Shorter noninferior to standard acetylcysteine regimen for paracetamol overdose

A shorter acetylcysteine regimen shows similar safety and effectiveness to the standard regimen for moderate paracetamol overdoses ≤30 g, reveals a recent study. This almost halves the duration of treatment required.

“Paracetamol is a commonly overdosed medication worldwide,” the investigators said. “Early acetylcysteine treatment can prevent hepatotoxicity.”

Two hundred four patients with acute paracetamol overdose, presenting within 8 h, were included in this multicentre, noninferiority, randomized controlled trial conducted at three hospitals. Participants were randomly allocated to either the standard 20-h acetylcysteine (200 mg/kg/4 h, 100 mg/kg/16 h; n=107) regimen or a short 12-h acetylcysteine (200 mg/kg/4 h, 50 mg/kg/8 h; n=97) regimen.

The primary outcome was the absolute difference between alanine aminotransferase (ALT) 24 h postingestion and at admission (ΔALT24), while secondary outcomes were ALT >150 U/L and ≥2x admission value at 24 h, systemic hypersensitivity, and gastrointestinal adverse effects.

The two treatment groups had similar baseline characteristics, including age, gender, dose ingested, paracetamol concentration, ALT, hospital, charcoal administration, and time until acetylcysteine treatment. [J Hepatol 2025;83:881-887]

The shorter acetylcysteine regimen demonstrated noninferiority to the standard regimen. Patients in the shorter regimen arm had a median ΔALT24 of ‒2 U/L compared to ‒1 U/L for those in the standard regimen arm. The difference in median of ‒1 U/L (95 percent confidence interval, ‒3 to 1) was less than the upper noninferiority margin of 5.

None of the patients on shorter acetylcysteine regimen had a 24-h ALT of ≥2x admission value and >150 U/L as opposed to one receiving the standard regimen. Moreveor, no participant had an ALT >1,000 U/L.

In terms of safety, the two groups showed a similar frequency of systemic hypersensitivity reactions (8 percent for short vs 10 percent for standard regimens). Gastrointestinal adverse effects were slightly greater in the shorter than the standard regimens (73 percent vs 65 percent).

“The findings will make acetylcysteine treatment easier for treating physicians, with a shortened length of stay,” the investigators said. “The protocol cannot be extended to high-risk paracetamol overdoses, including massive and staggered ingestions, without further study.”

Criteria for administration

The shorter 12-h regimen is applicable to any region or country that is using the standard two- or three-bag acetylcysteine regimen, except for the UK where SNAP is the standard treatment.

“The main difference between many parts of the world is the criteria for the administration of acetylcysteine, with different risk assessment tools, such as lower nomogram lines,” the investigators said. “However, it is important that the shorter regimen is only applied to the same group included in our study: acute ingestions of immediate release paracetamol <30 g presenting with 8 h of ingestion.”

In editorials published in the UK and Australia, researchers recommend a shorter total duration for patients deemed to be at low risk of hepatotoxicity. [Clin Toxicol (Phila) 2016;54:75-78; Clin Toxicol (Phila) 2016;54:75-78]

“The shorter SNAP protocol is now used across the UK for patients treated within 8 h of ingestion,” the investigators said. “The acetylcysteine infusion is only stopped at 12 h if paracetamol concentrations are <20 mg/L, international normalized ratio is ≤1.3, and ALT is <100 U/L and <2x the admission value at the end of a 12-h regimen.” [EClinicalMedicine 2019;11:11-17]