Routine flumazenil administration: an overlooked confounder in the non‐inferiority comparison of remimazolam and propofol?

Sim et al. compared remimazolam and propofol for postoperative delirium and recovery quality in older adults undergoing gastrectomy [1]. This study provides important evidence for remimazolam use in this vulnerable population. As stated explicitly in the methods, all patients allocated to the remimazolam group received 0.2 mg flumazenil at the end of surgery, while no sedative antagonist was given to those allocated to the propofol group. This creates an imbalance: the comparison is not between remimazolam and propofol monotherapy, but between remimazolam plus flumazenil and propofol alone. Flumazenil induces rapid sedation reversal but also abrupt central nervous system excitability fluctuations. These are core features of the confusion assessment method used to diagnose postoperative delirium. As noted by Penninga et al., even low-dose flumazenil can cause central nervous system hyperexcitability [2]. The authors did not evaluate flumazenil as a potential postoperative delirium confounder or adjust for its effects statistically. The incidence of postoperative delirium was similar in both groups. Two competing hypotheses explain this: flumazenil may have masked residual benzodiazepine-induced cognitive impairment; or its hyperexcitability may have independently increased the risk of postoperative delirium, counteracting rapid reversal benefits. The study cannot distinguish these, nor confirm equivalence of remimazolam monotherapy to propofol [2]. Future trials should include a remimazolam-without-flumazenil arm. For the current dataset, a sensitivity analysis using Firth's logistic regression could explore the association between flumazenil and postoperative delirium. The authors should also clarify their conclusion applies only to settings where flumazenil is used routinely.