The study condition of implementing similar anaesthetic depth with different anaesthetic agents may be challenging

Editor, We read with interest the recent randomised controlled trial by Cai et al., which compared remimazolam tosylate and propofol in frail elderly patients undergoing hip surgery under general anaesthesia.1 The authors demonstrated that remimazolam reduced the incidence of postoperative delirium (POD) compared with propofol (4.4% vs. 17.6%) in combination with the stabilised haemodynamic status during anaesthesia. However, we have several questions regarding the comparability of anaesthetic depth between the two groups using different intravenous anaesthetics, although we agree with Cai et al. that their study addressed a clinically relevant topic. The authors determined anaesthetic depth shown as Patient State Index (PSI) using the SedLine brain function monitor (Masimo Inc., Irvine, CA, USA).1 However, they did not adequately describe in their paper how they titrated the amount of each anaesthetic agent using the PSI values. A previous study reported that remimazolam anaesthesia was associated with a distinct electroencephalogram picture, including persistent alpha power and reduced phase lag entropy, and that patients undergoing remimazolam anaesthesia possibly showed falsely low PSI values.2 Also, we reported a case of intra-operative awareness under remimazolam anaesthesia that escaped detection by PSI, even though the index remained within its presumed adequate range.3 Therefore, these results indicate that PSI may not accurately reflect anaesthetic depth during remimazolam administration, underscoring the risk of relying solely on PSI for remimazolam, as algorithm calibration is primarily based on propofol.4 Cai et al.1 administered remimazolam with only a small total dose (median [IQR] 55 mg, 45 to 65.8]) over a short duration of 150 min. A previous multicentre trial involving ASA Class III patients documented that the mean maintenance dose of remimazolam was 0.56 to 0.57 mg kg−1 h−1,5 which is >1.5 times higher than the average dose used in Cai et al.'s study.1 Therefore, these results suggest that the remimazolam group in Cai et al.'s study received considerably lower amounts of remimazolam doses to achieve an appropriate anaesthetic depth. In addition, patients in the remimazolam group in Cai et al.'s study exhibited lower burst suppression frequency than those in the propofol group, indicating a lower anaesthetic depth in the remimazolam group despite equivalent PSI values in both groups.1 A review article documented that administering lower doses of sedative medication should result in lower rates of POD.6 Taken together, the observed anaesthetic depth discrepancies indicate that the increased POD in the propofol group in Cai et al.'s study1 might reflect more profound anaesthesia in the propofol group than in the remimazolam group. In summary, future evaluations incorporating strict age-adjusted titration and multimodal EEG monitoring will require demonstrating how different anaesthetic agents influence POD in elderly patients. However, the study condition of implementing similar anaesthetic depth with different anaesthetic agents may be increasingly challenging.