UMEM Educational Pearls

Acetaminophen (APAP) is the leading cause of acute liver failure worldwide. Standard treatment for APAP overdose is with N-acetylcysteine (NAC), which is highly effective if given within 8 hours of ingestion.  However, in delayed presenters or massive ingestions patients can still develop hepatotoxicity. Adjunctive therapies can be considered in these cases including augmented NAC dosing, renal replacement, and fomepizole.

A small amount of APAP is metabolized to N-acetyl-p-benzoquinone imine (NAPQI) by cytochrome 2E1. In therapeutic doses, the body is able to detoxify the NAPQI using glutathione. In overdose, glutathione stores get depleted and NAPQI can cause hepatotoxicity. Mitochondrial damage in APAP overdose is mediated by the c-Jun-N-terminal Kinase (JNK) pathway. 

NAC works to replenish glutathione stores and detoxify NAPQI. In large overdoses, increased dosing of NAC may be necessary. Fomepizole is typically used for its alcohol dehydrogenase inhibitor property to treat methanol and ethylene glycol poisoning. Fomepizole is also a cytochrome 2E1 and JNK inhibitor and can be used in APAP overdose to block the formation of NAPQI and mitigate mitochondrial damage.  Dialysis can be used to eliminate APAP from the body completely in massive overdoses or if significant acidosis or renal failure. 

This study is a case series of 14 patients treated for APAP overdose between 2017 – 2021 at a tertiary hospital

• Patients treated with standard NAC therapy
• They also received IV fompeizole loading dose of 15 mg/kg followed by 10mg/kg every 12 hours at the discretion of the treating team
• Most cases received only the loading dose
• Some cases also received renal replacement therapies
• Patients had “better than expected outcomes” based on initial presentation, APAP levels, liver function tests, and expected clinical course
• No unfavorable outcomes
• No side effects

Limitations of the study:

• Patients were treated with NAC which is the standard of care
• No formal protocol for the administration or identification of patients treated with fompeizole

In summary:

• NAC is the standard of care in acetaminophen poisonings
• Consider fomepizole as an adjunctive therapy in patients that are critically ill
• Consult your poison center 1-800-222-1222 or friendly toxicologist for help in identifying these patients

References

Stephanie L. Link, Garrett Rampon, Stephen Osmon, Anthony J. Scalzo & Barry H. Rumack (2022) Fomepizole as an adjunct in acetylcysteine treated acetaminophen overdose patients: a case series, Clinical Toxicology, 60:4, 472-477, DOI: 10.1080/15563650.2021.1996591