Remimazolam sedation for spinal anaesthesia surgery and its effect on perioperative cognitive function in elderly patients: a multicentre, placebo-controlled study

doi:10.21203/rs.3.rs-3145367/v1

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Remimazolam sedation for spinal anaesthesia surgery and its effect on perioperative cognitive function in elderly patients: a multicentre, placebo-controlled study

https://doi.org/10.21203/rs.3.rs-3145367/v1

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BACKGROUND

Remimazolam, a novel ultra-short-acting benzodiazepine, is a potential sedative for non-general anaesthesia surgery in the elderly. This study aimed to investigate the appropriate sedative dosage of remimazolam and its effects on perioperative cognitive function in elderly patients undergoing non-general anaesthesia surgery.

METHODS

This multicentre, placebo-controlled trial enrolled 330 elderly patients undergoing non-general anaesthesia procedures at eight centres in China from July 2021 to February 2022, with 238 ultimately completing the study. The primary endpoints were the dose of successful sedation with remimazolam and the changes in perioperative cognitive function. Adverse events were recorded to assess drug safety.

RESULTS

The induction dose of remimazolam for sedation in spinal anaesthesia in elderly patients was 5.38 mg (95% confidence interval [CI], 5.20 to 5.56), maintained at a rate of 0.223 mg·kg^− 1·h^− 1 (95% CI, 0.201 to 0.237) with no serious adverse effects. Compared with the saline group, there was no statistical difference in the Mini-Mental State Examination scores in the experimental group on Day2 morning (P : 0.886), Day2 afternoon (P : 0.864), and Day7 (P : 0.613), and no statistical difference in the Montreal Cognitive Assessment scores on Day2 morning (P : 0.687), Day2 afternoon (P : 0.827), and Day7 (P : 0.483).

CONCLUSIONS

Remimazolam besylate is an effective sedative drug during spinal anaesthesia in elderly patients, with a successful induction dose of 5.38 mg (95% CI, 5.20 to 5.56), maintained at a rate of 0.223 mg·kg^− 1·h^− 1 (95% CI, 0.201 to 0.237) and a good safety profile without altering the short-term postoperative cognitive function.

cognitive function

elderly

remimazolam

sedation

spinal anaesthesia

Ageing of the population poses a tremendous challenge for public health systems¹. Elderly patients are at an increased risk of perioperative organ damage due to progressive decline in organ function^2–4. Compared with general anaesthesia, spinal and local anaesthesia use fewer drugs, which reduces the accumulation of anaesthetic drugs and the impact on the patient's heart and lung perfusion^5–7. However, patients awake during surgery are highly prone to tension, anxiety, and fear, resulting in varying degrees of stress and an increased risk of cardiovascular and cerebrovascular complications and postoperative cognitive dysfunction⁸. Moderate sedation can reduce emotional tension and improve comfort⁹.

The most widely used sedative drugs are midazolam, propofol, and dexmedetomidine; however, they all have safety issues that cannot be overlooked¹⁰. Remimazolam is a novel ultra-short-acting benzodiazepine rapidly metabolised by nonspecific esterases in vivo to the inactive metabolite CNS7054. It has the advantages of rapid onset of action, shorter half-life compared to midazolam, good circulatory and respiratory stability, and immediate antagonism by flumazenil^11,12. Several trials have demonstrated that remimazolam has sedative efficacy comparable to propofol for gastroscopy and hysteroscopy, with no injection pain, low respiratory depression, and no impact on short-term postoperative cognitive function^13–17. Remimazolam can induce and maintain general anaesthesia; however, no sedation regimens using remimazolam during spinal anaesthesia have been reported in elderly patients.

Therefore, this study aimed to establish a successful sedation dose of remimazolam for spinal anaesthesia.

Ethical approval and study population

This study was a prospective, multicentre, randomised, single-blind, placebo-controlled clinical trial approved by the Medical Ethics Committee of Tianjin Medical University General Hospital (Tianjin, China; chairperson: Professor Zhixiang Zhang; approval number: IRB2021-YX-067-01; approval date 30/04/2021), and registration was completed using the Chictr.org.cn registration system (registration number: ChiCTR2100048744; principal investigator, Yi-ze Li, PhD; registration date: 13/03/2021; approval date 15/07/2021). Written informed consent was obtained from all patients or their families according to the CONSORT guidelines. We recruited 330 American Society of Anesthesiologists physical status I–III older patients aged ≥65 years from eight centres in China who were scheduled to undergo spinal anaesthesia procedures between July 2021 and February 2022. Patients with an allergy to any anaesthetic drug, contraindications to spinal anaesthesia, a history of severe respiratory pathology, psychiatric disorders, cognitive dysfunction, pregnancy, or breastfeeding were excluded.

Randomisation and masking

All eligible patients will be randomised using a grouping system at the School of Public Health, Tianjin Medical University. They were divided into a remimazolam group (R group) and a 0.9% sodium chloride injection group (saline group) in a 2:1 ratio. A single-blind design was used owing to the significant difference in sedation efficacy and appearance between the two groups, which prevented us from blinding the attending anesthesiologist. The study participants, post-anaesthesia care unit nurses, and statisticians were blinded to the trial subgroups.

Procedures

Within seven days preoperatively (days 7–1), a professionally trained fellow conducted a preoperative assessment of potential enrollees, including general condition, sleep rhythm (Pittsburgh Sleep Quality Index, PSQI), anxiety level (Hamilton Anxiety Scale, HAMA), delirium condition (Nursing Delirium Screening Scale, Nu-DESC), and cognitive function (Mini-Mental State Examination [MMSE]; Montreal Cognitive Assessment [MoCA]; Telephone-MoCA [T-MoCA] ).

On admission to the operating room (Day 1), the patient was routinely monitored using an electrocardiogram, blood pressure, oxygen saturation, temperature, and bispectral index (BIS). Since no studies have assessed the depth of sedation of remimazolam using the BIS index, we combined the Modified Observer Alertness/Sedation Assessment (MOAA/S) scale and the BIS index to assess the depth of sedation.

Sedation was initiated after the completion of spinal anaesthesia (epidural, lumbar, and combined lumbar and epidural anaesthesia) to ensure that the level of anaesthesia met surgical requirements. The remimazolam group was administered an initial dose of remimazolam besylate (5.0 mg), and 5 mL of 0.9% saline was administered to the placebo control group (saline group). If patients in the remimazolam group had a MOAA/S score ≥ 3 at 1–3 min after the initial dose administration, additional intravenous dosing (2.5 mg/dose at 2-min intervals) was allowed until the patients achieved adequate sedation level (MOAA/S score≤2). If the number of additional doses exceeded five during induction and the MOAA/S score was >4, sedation was considered to have failed.

After ensuring that sedation was induced (MOAA/S score≤2), maintenance dosing was initiated. Remimazolam besylate was continuously administered at a rate of 0.2 mg·kg^-1·h^-1 in the remimazolam group and 0.9% saline at a rate of 0.2 ml·kg^-1·h^-1 in the saline group. The maintenance dosing rate was adjusted according to the patient's MOAA/S score, increasing or decreasing by 0.1 mg·kg^-1·h^-1 each time and an additional dose of 2.5 mg/dose remimazolam besylate was allowed when necessary.

When the patient's mean arterial pressure (MAP) and heart rate (HR) decrease by more than 20% from the preoperative baseline or systolic blood pressure ≤ 80 mmHg, fluid therapy or vasoactive drugs are administered immediately. When the patient's oxygen saturation was < 90%, mask compression-assisted ventilation was initiated immediately, and if necessary, a laryngeal mask or endotracheal intubation was initiated.

The investigators assessed patients' cognitive function, sleep rhythm, anxiety, delirium, and fragility on Day 2 morning, Day 2 afternoon, and Day 7. Patient and investigator satisfaction levels were assessed. The total number of entirely satisfactory scores for both assessments was 10, with scores 0–3 being defined as poor, 4–7 as fair, and 8–10 as excellent. A flowchart of the study is presented in Supplementary Fig. S1.

Statistical analysis

This trial used a blank placebo as a control, and the sample size calculation was based on relevant literatures^{14, 19-23}. We assumed a sedation success rate of 93% in the propofol and remimazolam besylate groups and a 2:1 ratio in the trial: saline group. Therefore, the number of samples in the trial group was 176, and 88 in the saline group (α : 0.025 unilateral and power 80%). Considering the 20% lost visit rate, 220 cases required enrolment in the trial group and 110 in the saline group for 330 recruited patients.

Statistical analyses were performed using SAS (version 9.4; SAS Institute Inc., USA) and GraphPad Prism8 software for data analysis. Statistical significance was set at P < 0.05, and the confidence interval (CI) was 95%.

The statistical descriptions of the measurement data are presented as mean ± standard deviation, median, minimum, and maximum values. The changes from baseline within the group were analysed using a paired t-test, and the differences before and after treatment between the two groups were analysed using Analysis of Variance (ANOVA) or non-parametric tests. The count data were statistically described by frequency and percentage, and the changes before and after treatment between the two groups were evaluated using the χ² test, Fisher's exact probability method, or non-parametric tests.

We recruited 330 patients from July 2021 to February 2022; 306 patients were eligible and randomised to receive either remimazolam or placebo sedation in a 2:1 ratio. Of these, 21 refused to participate, 9 withdrew consent on the day of surgery, and 38 declined postoperative follow-up, resulting in 238 patients being analysed (Fig 1). Comparability was achieved between the two groups concerning the demographic and baseline characteristics (Table 1).

Dose of successful sedation

The sedation effects between the two groups are shown in Table 2. Sedation failed in two of the 187 patients who received remimazolam, and the sedation success rate was 98.93%; however, both patients declined postoperative follow-up. The remimazolam arm received an active induction dose of 5.38 mg (95% CI, 5.20 to 5.56), and the mean time to successful sedation (MOAA/S ≤ 2) was 1.61 min (95% CI, 1.40 to 1.81), the mean rate of maintenance was 0.223 mg·kg^-1·h^-1(95% CI, 0.201 to 0.237) and the mean time to first MOAA/S score of 5 during the recovery period was 8.03 min (95% CI, 7.68 to 8.37) after drug discontinuation.

Changes in cognitive function

Perioperative cognitive function changes in both arms are shown in Table 3. The MMSE and MoCA scores did not significantly differ between the two groups of patients at any time point (p > 0.05). The two groups' differences were insignificant in the preoperative baseline MMSE (P : 0.848) and MoCA scores (P : 0.956). Compared with the saline group, the MMSE scores did not significantly differ in the remimazolam group on Day2 morning (mean ± SD, 24.49 ± 0.22 vs 24.54 ±0.24; 95% CI, -0.75 to 0.65; P : 0.886), Day2 afternoon (mean ± SD, 24.55 ± 0.22 vs 24.49 ± 0.26; 95% CI, -0.66 to 0.78; P : 0.864), and Day7 (mean ± SD, 24.61 ± 0.22 vs 24.42 ± 0.26; 95% CI, -0.53 to 0.90; P : 0.613), nor did the MoCA scores significantly differ in the remimazolam group on Day2 morning (mean ± SD, 21.03 ± 0.29 vs 21.05 ± 0.34; 95% CI, -0.97 to 0.92; P : 0.956) and Day2 afternoon (mean ± SD, 21.23 ± 0.29 vs 21.04 ± 0.34; 95% CI, -0.75 to 1.13; P : 0.687). The T-MoCA scores did not significantly differ between the two groups at the telephone follow-up on the sixth postoperative day (Day7, mean ± SD, 14.41 ± 0.34 vs 14.05 ± 0.31; 95% CI, -0.64 to 1.35; P : 0.483).

Change in delirium, sleep and anxiety

The patients' perioperative delirium, anxiety, and sleep in both groups are shown in Table 4. The differences in the preoperative baseline Nu-DESC (P : 0.982), HAMA (P : 0.934), and PSQI scores (P : 0.862) between the two groups were not statistically significant. Compared with the preoperative baseline values, the delirium scores (Nu-DESC) of the patients in the two groups did not change significantly on the day of surgery (Day1) (P : 0.153), Day2 morning (P : 0.817), Day2 afternoon (P : 0.486), and Day7 (P : 0.787). The two groups did not differ significantly in terms of the patient’s delirium scores (Nu-DESC) on Day1 (P : 0.697), Day2 morning (P : 0.850), Day2 afternoon (P : 0.549), and Day7 (P : 0.604).

Compared with the preoperative period, the HAMA scores decreased on Day 2 morning (P < 0.0001), Day 2 afternoon (P < 0.0001), and Day 7 (P < 0.0001) in both groups. The difference in HAMA scores between the two groups was also statistically significant on Day 2 morning (P < 0.0001), Day 2 afternoon (P < 0.0001), and Day 7 (P < 0.0001). However, patients were considered to have anxiety only when their HAMA scores were ≥ 7^24, and the degree of perioperative anxiety was not significantly different between the two groups.

In terms of sleep quality (Pittsburgh Sleep Quality Index [PSQI] ), no statistical differences were observed between the two groups for all patients (P : 0.862) and those with sleep quality disorders (PSQI ≥ 8) (P : 0.078). On the Day2 morning, the difference in the PSQI scores between the groups (P : 0.301) and the change from the preoperative baseline scores (P : 0.135) was not statistically significant. The difference in PSQI scores (P : 0.0002) and the transition from preoperative baseline scores (P < 0.0001) were significantly different between the two groups at six days postoperatively (Day 7).

Postoperative satisfaction

The patient and researcher satisfaction scores for the two groups are shown in Supplementary Table S1. The patient and researcher satisfaction in the remimazolam group was higher than that in the saline group on Day 2 morning, Day 2 in the afternoon and Day 7. The differences were statistically significant (All P < 0.0001).

Safety analysis

The MAP and HR of patients in the remimazolam group decreased within the first five minutes after the sedation induction period. They were both lower than those in the saline group, but the differences were not significantly different from those in the saline group at all time points (P > 0.05, Fig 2A-B). Patients experienced a mild decrease in SpO₂after induction of remimazolam sedation, followed by a gradual recovery, and the lowest SpO₂ was not below 90% (Fig 2C).

The correlation between BIS and MOAA/S in the remimazolam group

We monitored the BIS index simultaneously with the MOAA/S scale during the procedures performed on the patients in the remimazolam group (Figure 2D). During the maintenance period of sedation, the BIS values were always > 70 (mean ± SD:71.00 ± 7.78~75.79 ± 9.47), significantly different from the actual sedation state of the patients. However, the MOAA/S score decreased rapidly to < 2 approximately two minutes after the start of induction, which was generally consistent with the actual sedation level of the patients. The results showed that the BIS values did not correlate with the MOAA/S score at the same time point and that the MOAA/S score correlated strongly with the depth of sedation in the remimazolam group.

The use of vasoactive drugs during surgery did not differ significantly between the groups. The use of remimazolam did not increase the number of doses of phenylephrine (P : 0.236), atropine (P : 0.619), dopamine (P : 0.291), metaraminol bitrate (P : 0.971), methoxamine(P : 0.564), or ephedrine (P : 0.0.291) compared with that in the saline group. In terms of adverse effects, the incidences of nausea (P : 0.983), vomiting (P : 0.602), drowsiness (P : 0.321), headache (P : 0.484), dizziness (P : 0.321), and glossocoma (P : 0.321) did not significantly increase in the remimazolam group, whereas the incidence of chills (P < 0.0001) decreased. (Supplementary Table S2).

The main results of this multicentre trial were as follows: (i) the effective dose of remimazolam besylate for sedation in elderly patients under spinal anaesthesia was 5.38 mg, and an induction period dosing regimen with an initial dose of 5 mg with a supplemental dose of 2.5 mg and a maintenance infusion rate of 0.223 mg·kg^− 1·h^− 1 was appropriate; (ii) remimazolam besylate did not affect short-term postoperative cognitive function in elderly patients.

Unlike midazolam, remimazolam besylate has special pharmacokinetic and pharmacodynamic characteristics and can be used to maintain sedation during short-acting procedures, such as gastrointestinal endoscopy, hysteroscopy, and fibreoptic bronchoscopy^{14, 15, 23, 25}. Remimazolam has minimal circulatory and respiratory effects on patients, is rapidly antagonised by flumazenil²⁶, and is suitable for elderly patients. The use of 0.1 mg·kg^− 1 remimazolam in elderly patients undergoing upper gastrointestinal endoscopy did not affect their short-term postoperative cognitive function¹³. Remimazolam is relatively safe for induction (1 mg·kg^− 1·h^− 1) and maintenance (0.1 mg·kg^− 1·h^− 1) in elderly patients receiving general anaesthesia^{27, 28}. However, specific guideline dosing regimens for remimazolam besylate for sedation during spinal anaesthesia surgery in elderly patients have not yet been reported.

Based on the results of previous studies^{16, 20} and the manufacturer’s recommendations, we selected a titrated dosing regimen for the induction phase and an individualised dosing regimen for the maintenance phase. In our trial, two cases of sedation failure occurred, and the sedation efficiency was 98.93%, which is in line with a Chinese phase III clinical trial²⁹. Another trial used a single dose of remimazolam besylate to administer sedation to elderly male patients with a 50% effective dose (ED90) of 0.063 mg·kg^− 1 and 95% effective dose (ED95) 0.079 mg·kg^{− 1 30}. In some cases, it may be lower than the effective dose of 5.38 mg for successful sedation with this regimen. One reason could be that the criterion for successful sedation in this trial was MOAA/S ≤ 3, whereas in our trial, MOAA/S ≤ 2 was defined as the criterion for adequate sedation. Another possible reason is that, in our trial, the median age was 69.9 years, the median Body Mass Index (BMI) was 24.0 kg·m^− 2, and the subject population was balanced between men and women. In contrast, that trial recruited only male patients with a mean BMI of 21.87 kg·m^− 2 and a mean age of 74.80 years.

Another finding of our trial was that when sedation was administered to elderly patients, unlike midazolam, remimazolam besylate did not increase the risk of postoperative cognitive dysfunction, consistent with previous trials¹³. More importantly, in our trial, the surgery and sedation duration was longer, and the total dose administered was lower. Moreover, remimazolam besylate did not increase the incidence of postoperative delirium or affect patient anxiety. Remimazolam besylate can alter the patient's sleep rhythm, improve subjective well-being and comfort, and enhance cooperation in allowing repeat follow-up visits. Moreover, the satisfaction survey with the attending anesthesiologists yielded results consistent with past studies³¹. The attending physicians were willing further to explore the remimazolam dosing regimen in different procedures.

Regarding safety, compared to the saline group, patients in the remimazolam group experienced no hemodynamic deterioration, with no significant differences in MAP and HR between the two groups. The use of vasoactive drugs and the incidence of postoperative adverse effects, such as nausea, vomiting, dizziness, drowsiness, headache, and glossocoma, were similar to those in the saline group. The incidence of chills was significantly lower in the remimazolam group.

In a phase III trial comparing the efficacy and safety of remimazolam and propofol for colonoscopy, the incidence of treatment-emergent total adverse events was lower in the remimazolam group (49.48% vs 68.42%). However, dizziness (23.71%) and gait disturbance (26.29%) were the main adverse effects ³². A key reason for this discrepancy may be that, unlike gastroscopy, in which patients are subjected to varying degrees of mechanical trauma, sedation was initiated only after satisfactory analgesia was determined from the spinal anaesthesia in the present study. Therefore, when remimazolam was used for sedation during spinal anaesthesia procedures, fewer adverse effects occurred because the dose of the sedative drug was significantly lower. Moreover, we selected patients in good physical condition and used a standardised body weight dosing regimen of 0.2 mg·kg^− 1·h^− 1 remimazolam by continuous pumping during the maintenance period of sedation.

Although our dosing protocol was used for sedation under spinal anaesthesia in elderly patients, it may provide a reference for conscious sedation protocols in elderly patients in other situations (e.g., intraoperative sedation under local infiltration anaesthesia, outpatient surgery sedation, and sedation in intensive care unit). However, our study had several limitations. First, the remimazolam besylate (the initial dose is 5.0 mg and the supplemental dose is 2.5 mg) is associated with potential risks, which may lead to deep sedation in elderly patients and increase the incidence of Adverse Events (AEs). However, no AEs occurred in our trial. Second, we recruited patients in relatively good condition with well-treated comorbidities but receiving long-term and regular treatment. Patients with obesity and severe comorbidities were omitted; therefore, individualised dosing is required on a case-by-case basis in clinical practice. Third, the combination of opioids and benzodiazepines may have a synergistic effect and deepen the sedation depth. In our protocol, sedation procedures were performed after spinal anaesthesia with promising anaesthetic effects without a combination of opioids. Therefore, we could not assess the effect of remimazolam besylate with opioids and could only provide a reference range for appropriate dosing for sedation in elderly patients. The correlation between BIS and MOAA/S is shown in Fig. 2D. Although we used MOAA/S scores combined with the BIS index to assess sedation, the correlation in practice could be more robust, and a more reproducible and standardised depth-of-anaesthesia monitoring device. This should be investigated in future clinical trials.

The initial sedative dose of remimazolam besylate for non-general anaesthesia surgery in elderly patients is 5.38 mg and is effective when maintained at a rate of 0.223 mg·kg^− 1·h^− 1. Remimazolam besylate does not cause significant hemodynamic fluctuations and does not increase the risk of postoperative cognitive dysfunction or delirium. It also improves the quality of patients’ sleep and provides them with a comfortable anaesthesia experience.

95% CI : 95% confidence interval

ASA : American Society of Anesthesiologists

BMI : body mass index

CONSORT : Consolidated Standards of Reporting Trials

PSQI : Pittsburgh Sleep Quality Index

HAMA : Hamilton Anxiety Scale

Nu-DESC : Nursing Delirium Screening Scale

MMSE : Mini-Mental State Examination

MoCA : Montreal Cognitive Assessment

T-MoCA : Telephone-MoCA

BIS : bispectral index

MOAA/S : Modified Observer Alertness/Sedation Assessment

MAP : Mean arterial pressure

HR : Heart rate

ED90 : 50% effective dose

ED95 : 95% effective dose

Ethics approval and Consent to Participate

This study was approved by the Medical Ethics Committee of Tianjin Medical University General Hospital (Tianjin, China; chairperson: Professor Zhixiang Zhang; approval number: IRB2021-YX-067-01; approval date 30/04/2021). Informed consent was obtained from all participants in this study and was signed by the participants themselves or their legal guardians.

Availability of Data and Materials

The data supporting the findings of this study will be obtained from the corresponding author according to a reasonable request.

Consent for Publication

Patient consent for publication.

Not applicable.

Funding

This study was supported by grants from the National Natural Science Foundation of China (82071243,82171205), Natural Science Foundation of Tianjin City(20JCYBJC00460), and Tianjin Health and Health Science and Technology Program Project (TJWJ2022XK012,2021176).

Competing interests

The authors declare no competing interests.

Author contributions

YH.Y., YZ.L. are the guarantor of the content of the manuscript, including the data and analysis. JM.K., YJ.L., YL.Z. contributed to data collection and analysis, wrote the initial draft of this manuscript. JM.K., KJ.N. contributed to data analysis. Y.X., D.Q., WW.Z., Q.Z., Y.L., T.H., YM.Z., LJ.Y., J.X., SS.W., Y.Y., Q.L,YX.Z. contributed to data collection. LL.Z., YH.Y., YZ.L. contributed to trial design and editing of this manuscript.

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Table 1 Patient and anaesthetic characteristics. Data are mean ± standard deviation, or n (%). ASA, American Society of Anesthesiologist; BMI, body mass index.
	Remimazolam (n=160)	Saline (n=78)
Sex
Male	73(46%)	40(51%)
Female	87(54%)	38(49%)
Age（yr）	69.9 ± 4.7	69.4 ± 4.5
Body weight (kg)	66.7 ± 10.9	67.5 ± 9.9
BMI( kg·m^-2)	24.0 ± 2.4	25.1 ± 2.7
ASA physical status
2	142(89%)	74(95%)
3	18(11%)	4(5%)
MAP（mmHg）	95.4 ± 7.2	97.2 ± 8.0
HR（beats·min^-1）	76.1 ± 7.5	76.4 ± 7.6
Surgery history, n	44	35
Duration of Sedation (min)	75.1 ± 22.4	69.5 ± 17.3
Duration of surgery (min)	77.1 ± 21.6	73.3 ± 17.4

Table 2 Dose of successful sedation. Unless specified, all values are expressed as mean (95% CI).
	Remimazolam（n=160）	Saline(n=78)
Sedation success time（min）	1.61 (1.40 to 1.81）	-
remimazolam induction dose (mg)	5.38 (5.20 to 5.56)	-
remimazolam maintenance dose (mg·kg^-1·h^-1)	0.223 (0.201 to 0.237)	-
total dose of remimazolam per patient (mg)	23.50 (21.94 to 25.06)	-
Wake-up time (min)	8.03 (7.68 to 8.37)	-

Table 3 Per-protocol analysis. Data are n(%) or mean ± standard deviation. CI, confidence interval; MMSE, Mini-Mental State Examination; MoCA, Montreal Cognitive Assessment.
	Remimazolam （n=160）	Saline （n=78）	Odds ratio ± 95% CI or mean difference	P-value
MMSE score(Preoperative）	24.59 ± 0.22	24.53 ± 0.25	0.07 (-0.63 to 0.77)	0.848
MMSE score(Day2 morning)	24.49 ± 0.22	24.54 ± 0.24	-0.05 (-0.75 to 0.65)	0.886
Change from preoperative score	-0.11 ± 0.05	0.01 ± 0.06	-0.12 (-0.28 to 0.04)	0.136
Score <26	93(58.1%)	49(62.8%)	-0.59 (-1.25 to 0.07)	0.079
MMSE score(Day2 afternoon)	24.55 ± 0.22	24.49 ± 0.26	0.06 (-0.66 to 0.78)	0.864
Change from preoperative score	-0.04 ± 0.05	0.04 ± 0.06	-0.01 (-0.16 to 0.15)	0.948
Score <26	92(57.5%)	51(65.4%)	-0.54 (-1.20 to 0.11)	0.105
MMSE score(Day7)	24.61 ± 0.22	24.42 ± 0.26	0.18 (-0.53 to 0.90)	0.613
Change from preoperative score	0.01 ± 0.04	-0.10 ± 0.06	0.12 (-0.02 to 0.25)	0.092
Score <26	89(55.6%)	51(65.4%)	-0.54 (-1.19 to 0.12)	0.107
MOCA score(Preoperative)	21.03 ± 0.29	21.05 ± 0.34	-0.03 (-0.97 to 0.92）	0.956
MOCA Score(Day2 morning)	21.23 ± 0.29	21.04 ± 0.34	0.19 (-0.75 to 1.13)	0.687
Change from preoperative score	0.27 ± 0.06	0.22 ± 0.10	0.05 (-0.17 to 0.27)	0.654
MOCA score(Day2 afternoon)	21.36 ± 0.29	21.26 ± 0.35	0.11 (-0.85 to 1.06)	0.827
Change from preoperative score	0.34 ± 0.07	0.21 ± 0.09	0.13 (-0.10 to 0.36)	0.261
T-MOCA score(Day7)	14.41 ± 0.34	14.05 ± 0.31	0.36 (-0.64 to 1.35)	0.483

Table 4 Per-protocol analysis.Data are n (%) or mean ± standard deviation. CI, confidence interval; Nu-DESC, Nursing Delirium Screening Scale; HAMA ,Hamilton Anxiety Scale; PSQI,Pittsburgh sleep quality index.
	Remimazolam (n=160)	Saline (n=78)	Mean difference (95% CI)	P-value
Nu-DESC score(Preoperative)	0.03 ± 0.02	0.03 ± 0.03	-0.001 (-0.06 to 0.05)	0.982
Nu-DESC score(Day1)	0.03 ± 0.02	0.04 ± 0.04	-0.01 (-0.08 to 0.05)	0.697
Change from preoperative score	0 ± 0	0.01 ± 0.01	-0.01 (-0.03 to 0.005)	0.153
Nu-DESC score(Day2 morning)	0.03 ± 0.02	0.03 ± 0.03	0.01 (-0.05 to 0.06)	0.850
Change from preoperative score	0.01 ± 0.02	0 ± 0	0.01 (-0.05 to 0.06)	0.817
Nu-DESC score(Day2 afternoon )	0.01 ± 0.01	0.03 ± 0.03	-0.01 (-0.06 to 0.03)	0.549
Change from preoperative score	-0.01 ± 0.01	0 ± 0	-0.01 (-0.05 to 0.02)	0.486
Nu-DESC score (Day7)	0.01 ± 0.01	0.01 ± 0.01	-0.01 (-0.03 to 0.02)	0.604
Change from preoperative score	-0.02 ± 0.01	-0.01 ± 0.01	-0.01 (-0.05 to 0.04)	0.787
HAMA score(Preoperative)	5.33 ± 0.31	5.28 ± 0.38	0.04 (-0.98 to 1.06)	0.934
Score≥7	70(43.8%)	32(41.0%)	0.49 (-0.33 to 1.31)	0.240
HAMA score (Day2 morning)	1.82 ± 0.20	4.93 ± 0.35	-3.12 (-3.86 to -2.38)	<0.0001
Change from preoperative score	-3.51 ± 0.19	-0.35 ± 0.13	-3.16 (-3.72 to -2.60)	<0.0001
Score≥7	18(11.3%)	32(41.0%)	-0.46 (-1.01 to 0.90)	0.101
HAMA score(Day2 afternoon)	1.18 ± 0.16	4.33 ± 0.35	-3.16 (-3.83 to -2.49)	<0.0001
Change from preoperative score	-4.15 ± 0.22	-0.95 ± 0.19	-3.20 (-3.87 to -2.53)	<0.0001
Score≥7	11(6.9%)	32(41.0%)	-0.26 (-0.64 to 0.13)	0.182
HAMA score(Day7)	0.69 ± 0.12	3.51 ± 0.36	-2.82 (-3.41 to -2.23)	<0.0001
Change from preoperative score	-4.63 ± 0.25	-1.77 ± 0.25	-2.86 (-3.66 to -2.07)	<0.0001
Score≥7	3(1.88%)	26(33.3%)	-0.46 (-1.24 to 0.32)	0.235
PSQI score (Preoperative)	5.06 ± 0.16	5.10 ± 0.18	-0.05 (-0.57 to 0.48)	0.862
Score≥8	13(8.13%)	9(11.54%)	1.73 (-0.21 to 3.67)	0.078
PSQI score(Day2 morning)	4.74 ± 0.17	5.01 ± 0.16	-0.28 (-0.80 to 0.25)	0.301
Change from preoperative score	-0.32 ± 0.09	-0.09 ± 0.11	-0.23 (-0.53 to 0.07)	0.135
Score≥8	11(6.88%)	6(7.69%)	1.76 (-1.41 to 4.92)	0.255
PSQI score (Day7)	4.32 ± 0.18	5.35 ± 0.14	-1.03 (-1.56 to -0.49)	0.0002
Change from preoperative score	-0.74 ± 0.12	0.24 ± 0.13	-0.98 (-1.36 to -0.60)	<0.0001
Score≥8	9(8.49%)	5(6.41%)	1.51 (-2.49 to 5.51)	0.427

No competing interests reported.

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Remimazolam sedation for spinal anaesthesia surgery and its effect on perioperative cognitive function in elderly patients: a multicentre, placebo-controlled study

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