Paracetamol adducts following overdose treated with a shorter acetylcysteine infusion: findings from the NACSTOP 2 trial

Introduction: Paracetamol protein adducts in the circulation are a specific biomarker of paracetamol oxidation, and a highly sensitive measure of potential hepatic injury following overdose. We performed an analytical sub-study of adducts during a clinical trial (NACSTOP2) of abbreviated (12 hour) versus control (20 hour) acetylcysteine to identify any signal of decreased antidotal effectiveness with shortened therapy. Methods: We measured adducts from a convenience sample of subjects enrolled in the randomised-controlled NACSTOP2 trial evaluating a 12-hour (“abbreviated”; 200 mg/kg over four hours, 50 mg/kg over 8 hours) vs 20-hour acetylcysteine regimen (“control”; 200 mg/kg over four hours, 100 mg/kg over 16 hours). Adducts were assayed using high-performance liquid chromatography with electrochemical detection. Results: The median alanine transaminase 20 hours after the initiation of acetylcysteine were 13 U/L (IQR 10–25 U/L) in the abbreviated 12-hour regimen group (n = 29), compared to the control group 14 U/L (IQR 10–19 U/L; n = 28) (P = 0.46). Adduct concentrations after 20 hours post initiation of acetylcysteine were similarly low in both groups: median 0.18 µmol/L, (IQR 0.09–0.24 µmol/L) to the control 0.17 µmol/L (IQR 0.11–0.27), P = 0.43. Discussion: In both the NACSTOP and NACSTOP 2 trials, adduct concentrations remained low in this selected cohort of low risk patients, supporting abbreviation of the acetylcysteine regimen. Conclusions: In selected low-risk patients, paracetamol adduct formation remained similarly low whether acetylcysteine was stopped after 12 hours or continued for the standard 20 hours.