Endoscopic retrograde cholangiopancreatography (ERCP) is a complex endoscopic procedure that often requires deep sedation to ensure patient comfort and procedural success. Sedation during ERCP carries inherent risks, particularly respiratory depression and hypoxemia, which are exacerbated by the use of opioids. Dexmedetomidine has gained attention as a sedative agent because it provides stable hemodynamics [1] and minimal respiratory suppression [2] compared with other sedatives. However, opioids are frequently required as adjuncts to achieve adequate analgesia and sedation, and their use increases the risk of respiratory compromise [3].

Nasal high flow (NHF) oxygen therapy delivers heated and humidified oxygen at high flow rates, reducing dead space ventilation, improving oxygenation, and decreasing the work of breathing [4, 5]. NHF has also been shown to enhance patient comfort and reduce dyspnea perception [5, 6], which may contribute to more stable ventilation during sedation. Previous studies have suggested that NHF may reduce hypoxemia during ERCP, although these investigations primarily focused on oxygenation [7]. Whether NHF can influence ventilation stability or reduce opioid requirements under dexmedetomidine‐based sedation remains unknown. The aim of this randomized controlled trial was to evaluate if NHF reduces opioid requirements compared with low‐flow oxygen (LFO) therapy during ERCP under dexmedetomidine‐based sedation, while maintaining adequate oxygenation and ventilation. The planned sample size was 118 patients (59 per group), based on a priori power calculation using exploratory data on pethidine requirements. Despite several extensions of the study period, recruitment remained challenging, and enrollment concluded with 94 patients.

This randomized controlled trial demonstrated that NHF significantly reduced opioid requirements compared with LFO during ERCP under dexmedetomidine‐based sedation, while maintaining oxygenation and ventilation. Reducing opioid exposure is clinically important because opioids carry dose‐dependent risks of respiratory depression, hypoxemia, and delayed recovery [3]. The present study provides new evidence that NHF not only prevents hypoxemia but also decreases opioid demand during endoscopic procedures.

The mechanisms underlying reduced opioid use with NHF are likely multifactorial. First, NHF decreases the work of breathing, stabilizing ventilation and reducing hypercapnia‐induced arousal [4, 5, 6, 11, 12, 13]. Second, NHF improves patient comfort and reduces dyspnea perception, which helps maintain stable sedation depth [14]. These mechanisms align with physiological studies showing that dyspnea perception activates cortical regions such as the insula and cingulate cortex [15, 16]. By alleviating the respiratory effort and level of discomfort, NHF may indirectly stabilize sedation and reduce opioid demand. These mechanistic explanations represent possible physiological interpretations and remain hypothetical, as they were not directly demonstrated by the present study.

These results align with and extend the findings of the randomized controlled trial by Sawase et al., which compared NHF without supplemental oxygen to LFO during ERCP and found comparable rates of hypoxemia and hypercapnia between the two approaches [7]. A recent multicenter trial, RENOVATE, which compared respiratory support with NHF and noninvasive ventilation in a broad range of patients with acute respiratory failure, revealed that in all groups—except cardiogenic pulmonary edema—fewer patients required dexmedetomidine for sedation [17].

The respiratory threshold for spontaneous breathing during sedation—defined as the apneic threshold on the CO₂ response curve—is determined by the interaction between sedative drug concentration and comprehensive stress, including pain, dyspnea, and general discomfort [3]. At a given sedative level, weaker stress is associated with a relative elevation of the respiratory threshold, leading to a reduced respiratory rate and increased arterial partial pressure of carbon dioxide (PaCO₂). In contrast, stronger stress enhances ventilatory drive, resulting in an increased respiratory rate and a relative reduction in PaCO₂.

Previous studies have demonstrated that NHF reduces respiratory effort and alleviates dyspnea [4]. Therefore, when a balance is achieved between different combinations—such as stress reduction via NHF with low opioid doses versus greater stress under LFO requiring high opioid doses—the respiratory rate and PaCO₂ may remain at comparable levels despite differences in opioid exposure. In the present study, although the respiratory rate and TcCO₂ did not differ between the groups, this may reflect titration of pethidine in response to procedure‑interfering movement, which likely equalized perceived procedural stress between groups. This interpretation represents a possible explanation for the observed respiratory parameters and is not presented as a conclusion directly demonstrated by the study. Pethidine was administered as needed in response to patient movement or procedural discomfort, which may have resulted in broadly comparable levels of stress between the groups. This titration strategy may explain the absence of intergroup differences in the respiratory rate and TcCO₂ AUC.

In addition, PSi values were lower in the NHF group, suggesting deeper sedation [9]. In general, deeper sedation is associated with an upward shift of the apneic threshold on the CO₂ response curve and reduced ventilatory responsiveness. However, TcCO₂ remained comparable between groups in this study. This observation may reflect enhanced CO₂ clearance with NHF [18]. Alternatively, the difference in pethidine dosing between groups may have been insufficient to produce clinically apparent respiratory depression under dexmedetomidine‐based sedation, known to preserve ventilatory drive relative to other sedatives [2].

Furthermore, opioid‐related respiratory effects may have become apparent after the discontinuation of NHF, when the supportive effects of high‐flow therapy were removed. However, postprocedural respiratory measurements were not collected in this study, and further investigation is necessary.

The NHF group exhibited lower PSi and EMG% compared with the LFO group. Lower PSi reflects deeper and more stable sedation depth [9], while reduced EMG% indicates suppression of muscle activity and arousal responses [10]. These findings suggest that NHF enhances sedation stability by reducing respiratory discomfort and minimizing patient movement. Other EEG‐derived indices (SR%, ARTF%, and SEF Hz) did not differ between groups, which indicates that NHF primarily influences arousal‐related components rather than EEG frequency characteristics [10].

NHF reduced pethidine requirements while maintaining comparable respiratory parameters when normalized by sedation duration. The observation that lower opioid exposure coincided with deeper sedation (lower PSi) supports the hypothesis that NHF alleviates respiratory stress and the work of breathing [4, 5, 6, 11, 12]. Although the respiratory rate and TcCO₂ did not differ between the groups, this may reflect the sedation titration strategy designed to maintain comparable sedation depth, rather than indicating the absence of physiological effects of NHF. Importantly, reducing opioid dosing during ERCP may lower the risk of post‐procedural respiratory depression in the ward setting [3]. Therefore, the stress‐reducing effect of NHF during ERCP carries meaningful clinical significance.

The respiratory rate in the NHF group was measured using two devices. The Radical‐7 uses a microphone attached to the skin with adhesive, whereas the Airvo 3 measures breathing frequency by detecting pressure pulses during NHF via an asymmetrical cannula interface with a large cross‐sectional area of the nasal prongs. Both methods provide continuous monitoring of breathing. The strong correlation with Airvo 3 (r = 0.8686) and the narrow Bland–Altman limits of agreement (bias −0.34 breaths/min, limits of agreement −5.06 to 4.37) demonstrate that both devices offer similar respiratory‐rate monitoring under dexmedetomidine‐based sedation (Figure 3).

This randomized controlled trial demonstrated that NHF significantly reduced opioid requirements compared with LFO during ERCP performed under dexmedetomidine‐based sedation. NHF with supplemental oxygen maintained adequate oxygenation and ventilation while providing deeper and more stable sedation, as indicated by lower processed EEG‐derived indices and reduced EMG activity. The decreased opioid exposure may help mitigate the risk of post‐procedural respiratory depression in the ward setting. The ability of NHF to provide respiratory support, ensure adequate oxygenation, and allow monitoring of breathing makes it a promising modality during procedural sedation; further multicenter studies are required.

Conception and design: Takao Ayuse, Shuntaro Sato, Taiga Ichinomia, Rintaro Yano, Kosuke Takahashi, Masanori Fukushima, Masafumi Haraguchi, Eisuke Ozawa, Stanislav Tatkov, Tetsuya Hara, and Hisamitsu Miyaaki. Analysis and interpretation of the data: Tomotaka Mori, Takao Ayuse, Shuntaro Sato, Taiga Ichinomia, Akane Shimakura, Yasuhiko Nakao, Ryu Sasaki, Satoshi Miuma, and Stanislav Tatkov. Drafting of the article: Tomotaka Mori, Shuntaro Sato, Taiga Ichinomia, and Stanislav Tatkov. Critical revision of the article for important intellectual content: all authors. Final approval of the article: all authors.

Stanislav Tatkov is an employee of Fisher & Paykel Healthcare Ltd., the manufacturer of the nasal high flow devices used in this study. Takao Ayuse received funding and support from Fisher & Paykel Healthcare Ltd. The other authors declare no conflicts of interest.