Remimazolam vs Propofol for Motor and Somatosensory Evoked Potentials in Spinal Tumor Surgery

BACKGROUND

Intraoperative neurophysiological monitoring (IONM), combining transcranial motor evoked potentials (MEP) and somatosensory evoked potentials (SEP), is widely used during spinal tumor resection to identify impending spinal cord injury at a reversible stage. Both MEP and SEP are sensitive to anesthetic technique. Propofol-based total intravenous anesthesia (TIVA) is commonly used for MEP monitoring, but propofol reduces MEP amplitude in a dose-dependent manner, which may lead to false-positive alerts, unnecessary interruption of surgery, or a reduction in anesthetic depth to preserve signals. Remimazolam is a novel ultra-short-acting benzodiazepine with an organ-independent esterase metabolism and a rapid, predictable offset. Small crossover and observational studies suggest remimazolam may preserve MEP amplitude, but adequately powered parallel-group randomized evidence in spinal tumor surgery is lacking.

OBJECTIVES

Primary: to determine whether remimazolam-based TIVA preserves MEP amplitude better than propofol-based TIVA during the critical period of tumor manipulation in patients undergoing elective spinal tumor resection.

Key secondary: to compare the incidence of intraoperative IONM alert events between the two anesthetic regimens.

DESIGN

Prospective, single-center, randomized, parallel-group, superiority trial with participant and outcome-assessor blinding. The anesthesia provider performing the intervention is not blinded for safety reasons; the statistician analyzing the data is blinded to group allocation.

Randomization: stratified block randomization with stratification by tumor location (intramedullary, extramedullary intradural, epidural). Randomly permuted blocks of size 4 or 6 are generated using SPSS 26.0 by an independent statistician. Allocation is concealed in sequentially numbered, opaque, sealed envelopes opened immediately before induction of anesthesia.

PARTICIPANTS AND SETTING

190 participants (95 per group) undergoing elective spinal tumor resection at Beijing Tsinghua Chang Gung Hospital.

INTERVENTIONS

Remimazolam arm: induction with remimazolam 0.2-0.3 mg/kg intravenously, maintenance infusion 1-2 mg/kg/h.

Propofol arm: induction with propofol 1.5-2.5 mg/kg intravenously, maintenance infusion 4-6 mg/kg/h.

Both arms receive identical co-interventions: sufentanil 0.3-0.5 micrograms/kg at induction, remifentanil 0.08-0.15 micrograms/kg/min for maintenance, and a single dose of rocuronium 0.6 mg/kg at induction with no intraoperative top-up. Depth of anesthesia is titrated to a bispectral index of 40-60. Train-of-four ratio is confirmed to be at least 0.9 before baseline IONM recording. Core temperature is maintained at 36.0-37.5 degrees Celsius. Mean arterial pressure is maintained within 10 percent of baseline and not below 80 mmHg, and heart rate between 50 and 100 beats per minute, using vasoactive agents as required.

OUTCOME MEASURES

Primary: mean MEP amplitude of target muscles during the critical period of tumor manipulation (time points T2 to T4), expressed as a percentage of the baseline (T0) amplitude, that is, the MEP amplitude preservation ratio.

Key secondary: incidence of intraoperative IONM alert events, defined as a decrease in MEP amplitude of 50 percent or more from baseline, or prolongation of SEP latency of 10 percent or more.

Other secondary: change in SEP N20 or P37 latency and amplitude; change rate of MEP amplitude; coefficient of variation of MEP amplitude; intraoperative hemodynamics including mean arterial pressure, heart rate and vasoactive drug requirement; time to extubation; post-anesthesia care unit length of stay; Quality of Recovery-15 score on postoperative days 1 and 2; Japanese Orthopaedic Association score before surgery and at postoperative days 1 and 30; and incidence of adverse and serious adverse events.

Exploratory: correlation between the coefficient of variation of MEP amplitude and change in the Japanese Orthopaedic Association score, assessed by Spearman correlation.

SAMPLE SIZE

Based on an anticipated standardized effect size of 0.50 for the primary endpoint, a two-sided alpha of 0.05 and 90 percent power, 85 participants per group are required. Allowing for a 10 percent dropout rate, 95 participants per group (190 in total) will be enrolled. A blinded internal pilot re-estimation of the effect size will be performed when approximately 50 percent of participants have completed the primary endpoint assessment. If the observed effect size is below 0.40, the sample size assumption will be reassessed with the steering committee; if it is between 0.40 and 0.50, enrollment may be extended up to 148 per group; if it is at least 0.50, the planned sample size of 95 per group will be retained.

STATISTICAL ANALYSIS

The primary analysis will follow the intention-to-treat principle, with a per-protocol analysis as a sensitivity analysis. The primary endpoint will be analyzed using analysis of covariance with adjustment for baseline MEP amplitude, tumor type, tumor level, age and body mass index. The superiority margin is zero, that is, any statistically significant difference in favor of remimazolam will support superiority. Continuous secondary endpoints will be compared using t-tests or Mann-Whitney U tests as appropriate; categorical endpoints using chi-square or Fisher exact tests. Analyses will be performed using SAS 9.4 or R version 4.3.x, with SPSS 26.0 for randomization.

STUDY DURATION

Total duration of 16 months, with 12 months of enrollment and 30-day postoperative follow-up, including an internal pilot re-estimation at approximately 50 percent enrollment.