Clinical impact of fomepizole as an adjunct therapy in high-risk acetaminophen overdose

Clinical question

For patients with a high-risk acetaminophen overdose receiving N-acetylcysteine (NAC), does adding fomepizole improve clinically important outcomes?

Bottom line

In this retrospective cohort reported to four U.S. poison centers, adding fomepizole to NAC was not associated with better adjusted National Poison Data System outcome severity, ICU admission, or duration of NAC than NAC alone. No fomepizole adverse effects were reported. The study does not support routine adjunctive fomepizole for all high-risk acetaminophen overdoses, but its observational design and limited exposed group cannot exclude benefit in a selected subgroup.

PICO

Population. Patients reported to four U.S. poison centers from January 2018 through December 2022 with a high-risk acetaminophen overdose. High risk was defined as a serum acetaminophen concentration of at least 300 mcg/mL at four or more hours after ingestion, or an acetaminophen concentration multiplied by AST or ALT of at least 10,000. The investigators excluded patients with pre-existing liver disease, inadequate data, toxic-alcohol co-ingestion, or hepatotoxic co-ingestion.

Intervention. Fomepizole given in addition to NAC.

Comparator. NAC alone.

Outcomes. The analysis assessed NPDS medical outcome severity, ICU admission, and NAC duration. It also recorded reported adverse effects attributed to fomepizole.

What did the study find?

The cohort included 391 high-risk exposures. After adjustment, the authors did not find a statistically significant improvement in NPDS outcome severity, ICU admission, or NAC duration with adjunctive fomepizole compared with NAC alone. A timing analysis that separated fomepizole given within 24 hours from later administration likewise did not show a significant difference in those outcomes. No adverse effects from fomepizole were reported in the dataset.

These results are useful because they address outcomes that matter to patients and clinicians, rather than only biochemical pathways. They do not establish that fomepizole is ineffective in every circumstance: the comparator was not assigned randomly, and the study may not have had enough precision to rule out a smaller effect or an effect in a narrowly defined group.

Appraisal

This was a retrospective poison-center cohort, not a randomized trial. Patients receiving fomepizole may have differed from those receiving NAC alone in ways that are difficult to fully measure, including perceived clinical severity, consultation patterns, time from ingestion, or local treatment practice. Adjustment can reduce observed imbalance, but it cannot remove unmeasured confounding. Poison-center reports also depend on the completeness and consistency of clinical follow-up and documentation.

The high-risk definition makes the results more relevant to severe acetaminophen exposures than to routine low-risk ingestions. At the same time, the study’s exclusion criteria and participating poison-center setting limit direct generalization to every practice environment. “No reported adverse effects” should be read as an observation from this cohort, not proof that adverse effects cannot occur.

The study did not demonstrate a clinical advantage for routine addition of fomepizole. It also does not define a universal threshold at which a clinician should add it, nor does it replace local toxicology consultation or established NAC protocols.

Practical interpretation

For a high-risk acetaminophen overdose, NAC remains the established treatment in this study’s comparison. The available cohort evidence does not justify presenting fomepizole as a routine add-on that improves ICU use, treatment duration, or poison-center outcome severity. When considering an adjunct in an unusual or severe presentation, frame the decision as individualized and involve the local poison center or medical toxicology service. Document the exposure timeline, acetaminophen concentration, aminotransferases, co-ingestants, and the reason an adjunct is being considered.

Avoid teaching that a mechanistic rationale alone proves outcome benefit. A treatment can be biologically plausible and still lack demonstrated patient-centered improvement in a nonrandomized cohort.

Limits to carry forward

• Retrospective, nonrandomized design: association cannot establish causal benefit or no benefit.
• Exposed sample and event structure may not exclude a smaller benefit or a benefit in a selected subgroup.
• The results apply to the paper’s high-risk definition and poison-center population.
• No reported adverse effects is not equivalent to a zero-risk finding.

Learning pearls

1. Separate a plausible adjunct from a routinely indicated adjunct.
2. Use the cohort’s actual outcomes: no significant improvement in severity, ICU admission, or NAC duration.
3. Keep NAC central to management and use toxicology expertise for exceptional cases.
4. Do not infer a fomepizole dose, duration, or universal patient-selection rule from this study.

ACPE UAN: 0683-0000-26-036-H01-P

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Study source: PMID:41886998