Transcutaneous Carbon Dioxide Therapy Significantly Accelerates Diabetic Foot Ulcer Healing: A Multicentre Randomised Controlled Trial

<b>Background/Objectives:</b> Diabetic foot ulcers (DFUs) represent common and severe complications of diabetes mellitus (DM). The aim of our parallel-group, open-label, superiority, multicentre randomised controlled trial (RCT) was to evaluate the effectiveness of transcutaneous gaseous carbon dioxide therapy (hereinafter CO₂ therapy) in ulcer healing in patients with non-healing DFUs. <b>Methods:</b> A total of 115 participants (89 males and 26 females, aged 65.7 ± 10.9 years) with a non-healing DFU were randomised to the intervention (76 participants) and control (39 participants) group. Participants in the intervention group received standard of care, combined with CO₂ therapies administered every weekday for four consecutive weeks. Participants in the control group received only standard of care. <b>Results:</b> After 4 weeks, 49 (64.5%) ulcers in the intervention group healed, compared with three (7.7%) in the control group (primary outcome). The percentage ulcer area reduction from baseline (secondary outcome) was significantly larger (<i>p</i> ≤ 0.001) in patients from the intervention group, with the median value 100% (18.4-100%), compared to the patients from the control group, with the median value 40% (-300-100%). Patients receiving CO₂ therapy had 35.4-fold higher odds of ulcer healing versus controls (OR 35.4, 95% CI 6.68-187.53; <i>p</i> < 0.001), and in multivariate logistic regression, CO₂ therapy remained independently associated with healing, while larger baseline ulcer area was associated with lower odds of healing (OR 0.654, 95% CI 0.438-0.977; <i>p</i> = 0.038). No adverse effects were reported. <b>Conclusions:</b> CO₂ therapy significantly contributes to ulcer healing in patients with non-healing DFUs, with no observable adverse effects, demonstrating significant potential as an effective and safe complementary treatment of DFUs in conjunction with standard of care.