The mechanistic reconstruction of re-sedation in remimazolam–flumazenil reversal: a scoping review protocol

Background：Remimazolam is an ultra-short-acting benzodiazepine whose hydrolysis by carboxylesterase-1 (CES1) enables rapid pharmacological reversal with flumazenil. A pharmacokinetic mismatch between these agents produces resedation in 9–22% of patients after prolonged anesthesia. Twelve meta-analyses have failed to resolve the flumazenil dosing question because all pooled pharmacokinetically heterogeneous contexts, committing an ecological fallacy. No consensus re-sedation definition exists and no guideline addresses remimazolamspecific reversal. Methods：Adhering to JBI methodology and reported per PRISMA-ScR, this scoping review applies a Population-Concept-Context framework. Studies are stratified by clinical context (procedural sedation versus prolonged anesthesia/ICU) and CES1 developmental stage, with pediatric and adult data maintained in strict separation. Six databases will be searched for English-language publications. The washout interval serves as the primary mechanistic extraction variable; a four-level missing data classification anticipates and documents reporting gaps as a key finding. Opioid co-exposure is classified by context-sensitive half-time duration class rather than potency equivalents. A six-dimension theoretical framework organizes thematic synthesis, while a four-tiered analytical structure proceeds from descriptive summary through a hypothesis-generating mechanistic overlay (governed by a prespecified SWiM-based contingency plan), thematic synthesis with a signal-conflict framework, and an evidence gap map. Four deliverables carry explicit epistemic guardrails: a structured evidence gap map, an exposure-response landscape visualization for future trial design, a candidate re-sedation definition for Delphi standardization, and a candidate Minimum Reporting Set for remimazolam reversal trials. Discussion：By confronting the ecological fallacy that has compromised prior syntheses and integrating pharmacokinetic, pharmacodynamic, pharmacogenomic, and pharmacovigilance dimensions within a single framework, this review seeks to build the mechanistic foundation for evidence-based remimazolam reversal guidelines.