Clinical outcomes of “massive” acetaminophen overdose treated with standard vs. augmented dose acetylcysteine

Introduction: Contemporary literature has defined “massive” acetaminophen overdose as serum acetaminophen concentration plotting above the 300 mcg/mL line on the Rumack-Matthew nomogram. An alternative augmented acetylcysteine dosing protocol increases the dose proportionally corresponding to the 300-, 450-, and 600 mcg/mL line. The aim of this study is to compare the development of hepatotoxicity (AST/ALT >1,000 U/L) for patients meeting massive acetaminophen overdose criteria who were treated with standard versus augmented acetylcysteine dosing stratified by time-to-acetylcysteine, defined as early (< 8 hours) versus late (> 8 hours).Methods This was a single-center retrospective cohort study of acute acetaminophen overdoses reported to a regional poison center from January 2010 to March 2025. Cases were reviewed before and after the poison center adopted augmented acetycysteine dosing for massive acetaminophen overdoses in January 2020. The group who received standard acetylcysteine dosing served as the control. Cases were included if a single acute acetaminophen concentration plotted above the 300-, 450-, or 600 mcg/mL nomogram line. Standard univariate statistical analysis was conducted to describe the cohort, and a multivariate logistic model was utilized to calculate odds ratios for risk of hepatotoxicity.Results Of 174 included cases, 107 received standard acetylcysteine dosing and 67 received augmented acetylcysteine dosing. Among cases that received acetylcysteine less than eight hours post-ingestion, the incidence of hepatotoxicity was 8.7% (4/46) in the standard dose cohort compared to 8.6% (3/35) in the augmented dose cohort (unadjusted OR 0.98, 95% CI 0.21–4.71) Among those that received acetylcysteine greater than eight hours post-ingestion, the incidence of hepatotoxicity was 34.4% (21/61) in the standard dose cohort compared to 37.5% (12/32) in the augmented dose cohort (unadjusted OR 1.14, 95% CI 0.47–2.78).DiscussionAugmented acetylcysteine dosing did not reduce hepatoxicity compared with standard dosing in massive acetaminophen ingestions. Early initiation of acetylcysteine remains the most important factor associated with prevention of hepatotoxicity. Interpretation is limited based on small sample sizes, potentially inaccurate ingestion histories, and reliance on poison center dataConclusion In this cohort of massive acetaminophen overdose, there was no difference in incidence of hepatotoxicity between standard versus augmented acetylcysteine dosing when stratified by time-to-acetylcysteine post-ingestion.