Interpreting bispectral index monitoring during remimazolam and propofol anaesthesia: a reply

We thank Wang et al. [1] for their thoughtful comments on our study [2]. We agree that the bispectral index (BIS) may not be an ideal or fully validated measure of anaesthetic depth during remimazolam-based anaesthesia. Clinically, adequate remimazolam anaesthesia may occur at BIS values higher than those typically seen with propofol, which is consistent with published evidence [3] and our clinical experience. We used BIS as one reference for anaesthetic depth, not as the sole basis for drug administration. Anaesthetic titration also considered haemodynamic responses; clinical signs; surgical stimulation; and the judgement of the attending anaesthetist. Because there is currently no validated monitoring index designed specifically for remimazolam-based sedation or anaesthesia, a BIS of 40–60 was used only as a reference range, not as proof of equivalent hypnotic depth between remimazolam and propofol. The remimazolam infusion was adjusted within the protocol-specified range according to the overall clinical condition of patients, rather than simply to target BIS below a fixed threshold. We also agree that anaesthetic dose and exposure may influence emergence quality and delirium-related outcomes. This issue is acknowledged in the limitations section of the discussion. The relationships among remimazolam dose, drug exposure, BIS values and recovery profile require further study. Importantly, this limitation does not change the main clinical conclusion of our trial. Our study was designed to compare two clinically used anaesthetic regimens in older patients undergoing lung resection, not to perform a pharmacological experiment under strictly matched electroencephalographic or exposure conditions. Under the regimen studied, remimazolam anaesthesia without routine flumazenil reversal, guided by BIS, haemodynamics and clinical assessment, did not meet the prespecified non-inferiority criterion compared with propofol for postoperative delirium, with excess events mainly occurring during emergence. Thus, our findings should be interpreted as showing that the remimazolam-based regimen used in our trial was associated with less favourable emergence period neurocognitive outcomes than the propofol-based regimen. The findings also suggest that anaesthetists should pay close attention to emergence quality, recovery trajectory and early neurocognitive status when using remimazolam in older patients having thoracic surgery.