Global Evidence on Glutathione and N-Acetylcysteine Therapy in Acute Respiratory Distress Syndrome: A Systematic Review and Meta-Analysis

Background Acute respiratory distress syndrome (ARDS) is often life-threatening, associated with high morbidity and mortality. N-acetylcysteine(NAC), a precursor to Glutathione(GSH), has been proposed as an adjuvant to counteract oxidative stress, inflammation, and endothelial damage in ARDS. Objective To systematically review the effectiveness of GSH and NAC in ARDS and high-risk patients in randomized controlled trials(RCTs). Methods Systematic search of PubMed, Scopus, and Web of Science for RCTs evaluating GSH and NAC in patients with or at risk of ARDS was conducted. Eligible trials compared GSH and or NAC (any regimen, route, or dose) with placebo or usual care and reported clinical outcomes. The Cochrane RoB 2.0 was used to evaluate the risk of bias. Data were qualitatively synthesized and pooled where feasible according to random-effects models. Results Six RCTs (n = 452 patients; 229 NAC, 223 control) were included. NAC did not reduce 28-day mortality (RR 0.83; 95% CI 0.58–1.18). NAC slightly reduced hospital stay (MD − 0.30; CI − 0.50 to − 0.10; p = 0.004) but had no clear effect on oxygenation, ventilator-free days, SOFA scores, or the need for mechanical ventilation. Certainty of evidence was limited by small sample sizes, heterogeneity in dosing regimens, and risk of bias in several domains. Conclusions NAC may confer modest physiological benefits but does not demonstrate consistent improvements in key clinical outcomes for ARDS. Aetiology, timing, and dosage strategy may all have an impact on its efficacy. To establish the function of NAC in ARDS, larger multicenter RCTs with standardized protocols are required. Trial registration ProsperoCRD420251155902; https://www.crd.york.ac.uk/PROSPERO/view/CRD420251155902.