Methodological Considerations in Interpreting the Hemodynamic and Respiratory Advantages of Remimazolam During Percutaneous Radiofrequency Ablation [Letter]

We read with interest the randomized controlled trial by Jiang et al 1 comparing remimazolam-remifentanil with propofolremifentanil anesthesia in patients with liver cancer undergoing percutaneous radiofrequency ablation (PRFA).The authors reported greater hemodynamic stability, less respiratory depression, and faster recovery with remimazolam.The study provides clinically relevant evidence for anesthetic management during PRFA; however, several methodological considerations may help refine the interpretation of these findings.First, the comparability of hypnotic depth between the two anesthetic regimens deserves further consideration.The protocol aimed to maintain the Cerebral State Index (CSI) between 40 and 60 in both groups, yet CSI values were significantly lower in the propofol group from T2 through T6, 1 and the authors interpreted this as indicating deeper cortical suppression with propofol.If CSI reflects comparable hypnotic states across the two drugs, the greater hypotension and respiratory depression observed with propofol may partly reflect deeper anesthesia rather than an intrinsic difference in cardiorespiratory safety.Conversely, processed electroencephalographic indices may not be directly interchangeable between these agents.Yang et al 2 titrated remimazolam and propofol to doses associated with loss of consciousness and still observed higher bispectral index values with remimazolam.Thus, either hypnotic depth differed between the groups or the processed EEG index does not represent equivalent hypnotic states across the two drugs.In either case, attributing the observed cardiorespiratory differences solely to the pharmacological properties of remimazolam warrants caution.Reporting the actual maintenance dose normalized to body weight and time, together with the proportion of intraoperative time spent within the prespecified CSI target, would help clarify this issue.Second, the relationship between the sample-size calculation and the prespecified primary analysis could be clarified.MAP measured at seven perioperative time points was defined as the primary outcome, and the principal analysis was based on the treatment-by-time interaction using a linear mixed-effects model. 1 However, the sample-size calculation was based on a single between-group difference in post-induction MAP from a previous study, 3 yielding a standardized effect size of d=0.9.The manuscript does not report assumptions regarding within-patient correlation, covariance structure, or the expected magnitude of the group-by-time interaction.Because power for a longitudinal interaction depends on these parameters rather than on a single cross-sectional difference alone, clarification of how the calculated sample size was aligned with the primary mixed-effects analysis would improve methodological transparency.Third, the reported respiratory advantage should be interpreted in the context of multiple secondary outcomes.Remimazolam was associated with a lower incidence of apnea (17.1% vs 36.6%;P=0.038), a higher respiratory rate, and a lower end-tidal carbon dioxide partial pressure, whereas tidal volume and peripheral oxygen saturation did not differ significantly between groups. 1 These respiratory variables were among numerous secondary outcomes, and no Therapy 2026:20 659605 1 Drug Design, Development and