Background <p>Intravenous anesthesia during endoscopic retrograde cholangiopancreatography (ERCP) is associated with a high incidence of respiratory depression. High-flow nasal cannula (HFNC) therapy uses a mild positive pressure load to enhance carbon dioxide washout and reduce rebreathing, thereby improving respiratory function. Therefore, it is widely used to prevent hypoxemia and hypercapnia. We aim to investigate the efficacy of a new HFNC device (AIRVO 3™) in improving respiratory status during sedated ERCP.</p> Methods <p>In a multicenter randomized controlled study involving two groups—the HFNC and low-flow nasal cannula (LFNC) groups, adult patients undergo ERCP under sedation. For sedation, either the dexmedetomidine or midazolam protocol is used according to the guidelines. Pethidine hydrochloride and pentazocine are administered intravenously as analgesics. The primary endpoint is the incidence of hypoxemia, defined as peripheral oxygen saturation (SpO₂) ≤ 90% during intravenous anesthesia. As a secondary outcome, percutaneous CO₂ concentration is measured to assess the device’s effectiveness in preventing hypercapnia. Furthermore, sedative and analgesic doses are evaluated to determine whether device use helps prevent the occurrence of hypercapnia and hypoxemia.</p> Discussion <p>This study aims to generate evidence supporting the utility of HFNC as a potential therapeutic device for ERCP under sedation by determining whether the incidence rates of hypercapnia and hypoxemia are lower in the HFNC group than in the LFNC group.</p> Trial registration {2a,2b} <p>The study was registered as <a href="https://rctportal.niph.go.jp/detail/jr?trial_id=jRCTs072240096">jRCTs072240096</a> on January 16, 2025.</p>