The aging of the population presents significant challenges to public health systems (Jensen et al., 2020). Elderly patients face an elevated risk of perioperative organ damage due to progressive decline in organ function (Olotu, 2021; Lim and Lee, 2020; Lee et al., 2021). In comparison to general anesthesia, spinal and local anesthesia require fewer drugs, reducing the accumulation of anesthetics and minimizing their impact on cardiac and pulmonary perfusion (Desai et al., 2018; Liu et al., 2014; Mounet et al., 2021). However, patients who remain awake during surgery are more likely to experience tension, anxiety, and fear, which may result in stress and elevate the risk of cardiovascular and cerebrovascular complications, as well as postoperative cognitive dysfunction (Urvoy et al., 2021). Postoperative delirium (POD) is a common and serious complication in the elderly following surgery. It involves a decline in neurocognitive function after anesthesia and surgery, representing a central nervous system complication (Rundshagen, 2014). POD is characterized by a marked reduction in cognitive abilities, such as memory, attention, coordination, orientation, verbal fluency, and executive function (Needham et al., 2017). POD is generally believed to result from a combination of factors, including patient age, type of surgery and anesthesia, pain severity, and educational background (Zhao et al., 2024). POD may persist for weeks to years, negatively adversely affecting recovery, prolonging hospital stays, and contributing to additional physical and mental health complications. It also elevates mortality rates and places a substantial burden on both patients and their families (Gu et al., 2019; Mason et al., 2010; Miller et al., 2018; Skvarc et al., 2018; Xiao et al., 2020). Recent studies have highlighted the important role of exosomes in regulating neuroinflammation and neuroprotection. Exosomes are nano-sized extracellular vesicles that carry bioactive molecules such as proteins, mRNAs, and miRNAs, and have been shown to modulate β-amyloid (Aβ) metabolism and reduce neuroinflammatory responses (Hosseini and Abolhasanpour, 2001). The etiology of POD is complex, and its exact mechanism remains unclear. However, the neuroinflammatory response triggered by surgery is widely regarded as the primary contributing factor and initial trigger in its development (Skvarc et al., 2018).

Commonly used sedatives include midazolam, propofol, and dexmedetomidine, each associated with specific safety concerns (Tran et al., 2019). Midazolam, for instance, is linked to an increased the risk of postoperative delirium (Aldecoa et al., 2017; Fick et al., 2019), while propofol may significantly affect hemodynamics (Fechner et al., 2024), and dexmedetomidine may cause transient bradycardia and hypertension (Coursin et al., 2001). Remimazolam, a novel ultra-short-acting benzodiazepine, undergoes rapid metabolized by nonspecific esterase into the inactive metabolite CNS7054. It offers rapid onset of action, a shorter half-life than midazolam, favorable circulatory and respiratory stability, and can be immediately antagonized by flumazenil (Sheng et al., 2020; Sneyd and Rigby-Jones, 2020). Clinical trials have shown that remimazolam provides sedation efficacy comparable to propofol for procedures like gastroscopy and hysteroscopy, with the added benefits of painless injection, minimal respiratory depression, and no adverse effects on short-term postoperative cognitive function (Doi et al., 2020; Guan et al., 2021; Tan et al., 2022; Zhang et al., 2022; Zhang et al., 2021). Moreover, remimazolam has been demonstrated to alleviate neuropathic pain, reduce the production of pro-inflammatory factor production such as TNF-α, IFN-γ, IL-6, IL-1β (Xie et al., 2021), and mitigate cerebral ischemia/reperfusion (I/R) injury (Shi et al., 2022). For elderly patients undergoing surgery with neuraxial anesthesia, the requirements for sedatives are relatively high. Additionally, since patients do not completely lose consciousness as they would under general anesthesia, they often experience heightened anxiety during the procedure. An ideal sedative should not only provide a comfortable diagnostic and therapeutic experience but also exhibit rapid onset, quick recovery after discontinuation, predictable dose-response relationships, no accumulation, and minimal adverse effects. In summary, we believe that remimazolam holds significant promise for use in elderly patients receiving neuraxial anesthesia. Despite its ability to induce and maintain general anesthesia, there are currently no reports sedation regimens using remimazolam during neuraxial anesthesia in elderly patients.

This study, therefore, aims to identify the optimal sedation dose of remimazolam for neuraxial anesthesia and to evaluate its potential impact on perioperative cognitive function.

A total of 330 patients were recruited between July 2021 and February 2022. Eligible patients were randomized to receive either remimazolam or placebo sedation in a 2:1 ratio. Of the recruited participants, 21 refused to participate, 9 withdrew consent on the day of surgery, and 38 declined postoperative follow-up, leaving 238 patients for analysis (Figure 2). The two groups were comparable in terms of demographic and baseline characteristics (Table 1).

The main results of this multicenter trial are as follows: (i) the effective sedation dose of remimazolam besylate in elderly patients under neuraxial anesthesia was determined to be 5.38 mg. The appropriate induction dosing regimen consisted of an initial dose of 5 mg, a supplemental dose of 2.5 mg, and a maintenance infusion rate of 0.223 mg·kg⁻¹·h⁻¹; (ii) remimazolam besylate did not impair short-term postoperative cognitive function in elderly patients.

Unlike midazolam, remimazolam besylate has distinct pharmacodynamic and pharmacokinetic properties, making it suitable for maintaining sedation during short procedures, such as gastrointestinal endoscopy, hysteroscopy, and fiberoptic bronchoscopy (Zhang et al., 2022; Zhang et al., 2021; Kornstein et al., 2014; Wesolowski et al., 2016). Remimazolam exerts minimal effects on the circulatory and respiratory systems, can be rapidly antagonized by flumazenil (Nakayama et al., 2021), and is particularly suitable for elderly patients. Notably, the 0.1 mg·kg⁻¹ remimazolam dose in elderly patients undergoing upper gastrointestinal endoscopy did not affect short-term postoperative cognitive function (Tan et al., 2022). Remimazolam is relatively safe for both induction (1 mg·kg⁻¹·h⁻¹) and maintenance (0.1 mg·kg⁻¹·h⁻¹) in elderly patients undergoing general anesthesia (Chen et al., 2021; Nakanishi et al., 2021). However, specific guideline dosing regimens for remimazolam besylate for sedation during neuraxial anesthesia in elderly patients have not yet been established.

Based on prior studies (Doi et al., 2020; Rex et al., 2018) and the manufacturer’s recommendations, we selected a titrated dosing regimen for induction and an individualized dosing regimen for maintenance. In our trial, two cases of sedation failure led to a sedation efficiency of 98.93%, consistent with the results of a Phase III clinical trial in China (Zhao et al., 2022). Another study reported effective sedation in elderly male patients with a single dose of remimazolam besylate, achieving a 50% effective dose (ED₅₀) of 0.063 mg·kg⁻¹ and a 95% effective dose (ED₉₅) of 0.079 mg·kg⁻¹ (Ichijima et al., 2022). In some cases, the effective dose required for successful sedation may be lower than 5.38 mg with this regimen. This discrepancy may stem from our definition of successful sedation as MOAA/S ≤ 2, in contrast to MOAA/S ≤ 3 in the other study. Our trial’s median age was 69.9 years, with a median Body Mass Index (BMI) of 24.0 kg·m⁻² and a balanced gender distribution. In contrast, the other study only included male patients with a mean BMI of 21.87 kg·m⁻² and a mean age of 74.8 years.

Another finding of our trial was that, unlike midazolam, remimazolam besylate did not increase the risk of postoperative cognitive dysfunction in elderly patients, consistent with previous trials (Tan et al., 2022). In this study, both MMSE and MoCA were used to assess postoperative cognitive dysfunction. The MMSE is widely recognized as a brief cognitive assessment tool for measuring cognitive impairment (Arevalo-Rodriguez et al., 2015). However, multiple systematic reviews and meta-analyses have shown that MoCA is more sensitive than MMSE in detecting subtle changes in cognitive function (Arevalo-Rodriguez et al., 2015; Abd Razak et al., 2019; Ciesielska et al., 2016). Compared to the MMSE, the MoCA involves more complex tasks, such as a larger word count, fewer learning trials, and a longer delay before the memory recall test (Nasreddine et al., 2005). These make MoCA scores more influenced by education and cognitive ability. We selected the MMSE for preliminary screening and the MoCA for a more detailed assessment of cognitive function.

Notably, although the surgery and sedation duration in our trial were longer, the total administered dose was lower. Additionally, remimazolam besylate did not increase the incidence of postoperative delirium or adversely impact patient anxiety. Furthermore, remimazolam besylate had positive effects on sleep rhythm, subjective wellbeing, comfort, and patient cooperation during follow-up visits. Satisfaction survey of the attending anesthesiologists yielded results consistent with previous studies (Chen et al., 2020). Moreover, the attending physicians expressed a willingness to explore the remimazolam dosing regimen further in different procedures.

In terms of safety, no hemodynamic deterioration was observed in the remimazolam group, although HR and MAP showed significant differences compared to the control group. However, all vital signs were within the safe range, which positively impacted the anesthesia experience of the patients. The use of vasoactive drugs and the incidence of postoperative adverse effects, including nausea, vomiting, dizziness, drowsiness, headache, and gloss coma, were similar to those in the saline group. Notably, the incidence of chills was significantly lower in the remimazolam group compared to the saline group. Increased muscle activity during anesthesia recovery can raise oxygen consumption by up to five times. Hypoxemia, lactic acidosis, and hypercarbia can complicate anesthesia recovery, particularly in patients already at risk for hypoxemia due to other factors. Even without these complications, patients often experience discomfort due to shivering, and prevention of this syndrome is highly valued (Crossley, 1995). In a phase III trial comparing the efficacy and safety of remimazolam and propofol for colonoscopy, the incidence of treatment-emergent adverse events was lower in the remimazolam group (49.48% vs. 68.42%). However, dizziness (23.71%) and gait disturbance (26.29%) were the primary adverse effects observed. A key reason for this discrepancy may be that, unlike in gastroscopy, where patients experience varying degrees of mechanical trauma, sedation was initiated after satisfactory analgesia was determined from the neuraxial anesthesia in the present study. Consequently, when remimazolam was used for sedation during neuraxial anesthesia procedures, fewer adverse effects occurred because the dose of the sedative drug was significantly lower. Moreover, we selected patients in good physical health and employed a standardized body weight dosing regimen of 0.2 mg·kg⁻¹·h⁻¹ remimazolam administered via continuous infusion during the maintenance period of sedation.

The correlation between BIS and MOAA/S is shown in Figure 3D. However, the MOAAS score is actually used as the leading indicator for evaluating the sedation levels because evidence suggests that BIS is more suitable for monitoring sedation with propofol (Zhao et al., 2023). In benzodiazepine-based sedation therapy, the BIS index often remains high and can be influenced by other drugs, including anesthetics (Ibrahim et al., 2001). At the same time, the assessment of the BIS index can be influenced by electromyographic (EMG) activity. Literature reports two cases where the BIS index failed to measure anesthesia depth accurately: one case saw a paradoxical increase in the BIS index with rising propofol concentration, correlating with increased myoelectric activity, while in another case, administering a non-depolarizing muscle relaxant decreased the BIS index value despite a constant anesthetic concentration (Bruhn et al., 2000). Consequently, the BIS index may not be fully applicable for evaluating sedation levels in patients undergoing neuraxial anesthesia (Bruhn et al., 2000), warranting further investigation in future clinical trials.

In addition, there was a statistically significant difference in satisfaction between patients and attending anesthesiologists, which we believe serves as supportive evidence for the use of remimazolam in such anesthesia procedures. Through discussions with the attending anesthesiologists involved in clinical drug administration and observation, we learned that anesthesiologists’ satisfaction is primarily influenced by the patient’s level of cooperation during surgery and the occurrence of adverse events. On the other hand, patient satisfaction is more closely related to the degree of tension and anxiety experienced during the surgery and anesthesia, as well as whether they were affected by fear of the procedure. Additionally, postoperative adverse reactions such as nausea, vomiting, and shivering also play a role in patient satisfaction.

Although our dosing protocol was designed specifically for sedation during neuraxial anesthesia in elderly patients, it may also serve as a reference for conscious sedation protocols in elderly patients in other contexts. However, our study had several limitations. First, our study enrolled patients in relatively good health, with well-treated comorbidities and on long-term, regular treatment regimens. Patients with obesity and severe comorbidities were excluded; therefore, in clinical practice, individualized dosing should be considered on a case-by-case basis, because our research findings do not have universal applicability to the above two groups of patients. Second, the concurrent use of opioids and benzodiazepines might exert a synergistic effect that deepens the sedation level. In our protocol, sedation procedures were performed after achieving satisfactory neuraxial anesthesia with promising anesthetic effects, without the use of opioids. Consequently, we could not evaluate the impact of remimazolam besylate in conjunction with opioids and can only offer a reference range for appropriate dosing in elderly patients. Third, different types of surgery pose varying risks for the development of POD. However, the type of surgery was not included as one of the screening criterions in this study, representing a limitation. Fourth, In our study, we adopted a single-blind method where the participants were unaware of their group assignment. Although the interventions administered to the experimental and control groups appeared identical, the anesthesiologists could not be blinded due to the noticeable differences in clinical effects. However, we ensured that the postoperative nursing staff and follow-up evaluators remained unaware of the participants’ group assignments. While this approach mitigated significant bias in the experimental results caused by the lack of blinding to some extent, we acknowledge that the study outcomes may still have been subtly influenced as a result. Finally, regarding the impact of remimazolam on patients’ postoperative cognitive function, we only conducted statistical analyses on short-term outcomes (the morning and afternoon of postoperative day 2, as well as postoperative day 7). Data on its effects on patients’ long-term cognitive function are lacking. Therefore, future studies need to refine and further explore this aspect.

Although spinal anesthesia alone can help patients undergo surgery, administering remimazolam for sedation is more suitable for clinical practice. This preference is based on several factors. First, it results in more stable intraoperative vital signs, such as blood pressure. Second, the use of remimazolam significantly reduces the incidence of perioperative shivering. Lastly, patient satisfaction is higher, aligning with the principles of comfort-focused healthcare. These benefits make remimazolam a valuable option for enhancing both patient outcomes and the overall quality of perioperative care.

In conclusion, the initial sedation dose of remimazolam besylate in non-general anesthesia surgeries for elderly patients is 5.38 mg, with maintenance dose of 0.223 mg·kg⁻¹·h⁻¹. Remimazolam besylate does not cause significant hemodynamic fluctuations, nor does it increase the risk of postoperative cognitive dysfunction or delirium. Additionally, it improves sleep quality and enhances the overall anesthesia experience for patients.