Efficacy and Safety of Remimazolam Mesylate in General Anesthesia Induction and Maintenance in Elderly Patients: A Single-Center, Randomized, Positive-Drug, Paralleled, Controlled Study

doi:10.21203/rs.3.rs-1820076/v1

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Efficacy and Safety of Remimazolam Mesylate in General Anesthesia Induction and Maintenance in Elderly Patients: A Single-Center, Randomized, Positive-Drug, Paralleled, Controlled Study

https://doi.org/10.21203/rs.3.rs-1820076/v1

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Objective

To evaluate the efficacy and safety of remimazolam mesylate for general anesthesia in elderly patients.

Methods

Patents aged 60 to 80 years who were scheduled to undergo surgery were randomized into three groups: Group A (remimazolam mesylate 6 mg/kg/h), Group B (remimazolam mesylate 12 mg/kg/h), or Group C (propofol 2.0-2.5 mg/kg). Primary efficacy indicators (success rate of anesthesia sedation), secondary efficacy indicators (BIS value, anesthesia induction time, anesthesia awakening time), safety efficacy indicators (incidence of anesthetic hypotension; incidence of anesthetic hypoxemia) and incidence of adverse events (intravenous pain, nausea and vomiting, etc.) were routinely monitored.

Results

The success rate of anesthesia sedation was 95% in the 6 mg/kg/h remimazolam mesylate group and 100% in the 12 mg/kg/h remimazolam mesylate and propofol groups. Noninferiority of remimazolam mesylate [95% confidence interval (0.04; 0.047)]. There were statistically significant differences in anesthesia awakening time, use of norepinephrine, and adverse events (P < 0.05). There were no significant differences in the time of anesthesia induction or incidence of bradycardia and hypotension among the three groups. However, compared with the propofol group, the awakening time in the remimazolam tosylate groups was significantly shorter (P < 0.05), the effect on heart rate was lower, and there was no pain from intravenous injection. The intraoperative BIS values of the three groups were all maintained at 40–63, and no intraoperative awareness was found. At the same time, the use of norepinephrine in the remimazolam tosylate groups was significantly reduced (P < 0.05).

Conclusions

Remimazolam mesylate is well tolerated and noninferior to propofol with regard to efficacy as a sedative hypnotic for general anesthesia. Remimazolam mesylate can accelerate recovery from anesthesia, have less impact on heart rate, and decrease the use of vasoactive drugs and intravenous pain.

Clinical trial registration:

Remimazolam mesylate

Propofol

General anesthesia

Elderly patients

With the transformation of disease patterns and the aging population, the demand for surgical operations has greatly increased[1]. The proportion of surgery in elderly patients has also increased yearly[2]. Because elderly patients have reduced cardiovascular regulation and stress capacity to external injury, often in combination with cardiovascular and cerebrovascular system diseases[3], they are prone to severe hemodynamic fluctuations and even cardiovascular and cerebrovascular events during induction of anesthesia and intubation. Such age-related physiological and pharmacokinetic changes, as well as the presence of comorbidities and polypharmacy, complicate drug therapy in elderly individuals, thereby greatly increasing the risk of anesthesia[4]. Therefore, rational selection and appropriate application of anesthesia-inducing drugs are crucial for elderly patients who require general anesthesia for surgery.

Propofol, a commonly used intravenous anesthesia drug, has a rapid onset of action and a short duration of action[5, 6]. Propofol can inhibit the gag reflex to a certain extent and reduce some of the adverse stress reactions during tracheal intubation. However, because of the inhibitory effect on the respiratory and circulatory systems and other adverse reactions^[7], especially injection site pain, its application is limited to a certain extent for elderly patients. Hence, there is a continuing, unmet need for short-acting anesthetics with rapid onset, well-controlled depth of anesthesia, complete, rapid, and predictable recovery, benign safety, and independence from renal or hepatic metabolism.

Remimazolam mesylate is a new type of ultrashort-acting benzodiazepine that inhibits neuronal action, reduces neuronal excitability and causes decreased body activity, sedation and amnesia[8]. Despite an increase in heart rate at 2 minutes after remimazolam administration, vital signs remain stable[9]. Pharmacokinetic modeling has shown that remimazolam has a high clearance rate, which is largely independent of body weight, and a small volume of distribution [10, 11]. Its maximum half-life is less than 1 hour and remains unchanged when infused over 3 hours[12]. Previous studies[13, 14] have indicated equivalent anesthetic effects for remimazolam and propofol in colonoscopy diagnosis and hip replacement in elderly patients, with the former being significantly safer. In addition, phase II/III clinical trials in Japan have shown that remimazolam not only induces and maintains sedation during general anesthesia but is also noninferior to propofol in terms of efficacy[15]. Nevertheless, the efficacy and safety of remimazolam versus propofol for general anesthesia in elderly patients is still unclear. With the characteristics of rapid onset of action, short maintenance and recovery time, no accumulation[11], metabolism not dependent on liver and kidney function[16], and no serious side effects, remimazolam may become an ideal drug for induction and maintenance of anesthesia in elderly patients.

This trial was conducted to confirm the efficacy and safety of remimazolam mesylate during general anesthesia in elderly patients. To provide clinical experience and theoretical basis for remimazolam mesylate for general anesthesia in elderly patients.

Ethics and registration

Study design

This was a prospective, single-blind, randomized, single-center, parallel-group study comparing the efficacy and safety of different doses of remimazolam mesylate (RT) relative to propofol. Sixty-six elderly patients requiring general anesthesia with tracheal intubation for elective surgery were recruited and included in the study based on inclusion and exclusion criteria, and the trial was randomized into three groups: RT 6 mg/kg/h (Group A), RT 12 mg/kg/h (Group B), and propofol (Group C), with a sample size ratio of 1:1:1 in each group. Differences in the primary efficacy index, secondary efficacy index and safety evaluation index between the three groups were compared and analyzed according to the intention-to-treat principle, and the occurrence of adverse events (AEs) and adverse drug reactions (ADRs) during the trial period was recorded, as shown in Fig. 1. The trial was registered with Chinese Clinical Trial Registry (ChiCTR number: 2100047274) and conducted in accordance with the Declaration of Helsinki and the ethical principles of International Ethical Guidelines for Human Biomedical Research issued by International Committee for the Organization of Medical Sciences. The protocol was approved by Medical Ethics Committee of Dongguan People's Hospital. Written informed consent was obtained from each patient before the start of any protocol-specified procedures (Fig. 1).

Patient eligibility

Elderly patients who required general anesthesia with tracheal intubation for elective surgery at Affiliated Dongguan Hospital, Southern Medical University (Dongguan People's Hospital) were enrolled.

Inclusion criteria: I a full understanding of the purpose and significance of this trial, voluntarily participated in this clinical trial, and signed the informed consent form; II requiring general anesthesia with tracheal intubation for elective surgery; Ⅲ age 60–80 years old, with no restriction on sex.

Exclusion criteria: Ⅰ hypersensitivity to the components or components of drugs such as remimazolam mesylate, propofol, or sufentanil that may be used in the study; Ⅱ long-term application of narcotic analgesics, sedatives or nonsteroidal anti-inflammatory drugs; Ⅲ opioid dependence or tolerance; Ⅳ systemic hypotension despite use of vasoactive drugs; Ⅴ bradycardia with a heart rate < 55 beats/min; Ⅵ high atrioventricular block without a pacemaker; Ⅶ combined craniocerebral injury and intracranial hypertension; Ⅷ severe cardiac, pulmonary, hepatic or renal abnormalities; Ⅸ a previous history of allergic disease; Ⅹ a previous history of psychiatric disorders; Ⅺ fat metabolism disorders; Ⅻ foreseeable difficult intubation; ⅫI other conditions judged to be unsuitable for participation in the clinical trial; XIV myasthenia gravis.

Criteria for exclusion of cases: Ⅰ the subject or family members voluntarily withdrew informed consent at any time; Ⅱ the subject developed a condition that met the exclusion criteria during the study or a clinical adverse event that jeopardized the safety of the subject, an abnormal laboratory test, or other medical condition that resulted in the possibility that the benefit to the subject from continued medication was less than the risk; Ⅲ the subject was found to be ineligible after randomization; Ⅳ other reasons for anesthesia that, in the opinion of the investigator, precluded continuation of the trial treatment.

Randomization

Numbering was based on the time of surgery. Random numbers were generated by SPSS 25.0 software, and the 66 patients were randomly divided into Groups A (RT 6 mg/kg/h), B (RT 12 mg/kg/h), or C (propofol induction period loading dose of 2.0-2.5 mg/kg), with equal sample sizes.

Procedures

None of the patients were administered medication before the study. After admission to the operating room, they were placed in a quiet supine position for 5 min, and peripheral venous access was opened and infused with compound sodium chloride injection. Heart rate (HR), oxygen saturation (SpO₂), modified observer’s assessment of alertness and Sedation (MOAA/S, as shown in Supplementary Table 1), and depth of anesthesia monitoring (BIS) were routinely monitored. Invasive arterial puncture was performed, and mean arterial pressure (MAP) was monitored. Denitrogenated oxygen was administered for 3 min (oxygen flow rate 5 L/min) before induction. Elderly patients scheduled to receive general anesthesia were randomized to receive induction period doses of RT 6 mg/kg/h, 12 mg/kg/h or propofol induction dose (2.0-2.5) mg/kg. After the patients were anesthetized, cis-atracurium besilate (0.2–0.3) mg/kg and sufentanil (0.4–0.6) µg/kg were administered intravenously with face mask pressure. Intraoperative anesthesia was maintained at a starting dose of 0.5 mg/kg/h in the RT groups, with each adjustment not exceeding 0.2 mg/kg/h. In the propofol group, the maintenance dose was 3 to 8 mg/kg/h. The BIS index was kept between 40 and 60, and intraoperative analgesia and muscle relaxation were maintained by intravenous pumping of remifentanil and cis-atracurium besilate. Sufentanil 5 µg and tropisetron 2 to 5 mg were slowly injected intravenously at 30 min to 1 h before the end of the operation.

If the patient's BIS value is consistently > 60 during the induction of anesthesia, remimazolam mesylate 0.05 mg/kg/dose can be administered intravenously until the BIS value is below 60, and the interval between the two doses cannot be less than 1 min. If the depth of anesthesia is not reached by three remimazolam mesylate injections, propofol or etomidate (drug selection according to the investigator's dosing habits) may be used and recorded. In the event of a remimazolam overdose, supportive, symptomatic treatment is given, as appropriate. The reversal agent for remimazolam mesylate is flumazenil. The recommended initial intravenous bolus dose is 0.3 mg. If the desired level of awakeness is reached within 60 seconds, it can be used as appropriate according to the instructions of flumazenil.

Treatment plan for adverse reactions during anesthesia. I Hypertension (an increase in MAP exceeding 20% of the baseline value), intravenous injection of urapidil 5 mg/time, depending on the blood pressure. Ⅱ Hypotension (a decrease in MAP exceeding 20% of the baseline value), intravenous infusion of norepinephrine 0.03–0.2 µg/kg/min, depending on the blood pressure. Ⅲ Bradycardia (HR < 55 beats/min), intravenous injection of atropine 0.2–0.3 mg/time. Ⅳ Tachycardia (HR > 120 beats/min), the investigators implemented treatment according to clinical experience, with intravenous injection of esmolol 20 mg/time if necessary. Ⅴ For hypoxemia (SpO₂ < 90%) after anesthesia and resuscitation, the method of raising the head and chin was immediately adopted, and the face mask was pressurized to assist with breathing if necessary. Such events were handled immediately and recorded.

Clinical outcomes and safety assessments

The primary efficacy endpoint was the success rate of sedation (percentage of patients successfully completing the procedure), as defined as follows: Ⅰ completion of the entire tracheal intubation general anesthetic procedure; Ⅱ no need for replacement and/or rescue sedation; for a BIS value consistently > 60 during induction of anesthesia, remimazolam mesylate 0.05 mg/kg/dose was administered intravenously until the BIS value was below 60, with an interval between doses. The interval between doses was not less than 1 minute, with a maximum of three supplemental doses given.

Secondary efficacy endpoints included the following: Ⅰ change in BIS value over time (time from induction of anesthesia until BIS value ≤ 60, value before tracheal intubation, intraoperative maintenance of BIS value); Ⅱ time to induction of anesthesia, as defined as the time from initial dose to obtaining adequate sedation (MOAA/S score ≤ 1; BIS value ≤ 60); Ⅲ time to awaken from anesthesia, as defined as the time from cessation of study drug to full alertness (MOAA/S score ≥ 4); Ⅳ incidence of hypotension; Ⅴ incidence of hypertension; Ⅵ incidence of hypoxemia. All secondary efficacy endpoints were analyzed in subjects with successful sedation.

This trial was conducted in accordance with the Declaration of Helsinki of the World Medical Assembly, which is to be just, respectful, and seek to maximize the benefit and avoid imitation of harm to the subject, and the available information is sufficient to support the clinical trial. Patient AEs, ADRs and vital signs (HR, respiration, BP, SpO₂) were closely monitored during sedation to assess the degree of sedation and to provide appropriate management and follow-up.

Safety assessment indicators: Ⅰ incidence of deep or shallow sedation (BIS value ≤ 40 or ≥ 60); Ⅱ incidence of anesthetic hypotension; Ⅲ incidence of anesthetic hypertension; Ⅳ incidence of anesthetic hypoxemia; Ⅴ incidence of intraoperative awareness; Ⅵ incidence of AEs and ADRs in subjects during the trial.

Sample size and statistical analysis

This study had a non-inferiority design, and the primary efficacy endpoint was the success rate of general anesthesia sedation in elderly patients. At the test level of 0.05 (one-sided), the power is not less than 80%, the success rate of anesthesia for the test drug remimazolam mesylate and the positive control drug propofol are both 99%, and the non-inferiority margin is -8%, and the dropout rate of subjects is estimated to be 10%. A total of approximately 66 elderly subjects undergoing elective general anesthesia were included, and the sample size ratio of each group was assigned to RT 6 mg/kg/h (group A), RT 12 mg/kg/h (group B), and propofol (group C) on a 1:1:1 basis.

Continuous variables conforming to a normal distribution are expressed as means ± SD, and continuous variables not conforming to a normal distribution are expressed as medians (RANGE or IQR); count data are expressed as N (%). For comparative analysis of differences in primary efficacy indices, secondary efficacy indices and safety evaluation indices among the three groups of patients according to the intention-to-treat (ITT) principle, continuous variables conforming to normal distribution were assessed by the t test, and those not conforming to normal distribution were assessed by the Mann–Whitney U test. Categorical variables were evaluated by the chi-square test or Fisher's exact test.

Patient characteristics.

A total of 66 eligible patients were enrolled in this study and randomized into three groups. Group A received remimazolam mesylate at 6 mg/kg/h (n = 22), Group B received remimazolam mesylate at 12 mg/kg/h (n = 22), and Group C received propofol at 2.0-2.5 mg/kg (n = 22). Sixty-six patients were included in the FAS population. For various reasons (patient decision, investigator decision, or exclusion criteria), 1 patient in Group A after several remedial doses withdrew due to persistent intraoperative hypertension, and 1 patient in Group C was excluded, primarily because of EEG monitoring malfunction (Fig. 2). Sixty-four patients were ultimately included in the per-protocol population.

At baseline examination, the demographic and baseline characteristics of the patients in the three groups were well balanced in terms of age, sex, height, weight, BMI, MAP, SpO2, and other demographic characteristics, as shown in Table 1. Overall, baseline demographics and clinical characteristics were comparable (all P value > 0.05). However, past history differed among the three groups (P value < 0.05). The RT (A) group consisted of 11 males and 11 females, with a mean age of 69.23 (± 5.40) years. The RT (B) group consisted of 10 males and 12 females, with a mean age of 67.05 (± 4.55) years. The propofol (C) group included 7 males and 15 females, with a mean age of 68.73 (± 5.68) years. The overall mean age was 68 years, and male patients accounted for 42.40%. Most patients had comorbidities, including cardiovascular disease (i.e., hypertension, congestive heart failure, coronary atherosclerotic heart disease, etc.), metabolic disease (i.e., insulin-dependent or noninsulin-dependent diabetes mellitus, etc.), respiratory disease (i.e., chronic obstructive pulmonary disease, pneumonia, etc.) and neurological disorders (i.e., hereditary diseases, infections, cancers, congenital and developmental disorders, degenerative diseases, etc.).

Table 1

Baseline characteristics of the patients
Characteristic	RT (6mg/kg/h)	RT (12mg/kg/h)	Propofol (2.0-2.5mg/kg)	Total (n = 66)	P Value* /F Value
Age,y					0.356^*/1.050
Mean ͟± SD	69.23 ± 5.40	67.05 ± 4.55	68.73 ± 5.68	68.33 ± 5.24
PROMedian	68.00	67.00	68.40	67.82
Minimum,maximum	61, 79	60, 76	60, 78	60, 79
Sex,No.(%)					0.446^*
Male	11(50)	10(45.5)	7(31.8)	28(42.4)
Female	11(50)	12(54.5)	15(68.2)	38(57.6)
Height,cm					0.832^*/0.185
Mean ͟± SD	160.05 ± 7.95	158.68 ± 9.52	158.59 ± 9.12	159.11 ± 8.78
Median	160.00	157.75	157.50	158.00
Minimum,maximum	145,173	140,175	142,176	140,176
Weight,kg					0.105^*/2.336
Mean ͟± SD	61.80 ± 10.18	55.05 ± 9.70	59.61 ± 11.74	58.82 ± 10.79
Median	62.25	55.50	60.50	59.82
Minimum,maximum	41.00, 83.00	39.50, 75.00	34.50, 82.50	34.5, 83.0
BMI,kg/m2					0.071^*/2.764
Mean ± SD	24.23 ± 4.42	21.74 ± 2.43	23.59 ± 3.81	23.19 ± 3.75
Median	24.12	22.09	23.62	22.98
Minimum,maximum	17.07, 35.00	16.96, 25.71	17.11, 31.24	16.96, 35.00
Past medical history					0.049^*#
Yes	13(59.1)	5(22.7)	9(40.9)	27(40.9)
No	9(40.9)	17(77.3)	13(59.1)	39(59.1)
Mean Arterial Pressure (MAP, mmHg)					0.080^*/2.623
Mean ͟± SD	96.97 ± 10.93	98.70 ± 10.00	92.00 ± 9.20	95.89 ± 10.32
Median	101.67	99.50	90.50	95.50
Minimum,maximum	73.00, 111.33	77.00, 114.00	73.33, 110.33	73.00, 114.00
oxygen saturation (SpO2,%)					0.260^*/1.378
Mean ͟± SD	97.95 ± 0.95	98.32 ± 0.88	97.77 ± 1.41	98.02 ± 1.12
Median	98	98	98	98
Minimum,maximum	96, 100	97, 100	95, 100	95, 100
Heart rate (beats/min)					0.944^*/0.057
Mean ͟± SD	75.05 ± 13.09	75.41 ± 12.40	74.23 ± 9.90	74.89 ± 11.70
Median	72.67	77.00	72.00	74.00
Minimum,maximum	54, 99	53, 98	60, 99	53, 99
The number in () shows % . ^*p values were calculated for the comparison of the three groups of RT A(6mg/kg/h), RT B(12mg/kg/h) and propofol groups using the Student t-test for continuous variables. BMI, body mass index; ASA, American Society of Anesthesiologists; SD, standard deviation ^# p values < 0.05

Anesthetic effects

The success rate of anesthetic sedation was 95.45% (21/22) in the RT A group and 100% (22/22) in the RT B and propofol groups. There was no significant difference in the success rate of anesthetic sedation among the three groups (Table 2, χ² = 1.848, P > 0.05).

Table 2

Primary efficacy endpoint in full analysis population and per-protocol population
		RT (6mg/kg/h)	RT (12mg/kg/h)	Propofol	chi-square test
					χ² value	P value
FAS	Included patients	22	22	22	1.848	1.000
FAS	Sedation success	21(95.45)	22(100.00)	22(100.00)
PPS	Included patients	21	22	21
PPS	Sedation success	21(100.00)	22(100.00)	21(100.00)
χ², chi-square test; FAS, full analysis set; PPS, per-protocol set

The mean BIS values during maintenance were comparable between the RT and propofol groups. During maintenance of anesthesia, the BIS ranged from 40 to 72 (Group A), 40 to 63 (Group B), and 40 to 69 (Group C), as shown in Table 3, Fig. 3. MOAA/S scores ≤ 1 and BIS values < 60 during anesthesia induction were observed in Groups A and B, confirming the effectiveness of anesthesia induction with remimazolam mesylate. The mean time from the start of anesthesia induction with remimazolam mesylate administration to loss of consciousness was 2.07 min in Group A, 1.53 min in Group B, and 1.92 min in Group C. There was no significant difference in anesthesia induction time when comparing all three groups (P = 0.223). The mean time from the end of remimazolam mesylate administration to awakening and extubation was 17.33 (± 2.87) minutes in Group A, 17.23 (± 2.31) minutes in Group B, and 26.62 (± 5.60) minutes in Group C. The results showed a significant difference between the remimazolam mesylate group (A and B) and the propofol group (Fig. 4, P < 0.05). We confirmed that the sedative effect of remimazolam mesylate was similar to that of propofol, even though the recovery time from anesthesia was decreased in the remimazolam mesylate group compared to the propofol group. After induction of anesthesia, there were significant differences in the incidence of hypotension and bradycardia among the three groups (P < 0.05, as shown in Fig. 5): the incidence of bradycardia in the propofol group was 42.86%, and the incidence of hypotension was 85.71%. There was no significant difference in the incidence of hypotension or bradycardia between the two groups treated with different doses of remimazolam mesylate (P > 0.05). The incidence of hypotension in the 6 mg/kg/h and 12 mg/kg/h RT groups was 19.05% and 9.09%, respectively, and none of the subjects in these groups developed bradycardia after induction of anesthesia.

Table 3

Characteristics of surgical intervention and RT efficacy parameters
Item	Treatment	RT(mg/kg/h)		Propofol(mg/kg)
		6	12	2.0-2.5
All subjects		22	22	22
ASA classification	II	22(100.0)	22(100.0)	22(100.0)
Surgical time (min)	Mean ± SD	187.14 ± 80.87	192.64 ± 66.90	188.39 ± 73.87
Efficacy rate	n/(%)	21(95)	22(100)	21(100)
BIS during maintenance	Range	40–72	40–63	40–69
The number in () shows % ; ASA American Society of Anesthesiologists,;
BIS Bipectral Index, SD standard deviation, min minutes, s seconds

As shown in Fig. 6, before anesthesia induction (T0), there was no significant difference in heart rate among the three groups (P = 0.256). However, heart rate was statistically significant after induction of anesthesia (T1) and 5 min after tracheal intubation (T2) (P values < 0.05). At T1, the mean heart rates of Groups A, B, and C were 76.38 (± 10.29) beats/min, 69.68 (± 10.32) beats/min, and 55.86 (± 5.81) beats/min, respectively. Compared with Group C, Group A and Group B were significantly different (P = 0.000 and 0.019, respectively). At T2, Group B (61.27 ± 9.42 beats/min) and Group C (58.29 ± 9.85 beats/min) had lower mean heart rates after intubation than Group A (76.90 ± 9.96 beats/min). There was no significant difference between the A and B groups or the B and C groups (P = 0.063 and 0.074, respectively).

Adverse reactions

The most frequently recorded AEs included blood pressure drop, intravenous pain, nausea, vomiting, and intraoperative awareness. In total, 19.05% and 9.09% of patients in the RT A group and RT B group had AEs, respectively, compared with 95.24% in patients given propofol. The overall difference between the three groups was not statistically significant (χ² = 41.656, P < 0.05). In addition, the incidence of intravenous pain was 0% in the RT group of the two different doses and 100% in the propofol group, with a significant difference (P < 0.05), as shown in Table 4.

Table 4

Safety assessment in full analysis population(n = 64)
	RT (6mg/kg/h,n = 21)	RT (12mg/kg/h,n = 22)	Propofol (n = 21)	χ2 / P value
All AEs (%)	4(19.05%)^*	3(13.64%)^*	20(95.24%)	38.523/0.000
Incidence of Hypertension (%)	1(4.76%)	1(4.55%)	0(0%)	0.616
Incidence of Nausea and Vomiting (%)	0(0%)	0(0%)	1(4.76%)	0.365
Incidence of Intravenous Pain(%)	0(0%)^*	0(0%)^*	21(100%)
Incidence of Intraoperative Awareness(%)	0(0%)	0(0%)	0(0%)
Total Number of Additional Sedatives (%)	1(4.76%)	2(9.09%)	0(0%)	0.382
The number in ( ) shows % ; χ², chi-square test,; Compared to Group C, ^*P < 0.05

There was no significant difference in mean arterial pressure of the three groups of patients at different time points (Fig. 7). There was a statistically significant difference in mean arterial pressure after the induction of anesthesia (P < 0.05); mean arterial pressure in the RT group was higher than that in the propofol group, with a statistically significant difference (all P < 0.05).

There was a statistically significant difference in the amount of vasoactive drugs used in the three groups (P = 0.003). There was no significant difference in the RT group with different doses. Doses of norepinephrine were 0.19 (± 0.15) mg and 0.23 (± 0.16) mg, respectively. Compared with the propofol group (0.42 ± 0.31 mg), the RT 6 mg/kg/h and RT 12 mg/kg/h groups were significantly different, and the use of vasoactive drugs during surgery was significantly reduced (P = 0.001, P = 0.008), as shown in Fig. 8. Neither Group A nor Group B was antagonized with flumazenil during anesthesia resuscitation.

Safety analysis

Table 4 and Fig. 5 summarize the safety assessments of the three groups in the full analysis. Overall, 9 patients (42.86%) in the propofol group developed bradycardia after induction of anesthesia, in contrast to none in the RT group, and there was a statistically significant difference among the three groups (χ² = 18.425, P < 0.05). In the RT groups with different doses, 4 and 2 subjects developed hypotension after the initial infusion of the study drug; 18 (85.71%) in the propofol group developed hypotension.

There were 2 adverse reactions in the propofol group, including 1 patient with postoperative nausea and vomiting and another with postoperative chills. One patient in the low-dose RT group required two additional remedy doses, with two patients in the high-dose RT group require a remedy dose of remimazolam mesylate. Still higher than 60, after switching to propofol to maintain anesthesia. In the RT group with different doses, 1 patient developed hypertension after tracheal extubation, and injected with urapidil 5 mg/time, and their vital signs returned to normal when they left the operating room. There was no hypoxemia or intraoperative awareness in the three groups of patients during anesthesia.

Commonly used drugs for induction of intravenous anesthesia in clinical practice are propofol and etomidate, each with advantages and disadvantages. In particular, propofol is often associated with severe cardiovascular and respiratory depression and may even lead to cardiac arrest[17, 18]. Therefore, preventing or reducing the occurrence of sedation-related complications is the best approach. The most striking finding is that although both remimazolam mesylate and propofol cause transient cardiovascular and respiratory depression, incidences of hypotension, treatment-related hypotension, and respiratory depression were lower in the remimazolam mesylate group than in the propofol group[19] and could be rapidly reversed by flumazenil[20].

Remimazolam mesylate is the toluenesulfonate of remimazolam, a new type of water-soluble ultrashort-acting benzodiazepine that mainly acts on aminobutyric acid A (GABAa) receptors, inhibits neuronal action, decreases neuronal excitability, and causes decreased body activity, sedation, and amnesia [21–23]. Remimazolam (CNS 7056) is designed for fast onset of a short, predictable duration of sedative action, with more rapid recovery than currently available drugs such as propofol. This pharmacodynamic profile is achieved by rapid hydrolysis of the drug's ester group by nonspecific tissue esterases to its pharmacologically inactive metabolite CNS 7054[12].

In this randomized trial, the two induction doses of remimazolam (6 and 12 mg/kg/h) showed noninferiority to propofol (2.0–2.5 mg/kg) in terms of efficacy when used as a sedative for general anesthesia. In fact, the success rate of anesthesia and sedation was 95% in the 6 mg/kg/h RT group and 100% in the 12 mg/kg/h RT and propofol groups. Noninferiority of remimazolam mesylate was observed [95% confidence interval (0.04; 0.047)]. Although the time to induction of anesthesia was not significantly different between the RT and propofol groups, the recovery time from anesthesia was longer in the latter. The RT groups had a lower incidence of hypotensive events and a shorter time to extubation. In addition, the incidence of bradycardia was lower in the RT groups than in the propofol group, the effects of different doses of remimazolam mesylate on heart rate and mean arterial pressure were smaller, with no intravenous pain during induction of anesthesia. Dongwoo Chae et al.[24] reported a nonsignificant effect of remazolam on heart rate, and the time to unconsciousness and respiratory depression after administration was successfully estimated from ED50/ED95 intravenous bolus.

During induction, both doses of remimazolam mesylate resulted in a rapid LoC, indicating the compound's ability to induce anesthesia. Maintenance was ensured by continuous intravenous infusion. The mean BIS values for all three groups were in the same range, indicating a similar and adequate depth of anesthesia. None of the patients in the RT 6 mg/kg/h, RT 12 mg/kg/h, or propofol group experienced intraoperative awareness. Importantly, the different doses of RT (17.33 ± 2.87 minutes, 17.23 ± 2.31 minutes) led to faster recovery from sedation (P < 0.05, Fig. 4) than propofol (26.62 ± 4.84 minutes). This is a potential advantage of RT over propofol. On the one hand, this advantage is attributed to the molecular design of RT, the ultrashort-acting nature of which leads to its rapid breakdown into inactive metabolites by popular tissue esterases[10]. On the other hand, this advantage may be attributed to the lower depth of sedation induced by RT. As shown by the sedation curve, propofol induced earlier and deeper sedation (MOAA/S = 1) compared to RT (MOAA/S = 3), which resulted in a longer recovery time. Therefore, RT decreases the time to recovery from anesthesia. In terms of anesthesia recovery, the time of the RT group was significantly shorter than that of the propofol group (P < 0.05). There was no significant difference in anesthesia induction time or anesthesia recovery time between the RT 6 mg/kg/h group and the RT 12 mg/kg/h group.

All treatment regimens were very safe, with no deaths during the trial and no patients with severe AEs. Overall, a greater proportion of patients experienced AEs with propofol (95.24%) than with remimazolam mesylate (16.28%). Of these, the most common ADR was injection site pain, which occurred in all patients in the propofol group (100%) but not in all patients given remimazolam mesylate. In this trial, a greater proportion of patients in the propofol group (100%) then the groups given different doses of remimazolam mesylate (76.2% vs. 86.4%) required vasoactive drugs, with an intraoperative norepinephrine dosage of 0.42 (± 0.31) mg. There was no significant difference in the incidence of intraoperative hypotension (19.05% vs. 9.09%) or dosage of vasoactive drugs (76.19% vs. 86.36%) between the 6 mg/kg/h and 12 mg/kg/h RT groups. Additionally, 1 patient in the propofol group experienced nausea and vomiting postoperatively.

This disparity in favor of remimazolam mesylate deserves special attention due to the growing evidence of an impact of intraoperative hypotension on postoperative cognitive function in elderly patients. Nevertheless, the trial was not fully standardized in terms of concomitant medications and their potential impact on hemodynamics or general fluid management.

This clinical trial was a single-blind study, with no confidentiality among the investigators. There is overall a lack of multicenter, large-scale clinical data, and most anesthesiologists adjust their medication based on clinical parameters, such as blood pressure and heart rate, and similar parameters are used to assess the efficacy of anesthetics. This trial is no exception, and biases in the results may exist. Notably, the BIS values showed the adequate depth of anesthesia in all groups, the intraoperative BIS value of the three groups could be maintained at 40 to 63, and there was no intraoperative awareness, indicating a high degree of objectivity for the results of this trial.

In summary, this trial demonstrates the noninferiority of remimazolam mesylate in combination with remifentanil and cisatracurium for induction and maintenance of general anesthesia compared with propofol. Therefore, remimazolam mesylate can be used as an adjunct to intravenous general anesthesia. In addition, remimazolam mesylate may play a more important role in elderly and critically ill patients because of its reduced effect on hemodynamics.

We conclude that remimazolam mesylate is well tolerated and noninferior to propofol with regard to efficacy as a sedative hypnotic for general anesthesia in elderly patients. The former can accelerate recovery from anesthesia, have less impact on heart rate, and decrease the use of vasoactive drugs and intravenous pain.

ADR

Adverse Drug Reaction

Adverse Event

Blood Pressure

BIS

Electroencephalographic Bifrequency Index

Heart Rate

ITT

Intention-to-treat Principle

Remimazolam Mesylate

SpO₂

Blood Oxygen Saturation

LoC

Loss of Consciousness

MAP

Mean Arterial Pressure

MOAA/S

Modified Observer’s Assessment of Alertness and Sedation

Norepinephrine.

Acknowledgments

I would like to thank everyone who helped me invaluable in this research. I really learned a lot from all of you. First, I would like to thank Director Haihui, under whose guidance I have completed all stages of writing this paper. His constant encouragement and guidance, not only in academic pursuits but also in clinical work, have given me great inspiration. Second, I would like to thank all my colleagues who participated in this research, it is the joint efforts of all of you that contributed to this research. Finally, I would like to thank my dear parents, boyfriends, and best friends who always support me unconditionally, interact with me, and provide valuable advice.

Funding

This trial was supported by Guangdong Hospital Pharmacy Research Fund (2020XC56).

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author or Chinese Clinical Trials Registry (http://www.chictr.org.cn, ChiCTR2100047274) on reasonable request.

Ethics approval and consent to participate

This study was approved by the Clinical Trials Ethics Committee of Dongguan People's Hospital (KYKT2020-054), and registered at http://www.chictr.org.cn (11/06/2021, ChiCTR2100047274). The study protocol followed the CONSORT guidelines. The study protocol was performed in the relevant guidelines. An informed consent form specifically designated for the study was provided and explained in detail to each participant at a preanesthesia visit on the afternoon before surgery, and the patient's written informed consent was obtained. Informed consent was obtained from all participants who withdrew from the study unconditionally before the intervention or from relatives and / or legal guardians if the participant was unable to sign the informed consent due to special circumstances.

Consent for publication

Not applicable.

Competing interests

The authors declare that there are no conflicts of interest.

Author contributions

All authors contributed to the concept and design of the trial. The material preparation and data collection were performed by XWL, ZJZ, DW and SPP. The data analysis was performed by FY and LDG. The first draft of the manuscript was written by FY and HHX, and all authors commented on previous versions of the manuscript. All authors read and approved the final draft.

Corresponding author

Correspondence to Haihui Xie.

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No competing interests reported.

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Efficacy and Safety of Remimazolam Mesylate in General Anesthesia Induction and Maintenance in Elderly Patients: A Single-Center, Randomized, Positive-Drug, Paralleled, Controlled Study

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