Remimazolam reduces State-Trait Anxiety Inventory-State Scale scores in hemorrhoid surgery with spinal-epidural anesthesia: A randomized trial

Abstract

BACKGROUND

In the field of anesthesia for procedure for prolapse and hemorrhoids (PPH) surgery, combined spinal-epidural (CSE) anesthesia has been a common approach. However, exploring new combinations to optimize patient outcomes remains crucial. Remimazolam, a short-acting benzodiazepine, shows potential for improving sedation and reducing patient anxiety. The effects of combining remimazolam with CSE anesthesia, compared to traditional CSE anesthesia alone, on patient anxiety, sedation depth, and hemodynamics during PPH surgery have not been fully elucidated.

AIM

To compare remimazolam-CSE vs CSE alone on State-Trait Anxiety Inventory-State scale (STAI-S) scores, sedation, and hemodynamics in PPH surgery.

METHODS

This study is a single-center, prospective, randomized controlled trial. Between November 23, 2022, and August 6, 2024, 60 eligible patients were randomly assigned to the CSE anesthesia group or the remimazolam-combined CSE anesthesia group (30 patients each). STAI-S scores, Ramsay sedation scores, and hemodynamic parameters (systolic blood pressure, diastolic blood pressure, heart rate) were measured at multiple time points. Two-way mixed-effects ANOVA and post-hoc analyses were performed.

RESULTS

The Combined group demonstrated significantly lower STAI-S scores before leaving the operating room [mean: 28.80 vs 54.03, mean difference (95%CI): 25.23 (21.24-29.23), P < 0.001] and 24 hours post-operation [mean: 45.07 vs 54.53, mean difference (95%CI): 9.47 (6.29-12.64), P < 0.001] than the CSE group. Moreover, the Combined group achieved a deeper sedation level during intraoperative maintenance [median: 5.00 (IQR: 5.00-5.00) vs 2.00 (IQR: 2.00-2.00); median difference (95%CI): 3.00 (3.00-3.00), P < 0.001]. Regarding hemodynamics, a significant inter-group difference in systolic blood pressure was observed at the start of the surgery [mean: 128.8 vs 114.7 for the Combined and CSE groups, mean difference (95%CI): 14.17 (0.77-27.57), adjusted P = 0.033].

CONCLUSION

Remimazolam-combined anesthesia outperformed CSE anesthesia in reducing STAI-S scores, enhancing intraoperative sedation, and stabilizing systolic blood pressure at a critical stage, indicating its superiority in perioperative management.

Key Words: Procedure for prolapse and hemorrhoids surgery; Combined spinal-epidural anesthesia; Remimazolam-based combined anesthesia; State-Trait Anxiety Inventory-State Scale scores; Sedation depth; Hemodynamics

Core Tip: In procedure for prolapse and hemorrhoids (PPH) surgery, traditional combined spinal-epidural (CSE) anesthesia commonly encounters challenges of insufficient intraoperative sedation and hemodynamic fluctuations. This study confirms that a remimazolam-based CSE anesthesia protocol significantly reduces patient anxiety before leaving the operating room and at 24 hours post-operation, while achieving deep sedation and stabilizing systolic blood pressure during critical surgical phases. The rapid onset of remimazolam's sedative effect and its anxiolytic properties offer an optimized approach to perioperative management of CSE anesthesia in PPH surgery.

INTRODUCTION

The perioperative psychological stress associated with surgical procedures, particularly those involving sensitive anatomical regions, remains a critical concern in modern anesthesia practice[1]. Procedure for prolapse and hemorrhoids (PPH) surgery, a minimally invasive technique for treating severe hemorrhoids, is no exception. Despite its efficacy, PPH surgery often induces heightened anxiety due to its perianal location, postoperative pain concerns, and perceived social stigma. Psychological distress in these patients manifests through elevated State-Trait Anxiety Inventory-State scale (STAI-S) scores, reflecting acute preoperative anxiety that can exacerbate sympathetic nervous system activation, leading to hemodynamic instability and delayed recovery[2]. Current anesthesia protocols, such as standard Combined Spinal-Epidural (CSE) anesthesia, provide effective analgesia but fail to address psychological stress adequately, leaving patients vulnerable to intraoperative awareness and postoperative anxiety-related complications.

Remimazolam, a novel ultra-short-acting benzodiazepine, offers a promising solution to this unmet need. As a selective agonist of γ-aminobutyric acid type A (GABAA) receptors, remimazolam enhances chloride ion influx into neurons, hyperpolarizing membranes and inhibiting neuronal excitability. This mechanism not only produces rapid-onset sedation and anxiolysis but also stabilizes hemodynamics by reducing sympathetic tone[3]. Preclinical and clinical studies in non-PPH settings, including endoscopic procedures and pediatric surgeries, demonstrate remimazolam’s ability to mitigate anxiety and maintain cardiovascular stability with minimal respiratory depression[4,5]. However, its application in PPH surgery remains under investigated. Existing research primarily focuses on general surgical contexts, leaving a critical gap in understanding its effects on anxiety, hemodynamics, and postoperative outcomes specific to PPH patients.

Against this backdrop, this randomized, double-blind, single-center trial aims to evaluate the efficacy of remimazolam-combined CSE anesthesia compared to standard CSE anesthesia in PPH surgery. The study will assess preoperative and postoperative anxiety levels using STAI-S scores and monitor hemodynamic parameters [e.g., heart rate (HR), blood pressure] to determine stability during surgery. We hypothesize that patients in the remimazolam-combined CSE group will exhibit significantly lower STAI-S scores and more stable hemodynamics than those in the standard CSE group, driven by remimazolam’s dual action on anxiety reduction and sympathetic modulation. This research will address the current lack of evidence on remimazolam’s role in PPH surgery, potentially optimizing anesthesia protocols to enhance patient comfort and perioperative outcomes.

MATERIALS AND METHODS

Trial design

This prospective, single-center, randomized controlled trial was carried out at the Hunan Provincial People's Hospital. The First Affiliated Hospital of Hunan Normal University granted ethical approval to perform the study within its facilities, Ethical Application No.[2022]-51, ethical approval was obtained for protocol version 3.0, dated 2022-05-21. Prior to the initiation of the study, detailed information about the trial procedures, potential risks, benefits, and patients’ rights was provided to all eligible patients or their legal representatives. Informed consent forms were obtained from the individuals themselves or their authorized representatives. After trial commencement, no important changes to the study methods (including eligibility criteria, intervention delivery, and outcome assessments) were made. All procedures were strictly followed as outlined in the pre-registered protocol.

Participants

Between November 23, 2022 and August 6, 2024, patients aged 18-60 years classified as American Society of Anesthesiologists physical status I-II, who were scheduled to undergo procedure for PPH and provided informed consent, were enrolled in this study. Exclusion criteria included: (1) Patients who declined participation; (2) Those with contraindications to spinal anesthesia; (3) individuals with known allergies to local anesthetics; (4) Patients with significant airway anatomical abnormalities (including the nose, mouth, pharynx, and larynx) or acute and chronic respiratory diseases, as well as those with moderate to severe obstructive sleep apnea syndrome; (5) Individuals with psychiatric disorders or cognitive impairments that hindered cooperation; and (6) Any other conditions deemed unsuitable for study participation by the researchers. The criteria for ending the trial: The predetermined sample size has been recruited.

Randomization and blinding

After obtaining informed consent, participants were randomly allocated in a 1:1 ratio to either the standard CSE Anesthesia group (CSE group) or the remimazolam-combined CSE anesthesia group (Combined group) using a computer-generated randomization process, with the allocation details stored in sealed, opaque envelopes. For the double-blind design, remimazolam and the control anesthetic were placed in identical-looking syringes labeled only with unique codes. When patients entered the operating room, the designated anesthesiologist opened the envelope and prepared the corresponding anesthetic without revealing the group information to the patients, ensuring that both the medical staff administering the anesthesia and the patients remained unaware of the group assignments throughout the study. Assessors responsible for evaluating anxiety levels and hemodynamic parameters were also blinded to the group allocations.

All data were meticulously recorded in the electronic medical records system (EMR), and access to the EMR was restricted to authorized personnel overseeing data collection and analysis to maintain confidentiality regarding the group assignments. To ensure quality control, all research staff received standardized training on study procedures, data collection, and patient management prior to the trial, and regular data audits were scheduled every month to check for data integrity and compliance with the study protocol.

Anesthesia introduction and maintenance

Upon arrival in the operating room, all patients were standardly monitored with HR, 5-lead continuous electrocardiogram, non-invasive blood pressure, and oxygen saturation. Peripheral intravenous access was established, and oxygen was administered via nasal cannula at 2 L/minute to maintain adequate oxygen supply. Considering the anatomical characteristics and requirements of PPH surgery, standard CSE anesthesia was performed at the L3-4 interspace, which is a commonly used and relatively safe approach for achieving effective anesthesia in this type of surgery.

For the CSE group, an epidural needle was inserted, and once the epidural space was reached, a spinal needle was used to puncture the subarachnoid space. After confirming the free flow of cerebrospinal fluid, 3 mL of 0.5% ropivacaine was slowly injected over approximately 20 seconds. Following the injection, an epidural catheter was placed. Once anesthesia was administered, the patient was instructed to assume the supine position, and the anesthetic level was tested, aiming to achieve a sensory block at the T10 Level. This level of anesthesia is sufficient to meet the requirements of PPH surgery while minimizing potential adverse effects on other physiological functions. After confirming the anesthesia level, the patient was repositioned to the prone position to begin the surgery.

For the Combined group, the standard CSE procedure was followed as described above. After positioning, remimazolam (Byfavo^®, Hengrui Medicine, Jiangsu Province, China) was prepared by a blinded pharmacist as a 1 mg/mL solution (total volume 50 mL), then administered intravenously at a loading dose of 0.1 mg/kg over 1 minute, followed by continuous infusion at 0.4 mg/kg/hour. Intraoperatively, the depth of sedation was monitored using the Bispectral Index (BIS), and surgery commenced once the BIS value dropped to 60. The infusion rate of remimazolam was adjusted based on BIS readings to maintain the BIS value between 40 and 60. Ten minutes before the surgery ended, the remimazolam infusion was stopped, and flumazenil 0.3 mg was administered to reverse the residual effects of remimazolam. For the Placebo group, 0.9% saline (50 mL) was administered intravenously following an identical protocol: A loading dose matching the Combined group's volume (0.1 mg/kg-equivalent), continuous infusion at 0.4 mg/kg/hour-equivalent rate, and a 3 mL final injection (matching flumazenil volume) 10 minutes before surgery ended. All solutions were labeled with randomized codes to ensure double blinding.

Surgical management

The surgical approach was determined preoperatively by the surgeon and explained to the patient. All procedures were performed by the same surgical team. For the Procedure for PPH, a circular stapler was used to excise and anastomose the prolapsed hemorrhoidal tissue. After positioning the patient, a digital rectal examination was performed to confirm the location of the prolapsed hemorrhoids. A purse-string suture was placed around the mucosa, and the circular stapler was inserted to excise the tissue and perform the anastomosis. After deploying the stapler, the prolapsed tissue was removed, and the mucosal defect was closed. The surgical site was irrigated, and the incisions were closed. The patient was monitored for bleeding and complications and observed during recovery.

STAI-S

The State-Trait Anxiety Inventory (STAI) was developed by Spielberger et al[6] in collaboration with other prominent researchers. Due to its good reliability and validity, it has been widely used in psychological and medical research fields globally. It can measure the anxiety levels of individuals in specific situations accurately and reliably. The STAI is divided into two parts: The STAI-S and the STAI-Trait scale. In this study, the STAI-S was mainly used to assess the immediate anxiety feelings and emotional experiences of patients at different timepoints during the perioperative period, such as nervousness, worry, and unease. The STAI-S consists of 20 items, and each item adopts four options ranging from 1 to 4. Assessment for each item: 1: Completely without, 2: Some, 3: Middle degree, 4: Obvious. These items assist in surveying the frequency of such symptoms, like “I feel extremely anxious” or “I feel content”. Of the 20 items, 10 are negatively worded. When calculating scores, these negatively worded items require reverse scoring. The total score ranges from 20 to 80 points. The higher the score, the more intense the anxiety an individual experiences at the moment.

Outcome measures

The primary outcome was to assess patients’ perioperative anxiety levels, achieved by recording STAI-S scores at three specific time points: T_S0 (upon entry into the operating room), T_S1 (prior to leaving the operating room), and T_S2 (24 hours postoperatively). T_S0 serves as the pre-operative anxiety baseline - patients’ anxiety often heightens due to unfamiliar surroundings and surgical concerns, making it a critical starting point for tracking anxiety changes. T_S1 measures immediate postoperative anxiety: Patients may experience relief or increased post-surgery, and comparing T_S1 to T_S0 scores reveals the intervention’s impact on intraoperative anxiety. T_S2, 24 hours postoperatively, evaluates early recovery anxiety, when patients face pain and mobility challenges. Comparing T_S2 scores with T_S0 and T_S1 clarifies anxiety trajectories from pre-operation to early recovery, indicating whether the intervention alleviates anxiety during this stage.

For the secondary outcome, the Numeric Pain Rating Scale scores were measured 24 hours postoperatively. Additional outcome measures included the monitoring of non-invasive blood pressure and HR at five different time points. These time points were T0 (upon patients' entry into the operating room), T1 (prior to positioning), T2 (at the commencement of surgery), T3 (10 minutes after the start of the surgical procedure), and T4 (when patients were discharged from the operating room). No changes to the trial outcomes were made after commencement.

Sample size calculation

Based on preliminary data, the STAI-S scores at the end of surgery were 30 for the Combined group and 30 for the CSE group (n = 10, pre-experiment data). A sample size calculation was performed using GPower software, with a power of 0.8 and a significance level of 0.05. The calculation determined that a minimum of 30 participants per group would be required, resulting in a total sample size of 60 participants.

Statistical analysis

Data analysis was carried out using GraphPad Prism 9.5.0 software. Initially, the Shapiro-Wilk test was used to evaluate the normality of sample data. For data conforming to a normal distribution, independent samples t-tests were applied for comparisons, and the outcomes were presented as mean ± SD. In cases where data were non-normally distributed, the Mann-Whitney U test was utilized, with results reported as the median or interquartile range (Q1, Q3). For categorical data, we assessed whether the conditions for the χ² test were met. If so, the χ² test was used to verify the null hypothesis of no association between variables; if not, Fisher’s exact test was adopted. The results are presented as ratios and percentages. The significance level was set at P < 0.05.

In addition, for the repeated measurement data of the two groups at multiple time points (e.g., systolic blood pressure, diastolic blood pressure, HR, and STAI-S scores), considering the possible violation of the sphericity assumption, a two-way analysis of variance (mixed model) with Geisser-Greenhouse correction was conducted in GraphPad Prism. Subsequently, Bonferroni’s multiple comparison test was performed to determine the intergroup differences at each time point. Bonferroni correction (α = 0.01) was applied for multiple comparisons to control the type I error rate.

RESULTS

Patient demographics

Between November 23, 2022, and August 6, 2024, a total of 60 patients were screened for eligibility. Notably, no patients were excluded during the screening process, there was no loss to follow-up, and no serious adverse events occurred. All patients were enrolled and included in the analysis. The patients who provided informed consent were then randomly allocated into two groups using a computer - generated random sequence, with 30 patients in each group. The Consolidated Standards of Reporting Trials diagram, which provides a visual representation of the flow of participants at each stage of the trial, is shown in Figure 1. Patient demographics and surgical characteristics, summarized in Table 1 to facilitate a clear comparison between the two groups, revealed no significant differences between the two groups.

Figure 1 Flow diagram of the patients. Combined spinal-epidural (CSE) group: CSE anesthesia group. Combined group: Remimazolam-combined CSE anesthesia group. CSE: Combined spinal-epidural.

Table 1 Baseline demographic and perioperative characteristics, n (%).

	CSE group, n = 30	Combined group, n = 30	P value
Age (years)	43.07 ± 12.84	41.03 ± 12.02	0.511
Gender			0.439
Female	16 (53.33)	13 (43.33)
Male	14 (46.67)	17 (56.67)
Weight (kg)	62.73 ± 12.68	64.00 ± 13.52	0.699
Height (cm)	164.13 ± 7.92	166.07 ± 9.34	0.348
ASA classification			0.818
I	50 (90.9)	47 (92.1)
II	5 (9.1)	4 (7.9)
Anesthesia induction to incision time (minutes)	15.00 (15-20)	15.00 (15-20)	0.756
Surgical duration (minutes)	49.23 ± 20.15	53.67 ± 23.88	0.312
Post-surgical exit time from operating room (minutes)	10.00 (5-15)	10.00 (10-10)	0.234
Hospital stay (days)	5.93 ± 2.26	5.67 ± 2.96	0.149

ASA: American Society of Anesthesiologists; CSE: Combined spinal-epidural.

Primary outcome

A two-way mixed-effects ANOVA was employed to explore the impacts of time (T_S0: Upon patients’ entry into the operating room, T_S1: Prior to leaving the operating room, and T_S2: 24 hours postoperatively), group (CSE group vs Combined group), and their interaction on the STAI-S scores.

The analysis revealed significant main effects of time [F (1.707, 98.99) = 83.56, P < 0.001] and group [F (1, 58) = 201.4, P < 0.001], indicating that STAI-S scores varied across measurement points and differed substantially between the CSE and Combined groups. A significant time × group interaction [F (2, 116) = 110.0, P < 0.001] further suggested divergent trajectories of anxiety scores over time (Table 2). Post-hoc comparisons with Bonferroni adjustment demonstrated no significant baseline difference at T_S0 (mean difference = -0.87, 95%CI: -3.14-1.41, P > 0.9999). However, at T_S1 (prior to leaving the operating room), the CSE group (mean = 54.03) showed significantly higher anxiety scores compared to the Combined group (mean = 28.80), with a mean difference of 25.23 (95%CI: 21.24-29.23, P < 0.001). By T_S2 (24 hours post-operation), the difference remained significant but attenuated (CSE group: Mean = 54.53; Combined group: Mean = 45.07; mean difference = 9.47, 95%CI: 6.29-12.64, P < 0.001) (Figure 2A, Table 3).

Figure 2 Comparison of State-Trait Anxiety Inventory-State scale scores, systolic blood pressure, diastolic blood pressure, and heart rate between combined spinal-epidural group and Combined group across time points. A: Shows a violin plot of State-Trait Anxiety Inventory-State scale; B-D: Line graphs of systolic blood pressure, diastolic blood pressure, and heart rate respectively, with data as mean ± SEM. T_S0 was the time upon entry into the operating room. T_S1 was the time prior to leaving the operating room. T_S2 was the 24 hours postoperatively. T1 was the time prior to positioning. T2 was the time at the commencement of surgery. T3 was 10 minutes after the start of the surgical procedure. T4 was the time when patients were discharged from the operating room. Combined spinal-epidural (CSE) group: CSE anesthesia group. Combined group: Remimazolam-combined CSE anesthesia group. ^aP < 0.05, ^bP < 0.0001. CSE: Combined spinal-epidural; STAI-S: State-Trait Anxiety Inventory-State scale.

Table 2 Comprehensive mixed-effects model results for State-Trait Anxiety Inventory- State scale scores and hemodynamic variables.

Variable	Effect	Fdf1, df2 value	P value	Geisser-Greenhouse's epsilon
STAI-S	Time	F1.71, 98.99 = 83.56	< 0.001a	0.8534
	Group	F1, 58 = 201.4	< 0.001a
	Time × group	F2, 116 = 110.0	< 0.001a
SBP	Time	F3.28, 190.5 = 10.04	< 0.001a	0.8210
	Group	F1, 58 = 4.34	0.042a
	Time × group	F4, 232 = 2.44	0.048a
DBP	Time	F2.87, 166.5 = 3.96	0.010a	0.7176
	Group	F1, 58 = 0.75	0.391
	Time × group	F4, 232 = 0.26	0.901
HR	Time	F2.72, 157.7 = 0.85	0.462	0.6796
	Group	F1, 58 = 0.07	0.796
	Time × group	F4, 232 = 1.06	0.380

^aP < 0.05.

P values were calculated using a two-way mixed-effects ANOVA. F_{df1, df2}: F statistics with df1 (degrees of freedom for the effect) and df2 (degrees of freedom for error), sphericity was assessed using Mauchly’s test, and the Greenhouse - Geisser correction was applied where sphericity was violated. Time: Main effect of time points. Group: Main effect of experimental groups. Time × Group: Interaction effect between time points and experimental groups. STAI-S: State-Trait Anxiety Inventory-State scale scores; SBP: Systolic blood pressure (mmHg); DBP: Diastolic blood pressure (mmHg); HR: Heart rate (beats/minute).

Table 3 Comparison of State-Trait Anxiety Inventory-State scale scores and hemodynamic variables across time points.

Variable	Time point	CSE group, n = 30	Combined group, n = 30	Mean difference (95%CI)	Adjusted P value
STAI-S	TS0	51.93	52.80	-0.87 (-3.143-1.409)	> 0.999
	TS1	54.03	28.80	25.23 (21.24-29.23)	< 0.001a
	TS2	54.53	45.07	9.47 (6.29-12.64)	< 0.001a
SBP	T0	126.0	121.4	4.60 (-7.92-17.12)	> 0.999
	T1	125.6	120.0	5.63 (-7.71-18.97)	> 0.999
	T2	128.8	114.7	14.17 (0.77-27.57)	0.033a
	T3	120.1	111.2	8.87 (-3.18-20.91)	0.273
	T4	121.0	111.4	9.60 (-0.89-20.09)	0.089
DBP	T0	72.80	70.87	1.93 (-8.38-12.25)	> 0.999
	T1	73.70	71.93	1.77 (-10.39-13.92)	> 0.999
	T2	72.93	68.97	3.97 (-6.38-14.31)	> 0.999
	T3	70.60	67.20	3.40 (-5.92-12.71)	> 0.999
	T4	70.07	66.67	3.40 (-4.02-10.82)	> 0.999
HR	T0	76.94	76.28	1.967 (-5.86-9.79)	> 0.999
	T1	76.67	77.00	-0.33 (-9.33-8.66)	> 0.999
	T2	78.70	75.53	3.17 (-6.65-12.98)	> 0.999
	T3	77.17	76.00	1.17 (-6.41-8.75)	> 0.999
	T4	73.60	76.27	-2.67 (-11.05-5.72)	> 0.999

^aP < 0.05.

P values were calculated using post-hoc analysis Bonferroni correction, multiple comparisons test was conducted to assess intergroup differences at each time point, with effect sizes expressed as mean differences (95%CI). STAI-S: State: Trait Anxiety Inventory - State scale scores; SBP: Systolic blood pressure (mmHg); DBP: Diastolic blood pressure (mmHg); HR: Heart rate (beats/minute); CSE: Combined spinal-epidural.

Secondary outcomes

In the analysis of sedation depth (Table 4), the Combined group demonstrated significantly higher Ramsay sedation scores at T2 and T3 compared to the CSE group [median: 5.00 (IQR: 5.00-5.00) vs 2.00 (IQR: 2.00-2.00); median difference = 3.00, 95%CI: 3.00-3.00, P < 0.001]. This finding indicates that the Combined group achieved deeper sedation during the intraoperative maintenance phase (T2-T3) likely attributable to the pharmacological profile of remimazolam. As a novel benzodiazepine, remimazolam offers rapid onset, predictable recovery, and titratable sedation depth. Its integration into the combined anesthesia protocol played a pivotal role in enhancing sedation efficacy at these critical stages, enabling patients to attain profound sedation levels. No statistically significant differences were observed at T0, T1, or T4 (median scores: 2.00 for both groups; P ≥ 0.492), suggesting comparable sedation levels between groups during preoperative preparation (T0-T1) and late recovery (T4). The gradual decline in remimazolam’s effect by T4 Likely contributed to the convergence of sedation states between groups, mirroring their similar preoperative profiles. This implies that neither protocol conferred distinct advantages in sedation management during early or late perioperative phases.

Table 4 Comparison of Ramsay sedation scores at different postoperative time points.

Time point	CSE group, n = 30	Combined group, n = 30	Median difference (95%CI)	P value
T0	2.00 (2.00-2.00)	2.00 (2.00-2.00)	0.00 (0.00-0.00)	0.492
T1	2.00 (2.00-2.00)	2.00 (2.00-2.00)	0.00 (0.00-0.00)	0.492
T2	2.00 (2.00-2.00)	5.00 (5.00-5.00)	3.00 (3.00-3.00)	< 0.001a
T3	2.00 (2.00-2.00)	5.00 (5.00-5.00)	3.00 (3.00-3.00)	< 0.001a
T4	2.00 (2.00-2.00)	2.00 (2.00-2.00)	0.00 (0.00-0.00)	> 0.999

^aP < 0.05.

P values were calculated using the Mann-Whitney U test, with Hodges-Lehmann estimated median differences (95%CI). T1 was the time prior to positioning. T2 was the time at the commencement of surgery. T3 was 10 minutes after the start of the surgical procedure. T4 was the time when patients were discharged from the operating room. CSE: Combined spinal-epidural.

A two-way ANOVA (mixed-effects model) was conducted to analyze systolic blood pressure, diastolic blood pressure, and HR data from 60 patients in the CSE and Combined groups across five time points (T0 to T4), with Bonferroni correction applied for multiple comparisons. The results revealed significant effects of time on systolic blood pressure [P < 0.001, F (3.284, 190.5) = 10.04], while the effects on diastolic blood pressure [P = 0.0103, F (2.870, 166.5) = 3.957] and HR [P = 0.4617, F (2.718, 157.7) = 0.8450] were weaker or non-significant. A significant group effect was observed for systolic blood pressure [P = 0.0416, F (1, 58) = 4.341], with the predicted mean being 124.3 for the CSE group and 115.7 for the Combined group, resulting in a mean difference of 8.573 (95%CI: 0.3364-16.81). In contrast, no significant group effects were found for diastolic blood pressure [P = 0.3911, F (1, 58) = 0.7466] or HR [P = 0.7958, F (1, 58) = 0.06756]. Additionally, the interaction between time and group was significant for systolic blood pressure [P = 0.0478, F (4, 232) = 2.439], suggesting differing trends over time between the two groups, but not for diastolic blood pressure [P = 0.9006, F (4, 232) = 0.2644] or HR [P = 0.3797, F (4, 232) = 1.055; Table 2].

Post-hoc analysis using Bonferroni correction showed a significant difference in systolic blood pressure between the CSE and Combined groups only at the T2 time point (mean difference = 14.17, adjusted P = 0.0333), with no significant differences at T0, T1, T3, or T4 (adjusted P > 0.05 for all). As shown in Table 3, no significant differences in diastolic blood pressure or HR were observed at any time point (all adjusted P > 0.05). Trend analysis indicated that the CSE group exhibited an initial increase in systolic blood pressure from T0 to T2, followed by a decline, while the Combined group demonstrated an overall decreasing trend. Diastolic blood pressure and HR remained relatively stable over time in both groups, with no notable trends (Figure 2B-D).

DISCUSSION

This study investigated the differential effects of CSE with remimazolam vs CSE anesthesia alone on perioperative anxiety, sedation depth, and hemodynamic stability. Remimazolam, a novel ultra-short-acting benzodiazepine, demonstrates distinct pharmacological advantages: It selectively activates GABAA receptors to mediate sedation and anxiolysis, undergoes rapid hydrolysis by tissue esterases to an inactive metabolite (CNS7054), and exhibits rapid onset (1-2 minutes), short half-life (7-10 minutes), and predictable recovery[7,8]. These properties allow it to achieve deep sedation while circumventing the accumulation risks associated with conventional benzodiazepines such as midazolam[9].

The primary outcome revealed significantly reduced anxiety levels in the Combined group during the immediate postoperative recovery phase (T_S1) compared to the CSE group, with this anxiolytic advantage persisting partially into the 24-hour postoperative period (T_S2). Secondary outcomes demonstrated that the remimazolam-based protocol achieved superior intraoperative sedation depth (Ramsay score = 5) alongside decreased blood pressure, evidenced by a 14.17 mmHg reduction in mean intraoperative systolic blood pressure relative to the CSE group. Below, we integrate these findings with pharmacological mechanisms and current evidence to provide a comprehensive interpretation.

Compared to the CSE group, the Combined group showed significantly reduced STAI-S scores at T_S1 (prior to OR discharge; mean difference, 25.23; 95%CI: 21.24-29.23). This anxiolysis is attributed to remimazolam’s pharmacological properties: Residual drug concentrations reduced anxiety despite meeting operating room discharge criteria, while unconsciousness during surgery coupled with gradual emergence further alleviated anxiety. In contrast, CSE patients’ intraoperative awareness heightened sensitivity to environmental stressors (e.g., procedural noises), surgical stress, and anticipatory discomfort, triggering progressive STAI-S elevation. By 24 hours postoperatively (T_S2), both groups entered recovery where physiological stressors (e.g., wound pain, restricted mobility) overshadowed anesthesia-related anxiety differences. Crucially, although the Combined group's scores increased from T_S1 to T_S2, their absolute anxiety levels remained significantly lower than those of the CSE group (mean difference: 9.467; 95%CI: 6.289-12.64). This may reflect CSE patients’ adaptation to postoperative status and active psychological adjustment motivated by high T_S1 anxiety; meanwhile sustained smooth emergence transition with low anxiety in the Combined group.

The STAI-S, recognized as one of the "gold standard" tools for assessing preoperative anxiety, has its reliability and validity verified by numerous studies (Cronbach’s α > 0.85)[10]. Clinically, a score of ≥ 44 (out of 80) is universally regarded as the threshold for clinically significant anxiety[10,11]. Studies have shown that a 10-point reduction in STAI-S score is considered a clinically significant improvement, which is significantly associated with a decrease in perioperative adverse events[12]. From the perspective of enhanced recovery after surgery (ERAS), preoperative anxiety management has become a critical component in optimizing postoperative rehabilitation[13]. Changes in STAI-S scores are significantly correlated with anesthesia recovery quality, analgesic requirements, and early rehabilitation efficiency. In clinical practice, screening high-anxiety-risk patients using STAI-S and implementing personalized interventions can effectively reduce postoperative pain sensitivity and opioid consumption, providing important support for the smooth implementation of ERAS pathways[14].

These findings align with established evidence that benzodiazepines are among the most used medications for treating anxiety, insomnia, and as pre-anesthetic agents[15]. Gamma-aminobutyric acid (GABA), as the primary inhibitory neurotransmitter in the central nervous system, plays a crucial role in regulating neuronal transmission in the brain[16]. Currently, drugs targeting GABAergic transmission have been widely used in the clinical treatment of anxiety disorders. GABA receptors are mainly divided into ionotropic GABAA receptors and metabotropic GABAB receptors[17]. Research has found that acting on the α2 subunit of the GABAA receptor exhibits significant anxiolytic-like effects. Meanwhile, mice with a deficiency in the B1 subunit of the GABAB receptor display anxiety and panic-like behaviors[18]. These findings fully confirm that GABAergic transmission and alterations in GABA receptors play a vital role in the occurrence and development of anxiety states.

In the neural circuit of the brain that regulates anxiety, the amygdala-prefrontal cortex (PFC) pathway is of great significance[19]. The basolateral amygdala complex (BLA) receives threatening information and then activates the central nucleus (CeA), triggering the somatic manifestations of anxiety. The medial PFC and the anterior cingulate cortex are also involved. The PFC can regulate the activity of BLA neurons to control anxiety, and the activity of the PFC is abnormal in some patients with anxiety disorders. The GABAergic interneurons in the amygdala not only regulate the activation of the CeA by the BLA but also serve as the main targets of excitatory projections from the PFC. They play a key regulatory role in the transmission of anxiety-related information and affect the formation of anxiety.

Remimazolam, as a selective agonist of GABAA receptors, has shown certain efficacy in anti-anxiety. However, the metabolite of remimazolam, CNS7054, has no significant agonistic effect on GABAA receptors[8,20]. The results of this study show that 24 hours postoperatively, the STAI-S scores of patients in the Combined group were still lower than those in the CSE group. The difference in surgical experience provides another reasonable explanation for this phenomenon: Remimazolam can make patients completely forget the surgical process, which likely reduces postoperative recall of traumatic experiences - a recognized risk factor for anxiety[21]. Neuropsychological studies have shown that compared with patients who can recall intraoperative discomfort, unconscious patients generate fewer intrusive memories. This difference in memory may regulate the activity of the hippocampal-amygdala fear neural circuit[22]. Therefore, we speculate that the use of remimazolam induces loss of consciousness during surgery, thereby reducing overactivation of this neural circuit. The combination of neurochemical regulation and cognitive-emotional memory processing jointly explains why the anxiety scores of remimazolam-treated patients were lower than those in the CSE group both immediately after surgery and 24 hours postoperatively.

The study demonstrated that the Combined group achieved deep sedation (Ramsay score = 5) at T2 and T3 time points, attributable to remimazolam’s rapid onset and sustained intraoperative efficacy. Its short half-life facilitated a rapid return to baseline consciousness by time point T4 (median sedation score = 2.00 in both groups). Comparative trials by Zhou et al[23] highlighted remimazolam’s unique pharmacokinetic profile, enabling profound procedural sedation while circumventing post-anesthetic recovery delays - a critical advantage in ambulatory surgery settings with rising caseloads. Pharmacokinetic analysis revealed that following a 4-hour administration, the calculated context-sensitive half-time was 6.8 ± 2.4 minutes. The onset of unconsciousness occurred at 5 ± 1 minutes post-initiation, while restoration of complete wakefulness occurred 19 ± 7 minutes after terminating the infusion[24]. A meta-analysis of relevant studies revealed that during endoscopic surgery, remimazolam was associated with a significantly lower risk of respiratory depression compared to propofol[25]. This clearly indicates that remimazolam holds an advantage in respiratory depression safety. These characteristics solve two key perioperative problems: Accelerating surgical turnover and reducing sedation-related complications.

In this study, remimazolam had an impact on hemodynamic stability. The systolic blood pressure of the CSE group at the time point was significantly higher than that of the Combined group, with a difference of 14.17 mmHg (P = 0.033). This discrepancy likely reflects anxiety-induced sympathetic hyperactivity in conscious CSE patients, compounded by incomplete spinal sympathetic blockade sustaining catecholamine release. Remimazolam has been demonstrated in multiple clinical studies to induce blood pressure reduction through central GABAergic suppression and peripheral vasodilation[3]. However, its incidence of hypotension remains significantly lower than propofol, with studies reporting rates of 20% and 24% in the 6 and 12 mg/kg/hour dosing groups for remimazolam, compared to 49.3% in the propofol group[26]. Crucially, despite marked SBP elevation in the CSE group during skin incision (acute nociceptive stimulus), both regimens-maintained pressures below the critical threshold of 160 mmHg - a level associated with increased myocardial infarction risk[27]. Based on these findings, the CSE group’s transient hypertension during early intraoperative phases could necessitate closer monitoring in high-risk patients. These findings highlight the necessity of proactive anxiety management and real-time hemodynamic monitoring, particularly in procedures involving abrupt nociceptive inputs, to mitigate sympathetic overactivation and optimize perioperative safety.

In summary, this study pioneers the integration of CSE anesthesia with remimazolam for PPH surgery. Beyond optimizing perioperative hemodynamic stability and sedation efficacy, the protocol introduces a novel psychological evaluation dimension via serial STAI-S assessments, marking a distinct advancement over conventional studies focusing solely on physiological parameters. Remimazolam exhibits dual effects: It alleviates perioperative anxiety, suppresses sympathetic overactivation, and reduces catecholamine release to stabilize the psychosomatic state, while modulating cardiovascular activity, reducing sympathetic tension, and maintaining hemodynamic stability. These characteristics enable patients under the remimazolam-integrated CSE protocol to experience improved surgical comfort. Clinically, the findings highlight the need for proactive, personalized psychological support measures to alleviate patient anxiety and optimize treatment outcomes and rehabilitation quality.

This study has inherent limitations. The sample size was relatively small, potentially limiting the generalizability of results to diverse patient populations receiving remimazolam-combined anesthesia. Additionally, the study focused on short-term outcomes and specific indicators, with long-term effects of remimazolam and its efficacy in special populations (e.g., elderly patients, those with hepatorenal insufficiency) remaining unexplored. Future research should prioritize: (1) Expanding sample size and patient diversity; (2) Conducting long-term follow-ups to assess safety and efficacy; and (3) Evaluating long-term psychological impacts via 7-day/30-day postoperative anxiety score assessments. Multi-center trials with extended monitoring periods are recommended to validate protocol durability.

CONCLUSION

In conclusion, in Procedure for PPH surgery, compared with standard CSE alone, the anesthesia protocol combined with remimazolam significantly reduced patient STAI-S scores, particularly before leaving the operating room and 24 hours postoperatively. The protocol also achieved deeper sedation and better-controlled systolic blood pressure at key intraoperative time points. The findings indicate that remimazolam-combined CSE anesthesia demonstrates advantages in optimizing perioperative outcomes, although further research is warranted to validate this conclusion.

ACKNOWLEDGEMENTS

We express our sincere gratitude to Dr. Xing Huang from Hunan Provincial People's Hospital for his outstanding surgical expertise and meticulous clinical supervision throughout this study. Moreover, we would like to extend our heartfelt appreciation to the operating room nurses and ward nurses of Hunan Provincial People's Hospital. Their invaluable contributions have been instrumental in the successful implementation of this research.