Routine flumazenil administration confounds emergence time comparisons between remimazolam and propofol: a methodological concern

Abstract

This letter to the editor identifies a critical methodological concern in a recent clinical trial by Qin et al. that compared the emergence profiles of remimazolam and propofol in pediatric anesthesia. We argue that the study’s findings are confounded by a fundamental"asymmetry in interventions”. The remimazolam group routinely received flumazenil for pharmacological reversal, while the propofol group emerged spontaneously via natural metabolism.

Dear editor,

We read Qin et al. [1] recent article entitled “Emergence profiles of remimazolam-flumazenil versus propofol for general anesthesia in pediatric strabismus correction surgery: a randomized clinical trial” published in your journal. Their study investigates the application of remimazolam, a novel ultra-short-acting benzodiazepine, in pediatric anesthesia: a topic of significant clinical importance. We agree with the authors that remimazolam demonstrates superior hemodynamic stability, a finding well-supported by previous studies. However, we wish to highlight a fundamental methodological concern in the study design that may affect interpretation of the emergence profile results: the asymmetry in interventions between treatment groups.

Patients in the remimazolam group routinely received flumazenil (0.2–0.3 mg) postoperatively to reverse sedation. In contrast, the propofol group emerged spontaneously through natural drug metabolism without equivalent pharmacological intervention. While this design effectively compares two distinct clinical regimens (remimazolam-flumazenil combination vs. propofol alone), it confounds the comparison of the anesthetics’ intrinsic emergence profiles. The substantial difference in emergence time primarily reflects the pharmacological action of flumazenil rather than the inherent metabolic characteristics of remimazolam. Flumazenil, a specific benzodiazepine receptor antagonist, acts within 1–2 min by competitively displacing remimazolam from GABA-A receptors. Therefore, the rapid emergence observed is primarily driven by active pharmacological reversal, not the intrinsic pharmacokinetic properties of remimazolam. Furthermore, a critical mechanism often overlooked is the interaction between flumazenil and endogenous benzodiazepine ligands, known as “endozepines.” Dahaba et al. (2009) [2] demonstrated that flumazenil administration can increase Bispectral Index (BIS) values and expedite recovery even in patients who have not received benzodiazepines. This suggests that flumazenil may exert an intrinsic arousal effect by reversing the inhibitory influence of endozepines on GABA-A receptors. Consequently, without a double-dummy design or a remimazolam-only arm, it is impossible to distinguish whether the rapid emergence observed by Qin et al. is due to the remimazolam itself or the intrinsic alerting effects of flumazenil.

Moreover, routine flumazenil administration warrants clinical scrutiny. Flumazenil is indicated for severe benzodiazepine-induced sedation or respiratory depression, not for routine emergence facilitation. This practice raises several concerns. First, flumazenil’s elimination half-life (approximately 40–80 min in children) is considerably shorter than that of remimazolam, creating a theoretical risk of re-sedation after the antagonist’s effect wanes. While we acknowledge that direct comparisons between adult and pediatric populations require caution due to physiological differences, data from adult studies serve as a cautionary reference. For instance, Oh et al. (2023) reported a re-sedation incidence of 22% in adult patients receiving remimazolam followed by flumazenil reversal [3]. Although pediatric patients may exhibit faster metabolic clearance, the fundamental pharmacokinetic mismatch between the long-acting sedative and the short-acting antagonist remains a critical safety consideration that warrants vigilance. Second, routine flumazenil administration increases healthcare costs and may introduce preventable adverse effects, such as acute withdrawal syndrome in benzodiazepine-dependent patients or seizures in cases of mixed drug overdose [4].

To assess remimazolam’s intrinsic emergence characteristics, we reviewed studies comparing remimazolam and propofol without routine antagonist use. Several recent studies with alternative designs offer contrasting findings. For example, Fang et al. (2025) conducted a multicenter, randomized, single-blind controlled trial comparing remimazolam and propofol in pediatric surgery [5]. Both groups underwent spontaneous emergence without flumazenil administration. The study concluded that remimazolam was noninferior to propofol for anesthesia maintenance but found no pronounced emergence time advantage compared to propofol. Similarly, Zhang et al. (2024) studied adult patients undergoing cerebral endovascular procedures and found that without flumazenil, mean emergence time was 16.1 min in the remimazolam group versus 19.0 min in the propofol group [6], a substantially smaller difference than that reported by Qin and colleagues.

We suggest that future research should employ study designs capable of differentiating the intrinsic emergence properties of remimazolam from the effects of pharmacological reversal. This approach would allow for a more equitable comparison against propofol, which relies on spontaneous metabolism. Given the unique pharmacokinetic and pharmacodynamic characteristics of pediatric patients, conducting additional high-quality studies in this population is essential to inform evidence-based clinical practice.

These comments aim to foster constructive methodological discussion, not to diminish the value of Qin et al.‘s work. Their study provides important clinical data on remimazolam use in pediatric anesthesia, particularly regarding its hemodynamic stability. We hope this discussion stimulates further research that comprehensively evaluates the true differences between remimazolam and propofol in pediatric anesthesia, thereby providing more reliable, evidence-based guidance for clinical practice.

Authors’ contributions

H.C. wrote the main manuscript text. Q.Z. and Y.Z. critically revised the manuscript. Y.Z. conceived the letter. All authors reviewed and approved the final manuscript.

Funding

The authors received no funding for this work.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Competing interests

The authors declare no competing interests.