Shorter 12-Hour Acetylcysteine Regimen Safe and Effective for Moderate Paracetamol Overdose: SARPO Trial Finds

Paracetamol overdose is one of the most common causes of drug poisoning globally. Timely administration of acetylcysteine remains the cornerstone of treatment to prevent liver damage. Traditionally, a 20-hour intravenous acetylcysteine regimen—300 mg/kg split across 4 hours and 16 hours—is the standard protocol. However, prolonged treatment can be uncomfortable and resource-intensive for both patients and healthcare providers.

To assess whether a shorter treatment duration could offer similar clinical outcomes, researchers conducted a non-inferiority randomized trial across three hospitals. A total of 204 patients with acute paracetamol overdoses of 30 grams or less, who presented within 8 hours of ingestion, were randomly assigned to receive either the conventional 20-hour treatment or a condensed 12-hour regimen (200 mg/kg over 4 hours followed by 50 mg/kg over 8 hours).

The study's primary focus was to measure the change in alanine aminotransferase (ALT) levels 24 hours post-ingestion compared to baseline, a key marker of liver injury.

The study led to the following findings:

• The shorter acetylcysteine regimen showed a median ALT change of -2 U/L compared to -1 U/L in the standard regimen group.
• The difference in ALT change was within the acceptable non-inferiority margin.
• No patients in the shorter regimen group had significant liver enzyme elevations (ALT ≥2x baseline and >150 U/L).
• No patient in either group recorded ALT levels exceeding 1,000 U/L.
• Systemic hypersensitivity reactions occurred in 8% of patients on the shorter regimen and 10% on the standard regimen.
• 73% of the short regimen group and 65% of the standard group reported gastrointestinal side effects.
• The shorter regimen nearly halved the overall treatment duration and length of hospital stay.

The researchers emphasize that while the 12-hour protocol is promising for uncomplicated, single-time ingestions of paracetamol ≤30 g, it should not be generalized to high-risk cases such as staggered ingestions, overdoses with uncertain timing, or modified-release formulations.

Despite some limitations—including strict inclusion criteria and a slight imbalance in randomization across subgroups—the study supports the feasibility of a simplified treatment approach. According to the authors, this protocol could potentially be applied to about one-third of acute paracetamol overdose cases, reducing the burden on emergency services and improving patient comfort without compromising safety.

Reference:

Isbister, G., Chiew, A., Buckley, N., Harris, K., Berling, I., Downes, M., Page, C., & Isoardi, K. (2025). A non-inferiority randomised controlled trial of a shorter acetylcysteine regimen for paracetamol overdose – the SARPO trial. Journal of Hepatology. https://doi.org/10.1016/j.jhep.2025.05.008