N-Acetylcysteine (NAC) Supplementation Guidelines
Primary Indication: Acetaminophen Overdose
NAC is FDA-approved and strongly recommended as an antidote for acetaminophen overdose, where it should be administered immediately within 24 hours of ingestion to prevent or lessen hepatic injury. 1
Dosing for Acetaminophen Toxicity
- Loading dose: 140 mg/kg orally 2, 1
- Maintenance dose: 70 mg/kg every 4 hours for 17 total doses 2, 1
- Preparation: Dilute 20% solution to 5% concentration using diet cola or other diet soft drinks (3 mL diluent per 1 mL NAC) 1
- Timing is critical: Most effective when started within 8-10 hours of ingestion, though still beneficial up to 48 hours post-ingestion 2
When to Initiate NAC for Acetaminophen
Administer NAC immediately in any of these scenarios: 2, 1
- Known or suspected acetaminophen overdose within 24 hours
- Acetaminophen level plots above the Rumack-Matthew nomogram line (drawn 4-24 hours post-ingestion)
- Aminotransferases exceeding 3,500 IU/L (highly correlated with acetaminophen poisoning even without clear history) 2
- Do not wait for acetaminophen levels before starting treatment 1
Do not administer NAC when acetaminophen level is clearly below the toxic line on the Rumack-Matthew nomogram and ingestion occurred at least 4 hours before the level was drawn 2
Acute Liver Failure (ALF)
Acetaminophen-Associated ALF
The American Gastroenterological Association strongly recommends NAC use for all acetaminophen-associated ALF cases. 2
- This recommendation carries strong support despite very low quality of evidence 2
- Improved mortality demonstrated (relative risk 0.65; 95% CI 0.43-0.99) 2
Non-Acetaminophen ALF
For non-acetaminophen-associated ALF, NAC should only be used within clinical trials. 2
- Overall mortality benefit not demonstrated in general non-acetaminophen ALF 2
- Post hoc analysis showed potential benefit in patients with stage 1 or 2 hepatic encephalopathy only 2
- Exception: Consider NAC in ALF of indeterminate cause, as these may be unrecognized acetaminophen cases 2
Non-Approved Uses: Limited Evidence
Contrast-Induced AKI Prevention
Oral NAC (1,200 mg twice daily for 2 days) may be administered alongside intravenous isotonic crystalloid for contrast-induced AKI prevention, but should never replace IV fluids in high-risk patients. 2
- Evidence is conflicting and a large 2011 trial (2,308 patients) showed no benefit 2
- Oral NAC is inexpensive and largely devoid of adverse effects, making it reasonable as adjunctive therapy 2
- Intravenous NAC should not be used for contrast-induced AKI prevention due to potentially serious adverse effects without proven efficacy 2
Other Conditions
NAC has been studied for various chronic conditions (COPD, idiopathic pulmonary fibrosis, male infertility, psychiatric disorders) but lacks robust evidence for routine supplementation outside of clinical trials 3, 4
Safety Profile and Side Effects
Oral Administration
Oral NAC is generally well-tolerated across a wide dose range (600-3,000 mg/day). 3
- Gastrointestinal symptoms (nausea, vomiting) are most common but occur at similar rates to placebo 3, 5
- Licensed maximum dose for chronic use is 600 mg/day, though higher doses studied without significant additional adverse effects 3
- The American Academy of Emergency Medicine emphasizes that side effects should not prevent completion of therapy for acetaminophen poisoning, as benefits far outweigh risks 6
Specific Adverse Effects
- Occasional nausea, vomiting, rare urticaria or bronchospasm with oral administration 2
- Allergic reactions with IV administration can be managed with discontinuation, antihistamines, and epinephrine for bronchospasm 2
- Meta-analysis showed no significant difference in odds ratio of side effects between NAC and placebo (OR 1.11; 95% CI 0.88-1.39) 5
- Possible dose-dependent increase in side effects at very high doses, though this requires further investigation 5
Critical Clinical Pearls
Administration Considerations
- If patient vomits within 1 hour of oral dose, repeat that dose 1
- For patients unable to retain oral NAC, administer via duodenal intubation 1
- Diluted solutions should be freshly prepared and used within 1 hour 1
- Unopened vials can be refrigerated up to 96 hours 1
- NAC is not approved for parenteral injection (except specific IV formulations for acetaminophen overdose) 1
Activated Charcoal Interaction
If activated charcoal is indicated for mixed drug overdose, perform gastric lavage before administering NAC, as activated charcoal adsorbs NAC and reduces its effectiveness. 1
Monitoring
For acetaminophen overdose, repeat SGOT, SGPT, bilirubin, prothrombin time, creatinine, BUN, blood sugar, and electrolytes daily if acetaminophen level is in the potentially toxic range 1