A randomized trial on the ED₅₀ and hemodynamic stability of a remimazolam-propofol combination for induction in elderly patients undergoing lumbar fusion surgery

The appropriate remimazolam dosage for induction in elderly patients undergoing lumbar fusion surgery, when used alongside a fixed propofol dose of 1 mg/kg, is yet to be determined. We aimed to estimate the effective doses (ED₅₀ and ED₉₅) of remimazolam with propofol and to characterise peri-induction hemodynamic effects. This prospective, two-phase study enrolled patients aged 65–80 years with ASA physical status I–II. In the dose-finding phase ( n = 27), Dixon’s up-and-down method was used to determine the ED₅₀ and ED₉₅ of remimazolam combined with propofol 1 mg/kg, with success defined as sustained BIS < 60 within 2 min without rescue medication. In the randomized phase, 90 patients were allocated to propofol–midazolam (Group A: propofol 1 mg/kg + midazolam 0.03 mg/kg), remimazolam monotherapy (Group B: 0.2 mg/kg), or propofol–remimazolam (Group C: propofol 1 mg/kg + remimazolam at the ED₅₀). All patients received standardized sufentanil (0.3 µg/kg) and rocuronium (0.6 mg/kg). MAP, HR, BIS, and adverse events were recorded at pre-induction (T₀), pre-intubation (T₁), 1, 3, and 5 min post-intubation (T₂–T₄), and 1 min before and after prone positioning (T₅–T₆). The ED₅₀ and ED₉₅ of remimazolam were 0.14 mg/kg and 0.19 mg/kg, respectively, when combined with 1 mg/kg propofol. The incidence of hypotension (primary outcome) was 63.3% in Group A, 20.0% in Group B, and 6.7% in Group C. Group C had a significantly lower incidence than Group A (risk difference [RD] − 56.7%, 95% CI − 76.1 to − 37.2, P < 0.001) and Group B had a significantly lower incidence than Group A (RD − 43.3%, 95% CI − 65.7 to − 20.9, P < 0.001). Hypertension was more frequent in Group B (30.0%) than in Group A (0%; RD 30.0%, 95% CI 13.6–46.4, P < 0.001) and Group C (3.3%; RD − 26.7%, 95% CI − 44.3 to − 9.1, P = 0.003). Linear mixed-effects modelling revealed significant Group×Time interactions for HR, MAP, and BIS (all P < 0.01). MAP was consistently lower in Group A than in Groups B and C from T₁ to T₆; HR was lower in Group A than in Groups B and C at most time points from T₂ to T₆; BIS was lower in Groups A and C than in Group B during the maintenance phase. Injection pain was less frequent in Group B (0%) than in Group A (23.3%; RD − 23.3%, 95% CI − 38.5 to − 8.2, P = 0.003). In elderly patients having lumbar fusion surgery, the ED₅₀ of remimazolam with 1 mg/kg propofol is 0.14 mg/kg. The model-based ED₉₅ estimate of 0.19 mg/kg (95% CI: 0.17–0.37) should be interpreted with caution as an extrapolation beyond the observed dose range. Using the ED₅₀ dose with propofol 1 mg/kg during induction improved hemodynamic stability, reducing hypotension compared to propofol–midazolam and lowering hypertension compared to remimazolam alone. Chinese Clinical Trial Registry, ChiCTR2400079846, registered 15 January 2024.