A non-inferiority randomised controlled trial of a Shorter Acetylcysteine Regimen for Paracetamol Overdose – the SARPO trial.

Paracetamol is a common overdose worldwide. Early acetylcysteine treatment can prevent hepatotoxicity. Multiple intravenous acetylcysteine regimens exist; the commonest recommending 300mg/kg over 20h. We investigated the effectiveness and safety of a shorter regimen in paracetamol overdoses ≤30g. In a multicentre non-inferiority randomised controlled trial, 204 patients from three hospitals with acute paracetamol overdose ≤ 30g presenting within 8h, were randomised to standard 20h acetylcysteine (200mg/kg/4h, 100mg/kg/16h) regimen or short 12h acetylcysteine (200mg/kg/4h, 50mg/kg/8h) regimen. The primary outcome was the absolute difference between alanine transaminase (ALT) 24h post-ingestion and admission ALT (ΔALT24). Secondary outcomes included ALT>150U/L at 24h and double admission ALT, systemic hypersensitivity and gastrointestinal adverse effects. The two groups were similar in age, gender, dose ingested, paracetamol concentration, baseline ALT, hospital, charcoal administration and time until acetylcysteine. The shorter regimen was non-inferior to the standard regimen. ΔALT24 for 107 patients given the shorter regimen was median -2U/L (Interquartile range [IQR]:-7 to 1U/L) compared to 97 given the standard regimen, median -1U/L (IQR:-5 to 1.5U/L); difference in medians of -1U/L; 95% confidence interval:-3 to 1U/L; less than the upper non-inferiority margin of 5). No patient receiving the shorter regimen had a 24h ALT double admission and >150U/L, compared to one receiving the standard regimen. No patient had an ALT>1000U/L. Systemic hypersensitivity reactions were similar between groups [9/107 (8%) for short versus 10/97 (10%) standard regimen]. Gastrointestinal adverse effects occurred in 78/107 patients (73%) receiving the short versus 63/97 (65%) receiving the standard regimen. The shorter 12h acetylcysteine regimen had the same effectiveness and safety as the standard 20h regimen in acute paracetamol overdoses ≤30g, almost halving the length of treatment required. Australian New Zealand Clinical Trials Registry number ACTRN12616001617459.