Effects of Remimazolam Dose and Bolus Injection Rate on Hiccups During Painless Colonoscopy: A Double-Blind Randomized Clinical Trial [Letter]

Effects of Remimazolam Dose and Bolus InjectionRate on Hiccups During Painless Colonoscopy: A Double-Blind Randomized Clinical Trial" published recently in Drug Design, Development and Therapy (ID: 609835) Their findings suggesting that both a higher remimazolam dose and a slower injection rate may reduce hiccup incidence are clinically interesting and potentially relevant to routine endoscopic practice.However, we would like to raise several points that may merit further clarification and discussion.First, although the study was designed as a 2×2 factorial trial, the statistical power for detecting interaction effects may have been limited.The authors concluded that no significant interaction existed between remimazolam dose and injection duration.Nevertheless, interaction analyses generally require substantially larger sample sizes than those needed for detecting main effects alone. 2Given that each subgroup included approximately 40 patients, the absence of a statistically significant interaction may reflect insufficient power rather than a true lack of interaction.Therefore, we believe the findings may be more appropriately interpreted as a failure to detect interaction, rather than definitive evidence that dose and injection rate act completely independently.Second, the relationship between remimazolam dose and hiccup incidence may potentially be influenced by differences in sedation depth.In the present study, the higher-dose regimen was also associated with fewer body movements, fewer supplemental boluses, and lower MOAA/S scores, suggesting deeper or more stable sedation.Consequently, the observed reduction in hiccups may not solely represent a direct dose-dependent pharmacologic effect, but could partially reflect improved suppression of airway and diaphragmatic reflex activity under deeper sedation conditions.Previous pharmacokinetic and pharmacodynamic studies have demonstrated that remimazolam effect-site concentration and clinical sedative depth are closely associated with administration strategy and bolus kinetics. 3Therefore, differences in hiccup incidence observed between groups may partially reflect variations in sedation depth resulting from different dosing strategies, rather than a direct pharmacologic effect of dose alone.Additional monitoring methods, such as bispectral index or effect-site concentration modelling, may help further distinguish the independent effects of drug dose from those of sedation depth in future investigations.Third, we found the discrepancy between hiccup incidence and hiccup duration particularly intriguing.Although slower injection reduced the overall incidence of hiccups, patients who developed hiccups in the 20-second groups appeared to experience longer hiccup durations.Whether hiccup duration has additional clinical implications beyond event incidence remains uncertain and warrants further investigation.Perioperative hiccups are increasingly recognized as clinically relevant events that may interfere with airway stability and procedural manipulation. 4Future studies incorporating clinically relevant outcomes, such as interruption of endoscopic manipulation, need for rescue medication, or procedural difficulty scores, may provide a more comprehensive evaluation of the practical impact of remimazolam-associated hiccups.