80% to 52% even in established liver failure. 1, 2, 3
The Rumack-Matthew nomogram does NOT apply beyond 24 hours; base treatment decisions on acetaminophen levels, liver function tests, and clinical presentation 2.
Special Clinical Scenarios Requiring NAC
Acute Liver Failure
Give NAC immediately to all patients with acute liver failure where acetaminophen ingestion is suspected or possible, even without confirmatory history. 1, 2, 3
- Mortality reduction: 80% to 52% 1, 2, 3
- Cerebral edema reduction: 68% to 40% 2
- Post-transplant survival improvement: 71.4% to 85.7% 1
- Transplant-free survival increase: 30% to 41% 1
High-Risk Populations
Treat patients with chronic alcohol use with NAC even when acetaminophen levels plot in the "non-toxic" range—severe hepatotoxicity occurs with doses as low as 4 g/day in alcoholics. 2, 3
Repeated Supratherapeutic Ingestions
Administer NAC for repeated ingestions of ≥10 g or 200 mg/kg (whichever is less) during a single 24-hour period, or ≥6 g or 150 mg/kg per 24-hour period for ≥48 hours. 1, 2
Treat if serum acetaminophen ≥10 mg/mL or if AST/ALT >50 IU/L 2.
Extended-Release Formulations
Continue NAC beyond the standard protocol for extended-release acetaminophen due to prolonged absorption—obtain serial acetaminophen levels at 14 hours or beyond. 2, 3
Unknown Time of Ingestion
Start NAC immediately when acetaminophen is detectable and timing cannot be determined—low or absent levels do NOT rule out poisoning if ingestion was remote or occurred over several days. 1, 2
Duration of Treatment
Discontinue NAC only when acetaminophen is undetectable AND liver function tests remain completely normal—any elevation in AST or ALT above normal mandates continuing treatment. 2
Criteria for Stopping NAC
- Acetaminophen level undetectable 2
- AST and ALT completely normal (not just "improving") 2
- No coagulopathy 2
- No clinical signs of hepatotoxicity 2
Mandatory Extended Treatment Scenarios
Continue NAC beyond 21 hours for: 2
- Delayed presentation (>24 hours post-ingestion)
- Extended-release acetaminophen
- Repeated supratherapeutic ingestions
- Unknown time of ingestion with detectable levels
- Any transaminase elevation
- Chronic alcohol use
Peak serum ALT correlates well with time to clear NAPQI from the liver, making ALT the optimal biomarker for discontinuation 4.
Critical Pitfalls to Avoid
Never delay NAC while awaiting acetaminophen levels if overdose is suspected—start immediately. 1, 2, 3
Very high aminotransferases (AST/ALT >3,500 IU/L) are highly correlated with acetaminophen poisoning and warrant NAC even without confirmatory history. 1
Do not stop NAC if transaminases are rising, coagulopathy develops, or acetaminophen remains detectable—restart immediately if hepatotoxicity develops after stopping. 2
Activated charcoal (1 g/kg) should be given just prior to starting NAC if patient presents within 4 hours, but never delay NAC for charcoal administration. 2, 3
Contrast-Induced Nephropathy: NOT Recommended
Do NOT use IV NAC for prevention of contrast-induced nephropathy—it is associated with potentially serious adverse effects without proven effectiveness. 7
Large randomized trials show no reduction in contrast-induced AKI with 1,200 mg oral NAC twice daily for 2 days compared to placebo 7. High-quality studies meeting methodological criteria demonstrate no effect (RR 1.05; 95% CI 0.73-1.53) 7. High-dose IV or oral NAC provides no detectable benefit over aggressive hydration in patients with moderate-to-severe renal insufficiency 8.
If oral NAC is used despite questionable efficacy, administer 1,200 mg by mouth twice daily for 2 days together with IV isotonic crystalloid—never use NAC in lieu of IV fluids 7.