Etiology of methemoglobinemia in the National Poison Data System®: an observational study

Methemoglobinemia is a recognized complication of exposure to numerous xenobiotics. Identifying xenobiotics most often linked to this condition can guide diagnosis and treatment. This study aims to summarize substances associated with methemoglobinemia using data from the National Poison Data System^® (NPDS^®) in order to identify more contemporary causes of methemoglobinemia. The primary objective is to identify the most frequent causative xenobiotics. Secondary objectives include describing xenobiotics linked to methylene blue treatment, deaths, and age-related patterns.

A retrospective cross-sectional analysis of NPDS^® database was queried from January 1, 2019, through November 30, 2025, by searching for cases in which methemoglobin was coded as a clinical outcome. Cases involving nonhuman exposures, unrelated effects, insufficient follow-up, unidentified products, viral illnesses, or xenobiotics not supported as causative agents of methemoglobinemia were excluded. Data collected included age, sex, implicated xenobiotic, reason for exposure, methylene blue administration, and outcome. Three trained reviewers abstracted and validated all cases. Descriptive statistics were used, reporting proportions for categorical variables and medians with interquartile ranges for continuous variables. Some xenobiotics were collated into larger groups, such as pharmaceutical and non-pharmaceutical nitrates/nitrites. Non-pharmaceutical nitrates/nitrites were defined as those coded amyl or butyl nitrates/nitrites (street drugs), intentional suicidal ingestions, or as intentional misuse or intentional abuse.

We screened 2,535 cases and excluded 1,290, leaving 1,245 for analysis. The median patient age was 43 years (IQR 25-60 years) and 50.5% (629) were female. Non-pharmaceutical nitrates/nitrites were the leading xenobiotic associated with methemoglobinemia at 31% (392), followed by dapsone at 26% (328), phenazopyridine at 15% (187), and local anesthetics at 10% (121). Overall, of the 96 fatalities, 56% (50) were associated with non-pharmaceutical nitrate/nitrite exposures. The most common culprit xenobiotics in cases administered methylene blue were non-pharmaceutical nitrates/nitrites. In children younger than six years, nitrate/nitrite exposures were pharmaceutical in origin, whereas in older age groups they were predominantly non-pharmaceutical.

This study identified non-pharmaceutical nitrates/nitrites as the most common xenobiotics associated with methemoglobinemia, methylene blue treatment, and mortality. Other classic xenobiotics such as dapsone, phenazopyridine, and local anesthetics were frequently treated but rarely fatal. Xenobiotics not typically linked to methemoglobinemia, such as acetaminophen and rasburicase, also appeared among the top ten causes.

Non-pharmaceutical nitrates/nitrites were the leading causes of methemoglobinemia, methylene blue use, and mortality Other leading contributors included both classically recognized causes of methemoglobinemia, as well as xenobiotics not commonly associated with the condition. These findings underscore the need for further research on xenobiotics associated with methemoglobinemia and heightened awareness of both established and emerging etiologies.