Application Effects of Remimazolam and on Elderly Patients Undergoing Hip Replacement

Objective To explore the anesthetic and analgesic effects of remimazolam and propofol in elderly patients undergoing hip replacement and their effects on respiratory and circulatory systems, stress and cognitive function. Methods 60 elderly patients undergoing elective hip replacement in the hospital were selected as the research subjects, and they were divided into the remimazolam group and the propofol group according to the admission sequence of patients. The remimazolam group was anesthetized with remimazolam, and the propofol group was anesthetized with propofol. The anesthesia-related indicators, perioperative pain degree [Visual Analogue Scale (VAS)], circulatory indicators [heart rate, mean arterial pressure (MAP)] before anesthesia (T 0 ), immediately before laryngeal mask insertion (T 1 ), at 5 min after laryngeal mask insertion (T 2 ), at 30 min after laryngeal mask insertion (T 3 ) and at 5 min after laryngeal mask removal (T 4 ), stress response indicators (plasma epinephrine, norepinephrine, cortisol) before anesthesia induction and at 24 h and 72 h after surgery, cognitive function [Mini-Mental State Examination (MMSE)] and adverse reactions were compared between the two groups. Results Among the 60 enrolled patients, only 1 case was excluded due to withdrawal, thus 30 cases in the remimazolam group and 29 cases in the propofol group were included. There were statistically signicant differences in the heart rate, MAP, plasma epinephrine, norepinephrine, cortisol and VAS score in the two groups from the aspects of interaction effect and time-point effect (P<0.05). The heart rate and MAP at T 1 , T 2 and T 3 in the two groups were signicantly decreased compared with those at T 0 , but the heart rate and MAP in the remimazolam group at T 1 , T 2 and T 3 were signicantly higher than those in the propofol group (P<0.05). There were no statistical differences in the anesthesia time, awakening time and extubation time between the remimazolam group and the propofol group (P>0.05). The levels of plasma epinephrine, norepinephrine and cortisol in the two groups were signicantly higher at 24 h and 72 h after surgery than those before anesthesia induction, and the above levels were signicantly lower in the remimazolam group than those in the propofol group (P<0.05). The VAS scores at each time point in the two groups were signicantly reduced compared to before surgery, but there was no statistically signicant difference between the two groups after surgery (P>0.05). The MMSE scores of the two groups were signicantly lower at 1 d and 3 d after surgery compared with those before anesthesia induction, but the score in the remimazolam group was signicantly higher than that in the propofol group (P<0.05). In addition, the incidence rates of adverse reactions were signicantly lower in the remimazolam group compared to the propofol group (P<0.05). Conclusion Compared with propofol, remimazolam can achieve equivalent anesthetic and analgesic effects in elderly patients undergoing hip replacement. However, the latter one can signicantly relieve respiratory and circulatory suppression, stress response and cognitive dysfunction, with good safety. rate and MAP compared to non-surgical patients, in a state of s stress during perioperative period and abnormal expression levels of plasma epinephrine, norepinephrine and cortisol the early researches Li compared the application effects of remimazolam and propofol in the surgical maintenance anesthesia of patients with tumors, and claried that the former drug had more advantages, but the differences in the inuence of the two drugs on circulation and stress status of surgical patients had not been explored. This study showed that there were statistical differences in the heart rate, MAP, plasma epinephrine, norepinephrine and cortisol in the two groups from the aspect of interaction effect, and the heart rate and MAP at T 1 , T 2 and T 3 in the two groups were signicantly decreased compared with those at T 0 , and the levels of plasma epinephrine, norepinephrine and cortisol in the two groups were signicantly increased at 24 h and 72 h after surgery compared with those before anesthesia induction but the levels were signicantly lower in the remimazolam group than those in the propofol group, and the heart rate and MAP at T 1 , T 2 and T 3 in the remimazolam group were signicantly higher than those in the propofol group, indicating that the inuence of remimazolam on circulation is smaller than that of propofol during induction and remimazolam can maintain a more stable heart rate and MAP after induction and is more conducive to relieving the stress response of elderly patients during anesthesia.


Introduction
Hip replacement can effectively relieve the joint pain, correct the deformity and recover and improve the joint motor function of patients, thus it is the most effective surgical intervention for elderly patients with hip diseases [1][2] . According to statistics, the incidence rate of postoperative cognitive dysfunction in elderly surgical patients is as high as 38% [3] , posing a serious threat to the surgical effects and prognosis of patients. Elderly patients with hip replacement, as a special group, have low body resistance and are often complicated with multiple underlying diseases, so they have high requirements for perioperative anesthesia and most of them prefer general anesthesia [4][5] . Propofol has been widely used in general anesthesia due to its rapid onset of action, short action time and fast metabolism, but on the other hand it also has limitations, such as a narrow therapeutic index and signi cant inhibitory effects on circulation and respiration, which may increase the surgical risk for elderly patients [6] . Remimazolam is a new type of benzodiazepine anesthetic drug which is suitable for clinical application of general anesthesia [7] . Chen et al. [8] indicated that benzenesulfonic remimazolam and propofol could have equivalent anesthetic effects in colonoscopy diagnosis and treatment, but the former one was signi cantly safer than the latter one. It can be seen that remimazolam and propofol have been clinically studied in the induction and maintenance of general anesthesia, but there is still no clear conclusion about the application effects of the two drugs in elderly patients undergoing hip replacement. This study adopts remimazolam and propofol to maintain anesthesia of 60 elderly patients undergoing elective hip replacement, and compares the differences in circulatory indicators, stress indicators, anesthetic effects and perioperative pain degree of the two so as to provide more reference for choosing a safe and effective anesthesia regimen for elderly patients undergoing hip replacement.
Page 3/8 1.2 Anesthesia methods 8 h of fasting for food and water was performed on the study subjects before surgery, and venous access was established after entering the room to detect the heart rate, mean arterial pressure (MAP) and blood oxygen saturation, and arterial pressure was measured by puncturing radial artery. Under ultrasound positioning, iliac fascia block was implemented with 40 ml of 0.25% ropivacaine. The block effect was observed after nerve block and the experiment would be excluded due to poor anesthetic effects (such as failure of block, no signi cant pain relief, complications of puncture, etc.). 0.4 ug/kg of sufentanil and 0.15 mg/kg of cis-atracurium were used for anesthesia induction, and the remimazolam group was given intravenous injection of 0.2-0.4 mg/kg of remimazolam during induction until loss of consciousness, and the propofol group selected 1.5-2 mg/kg of propofol for intravenous injection and connected to a ventilator after tracheal intubation by selecting constant volume mode of volume-controlled ventilation (VCV), volume tidal (V T ) of 6-8 ml/kg, inspiratory time/expiratory time (I:E) of 1:2, respiration rate (RR) of 10-16 times/min and end expiratory carbon dioxide partial pressure (P ET CO 2 ) of 35-45 mmHg. During maintenance of anesthesia, the remimazolam group was maintained by pumping remimazolam at 0.3-0.5 mg/kg/h while the propofol group was maintained by pumping propofol at 4-8 mg/kg/h, and both groups were treated with remifentanil at 0.1-0.25 ug/kg/min for anesthesia maintenance. 0.5 mg of metaraminol or 6 mg of ephedrine were intravenously injected when the intraoperative blood pressure was lower than 20% of the basal blood pressure.
Intravenous injection of 0.25 mg of nicardipine was implemented when the blood pressure was higher than 20% of the basal blood pressure. 0.3 mg of atropine or 6 mg of ephedrine were intravenously injected when heart rate was lower than 60 beats/min accompanied by hypotension or heart rate was lower than 50 beats/min lasting more than 1 min. Intravenous injection of 20 mg of esmolol was performed when heart rate was higher than 100 beats/min. The dosages of intravenous drugs were reduced by 20% at 5 min before the end of the surgery, and then the drugs were discontinued and 0.3 mg of umazenil was given for antagonism after the end of the surgery.When the patients were completely awake, they were sent to the anesthesia recovery room. After 30 min of observation in the anesthesia recovery room, they were sent back to the ward to record the occurrence of postoperative adverse reactions.

Observation indicators
(1) Anesthetic effects were evaluated by means of comparing the anesthesia-related indicators such as anesthesia time, awakening time and extubation time in the two groups. (2) Analgesic effects of patients were assessed by Visual Analogue Scale (VAS) score [9] during perioperative period (before surgery and at 3 min, 30 min, 60 min and 90 min after surgery). The full score of VAS was 10 points, and the higher the score, the better the analgesic effects. (3) Circulatory indicators such as heart rate and MAP were recorded before anesthesia (T 0 ), immediately before laryngeal mask insertion (T 1 ), at 5 min after laryngeal mask insertion (T 2 ), at 30 min after laryngeal mask insertion (T 3 ) and at 5 min after laryngeal mask removal (T 4 ). (4) The venous blood of elbow was collected from patients before anesthesia induction and at 24 h after surgery and 72 h after surgery to separate the plasma by conventional centrifugation, and the levels of stress indicators such as plasma epinephrine, norepinephrine and cortisol were detected by radioimmunoassay. (5) Cognitive function of patients was evaluated by Mini-Mental State Examination (MMSE) [10] which consisted of orientation, memory, attention and calculation, recall ability and language ability, with a total score of 27-30 points as normal cognitive function and score<27 points as cognitive dysfunction. (6) Adverse reactions were recorded.

Statistical analysis
SPSS22.0 statistical software was used to process the research data. Measurement data conforming to normal distribution were represented by the mean±standard deviation (±s), and measurement data between groups were compared by independent sample t test. Analysis of variance of repeated measurement data was adopted to compare the measurement data between groups at each time point, and the pairwise comparison between groups was performed by using LSD-t test. The enumeration data were described by cases [n (%)] and the between-group comparison was performed by c 2 test. P<0.05 was considered that the difference was statistically signi cant.

Results
2.1 Comparison of general data between the two groups 60 patients were enrolled in the study and only 1 case was excluded due to withdrawal, thus 30 cases in the remimazolam group and 29 cases in the propofol group were nally included. There were no statistical differences in the general data such as gender, age, body mass index (BMI) and ASA grading between the two groups of patients (P>0.05), as shown in Table 1. There were no statistical differences in the anesthesia time, awakening time and extubation time between the remimazolam group and the propofol group (P>0.05), as shown in Table 2. There were statistically signi cant differences in the interaction effect and time-point effect of VAS score in the two groups (P<0.05). The VAS scores of the two groups were signi cantly decreased at each time point after surgery compared with those before surgery (P<0.05), but the difference in the score between the two groups was not statistically signi cant after surgery (P>0.05), as shown in Table 3.

Circulation indicators
There were statistically signi cant differences in the interaction effect, between-group effect and time-point effect of heart rate and MAP in the two groups (P<0.05). The heart rate and MAP at T 1 , T 2 and T 3 were signi cantly reduced in the two groups compared with those at T 0 , but the heart rate and MAP at T 1 , T 2 and T 3 in the remimazolam group were signi cantly higher than those in the propofol group (P<0.05), as shown in Table 4. Note: a P<0.05 vs the propofol group; T 0 : before anesthesia induction, T 1 : immediately before laryngeal mask insertion, T 2 : 5 min after laryngeal mask insertion, T 3 : 30 min after laryngeal mask insertion, T 4 : 5 min after laryngeal mask removal

Stress indicators
The differences in the interaction effect, between-group effect and time-point effect of plasma epinephrine, norepinephrine and cortisol were statistically signi cant between the two groups (P<0.05). The levels of plasma epinephrine, norepinephrine and cortisol at 24 h after surgery and at 72 h after surgery were signi cantly enhanced in the two groups compared with those before anesthesia induction, but the levels in the remimazolam group were signi cantly lower than those in the propofol group (P<0.05), as shown in Table 5. There were statistically signi cant differences in the interaction effect, time-point effect and between-group effect of MMSE score in the two groups (P<0.05).
The MMSE scores of the two groups were signi cantly lower at 1 d and 3 d after surgery than those before anesthesia induction, but the scores in the remimazolam group at 1 d and 3 d after surgery were signi cantly higher than those in the propofol group (P<0.05), as shown in Table 6. The total incidence rate of adverse reactions in the remimazolam group was signi cantly lower compared with that in the propofol group (P<0.05), as shown in Table 7.

Discussion
The main pathological characteristics of elderly patients undergoing hip replacement are degenerative changes of tissues and organs, reduction or atrophy of body cells, declines of body reserve function and compensatory stress ability, and often accompanied by a variety of underlying factors (such as hypertension, diabetes mellitus, coronary heart disease, etc.) and decreased tolerance to anesthesia and surgery [11] . Studies have pointed out that the central nervous system and peripheral receptors in elderly patients are reduced and the drug concentration at the receptor site of each target organ is correspondingly signi cantly increased, resulting in a signi cantly enhanced drug effect, and the respiratory and circulatory inhibitory effects of anesthetics in elderly patients are signi cantly stronger than those of young patients and the drug eliminated half-life time is longer in elderly patients [12] , therefore how to choose a reasonable and effective anesthesia regimen for elderly patients with hip replacement has become an urgent problem to be solved in clinical application. In addition, this study displayed that the VAS scores of the two groups at each time point after surgery were signi cantly lower than those before anesthesia induction, and there were no signi cant differences in VAS score, anesthesia time, awakening time and extubation time between the groups, but the awakening time and extubation time of the remimazolam group were slightly shorter than those of the propofol group and the MMSE scores at 1 d and 3 d after surgery were signi cantly higher than those of the propofol group, preliminarily suggesting that the analgesic effects of remimazolam and propofol are similar in elderly patients with hip replacement but remimazolam may have certain advantages in shortening the awakening time and extubation time and inhibiting the cognitive dysfunction. Both remimazolam and propofol can satisfy the perioperative analgesic effects and effective anesthesia maintenance time of elderly patients, but during the anesthesia process, remimazolam can avoid the excessive and long-lasting sedation that occurs during propofol anesthesia and can have smaller inhibitory effects on the central nervous system of patients.
Under the dual stimulation of anesthesia and surgery, elderly patients undergoing hip replacement are often in a state of tension and anxiety, with accelerated body circulation, abnormal decreases in heart rate and MAP compared to non-surgical patients, in a state of body' s stress during perioperative period and abnormal expression levels of plasma epinephrine, norepinephrine and cortisol [13] . Although the early researches by Li Yaqi et al. compared the application effects of remimazolam and propofol in the surgical maintenance anesthesia of patients with tumors, and clari ed that the former drug had more advantages, but the differences in the in uence of the two drugs on circulation and stress status of surgical patients had not been explored. This study showed that there were statistical differences in the heart rate, MAP, plasma epinephrine, norepinephrine and cortisol in the two groups from the aspect of interaction effect, and the heart rate and MAP at T 1 , T 2 and T 3 in the two groups were signi cantly decreased compared with those at T 0 , and the levels of plasma epinephrine, norepinephrine and cortisol in the two groups were signi cantly increased at 24 h and 72 h after surgery compared with those before anesthesia induction but the levels were signi cantly lower in the remimazolam group than those in the propofol group, and the heart rate and MAP at T 1 , T 2 and T 3 in the remimazolam group were signi cantly higher than those in the propofol group, indicating that the in uence of remimazolam on circulation is smaller than that of propofol during induction and remimazolam can maintain a more stable heart rate and MAP after induction and is more conducive to relieving the stress response of elderly patients during anesthesia.
Remimazolam is a new type of ultra-short-acting benzodiazepine, which has high a nity with γ-aminobutyric acid receptor and can quickly act on GABA receptor and help the opening of the chloride ion channel, leading to the in ux of chloride ion and the hyperpolarization of the nerve cell membrane and then generating obvious anesthetic effects [14] , and studies have shown that benzodiazepines can signi cantly inhibit the in ammatory response of mice and effectively inhibit the concentrations of adrenocorticotropic hormone and cortisol during stress [15] . Propofol, as a short-acting intravenous anesthetic drug, plays a role in the induction and maintenance of general anesthesia, but has obvious inhibitory effects on the respiratory system and circulatory system of patients [16] . Therefore, remimazolam is more advantageous in anesthesia for elderly patients undergoing hip replacement. What' s more, remimazolam has short drug eliminated half-life time and its drug metabolism does not depend on cell P450 enzyme, thus compared with propofol, remimazolam has much rapider onset of action, faster metabolism and weaker drug interaction, which has higher safety in anesthesia application of elderly patients with surgery [17] . Although propofol has high lipophilicity and can quickly cross the blood-brain barrier to achieve a deep sedative effect in a short period of time, it has been found that propofol can induce a variety of cardiopulmonary complications (such as hypoxia, hypotension, arrhythmia and respiratory depression, etc.) while exerting sedative effects in clinical application, therefore it has certain limitations in the application for elderly patients [18] . Remimazolam has the advantages of rapid onset of action, fast metabolism, mild in uence on circulation and not easy accumulation in long-term application and plays an important role in the induction and maintenance of general anesthesia, and studies have con rmed that remimazolam has milder in uence on body' s circulation and acts as speci c antagonist compared to propofol, and it is more bene cial to reducing the occurrence of postoperative adverse reactions in patients [19] . This study similarly revealed that the total incidence rate of adverse reactions in the remimazolam group was signi cantly lower than that in the propofol group, which was generally consistent with the above-mentioned reports by Yu Wanqiu and others, suggesting that remimazolam has certain safety on elderly patients with hip replacement.
In conclusion, remimazolam has similar anesthetic effects as propofol on elderly patients undergoing hip replacement, but the former one has smaller in uence on the circulation of body, milder stress response, quicker awakening and higher safety. Generally speaking, general anesthesia with remimazolam may have higher safety in the surgery of elderly patients.

Conclusion
We concluded that in elderly patients' hip replacement, propofol and remimazolam can achieve equivalent anesthetic and analgesic effects; However, remimazolam can signi cantly relieve respiratory and circulatory suppression, stress response and cognitive dysfunction, more safety.