Gas Therapies for Chronic Wounds: Comparative Effectiveness, Safety, and Evidence Certainty—A Systematic Review and Network Meta-Analysis

Objective: To compare the efficacy and safety of gas-based therapies for chronic wounds using a systematic review and network meta-analysis (NMA). Methods: Following PRISMA 2020, we systematically searched PubMed, Embase, Web of Science, Cochrane CENTRAL, and CBM from inception to 1 October 2025, screened studies in duplicate, and resolved disagreements by arbitration (κ = 0.87). Randomized controlled trials (RCTs) enrolling adults with chronic wounds were eligible; the primary endpoint was complete wound healing. Pairwise meta-analysis used risk ratios (RRs) with 95% CIs; heterogeneity was assessed with Q/I2 and random-effects models were applied when appropriate. A frequentist NMA synthesized direct and indirect evidence, and treatments were ranked with SUCRA. Publication bias (Egger/Begg) and evidence certainty (GRADE) were evaluated. Results: Twenty-seven RCTs comprising 1673 participants were included. In pairwise pooling, gas therapies significantly increased complete healing versus standard care (random-effects RR = 2.17, 95% CI 1.61–2.94), with substantial heterogeneity (I2 = 75.7%); results were directionally consistent and robust to sensitivity analyses. Prespecified subgroup analyses suggested effect modification by intervention type and wound etiology. In the NMA, most gas modalities showed beneficial trends versus standard care; however, SUCRA ranking placed standard care highest (93.9%), a finding attributed by the authors to network structure and between-study variability. Ozone therapy and topical oxygen ranked next, whereas HBOT and cold atmospheric plasma ranked mid-range; CO2 therapy ranked lowest due to sparse evidence. Small-study effects were likely (Egger p < 0.001; Begg p = 0.013), and overall certainty was graded as moderate, limited primarily by heterogeneity, imprecision, and potential publication bias. Conclusions: Across RCTs, gas therapies as a class improve the probability of complete healing in chronic wounds relative to standard care, but effect sizes vary by modality and wound type. Given heterogeneity, possible publication bias, and inconsistencies within the evidence network, these findings should be applied with caution. HBOT remains the modality supported by the broadest evidence base, while large, high-quality, multicenter RCTs are needed to refine comparative effectiveness and safety rankings across gas therapies.