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

Global Evidence on Glutathione and N-Acetylcysteine Therapy in Acute Respiratory Distress Syndrome: A Systematic Review and Meta-Analysis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Global Evidence on Glutathione and N-Acetylcysteine Therapy in Acute Respiratory Distress Syndrome: A Systematic Review and Meta-Analysis Lokesh Shanmugam, A Sathya, Siva Ranganathan Green, Aswinth R, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8857692/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 4 You are reading this latest preprint version Abstract 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 . Acute Respiratory Distress Syndrome N-acetylcysteine Glutathione Oxidative Stress Antioxidant Therapy Systematic Review Meta-analysis Figures Figure 1 Figure 2 Figure 3 Introduction With mortality rates ranging from 30% to 45% despite better supportive care, acute respiratory distress syndrome (ARDS) is a potentially fatal condition linked to severe acute hypoxemic respiratory failure, which is characterised by non-cardiogenic pulmonary oedema and bilateral pulmonary infiltrates [ 1 , 2 ]. Dysregulated inflammation, oxidative stress, and increased alveolar–capillary permeability are all part of the pathogenesis of ARDS, which causes severe respiratory impairment [ 3 ]. While extracorporeal membrane oxygenation (ECMO), protected lung ventilation, and prone ventilation all improved outcomes, no pharmaceutical treatment has consistently reduced mortality, underscoring the need for adjuvant therapies targeting fundamental processes. The most common antioxidant in the lung, glutathione (GSH), is a tripeptide consisting of glutamate, cysteine, and glycine. It plays a significant role in immunological response, redox balance, and epithelial barrier function [ 4 , 5 ]. ARDS exacerbates oxidative damage, lipid peroxidation, and pro-inflammatory signalling by drastically lowering glutathione in alveolar lining fluid and plasma [ 6 – 8 ]. Mechanisms of Action of NAC/Glutathione in ARDS NAC prevents glutathione depletion by restoring intracellular glutathione (GSH), the primary endogenous antioxidant of lung epithelial cells and alveolar macrophages, as a donor of cysteine [ 9 , 10 ]. NAC enhances cellular resistance to reactive oxygen species (ROS), prevents lipid peroxidation, and preserves mitochondrial function in alveolar tissue by restoring GSH levels [ 11 ]. Additionally, NAC directly neutralises free radicals, including superoxide, hypochlorous acid, and hydroxyl radicals [ 12 ]. NAC has strong anti-inflammatory properties in addition to its redox effects. Tumour necrosis factor-alpha (TNF-α), IL-6, and interleukin (IL)-1β, which are important mediators of cytokine-induced lung damage, are downregulated as a result of its suppression of nuclear factor-kappa B (NF-κB) activation [ 13 , 14 ]. Additionally, NAC suppresses the NLRP3 inflammasome, which reduces IL-18 release and caspase-1 activation, hence reducing the hyperactive immunological response typical of ARDS [ 15 ] [ 7 ]. At the same time, NAC activates the Nrf2 antioxidant pathway, which raises the transcription of the cytoprotective enzymes superoxide dismutase, glutathione peroxidase, and heme oxygenase-1 [ 16 ].NAC maintains endothelial barrier by inhibiting ROS-mediated disruption of tight junction [ 17 ]. It cleaves disulfide bonds into multimers of von Willebrand factor (vWF), decreases platelet adhesion, and reduces microthrombi formation [ 18 ]. NAC further downregulates plasminogen activator inhibitor-1 (PAI-1), which increases fibrinolysis and prevents the prothrombotic state in ARDS and COVID-19 ARDS [ 19 ]. Evidence from Experimental, Translational, and Clinical Studies Fang et al. [ 20 ] showed that diminished glutathione and decreased GPX4 activity make epithelial cells sensitive to ferroptosis, linking antioxidant depletion directly to epithelial damage Similarly, Yang et al. (2025) and Yu et al. (2025) demonstrated that interventions that maintain glutathione pools—through O-GlcNAcylation of GPX4 or stimulation of the Nrf2/G6PDH pathway—reduced ferroptotic death and enhanced lung outcomes in ischemia–reperfusion and sepsis models [ 21 , 22 ]. Lin et al. [ 23 ] also validated that the natural product liriodendrin preserved cystine–glutathione homeostasis and GPX4 activity, supporting the preeminence of the glutathione axis in oxidative lung damage He et al. [ 24 ] found that NAC inhibited ACSL4-driven ferroptosis in secondary ARDS following myocardial ischemia, providing mechanistic credibility to its therapeutic value. Systems biology strategies have enlarged these mechanistic discoveries. Cui and Huang [ 25 ]. Based on multi-omics analysis, IT pointed towards glutathione metabolism genes as central regulators of ferroptosis in ARDS, of which YWHAE was identified as a core hub gene. According to Li et al. [ 26 ], glutathione is at the intersection of oxidative cell death pathways because it interacts not only with ferroptosis but also with cuproptosis and disulfidptosis. Zhu et al. [ 27 ] demonstrated COVID-19-specific evidence that TIPE2 maintained glutathione–GPX4 action, protecting macrophages against ferroptosis caused by the spike protein. Enteral nutrition supplemented with antioxidants and glutathione precursors increased oxygenation and decreased oxidative stress markers in patients with ARDS, according to Yalçınkaya et al. [ 28 ]. The clinical importance of redox equilibrium was highlighted by Lal and Corechi [ 29 ], who found a connection between poor outcomes in ARDS and alcohol use disorder, which causes glutathione store depletion. Clough et al. [ 30 ] established glutathione as a severity index by confirming that reduced pulmonary glutathione defences were linked to higher susceptibility to lung damage in models of preclinical hyperoxia. Clinical experiments have had conflicting results. NAC or procysteine have shown a physiological benefit in early RCTs, but there has been no conclusive survival benefit [ 31 , 32 ]. A meta-analysis by Zhang et al. (2017) concluded that NAC enhanced oxygenation and decreased ICU stay but not mortality, whereas subsequent synthesis of eight RCTs by Lu et al. reaffirmed these results [ 33 , 34 ]. Dewan and Shinde (2022) recently described an early clinical response using intravenous glutathione among 240 ARDS patients with decreased oxygen demands and shorter durations of hospitalization [ 35 ]. Interest was renewed in the COVID-19 pandemic: Yang et al. [ 36 ] discovered low glutathione and increased lipid peroxidation markers in bronchoalveolar fluid of patients with severe ARDS. Aisa-Alvarez et al. [ 37 ]and Taher et al. [ 38 ] noted an improvement in oxygenation with NAC supplementation, but survival advantages were inconsistent [ 36 – 38 ]. Larger series, such as González-Guzmán et al. [ 39 ], demonstrated enhanced survival with oral NAC in mechanically ventilated COVID-19 ARDS patients, whereas Gamarra-Morales et al. [ 40 ] reported physiological benefits without uniform mortality benefit [ 39 , 40 ]. Meta-analyses are also still unclear, with some indicating possible mortality decrease and others reporting no substantial effect [ 41 , 42 ]. NAC's mucolytic and antioxidant action in ARDS was summarised by Mokra and Mokry [ 43 ] as having positive effects in lowering oxidative stress, while the clinical findings were inconsistent due to variations in dosage and delivery. The synergistic potential of mixing glutathione precursors with vitamins and other antioxidants was also emphasised by Al-Kufaishi and Al-Musawi [ 44 ]. Worldwide experience with glutathione supplementation ranges from Europe to North America, the Middle East, and Asia, in a variety of ARDS etiologies such as sepsis, trauma, pneumonia, and viral illness [ 45 – 48 ]. In view of the uncertainties, a revised synthesis is indicated. The current systematic review and meta-analysis thus assesses randomized controlled trials of Glutathione and or NAC therapy in ARDS, with the twin objectives of establishing their efficacy and charting the worldwide experience in differing populations and clinical settings. Methods The search strategy employed both controlled vocabulary (e.g., MeSH, Emtree) and free-text keywords for N-acetylcysteine, Glutathione and ARDS. We performed a systematic literature search in PubMed, Scopus and Web of Science for pertinent studies between January 2010 and March 2025. For instance, the PubMed search query used the following keywords: ("N-acetylcysteine" OR "NAC" OR "acetylcysteine" OR "glutathione") AND ("acute respiratory distress syndrome" OR "ARDS" OR "acute lung injury" OR "ALI" OR "sepsis" OR "septic shock" OR "pneumonia" OR "mechanical ventilation" OR "burn injury"). Eligibility criteria: Population: Adults with ARDS (according to Berlin or other criteria) or at high risk (those with sepsis, pneumonia or mechanical ventilation). Intervention: any NAC or glutathione regimen (dose, route, timing)- whether nebulised, IV, or oral, including those used either as monotherapy or in combination with other antioxidants. Comparator: Placebo, no treatment or usual care. Outcomes: Primary: 28-day mortality and secondary (ICU/hospital length of stay, ventilator-free days, PaO2/FiO2, SOFA score, biomarkers). Study design: RCTs only. Restrictions: languages, publication types and date range (2010–2025). Exclusion criteria were used for studies published in languages other than English, preclinical or animal research, reviews, meta-analyses, case reports, and editorials, and also for studies with no full-text availability. The records extracted from the databases were transferred to a reference manager, and any duplicate records were discarded. Two reviewers independently assessed the titles and abstracts for eligibility, after which full texts of potentially qualifying articles were reviewed. Differences in study selection were addressed through discussion, and the third reviewer adjudicated when needed. This review has been registered in the International Prospective Register of Systematic Reviews (PROSPERO) under the registration ID CRD420251155902. The registration details are available at https://www.crd.york.ac.uk/PROSPERO/view/CRD420251155902 . Data Extraction Data extraction was performed independently by two reviewers employing a uniform data collection form to maintain consistency and reduce bias. Data extracted included study features (first author, publication year, country, clinical setting, and study design) and population characteristics like sample size, etiology of underlying ARDS, or risk factors in high-risk groups. Intervention features were documented, such as the dose, administration route, frequency, treatment duration of Glutathione or N-acetylcysteine, and timing relative to ARDS onset. Data on comparators, whether placebo, usual care, or other antioxidants, were also obtained. Outcomes were described as either clinical (mortality, mechanical ventilation duration, ICU or hospital length of stay, ARDS occurrence or severity) or biological (oxidative stress and inflammatory markers). The principal findings of every study were recorded in a systematic format. Risk of Bias Assessment Risk of bias was independently assessed by two reviewers using Cochrane Risk of Bias tool (RoB 2.0) across domains of randomization, deviations from intended interventions, missing outcome data, outcome measurement, and selective reporting. All the domains were graded as low risk, some concerns, or high risk of bias. Disagreements between reviewers were addressed by dialogue or, if needed, by a third reviewer’s judgement. Data Synthesis Due to the anticipated heterogeneity of study populations, Glutathione or N-acetylcysteine regimens, and reported outcomes, qualitative synthesis of findings was performed for most outcomes. Where sufficient homogeneity existed, defined as five or more randomized controlled trials reporting on similar outcomes, a quantitative synthesis by meta-analysis was completed. A random-effects model was used to adjust for variability among studies with regard to patient populations, intervention protocols, and clinical settings. Statistical Analysis Statistical calculations were conducted using MetaAnalysisOnline.com, a computer program for quick meta-analysis of clinical and epidemiologic studies (Fekete & Györffy, 2025). Pooled effect estimates were reported as risk ratios (RR) with 95% confidence intervals (CI) in binary outcomes (e.g., mortality, ARDS incidence) and mean differences (MD) with 95% CI in numeric outcomes (e.g., ventilator-free days, ICU stay). Between-study heterogeneity was determined by means of the I² statistic, which at 25%, 50%, and 75% indicates low, moderate, and high heterogeneity, respectively. Sensitivity analyses were to be performed to determine the stability of findings pooled by excluding high-risk studies. Subgroup analyses according to ARDS etiology (COVID-19 vs. non-COVID), route of NAC administration (intravenous vs. inhaled vs. oral), and timing of treatment (early vs. late ARDS) were also entertained based on data availability. Visual assessment of publication bias was to be performed using funnel plots whenever more than ten studies were included in an analysis. Ethical Considerations This review does not involve human subject information, primary data collection, or any forms of experimentation on individuals. Results Study identification . A total of 245 records were retrieved from PubMed (n = 90), Web of Science (n = 97), and Scopus (n = 58). After removal of 40 duplicates, 205 distinctive records were screened by title and abstract, of which 103 were excluded (non-human studies, wrong study type, non-English language, or irrelevant population). The remaining 102 articles were assessed for eligibility. Of these, 36 could not be retrieved in full text. Sixty-six full-text articles were reviewed in detail; 60 were excluded from the quantitative synthesis because they were non-randomized studies, used interventions other than NAC/glutathione, reported surrogate outcomes only, or were conducted in outpatient/mild disease populations. However, many of these were retained to inform the qualitative synthesis. Ultimately, six randomized controlled trials (RCTs) met all eligibility criteria and were included in the meta-analysis (Fig. 1 ). No clinical studies were identified in which Glutathione itself was administered as the interventional drug in patients with ARDS across the databases searched in the study. Characteristics of studies . A total of six randomized controlled trials (RCTs) with 452 patients were included, of whom 229 received NAC and 223 served as controls. Table 1 summarizes the characteristics of the included studies, covering patient populations, interventions, and outcomes. Table 2 presents the results of the risk of bias assessment. Two trials (de Alencar et al., 2021 and Taher et al., 2021) were rated at overall low risk of bias, three at some concerns, and one at high risk due to incomplete outcome. Given the few studies were included (< 10), statistical tests for funnel plot asymmetry were not performed. Publication bias was assessed descriptively using a funnel plot of the six RCTs. Visual inspection suggested a roughly symmetrical distribution of effect estimates around the mean, with larger studies clustering toward the top and smaller studies more dispersed toward the bottom, as expected. There was no clear evidence of missing studies on either side. However, given the small number of trials, interpretation of potential publication bias remains limited. Table 1 Characteristics of Included RCTs on NAC and ARDS First Author (Year) Country / Setting Population Sample Size (NAC / Control) Study Design Intervention (Dose & Route) Control Duration Primary Outcomes Key Results de Alencar et al. (2021) Brazil – Hospital das Clínicas, São Paulo Adults ≥ 18 yrs with severe COVID-19 (SaO₂ 24 bpm) 135 (68 / 67) Double-blind RCT IV NAC 21 g (~ 300 mg/kg) over 20 h Dextrose 5% (placebo) Single 20-h course Need for mechanical ventilation No significant difference in invasive ventilation (20.6% vs 23.9%; p = 0.64) or mortality Panahi et al. (2022) Iran – Tehran, single-center Hospitalized adults with COVID-19 pneumonia (no imminent intubation) 250 (125 / 125) Randomized open-label trial Inhaled NAC spray 200 µg q12h × 7 days Standard care 7 days 28-day mortality, CT and NEWS scores Mortality 3.2% vs 39.2% (p < 0.001); significant improvement in CT and NEWS scores Aisa-Álvarez et al. (2020) Mexico – Two ICUs (Mexico City) Adults with septic shock (Sepsis-3 criteria) 97 (total: NAC 20 / Control 21 + other antioxidant arms) Triple-masked RCT NAC 600 mg q12h × 5 days (oral/NG) + standard care Standard sepsis care 5 days Change in SOFA score NAC ΔSOFA − 0.62 (p = 0.18); no significant improvement; Vit C and melatonin effective Taher et al. (2021) Iran – Hamadan University Hospital ICU Mild-to-moderate COVID-19 ARDS (PaO₂/FiO₂ 100–300 mm Hg) 92 (47 / 45) Double-blind pilot RCT IV NAC 40 mg/kg/day continuous × 3 days Dextrose 5% (placebo) 3 days 28-day mortality; WHO ordinal scale No significant difference in mortality (25.5% vs 31.1%) or recovery (p > 0.05) Peivandi Yazdi et al. (2021) Iran – Mashhad University ICU Adults with sepsis (≥ 2 SIRS criteria) 60 (Intermittent 20 / Continuous 20 / Placebo 20) Pilot RCT (3-arm) IV NAC 100 mg/kg/24 h (intermittent or continuous) Isotonic saline (placebo) 24 h Total Antioxidant Capacity (TAC), Malondialdehyde (MDA) NAC ↑ TAC (p = 0.007) and ↓ MDA (p < 0.001) vs placebo; no clinical endpoints assessed Najafi et al. (2014) Iran – Tehran University ICUs Mechanically ventilated septic patients (ARDS-risk) 39 (21 / 18) Randomized controlled trial IV NAC 3 g q6h × 72 h (total 12 g/day × 3 days) Standard sepsis care 3 days IgM, HβD2, GSH levels No significant differences in GSH, IgM, HβD2, or mortality (p > 0.05) — trend toward higher GSH in NAC group Table 2 Risk of Bias Assessment (RoB 2.0) for Included RCTs Study (Year) Randomization Process Deviations from Intended Interventions Missing Outcome Data Measurement of Outcome Selection of Reported Result de Alencar et al., 2021 Low risk Low risk Low risk Low risk Low risk Aisa-Alvarez et al., 2021 Unclear Low risk Low risk Low risk Low risk Najafi et al., 2014 Low risk Some concerns (dose adjustments) Low risk Low risk Low risk Panahi et al., 2023 Low risk Low risk Some concerns (dropouts not fully explained) Low risk Low risk Peivandi Yazdi et al., 2020 Some concerns (randomization details unclear) Low risk Low risk Some concerns (no blinding of assessors) Low risk Taher et al., 2021 Low risk Low risk Low risk Low risk Low risk Mortality Four randomized controlled trials involving 420 patients reported 28-day mortality [ 37 , 38 , 49 , 50 ]. Pooled analysis showed no significant difference between NAC and control groups (RR 0.83, 95% CI 0.58–1.18, p = 0.29). There was no evidence of statistical heterogeneity across studies (I² = 0%, χ² = 0.85, p = 0.84). However, potential clinical heterogeneity remains given differences in study populations (COVID-19 vs. sepsis) and intervention regimens (inhaled vs. intravenous NAC) (Fig. 2 A). Hospital stay Four randomized controlled trials including 420 patients (209 NAC, 211 control), reported data on length of stay [ 37 , 38 , 49 , 50 ]. Panahi et al.[ 49 ] reported a mean hospital stay of 6.7 ± 3.5 days in the NAC group compared with 8.4 ± 4.6 days in the control group. Aisa-Alvarez et al.[ 37 ] observed mean hospital stays of 13.7 ± 8.8 versus 14.1 ± 8.9 days, respectively. Taher et al. (2021) reported 12.1 ± 5.3 versus 13.2 ± 6.1 days, while de Alencar et al. [ 50 ] noted mean ICU stays of 11.4 ± 6.2 versus 12.2 ± 5.9 days in the NAC and control groups, respectively. Pooled analysis demonstrated a significant reduction in length of stay with NAC compared with control (SMD = − 0.30; 95% CI: − 0.50 to − 0.10; p = 0.004) (Fig. 2 B). Need for Mechanical Ventilation Two randomized controlled trials comprising a total of 335 patients, evaluated the effect of NAC on the requirement for invasive mechanical ventilation [ 38 , 49 ]. In the study by Panahi et al.[ 49 ] 12 of 125 patients (9.6%) in the NAC group required mechanical ventilation compared with 21 of 125 patients (16.8%) in the control group (RR = 0.57; 95% CI: 0.29–1.11). Similarly, Taher et al.[ 38 ] reported that 8 of 42 patients (19.0%) in the NAC group required mechanical ventilation compared to 11 of 43 patients (25.6%) in the control group (RR = 0.74; 95% CI: 0.33–1.67) (Fig. 2 C). Pooled analysis evidenced a non-significant reduction in the risk of mechanical ventilation with NAC (RR = 0.64; 95% CI: 0.38–1.06; p = 0.084), with no evidence of heterogeneity. However, this estimate should be interpreted with caution as only two trials were included. Random-effects Mantel-Haenszel analysis of risk ratios found no significant group differences (RR 0.64, 95% CI 0.38–1.06), with nonsignificant overall effect and low heterogeneity, reflecting consistent effect directions and magnitudes across trials. Effect of NAC on Oxygenation (PaO₂/FiO₂ ratio, Day 5–7) Four randomized controlled trials, including a total of 420 patients, reported PaO₂/FiO₂ ratio at day 5–7 of treatment. The pooled analysis showed no statistically significant improvement in PaO₂/FiO₂ ratio with NAC compared to control (Standardized Mean Difference [SMD] = 0.17; 95% CI: − 0.03 to 0.36; p = 0.09) (Fig. 3 A). Between-study heterogeneity was negligible (I² = 0%, p = 0.94), and the prediction interval (–0.14 to 0.48) suggested that future studies are also unlikely to show a large clinical effect in either direction. Overall, while individual studies indicated modest increases in PaO₂/FiO₂ ratio, the pooled evidence does not support a clear benefit of NAC on short-term oxygenation in ARDS or ARDS-risk populations. Ventilator-Free Days Two RCTs, including a total of 124 critically ill patients (63 individuals in the NAC group and 61 individuals in the control group), reported ventilator-free days at 28 days. A meta-analysis showed that there was no statistically significant difference between NAC and control groups (SMD 0.20, 95% CI − 0.16 to 0.55, p = 0.28), with no evidence of heterogeneity (I² = 0%). The prediction interval (–2.09 to 2.49) was wide, indicating uncertainty in the true effect across different settings (Fig. 3 B). Overall, NAC did not significantly improve ventilator-free days compared with the control Sequential Organ Failure Assessment (SOFA) Score Two randomized controlled trials evaluated the effect of NAC on organ dysfunction using SOFA scores at Day 7. Pooled analysis showed no significant reduction in SOFA scores in the NAC group compared with controls (SMD − 0.31, 95% CI − 0.67 to 0.04; p = 0.085) (Fig. 3 C). Statistical heterogeneity was absent. The differences were not statistically significant, despite the fact that both studies showed a numerical trend towards lower SOFA values with NAC. These results imply that NAC does not consistently reduce multi-organ dysfunction in critically ill individuals with ARDS or at risk. Discussion The effectiveness of N-acetylcysteine (NAC) in patients with acute respiratory distress syndrome (ARDS) and high-risk ARDS populations was examined in this systematic review and meta-analysis. Across six small RCTs, NAC did not reduce mortality or major clinical outcomes in ARDS, though small reductions in hospital stay and favourable biomarker changes were observed. Notably, a small but statistically significant decrease in hospital length of stay was found with NAC, indicating possible advantages for recovery dynamics. The included trials differed in patient demographics (COVID-19 versus non-COVID ARDS, sepsis, and critically sick patients on mechanical ventilation) and intervention protocols (IV versus inhaled NAC), therefore this result should be regarded cautiously. The reason oxygenation metrics improved in certain trials but not in the pooled analysis could be partially explained by subgroup heterogeneity. NAC in ARDS has a compelling biological justification. Dysregulated inflammation, ROS buildup, endothelial and epithelial damage, and disruption of the alveolar-capillary barrier resulting in non-cardiogenic pulmonary oedema are the hallmarks of ARDS. As a precursor to glutathione, NAC directly scavenges ROS and restores intracellular antioxidant stores, lowering oxidative stress. Additionally, it reduces inflammatory cytokines like TNF-α, IL-6, and IL-8 via modulating nuclear factor-κB (NF-κB) activity. Additionally, NAC may improve ventilation–perfusion matching by influencing alveolar fluid clearance and endothelial nitric oxide bioavailability. These mechanisms are supported by observed decreases in inflammatory mediators and oxidative stress indicators in included investigations [ 51 , 52 ]. This mechanistic explanation is further supported by preclinical data. Through glutathione (GSH)-mediated mechanisms, PEGylated artesunate prodrugs reduced acute lung injury caused by LPS in murine models [ 53 ]. Through the AKT/GSK3β/Nrf2 pathway, cyasterone was demonstrated to reduce acute lung injury associated with sepsis, demonstrating a GSH-dependent antioxidant mechanism [ 54 ]. In septic ARDS models, rosmarinic acid decreased oxidative stress and bronchial epithelial ferroptosis [ 55 ], whereas Mucin 1 inhibited ferroptosis and improved antioxidant defence via the GSK3β/Keap1-Nrf2-GPX4 pathway [ 56 ]. In ARDS models, it has also been demonstrated that adipose-derived exosomes maintain the pulmonary endothelial barrier by downregulating oxidative stress pathways [ 57 ]. Similarly, in experimental ARDS, glutamine treatment, a precursor to GSH, decreased extracellular trap release and inflammation [ 58 ]. Studies on humans also demonstrate how NAC affects lung function and oxidative stress. In hospitalised COVID-19 patients, high-dose oral NAC enhanced oxidative markers [ 51 ], while inhaled NAC enhanced lung function following liver transplantation [ 59 ]. In paediatric pneumonia, NAC and Ambroxol enhanced inflammatory biomarkers, demonstrating a wider potential for redox modulation [ 60 ]. Nevertheless, these biochemical and physiological effects have not consistently translated into survival benefits. This discrepancy underscores the complexity of ARDS pathophysiology, which extends beyond oxidative stress alone. Neutrophil-mediated injury, dysregulated coagulation, microthrombosis, and fibroproliferation all contribute to outcomes, and targeting a single pathway may be insufficient. Timing may also be critical: NAC may exert greater benefit in early ARDS before irreversible epithelial and fibrotic changes occur, whereas late administration may have limited impact. Findings from prior reviews are broadly consistent. Zhang et al. [ 33 ], analyzing five RCTs in non-COVID ARDS (183 patients), found no significant mortality benefit and only a modest reduction in ICU stay. In contrast, Alam et al. [ 41 ], synthesizing studies in COVID-19 ARDS (20,503 patients, including observational cohorts), reported significant mortality reduction and improvements in oxygenation and inflammatory markers, though with high heterogeneity and variable study quality. Mechanistically, this divergence may reflect differences in ARDS etiology: viral-mediated ARDS, such as in COVID-19, is driven by excessive systemic inflammation, cytokine storm, and oxidative stress, pathways more directly targeted by NAC. Conversely, non-COVID ARDS often involves heterogeneous triggers such as trauma, aspiration, or sepsis, where oxidative stress is only one of multiple pathogenic drivers. The relationship between glutathione levels and oxidative stress was further confirmed through analyses of bronchoalveolar lavage fluid (BALF) and markers of oxidative stress. Spearman correlation analyses linking chest CT fibrosis scores, fibroproliferative markers, and pulmonary redox parameters—including glutathione levels—demonstrate the impact of reduced GSH on oxidative stress and lung injury in COVID-19 ARDS patients [ 61 , 62 ]. These findings align with preclinical evidence showing that modulation of GSH and associated antioxidant pathways can ameliorate epithelial and endothelial injury [ 63 – 65 ], highlighting a mechanistic rationale for continued investigation [ 66 , 67 ]. Taken together, the evidence suggests that NAC and other GSH-modulating therapies may offer modest physiological benefits, particularly through antioxidant and anti-inflammatory pathways, but do not consistently improve hard outcomes across unselected ARDS populations. Its efficacy may be context-dependent, with greater promise in virally mediated or sepsis-associated ARDS where oxidative stress is central. Future studies should therefore focus on well-designed, well-powered multicenter RCTs with uniform definitions of ARDS, meticulous NAC dosing protocols, and careful timing of intervention. Subgroup analyses stratified by ARDS etiology and stage of disease will be crucial to identify populations most likely to benefit. Limitations Limited number of RCTs (n = 6) and small total sample size (452 patients), reducing statistical power to detect mortality differences. Considerable clinical heterogeneity across studies, including variation in ARDS etiology (COVID vs non-COVID) and definitions, NAC dose/regimens and timing, route (IV, inhaled, oral), incomplete biomarker reporting, treatment duration and some risk of bias concerns. Outcomes were not standardized; some trials reported only surrogate biomarkers, limiting cross-trial comparability. Potential publication bias cannot be excluded given the small number of studies available for synthesis. Lack of subgroup analyses prevents firm conclusions about which ARDS phenotypes or clinical contexts benefit most from NAC. Lastly, this review did not search grey literature sources or clinical trial registries, which may have led to the omission of relevant unpublished or ongoing studies. Conclusion This systematic review synthesizes global evidence on the role of glutathione and its precursor N-acetylcysteine in the prevention and management of acute respiratory distress syndrome (ARDS) and ARDS-risk populations. Across six randomized controlled trials, current evidence does not support routine NAC use solely to improve mortality in ARDS. However, demonstrated consistent biological effects in reducing oxidative stress markers and inflammatory mediators, with some studies reporting improved oxygenation and clinical outcomes. Future trials should be larger, multicenter, with standardized NAC dosing, early administration, and clinically meaningful primary endpoints. Declarations Funding Information: This research did not receive any specific grants Author Contribution Conceptualization: Lokesh ShanmugamData curation: Lokesh Shanmugam, A Sathya, Aswinth R, Siva Ranganathan Green, Umarani R, Siddarth R, Siddarth P, Joshua ChadwickFormal analysis: Lokesh Shanmugam, A Sathya, Aswinth R, Siva Ranganathan Green, Umarani R, Siddarth R, Siddarth P, Joshua ChadwickProject administration: Lokesh ShanmugamSupervision: Lokesh ShanmugamValidation: Lokesh Shanmugam, A Sathya, Aswinth R, Siva Ranganathan Green, Umarani R, Siddarth R, Siddarth P, Joshua ChadwickWriting-original draft: Lokesh Shanmugam, A Sathya, Aswinth R, Siva Ranganathan GreenWriting-review & editing: Lokesh Shanmugam, A Sathya, Aswinth R, Siva Ranganathan Green, Umarani R, Siddarth R, Siddarth P, Joshua Chadwick Data Availability The data supporting the findings of this study are available from the corresponding author upon reasonable request. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8857692","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":602122017,"identity":"139ee0c3-e8ec-417d-9e0b-1a403a596157","order_by":0,"name":"Lokesh Shanmugam","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA1klEQVRIiWNgGAWjYBACPgY2BgbGBiBibwByDSwIa2GDa+E5ANIiQYoWiQQQnxgt7G2JD3/uqJPdPvP51Q0/CiQY+Nu7E/Br4Tl22Jj3zGHjObdzym72AB0mcebsBvxaJNLbpBnbDiTOkM5Ju8ED1GIgkUtQS/vPn211iTMkz6Td/EOclrRjDLxtzIkzJNiP3SbOFp5jydK8bYeNZ/DksN2WMZDgIegXfvY2w49Ah8nOYD/+7OabPzZy/O29+LUgAR4DMEmschBgf0CK6lEwCkbBKBhBAAC12UWIGEeOIQAAAABJRU5ErkJggg==","orcid":"","institution":"ICMR- National Institute of Epidemiology","correspondingAuthor":true,"prefix":"","firstName":"Lokesh","middleName":"","lastName":"Shanmugam","suffix":""},{"id":602122020,"identity":"88cd6b80-6c5b-4317-b022-986c0c439133","order_by":1,"name":"A Sathya","email":"","orcid":"","institution":"Stanley Medical College","correspondingAuthor":false,"prefix":"","firstName":"A","middleName":"","lastName":"Sathya","suffix":""},{"id":602122024,"identity":"718e065f-d910-43ac-ba57-db0b3c8e2c24","order_by":2,"name":"Siva Ranganathan Green","email":"","orcid":"","institution":"Mahatma Gandhi Medical College \u0026 Research Institute","correspondingAuthor":false,"prefix":"","firstName":"Siva","middleName":"Ranganathan","lastName":"Green","suffix":""},{"id":602122025,"identity":"c89e6daf-4e98-4709-8e96-a397c558f4ab","order_by":3,"name":"Aswinth R","email":"","orcid":"","institution":"Government Cuddalore Medical College \u0026 Hospital","correspondingAuthor":false,"prefix":"","firstName":"Aswinth","middleName":"","lastName":"R","suffix":""},{"id":602122027,"identity":"1853bd3d-9373-49e6-9d75-ce0f8a89eeb3","order_by":4,"name":"Siddharth P","email":"","orcid":"","institution":"Mahatma Gandhi Medical College \u0026 Research Institute","correspondingAuthor":false,"prefix":"","firstName":"Siddharth","middleName":"","lastName":"P","suffix":""},{"id":602122028,"identity":"ee9c6abe-237d-4a68-a076-5f6100979d1c","order_by":5,"name":"R Umarani","email":"","orcid":"","institution":"Government Cuddalore Medical College \u0026 Hospital","correspondingAuthor":false,"prefix":"","firstName":"R","middleName":"","lastName":"Umarani","suffix":""},{"id":602122029,"identity":"e01108d1-ef61-4f70-a45d-c64cba4c92dc","order_by":6,"name":"R Siddarth","email":"","orcid":"","institution":"Government Cuddalore Medical College \u0026 Hospital","correspondingAuthor":false,"prefix":"","firstName":"R","middleName":"","lastName":"Siddarth","suffix":""},{"id":602122030,"identity":"5b450a51-3248-4466-959a-48f3720c95b2","order_by":7,"name":"Joshua Chadwick","email":"","orcid":"","institution":"ICMR- National Institute of Epidemiology","correspondingAuthor":false,"prefix":"","firstName":"Joshua","middleName":"","lastName":"Chadwick","suffix":""}],"badges":[],"createdAt":"2026-02-12 05:23:16","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8857692/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8857692/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":104338194,"identity":"786c378c-4dbf-41e0-990d-2628ef8fdd2f","added_by":"auto","created_at":"2026-03-10 16:18:28","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":136342,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ePRISMA Flow chart\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"image1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8857692/v1/4aae65dd963c4a8d6ce74f97.jpg"},{"id":104338196,"identity":"87373304-3aaf-41be-81e1-30c6a64aa094","added_by":"auto","created_at":"2026-03-10 16:18:29","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":236131,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eForest plots for A. Mortality, B. Hospital stay, C. Need for Mechanical Ventilation, df, degrees of freedom; CI, confidence interval; NAC, N‑acetylcysteine; SD, standard deviation; MH = Mantel–Haenszel.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"image2.png","url":"https://assets-eu.researchsquare.com/files/rs-8857692/v1/95f6f4e6badde4ef07619082.png"},{"id":104338193,"identity":"bd283259-e7d1-4bc7-bcd1-f99a1ea9129b","added_by":"auto","created_at":"2026-03-10 16:18:28","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":258285,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eForest plots for A. Effect of NAC on Oxygenation, B. Ventilator-Free Days, C. Sequential Organ Failure Assessment (SOFA) Score. IV, inverse variance; df, degrees of freedom; CI, confidence interval; NAC, N‑acetylcysteine; SD, standard deviation.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"image3.png","url":"https://assets-eu.researchsquare.com/files/rs-8857692/v1/1856aa4cb171216cc2b00f0a.png"},{"id":104405600,"identity":"e1fa6aa8-4fa3-4159-9c05-e7fa54aa09dd","added_by":"auto","created_at":"2026-03-11 12:23:24","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1679868,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8857692/v1/91510b48-1e93-4dc1-a72e-8711b7431470.pdf"},{"id":104338195,"identity":"3b2e0d8b-efbb-448e-af7b-ae1f9e126672","added_by":"auto","created_at":"2026-03-10 16:18:28","extension":"xlsx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":171125,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementarysearchexlcusioncharacteristics.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-8857692/v1/c2c5cf14c995910ef8f6af5f.xlsx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Global Evidence on Glutathione and N-Acetylcysteine Therapy in Acute Respiratory Distress Syndrome: A Systematic Review and Meta-Analysis","fulltext":[{"header":"Introduction","content":"\u003cp\u003eWith mortality rates ranging from 30% to 45% despite better supportive care, acute respiratory distress syndrome (ARDS) is a potentially fatal condition linked to severe acute hypoxemic respiratory failure, which is characterised by non-cardiogenic pulmonary oedema and bilateral pulmonary infiltrates [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Dysregulated inflammation, oxidative stress, and increased alveolar\u0026ndash;capillary permeability are all part of the pathogenesis of ARDS, which causes severe respiratory impairment [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. While extracorporeal membrane oxygenation (ECMO), protected lung ventilation, and prone ventilation all improved outcomes, no pharmaceutical treatment has consistently reduced mortality, underscoring the need for adjuvant therapies targeting fundamental processes. The most common antioxidant in the lung, glutathione (GSH), is a tripeptide consisting of glutamate, cysteine, and glycine. It plays a significant role in immunological response, redox balance, and epithelial barrier function [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. ARDS exacerbates oxidative damage, lipid peroxidation, and pro-inflammatory signalling by drastically lowering glutathione in alveolar lining fluid and plasma [\u003cspan additionalcitationids=\"CR7\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e\n\u003ch3\u003eMechanisms of Action of NAC/Glutathione in ARDS\u003c/h3\u003e\n\u003cp\u003eNAC prevents glutathione depletion by restoring intracellular glutathione (GSH), the primary endogenous antioxidant of lung epithelial cells and alveolar macrophages, as a donor of cysteine [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. NAC enhances cellular resistance to reactive oxygen species (ROS), prevents lipid peroxidation, and preserves mitochondrial function in alveolar tissue by restoring GSH levels [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Additionally, NAC directly neutralises free radicals, including superoxide, hypochlorous acid, and hydroxyl radicals [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. NAC has strong anti-inflammatory properties in addition to its redox effects.\u003c/p\u003e \u003cp\u003eTumour necrosis factor-alpha (TNF-α), IL-6, and interleukin (IL)-1β, which are important mediators of cytokine-induced lung damage, are downregulated as a result of its suppression of nuclear factor-kappa B (NF-κB) activation [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Additionally, NAC suppresses the NLRP3 inflammasome, which reduces IL-18 release and caspase-1 activation, hence reducing the hyperactive immunological response typical of ARDS [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e] [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. At the same time, NAC activates the Nrf2 antioxidant pathway, which raises the transcription of the cytoprotective enzymes superoxide dismutase, glutathione peroxidase, and heme oxygenase-1 [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].NAC maintains endothelial barrier by inhibiting ROS-mediated disruption of tight junction [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. It cleaves disulfide bonds into multimers of von Willebrand factor (vWF), decreases platelet adhesion, and reduces microthrombi formation [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. NAC further downregulates plasminogen activator inhibitor-1 (PAI-1), which increases fibrinolysis and prevents the prothrombotic state in ARDS and COVID-19 ARDS [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e].\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eEvidence from Experimental, Translational, and Clinical Studies\u003c/h2\u003e \u003cp\u003eFang et al. [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e] showed that diminished glutathione and decreased GPX4 activity make epithelial cells sensitive to ferroptosis, linking antioxidant depletion directly to epithelial damage Similarly, Yang et al. (2025) and Yu et al. (2025) demonstrated that interventions that maintain glutathione pools\u0026mdash;through O-GlcNAcylation of GPX4 or stimulation of the Nrf2/G6PDH pathway\u0026mdash;reduced ferroptotic death and enhanced lung outcomes in ischemia\u0026ndash;reperfusion and sepsis models [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Lin et al. [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e] also validated that the natural product liriodendrin preserved cystine\u0026ndash;glutathione homeostasis and GPX4 activity, supporting the preeminence of the glutathione axis in oxidative lung damage He et al. [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e] found that NAC inhibited ACSL4-driven ferroptosis in secondary ARDS following myocardial ischemia, providing mechanistic credibility to its therapeutic value. Systems biology strategies have enlarged these mechanistic discoveries. Cui and Huang [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Based on multi-omics analysis, IT pointed towards glutathione metabolism genes as central regulators of ferroptosis in ARDS, of which YWHAE was identified as a core hub gene. According to Li et al. [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e], glutathione is at the intersection of oxidative cell death pathways because it interacts not only with ferroptosis but also with cuproptosis and disulfidptosis. Zhu et al. [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e] demonstrated COVID-19-specific evidence that TIPE2 maintained glutathione\u0026ndash;GPX4 action, protecting macrophages against ferroptosis caused by the spike protein. Enteral nutrition supplemented with antioxidants and glutathione precursors increased oxygenation and decreased oxidative stress markers in patients with ARDS, according to Yal\u0026ccedil;ınkaya et al. [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe clinical importance of redox equilibrium was highlighted by Lal and Corechi [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e], who found a connection between poor outcomes in ARDS and alcohol use disorder, which causes glutathione store depletion. Clough et al. [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e] established glutathione as a severity index by confirming that reduced pulmonary glutathione defences were linked to higher susceptibility to lung damage in models of preclinical hyperoxia. Clinical experiments have had conflicting results. NAC or procysteine have shown a physiological benefit in early RCTs, but there has been no conclusive survival benefit [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eA meta-analysis by Zhang et al. (2017) concluded that NAC enhanced oxygenation and decreased ICU stay but not mortality, whereas subsequent synthesis of eight RCTs by Lu et al. reaffirmed these results [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. Dewan and Shinde (2022) recently described an early clinical response using intravenous glutathione among 240 ARDS patients with decreased oxygen demands and shorter durations of hospitalization [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]. Interest was renewed in the COVID-19 pandemic: Yang et al. [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e] discovered low glutathione and increased lipid peroxidation markers in bronchoalveolar fluid of patients with severe ARDS. Aisa-Alvarez et al. [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]and Taher et al. [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e] noted an improvement in oxygenation with NAC supplementation, but survival advantages were inconsistent [\u003cspan additionalcitationids=\"CR37\" citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]. Larger series, such as Gonz\u0026aacute;lez-Guzm\u0026aacute;n et al. [\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e], demonstrated enhanced survival with oral NAC in mechanically ventilated COVID-19 ARDS patients, whereas Gamarra-Morales et al. [\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e] reported physiological benefits without uniform mortality benefit [\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e, \u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e]. Meta-analyses are also still unclear, with some indicating possible mortality decrease and others reporting no substantial effect [\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e, \u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e]. NAC's mucolytic and antioxidant action in ARDS was summarised by Mokra and Mokry [\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e] as having positive effects in lowering oxidative stress, while the clinical findings were inconsistent due to variations in dosage and delivery. The synergistic potential of mixing glutathione precursors with vitamins and other antioxidants was also emphasised by Al-Kufaishi and Al-Musawi [\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e]. Worldwide experience with glutathione supplementation ranges from Europe to North America, the Middle East, and Asia, in a variety of ARDS etiologies such as sepsis, trauma, pneumonia, and viral illness [\u003cspan additionalcitationids=\"CR46 CR47\" citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e]. In view of the uncertainties, a revised synthesis is indicated. The current systematic review and meta-analysis thus assesses randomized controlled trials of Glutathione and or NAC therapy in ARDS, with the twin objectives of establishing their efficacy and charting the worldwide experience in differing populations and clinical settings.\u003c/p\u003e \u003c/div\u003e"},{"header":"Methods","content":"\u003cp\u003eThe search strategy employed both controlled vocabulary (e.g., MeSH, Emtree) and free-text keywords for N-acetylcysteine, Glutathione and ARDS. We performed a systematic literature search in PubMed, Scopus and Web of Science for pertinent studies between January 2010 and March 2025. For instance, the PubMed search query used the following keywords: (\"N-acetylcysteine\" OR \"NAC\" OR \"acetylcysteine\" OR \"glutathione\") AND (\"acute respiratory distress syndrome\" OR \"ARDS\" OR \"acute lung injury\" OR \"ALI\" OR \"sepsis\" OR \"septic shock\" OR \"pneumonia\" OR \"mechanical ventilation\" OR \"burn injury\").\u003c/p\u003e \u003cp\u003eEligibility criteria: Population: Adults with ARDS (according to Berlin or other criteria) or at high risk (those with sepsis, pneumonia or mechanical ventilation). Intervention: any NAC or glutathione regimen (dose, route, timing)- whether nebulised, IV, or oral, including those used either as monotherapy or in combination with other antioxidants. Comparator: Placebo, no treatment or usual care. Outcomes: Primary: 28-day mortality and secondary (ICU/hospital length of stay, ventilator-free days, PaO2/FiO2, SOFA score, biomarkers). Study design: RCTs only. Restrictions: languages, publication types and date range (2010\u0026ndash;2025).\u003c/p\u003e \u003cp\u003eExclusion criteria were used for studies published in languages other than English, preclinical or animal research, reviews, meta-analyses, case reports, and editorials, and also for studies with no full-text availability.\u003c/p\u003e \u003cp\u003eThe records extracted from the databases were transferred to a reference manager, and any duplicate records were discarded. Two reviewers independently assessed the titles and abstracts for eligibility, after which full texts of potentially qualifying articles were reviewed. Differences in study selection were addressed through discussion, and the third reviewer adjudicated when needed.\u003c/p\u003e \u003cp\u003eThis review has been registered in the International Prospective Register of Systematic Reviews (PROSPERO) under the registration ID CRD420251155902. The registration details are available at \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.crd.york.ac.uk/PROSPERO/view/CRD420251155902\u003c/span\u003e\u003cspan address=\"https://www.crd.york.ac.uk/PROSPERO/view/CRD420251155902\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/p\u003e\n\u003ch3\u003eData Extraction\u003c/h3\u003e\n\u003cp\u003eData extraction was performed independently by two reviewers employing a uniform data collection form to maintain consistency and reduce bias. Data extracted included study features (first author, publication year, country, clinical setting, and study design) and population characteristics like sample size, etiology of underlying ARDS, or risk factors in high-risk groups. Intervention features were documented, such as the dose, administration route, frequency, treatment duration of Glutathione or N-acetylcysteine, and timing relative to ARDS onset. Data on comparators, whether placebo, usual care, or other antioxidants, were also obtained. Outcomes were described as either clinical (mortality, mechanical ventilation duration, ICU or hospital length of stay, ARDS occurrence or severity) or biological (oxidative stress and inflammatory markers). The principal findings of every study were recorded in a systematic format.\u003c/p\u003e\n\u003ch3\u003eRisk of Bias Assessment\u003c/h3\u003e\n\u003cp\u003eRisk of bias was independently assessed by two reviewers using Cochrane Risk of Bias tool (RoB 2.0) across domains of randomization, deviations from intended interventions, missing outcome data, outcome measurement, and selective reporting. All the domains were graded as low risk, some concerns, or high risk of bias. Disagreements between reviewers were addressed by dialogue or, if needed, by a third reviewer\u0026rsquo;s judgement.\u003c/p\u003e\n\u003ch3\u003eData Synthesis\u003c/h3\u003e\n\u003cp\u003eDue to the anticipated heterogeneity of study populations, Glutathione or N-acetylcysteine regimens, and reported outcomes, qualitative synthesis of findings was performed for most outcomes. Where sufficient homogeneity existed, defined as five or more randomized controlled trials reporting on similar outcomes, a quantitative synthesis by meta-analysis was completed. A random-effects model was used to adjust for variability among studies with regard to patient populations, intervention protocols, and clinical settings.\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eStatistical calculations were conducted using MetaAnalysisOnline.com, a computer program for quick meta-analysis of clinical and epidemiologic studies (Fekete \u0026amp; Gy\u0026ouml;rffy, 2025). Pooled effect estimates were reported as risk ratios (RR) with 95% confidence intervals (CI) in binary outcomes (e.g., mortality, ARDS incidence) and mean differences (MD) with 95% CI in numeric outcomes (e.g., ventilator-free days, ICU stay). Between-study heterogeneity was determined by means of the I\u0026sup2; statistic, which at 25%, 50%, and 75% indicates low, moderate, and high heterogeneity, respectively. Sensitivity analyses were to be performed to determine the stability of findings pooled by excluding high-risk studies. Subgroup analyses according to ARDS etiology (COVID-19 vs. non-COVID), route of NAC administration (intravenous vs. inhaled vs. oral), and timing of treatment (early vs. late ARDS) were also entertained based on data availability. Visual assessment of publication bias was to be performed using funnel plots whenever more than ten studies were included in an analysis.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eEthical Considerations\u003c/h3\u003e\n\u003cp\u003eThis review does not involve human subject information, primary data collection, or any forms of experimentation on individuals.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e \u003cem\u003eStudy identification\u003c/em\u003e. A total of 245 records were retrieved from PubMed (n\u0026thinsp;=\u0026thinsp;90), Web of Science (n\u0026thinsp;=\u0026thinsp;97), and Scopus (n\u0026thinsp;=\u0026thinsp;58). After removal of 40 duplicates, 205 distinctive records were screened by title and abstract, of which 103 were excluded (non-human studies, wrong study type, non-English language, or irrelevant population). The remaining 102 articles were assessed for eligibility. Of these, 36 could not be retrieved in full text. Sixty-six full-text articles were reviewed in detail; 60 were excluded from the quantitative synthesis because they were non-randomized studies, used interventions other than NAC/glutathione, reported surrogate outcomes only, or were conducted in outpatient/mild disease populations. However, many of these were retained to inform the qualitative synthesis. Ultimately, six randomized controlled trials (RCTs) met all eligibility criteria and were included in the meta-analysis (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). No clinical studies were identified in which Glutathione itself was administered as the interventional drug in patients with ARDS across the databases searched in the study.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cem\u003eCharacteristics of studies\u003c/em\u003e. A total of six randomized controlled trials (RCTs) with 452 patients were included, of whom 229 received NAC and 223 served as controls. Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e summarizes the characteristics of the included studies, covering patient populations, interventions, and outcomes. Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e presents the results of the risk of bias assessment. Two trials (de Alencar et al., 2021 and Taher et al., 2021) were rated at overall low risk of bias, three at some concerns, and one at high risk due to incomplete outcome. Given the few studies were included (\u0026lt;\u0026thinsp;10), statistical tests for funnel plot asymmetry were not performed. Publication bias was assessed descriptively using a funnel plot of the six RCTs. Visual inspection suggested a roughly symmetrical distribution of effect estimates around the mean, with larger studies clustering toward the top and smaller studies more dispersed toward the bottom, as expected. There was no clear evidence of missing studies on either side. However, given the small number of trials, interpretation of potential publication bias remains limited.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCharacteristics of Included RCTs on NAC and ARDS\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"10\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFirst Author (Year)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCountry / Setting\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePopulation\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSample Size (NAC / Control)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eStudy Design\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eIntervention (Dose \u0026amp; Route)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eControl\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eDuration\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003ePrimary Outcomes\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c10\"\u003e \u003cp\u003eKey Results\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ede Alencar et al. (2021)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBrazil \u0026ndash; Hospital das Cl\u0026iacute;nicas, S\u0026atilde;o Paulo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAdults\u0026thinsp;\u0026ge;\u0026thinsp;18 yrs with severe COVID-19 (SaO₂ \u0026lt; 94% or RR\u0026thinsp;\u0026gt;\u0026thinsp;24 bpm)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e135 (68 / 67)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eDouble-blind RCT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eIV NAC 21 g (~\u0026thinsp;300 mg/kg) over 20 h\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eDextrose 5% (placebo)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eSingle 20-h course\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNeed for mechanical ventilation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eNo significant difference in invasive ventilation (20.6% vs 23.9%; p\u0026thinsp;=\u0026thinsp;0.64) or mortality\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePanahi et al. (2022)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIran \u0026ndash; Tehran, single-center\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eHospitalized adults with COVID-19 pneumonia (no imminent intubation)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e250 (125 / 125)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eRandomized open-label trial\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eInhaled NAC spray 200 \u0026micro;g q12h \u0026times; 7 days\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eStandard care\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e7 days\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e28-day mortality, CT and NEWS scores\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eMortality 3.2% vs 39.2% (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001); significant improvement in CT and NEWS scores\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAisa-\u0026Aacute;lvarez et al. (2020)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMexico \u0026ndash; Two ICUs (Mexico City)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAdults with septic shock (Sepsis-3 criteria)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e97 (total: NAC 20 / Control 21\u0026thinsp;+\u0026thinsp;other antioxidant arms)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eTriple-masked RCT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNAC 600 mg q12h \u0026times; 5 days (oral/NG) + standard care\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eStandard sepsis care\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e5 days\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eChange in SOFA score\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eNAC ΔSOFA\u0026thinsp;\u0026minus;\u0026thinsp;0.62 (p\u0026thinsp;=\u0026thinsp;0.18); no significant improvement; Vit C and melatonin effective\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTaher et al. (2021)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIran \u0026ndash; Hamadan University Hospital ICU\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMild-to-moderate COVID-19 ARDS (PaO₂/FiO₂ 100\u0026ndash;300 mm Hg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e92 (47 / 45)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eDouble-blind pilot RCT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eIV NAC 40 mg/kg/day continuous \u0026times; 3 days\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eDextrose 5% (placebo)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e3 days\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e28-day mortality; WHO ordinal scale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eNo significant difference in mortality (25.5% vs 31.1%) or recovery (p\u0026thinsp;\u0026gt;\u0026thinsp;0.05)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePeivandi Yazdi et al. (2021)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIran \u0026ndash; Mashhad University ICU\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAdults with sepsis (\u0026ge;\u0026thinsp;2 SIRS criteria)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e60 (Intermittent 20 / Continuous 20 / Placebo 20)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ePilot RCT (3-arm)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eIV NAC 100 mg/kg/24 h (intermittent or continuous)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eIsotonic saline (placebo)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e24 h\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eTotal Antioxidant Capacity (TAC), Malondialdehyde (MDA)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eNAC \u0026uarr; TAC (p\u0026thinsp;=\u0026thinsp;0.007) and \u0026darr; MDA (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) vs placebo; no clinical endpoints assessed\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNajafi et al. (2014)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIran \u0026ndash; Tehran University ICUs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMechanically ventilated septic patients (ARDS-risk)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e39 (21 / 18)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eRandomized controlled trial\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eIV NAC 3 g q6h \u0026times; 72 h (total 12 g/day \u0026times; 3 days)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eStandard sepsis care\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e3 days\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eIgM, HβD2, GSH levels\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eNo significant differences in GSH, IgM, HβD2, or mortality (p\u0026thinsp;\u0026gt;\u0026thinsp;0.05) \u0026mdash; trend toward higher GSH in NAC group\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eRisk of Bias Assessment (RoB 2.0) for Included RCTs\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStudy (Year)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRandomization\u003c/p\u003e \u003cp\u003eProcess\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDeviations from Intended Interventions\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMissing Outcome Data\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eMeasurement of Outcome\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSelection of Reported Result\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ede Alencar et al., 2021\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLow risk\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eLow risk\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eLow risk\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eLow risk\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eLow risk\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAisa-Alvarez et al., 2021\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eUnclear\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eLow risk\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eLow risk\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eLow risk\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eLow risk\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNajafi et al., 2014\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLow risk\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSome concerns (dose adjustments)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eLow risk\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eLow risk\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eLow risk\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePanahi et al., 2023\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLow risk\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eLow risk\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSome concerns (dropouts not fully explained)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eLow risk\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eLow risk\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePeivandi Yazdi et al., 2020\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSome concerns (randomization details unclear)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eLow risk\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eLow risk\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSome concerns (no blinding of assessors)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eLow risk\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTaher et al., 2021\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLow risk\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eLow risk\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eLow risk\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eLow risk\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eLow risk\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eMortality\u003c/h2\u003e \u003cp\u003eFour randomized controlled trials involving 420 patients reported 28-day mortality [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e, \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e, \u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e, \u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e]. Pooled analysis showed no significant difference between NAC and control groups (RR 0.83, 95% CI 0.58\u0026ndash;1.18, p\u0026thinsp;=\u0026thinsp;0.29). There was no evidence of statistical heterogeneity across studies (I\u0026sup2; = 0%, χ\u0026sup2; = 0.85, p\u0026thinsp;=\u0026thinsp;0.84). However, potential clinical heterogeneity remains given differences in study populations (COVID-19 vs. sepsis) and intervention regimens (inhaled vs. intravenous NAC) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eHospital stay\u003c/h2\u003e \u003cp\u003eFour randomized controlled trials including 420 patients (209 NAC, 211 control), reported data on length of stay [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e, \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e, \u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e, \u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e]. Panahi et al.[\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e] reported a mean hospital stay of 6.7\u0026thinsp;\u0026plusmn;\u0026thinsp;3.5 days in the NAC group compared with 8.4\u0026thinsp;\u0026plusmn;\u0026thinsp;4.6 days in the control group. Aisa-Alvarez et al.[\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e] observed mean hospital stays of 13.7\u0026thinsp;\u0026plusmn;\u0026thinsp;8.8 versus 14.1\u0026thinsp;\u0026plusmn;\u0026thinsp;8.9 days, respectively. Taher et al. (2021) reported 12.1\u0026thinsp;\u0026plusmn;\u0026thinsp;5.3 versus 13.2\u0026thinsp;\u0026plusmn;\u0026thinsp;6.1 days, while de Alencar et al. [\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e] noted mean ICU stays of 11.4\u0026thinsp;\u0026plusmn;\u0026thinsp;6.2 versus 12.2\u0026thinsp;\u0026plusmn;\u0026thinsp;5.9 days in the NAC and control groups, respectively. Pooled analysis demonstrated a significant reduction in length of stay with NAC compared with control (SMD = \u0026minus;\u0026thinsp;0.30; 95% CI: \u0026minus;\u0026thinsp;0.50 to \u0026minus;\u0026thinsp;0.10; p\u0026thinsp;=\u0026thinsp;0.004) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eNeed for Mechanical Ventilation\u003c/h2\u003e \u003cp\u003eTwo randomized controlled trials comprising a total of 335 patients, evaluated the effect of NAC on the requirement for invasive mechanical ventilation [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e, \u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e]. In the study by Panahi et al.[\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e] 12 of 125 patients (9.6%) in the NAC group required mechanical ventilation compared with 21 of 125 patients (16.8%) in the control group (RR\u0026thinsp;=\u0026thinsp;0.57; 95% CI: 0.29\u0026ndash;1.11). Similarly, Taher et al.[\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e] reported that 8 of 42 patients (19.0%) in the NAC group required mechanical ventilation compared to 11 of 43 patients (25.6%) in the control group (RR\u0026thinsp;=\u0026thinsp;0.74; 95% CI: 0.33\u0026ndash;1.67) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eC). Pooled analysis evidenced a non-significant reduction in the risk of mechanical ventilation with NAC (RR\u0026thinsp;=\u0026thinsp;0.64; 95% CI: 0.38\u0026ndash;1.06; p\u0026thinsp;=\u0026thinsp;0.084), with no evidence of heterogeneity. However, this estimate should be interpreted with caution as only two trials were included.\u003c/p\u003e \u003cp\u003eRandom-effects Mantel-Haenszel analysis of risk ratios found no significant group differences (RR 0.64, 95% CI 0.38\u0026ndash;1.06), with nonsignificant overall effect and low heterogeneity, reflecting consistent effect directions and magnitudes across trials.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eEffect of NAC on Oxygenation (PaO₂/FiO₂ ratio, Day 5\u0026ndash;7)\u003c/h2\u003e \u003cp\u003eFour randomized controlled trials, including a total of 420 patients, reported PaO₂/FiO₂ ratio at day 5\u0026ndash;7 of treatment. The pooled analysis showed no statistically significant improvement in PaO₂/FiO₂ ratio with NAC compared to control (Standardized Mean Difference [SMD]\u0026thinsp;=\u0026thinsp;0.17; 95% CI: \u0026minus;\u0026thinsp;0.03 to 0.36; p\u0026thinsp;=\u0026thinsp;0.09) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eA). Between-study heterogeneity was negligible (I\u0026sup2; = 0%, p\u0026thinsp;=\u0026thinsp;0.94), and the prediction interval (\u0026ndash;0.14 to 0.48) suggested that future studies are also unlikely to show a large clinical effect in either direction. Overall, while individual studies indicated modest increases in PaO₂/FiO₂ ratio, the pooled evidence does not support a clear benefit of NAC on short-term oxygenation in ARDS or ARDS-risk populations.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eVentilator-Free Days\u003c/h2\u003e \u003cp\u003eTwo RCTs, including a total of 124 critically ill patients (63 individuals in the NAC group and 61 individuals in the control group), reported ventilator-free days at 28 days. A meta-analysis showed that there was no statistically significant difference between NAC and control groups (SMD 0.20, 95% CI \u0026minus;\u0026thinsp;0.16 to 0.55, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.28), with no evidence of heterogeneity (I\u0026sup2; = 0%). The prediction interval (\u0026ndash;2.09 to 2.49) was wide, indicating uncertainty in the true effect across different settings (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eB). Overall, NAC did not significantly improve ventilator-free days compared with the control\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003eSequential Organ Failure Assessment (SOFA) Score\u003c/h2\u003e \u003cp\u003eTwo randomized controlled trials evaluated the effect of NAC on organ dysfunction using SOFA scores at Day 7. Pooled analysis showed no significant reduction in SOFA scores in the NAC group compared with controls (SMD \u0026minus;\u0026thinsp;0.31, 95% CI \u0026minus;\u0026thinsp;0.67 to 0.04; p\u0026thinsp;=\u0026thinsp;0.085) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eC). Statistical heterogeneity was absent.\u003c/p\u003e \u003cp\u003eThe differences were not statistically significant, despite the fact that both studies showed a numerical trend towards lower SOFA values with NAC. These results imply that NAC does not consistently reduce multi-organ dysfunction in critically ill individuals with ARDS or at risk.\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe effectiveness of N-acetylcysteine (NAC) in patients with acute respiratory distress syndrome (ARDS) and high-risk ARDS populations was examined in this systematic review and meta-analysis. Across six small RCTs, NAC did not reduce mortality or major clinical outcomes in ARDS, though small reductions in hospital stay and favourable biomarker changes were observed.\u003c/p\u003e \u003cp\u003eNotably, a small but statistically significant decrease in hospital length of stay was found with NAC, indicating possible advantages for recovery dynamics. The included trials differed in patient demographics (COVID-19 versus non-COVID ARDS, sepsis, and critically sick patients on mechanical ventilation) and intervention protocols (IV versus inhaled NAC), therefore this result should be regarded cautiously. The reason oxygenation metrics improved in certain trials but not in the pooled analysis could be partially explained by subgroup heterogeneity.\u003c/p\u003e \u003cp\u003eNAC in ARDS has a compelling biological justification. Dysregulated inflammation, ROS buildup, endothelial and epithelial damage, and disruption of the alveolar-capillary barrier resulting in non-cardiogenic pulmonary oedema are the hallmarks of ARDS. As a precursor to glutathione, NAC directly scavenges ROS and restores intracellular antioxidant stores, lowering oxidative stress. Additionally, it reduces inflammatory cytokines like TNF-α, IL-6, and IL-8 via modulating nuclear factor-κB (NF-κB) activity. Additionally, NAC may improve ventilation\u0026ndash;perfusion matching by influencing alveolar fluid clearance and endothelial nitric oxide bioavailability. These mechanisms are supported by observed decreases in inflammatory mediators and oxidative stress indicators in included investigations [\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e, \u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThis mechanistic explanation is further supported by preclinical data. Through glutathione (GSH)-mediated mechanisms, PEGylated artesunate prodrugs reduced acute lung injury caused by LPS in murine models [\u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e]. Through the AKT/GSK3β/Nrf2 pathway, cyasterone was demonstrated to reduce acute lung injury associated with sepsis, demonstrating a GSH-dependent antioxidant mechanism [\u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e]. In septic ARDS models, rosmarinic acid decreased oxidative stress and bronchial epithelial ferroptosis [\u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e], whereas Mucin 1 inhibited ferroptosis and improved antioxidant defence via the GSK3β/Keap1-Nrf2-GPX4 pathway [\u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e]. In ARDS models, it has also been demonstrated that adipose-derived exosomes maintain the pulmonary endothelial barrier by downregulating oxidative stress pathways [\u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e57\u003c/span\u003e]. Similarly, in experimental ARDS, glutamine treatment, a precursor to GSH, decreased extracellular trap release and inflammation [\u003cspan citationid=\"CR58\" class=\"CitationRef\"\u003e58\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eStudies on humans also demonstrate how NAC affects lung function and oxidative stress. In hospitalised COVID-19 patients, high-dose oral NAC enhanced oxidative markers [\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e], while inhaled NAC enhanced lung function following liver transplantation [\u003cspan citationid=\"CR59\" class=\"CitationRef\"\u003e59\u003c/span\u003e]. In paediatric pneumonia, NAC and Ambroxol enhanced inflammatory biomarkers, demonstrating a wider potential for redox modulation [\u003cspan citationid=\"CR60\" class=\"CitationRef\"\u003e60\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eNevertheless, these biochemical and physiological effects have not consistently translated into survival benefits. This discrepancy underscores the complexity of ARDS pathophysiology, which extends beyond oxidative stress alone. Neutrophil-mediated injury, dysregulated coagulation, microthrombosis, and fibroproliferation all contribute to outcomes, and targeting a single pathway may be insufficient. Timing may also be critical: NAC may exert greater benefit in early ARDS before irreversible epithelial and fibrotic changes occur, whereas late administration may have limited impact.\u003c/p\u003e \u003cp\u003eFindings from prior reviews are broadly consistent. Zhang et al. [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e], analyzing five RCTs in non-COVID ARDS (183 patients), found no significant mortality benefit and only a modest reduction in ICU stay. In contrast, Alam et al. [\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e], synthesizing studies in COVID-19 ARDS (20,503 patients, including observational cohorts), reported significant mortality reduction and improvements in oxygenation and inflammatory markers, though with high heterogeneity and variable study quality. Mechanistically, this divergence may reflect differences in ARDS etiology: viral-mediated ARDS, such as in COVID-19, is driven by excessive systemic inflammation, cytokine storm, and oxidative stress, pathways more directly targeted by NAC. Conversely, non-COVID ARDS often involves heterogeneous triggers such as trauma, aspiration, or sepsis, where oxidative stress is only one of multiple pathogenic drivers.\u003c/p\u003e \u003cp\u003eThe relationship between glutathione levels and oxidative stress was further confirmed through analyses of bronchoalveolar lavage fluid (BALF) and markers of oxidative stress. Spearman correlation analyses linking chest CT fibrosis scores, fibroproliferative markers, and pulmonary redox parameters\u0026mdash;including glutathione levels\u0026mdash;demonstrate the impact of reduced GSH on oxidative stress and lung injury in COVID-19 ARDS patients [\u003cspan citationid=\"CR61\" class=\"CitationRef\"\u003e61\u003c/span\u003e, \u003cspan citationid=\"CR62\" class=\"CitationRef\"\u003e62\u003c/span\u003e]. These findings align with preclinical evidence showing that modulation of GSH and associated antioxidant pathways can ameliorate epithelial and endothelial injury [\u003cspan additionalcitationids=\"CR64\" citationid=\"CR63\" class=\"CitationRef\"\u003e63\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR65\" class=\"CitationRef\"\u003e65\u003c/span\u003e], highlighting a mechanistic rationale for continued investigation [\u003cspan citationid=\"CR66\" class=\"CitationRef\"\u003e66\u003c/span\u003e, \u003cspan citationid=\"CR67\" class=\"CitationRef\"\u003e67\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eTaken together, the evidence suggests that NAC and other GSH-modulating therapies may offer modest physiological benefits, particularly through antioxidant and anti-inflammatory pathways, but do not consistently improve hard outcomes across unselected ARDS populations. Its efficacy may be context-dependent, with greater promise in virally mediated or sepsis-associated ARDS where oxidative stress is central. Future studies should therefore focus on well-designed, well-powered multicenter RCTs with uniform definitions of ARDS, meticulous NAC dosing protocols, and careful timing of intervention. Subgroup analyses stratified by ARDS etiology and stage of disease will be crucial to identify populations most likely to benefit.\u003c/p\u003e \u003cdiv id=\"Sec18\" class=\"Section2\"\u003e \u003ch2\u003eLimitations\u003c/h2\u003e \u003cp\u003eLimited number of RCTs (n\u0026thinsp;=\u0026thinsp;6) and small total sample size (452 patients), reducing statistical power to detect mortality differences. Considerable clinical heterogeneity across studies, including variation in ARDS etiology (COVID vs non-COVID) and definitions, NAC dose/regimens and timing, route (IV, inhaled, oral), incomplete biomarker reporting, treatment duration and some risk of bias concerns. Outcomes were not standardized; some trials reported only surrogate biomarkers, limiting cross-trial comparability. Potential publication bias cannot be excluded given the small number of studies available for synthesis. Lack of subgroup analyses prevents firm conclusions about which ARDS phenotypes or clinical contexts benefit most from NAC. Lastly, this review did not search grey literature sources or clinical trial registries, which may have led to the omission of relevant unpublished or ongoing studies.\u003c/p\u003e \u003c/div\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis systematic review synthesizes global evidence on the role of glutathione and its precursor N-acetylcysteine in the prevention and management of acute respiratory distress syndrome (ARDS) and ARDS-risk populations. Across six randomized controlled trials, current evidence does not support routine NAC use solely to improve mortality in ARDS. However, demonstrated consistent biological effects in reducing oxidative stress markers and inflammatory mediators, with some studies reporting improved oxygenation and clinical outcomes. Future trials should be larger, multicenter, with standardized NAC dosing, early administration, and clinically meaningful primary endpoints.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eFunding Information:\u003c/h2\u003e \u003cp\u003eThis research did not receive any specific grants\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eConceptualization: Lokesh ShanmugamData curation: Lokesh Shanmugam, A Sathya, Aswinth R, Siva Ranganathan Green, Umarani R, Siddarth R, Siddarth P, Joshua ChadwickFormal analysis: Lokesh Shanmugam, A Sathya, Aswinth R, Siva Ranganathan Green, Umarani R, Siddarth R, Siddarth P, Joshua ChadwickProject administration: Lokesh ShanmugamSupervision: Lokesh ShanmugamValidation: Lokesh Shanmugam, A Sathya, Aswinth R, Siva Ranganathan Green, Umarani R, Siddarth R, Siddarth P, Joshua ChadwickWriting-original draft: Lokesh Shanmugam, A Sathya, Aswinth R, Siva Ranganathan GreenWriting-review \u0026amp; editing: Lokesh Shanmugam, A Sathya, Aswinth R, Siva Ranganathan Green, Umarani R, Siddarth R, Siddarth P, Joshua Chadwick\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eThe data supporting the findings of this study are available from the corresponding author upon reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eDiamond MPHSD et al (2025) Acute Respiratory Distress Syndrome. 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Med Hypotheses 143:110102. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.mehy.2020.110102\u003c/span\u003e\u003cspan address=\"10.1016/j.mehy.2020.110102\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"the-egyptian-journal-of-internal-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"Learn more about [The Egyptian Journal of Internal Medicine](https://ejim.springeropen.com/)","snPcode":"43162","submissionUrl":"https://submission.springernature.com/new-submission/43162/3","title":"The Egyptian Journal of Internal Medicine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Open","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Acute Respiratory Distress Syndrome, N-acetylcysteine, Glutathione, Oxidative Stress, Antioxidant Therapy, Systematic Review, Meta-analysis","lastPublishedDoi":"10.21203/rs.3.rs-8857692/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8857692/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eAcute 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.\u003c/p\u003e\u003ch2\u003eObjective\u003c/h2\u003e \u003cp\u003eTo systematically review the effectiveness of GSH and NAC in ARDS and high-risk patients in randomized controlled trials(RCTs).\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eSystematic 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.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eSix RCTs (n\u0026thinsp;=\u0026thinsp;452 patients; 229 NAC, 223 control) were included. NAC did not reduce 28-day mortality (RR 0.83; 95% CI 0.58\u0026ndash;1.18). NAC slightly reduced hospital stay (MD \u0026minus;\u0026thinsp;0.30; CI \u0026minus;\u0026thinsp;0.50 to \u0026minus;\u0026thinsp;0.10; p\u0026thinsp;=\u0026thinsp;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.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eNAC 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.\u003c/p\u003e\u003ch2\u003eTrial registration\u003c/h2\u003e \u003cp\u003eProsperoCRD420251155902; \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.crd.york.ac.uk/PROSPERO/view/CRD420251155902\u003c/span\u003e\u003cspan address=\"https://www.crd.york.ac.uk/PROSPERO/view/CRD420251155902\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/p\u003e","manuscriptTitle":"Global Evidence on Glutathione and N-Acetylcysteine Therapy in Acute Respiratory Distress Syndrome: A Systematic Review and Meta-Analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-03-10 16:18:20","doi":"10.21203/rs.3.rs-8857692/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewersInvited","content":"","date":"2026-03-04T22:37:17+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-03-04T19:34:15+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-02-26T07:33:38+00:00","index":"","fulltext":""},{"type":"submitted","content":"The Egyptian Journal of Internal Medicine","date":"2026-02-12T05:10:10+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"the-egyptian-journal-of-internal-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"Learn more about [The Egyptian Journal of Internal Medicine](https://ejim.springeropen.com/)","snPcode":"43162","submissionUrl":"https://submission.springernature.com/new-submission/43162/3","title":"The Egyptian Journal of Internal Medicine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Open","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"6b576739-dfbb-496a-8437-8aa8365129c7","owner":[],"postedDate":"March 10th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-03-10T16:18:20+00:00","versionOfRecord":[],"versionCreatedAt":"2026-03-10 16:18:20","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8857692","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8857692","identity":"rs-8857692","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}