Simplified Acetylcysteine Regimen for Acetaminophen Toxicity


The FDA-approved 3-bag intravenous n-acetylcysteine regimen for acetaminophen toxicity is being challenged by a simpler approach.

When it comes to medication regimens, simplicity is often the key to minimizing errors.

With regards to intravenous (IV) n-acetylcysteine for acetaminophen toxicity, the 3-bag infusion protocol is particularly prone to errors. These errors can occur as a result of a treatment team member’s unfamiliarity with this antidotal therapy, and they often manifest as delays between the end of one infusion and the beginning of another.

In one study, the 3-bag regimen was associated with up to a 33% incidence of errors.1

The search for a simplified regimen has been underway for some time.

Previous studies have investigated the safety and effectiveness of administering the total regimen dose of 300 mg/kg with various infusion strategies. Like much of emergency medicine and toxicology data, however, the extrapolation of these data was limited by the small sample sizes and often retrospective, observational, single-center study design.

While challenges in conducting higher methodological studies exist, new observational data continue to accumulate with promising results. The most recent attempt at a simplified regimen investigated a novel IV n-acetylcysteine infusion strategy in a critically understudied population: pediatrics.2

The authors of this study used a 2-bag infusion method consisting of a 150 mg/kg loading dose followed by a maintenance infusion of 15 mg/kg/hr until acetaminophen concentrations were <10 mg/L and liver enzyme concentrations were within normal limits, or at least trending in that direction.

Data were collected in a retrospective manner in pediatric patients treated with this regimen for acute or chronic overdoses of acetaminophen at a single institution over a 4-year period. Patients were excluded if they had a history of chronic liver disease or initiation of any other n-acetylcysteine regimen.

The final analysis included a total of 59 patients who ranged in age from 2 months to 18 years (median of 14 years). The degree of severity assessed by Rumack-Matthew nomogram noted that most patients fell into the probable risk and possible risk categories [21 (38%) and 22 (39%) respectively].

The effectiveness of the 2-bag n-acetylcysteine regimen was described in descriptive clinical outcomes.

Most patients (49) ingested acetaminophen intentionally, while 10 ingested it unintentionally. Additionally, 35 patients ingested other medications.

The authors considered diphenhydramine co-ingestions independently from the other co-ingestants listed because of the drug’s known ability to prolong gastrointestinal transit time for acetaminophen, which leads to higher acetaminophen concentrations that persist.

Only 2 patients developed hepatotoxicity defined as alanine transaminase or aspartate transaminase >1000 units/L; however, no patients developed manifestation of liver failure, encephalopathy, or bleeding, and no patients required liver transplantation.

The novel 2-bag regimen was well tolerated, with just 2 patients experiencing minor anaphylactoid reactions consisting of flushing, facial redness, and itching.

The authors concluded that this alternative IV n-acetylcysteine dosing regimen appears to be effective and well tolerated among pediatric patients compared with the current FDA-approved regimen.

While this is a promising alternative, the evidence may not be sufficient to suggest that it is acceptable to use in all patients.


  • Hayes BD, Klien-Schwarz W, Doyon S. Frequency of medication errors with intravenous acetylcysteine for acetaminophen overdose. Ann Pharmacother. 2008;42(6):766—70
  • Pauley KA, Sandritter TL, Lowry JA, Algren A. Evaluation of an alternative intravenous n-acetylcysteine regimen in pediatric patients. J Pediatr Pharmacol Ther. 2015 May-Jun;20(3):178—85.

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