Fixed 12-h vs 20–21-h IV acetylcysteine in acetaminophen poisoning: RCT systematic review and meta-analysis

Aim: Intravenous N-acetylcysteine regimens for acetaminophen poisoning are increasingly simplified to reduce infusion reactions and early emesis while maintaining hepatic protection, but direct regimen-to-regimen randomized evidence comparing fixed 12-hour and fixed 20–21-hour regimens is limited. Methods: We searched MEDLINE, Embase and CENTRAL (to 10 Dec 2025) for individually randomized trials comparing fixed 12-hour versus fixed 20–21-hour intravenous N-acetylcysteine, with Cochrane Risk of Bias 2 (RoB 2) assessment. With only two heterogeneous trials, we report trial-specific effects. Results: Two trials were included (SNAP n=222; SARPO n=204). For trial-defined hypersensitivity/anaphylaxis-like reactions, SNAP favored 12 hours (risk ratio [RR] 0.72; 95% confidence interval [CI] 0.58–0.88) and SARPO was imprecise (RR 0.82; 95% CI 0.35–1.92). SNAP also reported less early vomiting/retching or rescue antiemetic use at 2 h (RR 0.55; 95% CI 0.42–0.74). SARPO met non-inferiority for ΔALT24 (margin 5 U/L), with a median difference of −1 U/L (95% CI −3 to 1) in low-risk early presenters. Conclusions: Across two regimen-to-regimen RCTs, the studied 12-hour packages reduced trial-defined reactions (clear benefit in SNAP; uncertainty in SARPO). Overall certainty is very low and hepatic efficacy remains uncertain, relying on ALT surrogates and underpowered for rare critical outcomes.