Evaluation of N-acetylcysteine dose for the treatment of massive acetaminophen ingestion

Clin Toxicol (Phila). 2022 Apr;60(4):507-513. doi: 10.1080/15563650.2021.1984503. Epub 2021 Sep 28.


Methods: The use of N-acetylcysteine (NAC) remains the standard of care for treatment of acetaminophen (APAP) toxicity and overdose. Currently, there is growing evidence to suggest that massive acetaminophen overdose is associated with increased hepatotoxicity despite timely administration of NAC. This raises the question as to whether an increased dose of intravenous (IV) NAC should be used in the setting of massive APAP ingestion. This study aimed to evaluate the rate of hepatotoxicity after massive APAP overdose treated with 3 different NAC treatment regimens.

Methods: This was a retrospective cohort study conducted by electronic medical record review of cases reported to a statewide poison control system between 2007 and 2020. Inclusion criteria were single APAP or APAP combination-medication ingestion; acute massive acetaminophen (APAP) ingestion (defined as APAP concentration ≥ 2 times above the Rumack-Matthew 150 nomogram); received one of the three NAC regimens: standard dose IV NAC, oral (PO) NAC, or high dose IV NAC. The risk of hepatotoxicity was evaluated using a multivariate logistic regression model with standard dose IV NAC as the base variable for comparison.

Results: A total of 373 patients met inclusion for the study. Of those, 135 cases were treated with standard dose IV NAC, 121 cases treated with PO NAC, and 117 cases treated with high dose IV NAC. The risk of developing hepatotoxicity was not statistically significant between the high dose IV NAC (OR 1.05, 95% CI 0.52 - 2.09) or oral NAC (OR 0.69, 95% CI 0.33 - 1.46) when compared to standard dose IV NAC. When adjusted for APAP combination medications, initial APAP ratio, initial elevated AST/ALT, and treatment within 8 h, there remained no difference between treatment regimens.

Conclusion: This study was unable to detect a large absolute reduction in the rate of hepatotoxicity after massive APAP ingestion in patients treated with high dose IV NAC or PO NAC when compared to standard dose IV NAC; even when treatment was initiated within 8 h of ingestion.

Keywords: Acetaminophen poisoning; acetylcysteine; hepatotoxicity; massive ingestion.

MeSH terms

  • Acetaminophen
  • Acetylcysteine / therapeutic use
  • Analgesics, Non-Narcotic*
  • Chemical and Drug Induced Liver Injury* / drug therapy
  • Chemical and Drug Induced Liver Injury* / etiology
  • Drug Overdose* / drug therapy
  • Eating
  • Humans
  • Retrospective Studies


  • Analgesics, Non-Narcotic
  • Acetaminophen
  • Acetylcysteine