The difference in mean arterial pressure induced by remimazolam compared to etomidate in the presence of fentanyl at tracheal intubation: A randomized controlled trial

Background: Combined use of hypnotic and opioids during anesthesia inductions decreases blood pressure. Post-induction hypotension (PIHO) is the most common side effect of anesthesia induction. We aimed to compare the difference in mean arterial pressure (MAP) induced by remimazolam with that induced by etomidate in the presence of fentanyl at tracheal intubation.

Methods: We assessed 138 adult patients with American Society of Anesthesiologists physical status I–II who underwent elective urological surgery. Patients were randomly allocated to receive either remimazolam or etomidate as alterative hypnotic in the presence of fentanyl during anesthesia induction. Comparable BIS values were achieved in both groups. The primary outcome was the difference in the MAP at tracheal intubation. The secondary outcomes included the characteristics of anesthesia, surgery, and adverse effects.

Results: The MAP was higher in the etomidate group than in the remimazolam group at tracheal intubation (108 [22] mmHg vs. 83 [16] mmHg; mean difference, −26; 95% confidence interval [CI], −33 to −19; p < 0.0001). Heart rate was significantly higher in the etomidate group than in the remimazolam group at tracheal intubation. The patients’ condition warranted the administration of ephedrine more frequently in the remimazolam group (22%) than in the etomidate group (5%) (p = 0.0042) during anesthesia induction. The remimazolam group had a lower incidence of hypertension (0% vs. 9%, p = 0.0133), myoclonus (0% vs. 47%, p < 0.001), and tachycardia (16% vs. 35%, p = 0.0148), and a higher incidence of PIHO (42% vs. 5%, p = 0.001) than the etomidate group during anesthesia induction.

Conclusion: Remimazolam was associated with lower MAP and lower heart rate compared to etomidate in the presence of fentanyl at tracheal intubation. Patients in the remimazolam group had a higher incidence of PIHO, and their condition warranted the administration of ephedrine more frequently than in the etomidate group during anesthesia induction.

1 Introduction

Combined use of hypnotic and opioids during anesthesia inductions decreases blood pressure. Intraoperative hypotension is associated with perioperative cardiovascular events (Walsh et al., 2013), acute kidney injury (Maheshwari et al., 2018), and neurocognitive disorders (Bijker et al., 2012; Krzych et al., 2020). Post-induction hypotension (PIHO) is a type of intraoperative hypotension that occurs in up to 60% of patients (Green and Butler, 2016). It is difficult to distinguish the adverse outcomes of PIHO from intraoperative hypotension throughout the operation. However, it is clear that the duration and severity of PIHO before incision are strongly associated with acute kidney injury (Maheshwari et al., 2018). Patients with PIHO have increased mortality (8.8%), intensive care unit length of stay (7.9%), and postoperative mechanical ventilation (20.7%) (Green and Butler, 2016).

PIHO is mainly due to cardiovascular depression associated with anesthetic drugs. Intravenous induction of anesthesia using etomidate, a hypnotic drug, is considered one of the most suitable methods for providing hemodynamic stability. However, shortcomings of etomidate, such as adrenocortical depression and myoclonus, have prevented its widespread use. The selection of an effective and safe hypnotic drug for general anesthesia is challenging.

Remimazolam is a novel ultra-short-acting benzodiazepine sedative that acts on γ-aminobutyric acid type A receptors (GABA_ARs). This drug differs from propofol owing to its low potential for respiratory and cardiovascular depression. Remimazolam has been considered for different conditions, such as endoscopic procedures, intensive care unit settings, and general anesthesia (Doi et al., 2020a; Doi et al., 2020b; Chen et al., 2021; Rex et al., 2021). The lack of hemodynamic depression is a good characteristic of remimazolam (Doi et al., 2020a; Doi et al., 2020b; Zhu et al., 2021), and consequently, its single use in anesthesia induction and maintenance has recently been licensed (China, November 2021; South Korea, January 2021; Japan, January 2020). Some case reports have revealed that remimazolam has been successfully used in general anesthesia (Nakayama et al., 2021).

No randomized controlled clinical trials have compared differences in cardiovascular depression between remimazolam and etomidate. In view of the growing evidence on mild cardiovascular depression with remimazolam, we aimed to compare the difference in mean arterial pressure (MAP) induced by remimazolam with that induced by etomidate at tracheal intubation. We hypothesized that in the presence of fentanyl, the MAP is lower in the remimazolam group than in the etomidate group at tracheal intubation.

2 Methods

2.1 Study design and patients

This prospective, single-center, single-blinded, and randomized clinical trial was approved by the Medical Ethics Committee of the First Affiliated Hospital of Guangxi Medical University (identifier: 2021-KY-E−276). The trial was registered before patient enrollment at Chinese Clinical Trial Registry (http://www.chictr.org.cn/showproj.aspx?proj=137224; registration NO; ChiCTR2100053118; principal investigator: Xuehai Guan; date of registration: 12 November 2021) and was performed at the First Affiliated Hospital of Guangxi Medical University. All patients in the trial were informed of the purpose of the study, and they all provided written informed consent. This trial was performed in accordance with the Declaration of Helsinki and adhered to CONSORT guidelines.

One hundred and thirty-eight patients with American Society of Anesthesiologists (ASA) physical status I–II, aged between 18 and 60 years, competent enough to provide informed consent, and scheduled for elective surgery in urology under general anesthesia, were enrolled in this study. Patients with a history of severe hypertension (systolic blood pressure ≥ 180 mmHg or diastolic blood pressure ≥ 110 mmHg), severe heart (NYHA class III or IV); difficult airway (Mallampati class III or IV); chronic obstructive pulmonary disease or asthma; adrenocortical dysfunction (serum cortisol < 3 μg/dL); liver dysfunction (Child-Pugh class B or C); or chronic kidney diseases (glomerular filtration rate < 60 mL/min); severe anemia (hemoglobin < 60 g/L); shock; hyperthyroidism, hypothyroidism or gout caused by abnormal purine metabolism; electrolyte disorders; alcoholism and drug addiction; delayed gastric retention or emptying; and abuse of hormones or narcotic analgesics were excluded. Further exclusion criteria were pregnancy, allergy to the study drugs, and surgical procedures requiring controlled hypotension.

2.2 Randomization and masking

Random numbers were generated using EpiCalc 2000 software. Patients were randomly allocated to one of two groups, and each group received either etomidate or remimazolam as hypnotic. Sealed envelopes were used to conceal group allocation. A few minutes before anesthesia induction, an assistant who did not participate in anesthesia opened the envelope to prepare the drugs. Patients, surgeons, attending anesthetists in charge of the post-anesthesia care unit (PACU), and data collectors were blinded to the grouping. Attending anesthetists performing the anesthesia were not blinded to group allocation. Group allocation was revealed only after data collection and analysis.

2.3 Intervention, anesthesia, and study outcomes

Patients fasted for 6 h. Only clear liquids were allowed for up to 2 h before anesthesia. No premedication was administered. A 20-gauge cannula was inserted into the vein on the dorsum of the hand and Ringer’s lactate was infused to maintain patency (5 mL/kg/h). The patients were monitored for non-invasive blood pressure (NIBP), five-lead electrocardiography, pulse oximetry (SpO₂), and capnography by using an automatic monitor (C70, Comen, Shenzhen, China). The width of the cuff should cover 2/3 of the upper arm, and the length of the cuff should reach 2/3 of the circumference of the upper arm. NIBP was monitored by using a cyclic measuring way during anesthesia induction. During tracheal intubation, the cuff inflation started just with the beginning of intubation. The depth of anesthesia was monitored with a bispectral index (BIS; Covidien, MA, United States). Prior to the induction of anesthesia, 100% oxygen was administered for 3 min by placing a mask on the patient’s face. The doses and infusion rates of etomidate and remimazolam were based on drug instructions. In the etomidate group, anesthesia was induced using etomidate (Jiangsu Nhwa Pharmaceutical Co., Xuzhou, China) at 0.25 mg/kg/min until the BIS reached a range of 40–60. In the remimazolam group, anesthesia was induced using remimazolam tosilate (Jiangsu Hengrui Medicine Co., Lianyungang, China; diluted with normal saline to 1 mg/mL), starting at 10 mg/kg/h until the BIS reached a range of 40–60 and was maintained between 0.2–2 mg/kg/h (Doi et al., 2020a; Sheng et al., 2020). After loss of responsiveness (LOR, Modified Observer’s Assessment of Alertness/Sedation = 0, performed with 15 s intervals), cisatracurium (0.3 mg/kg IV; Sinopharm Chemical Reagent Co., Shanghai, China) and fentanyl (3 ug/kg IV; Yichang Humanwell Pharmaceutical Co., Yichang, China) was administered. The patients were intubated 3 min after cisatracurium administration. Remimazolam and etomidate were administered in a near-equipotent fashion by maintaining the BIS value between 40 and 60 from induction to 5 min after intubation. After stopping etomidate or remimazolam, anesthesia was maintained using a combination of propofol (Guangdong JiaBo Pharmaceutical Co., Qingyuan, China) and remifentanil (Yichang Humanwell Pharmaceutical Co., Yichang, China) using a target-controlled infusion pump in both groups. The infusion rates of propofol (plasma concentration: 2.5–4 μg/mL) and remifentanil (plasma concentration: 2.5–4 ng/mL) were regulated according to clinical signs and symptoms (changes in blood pressure and heart rate, tears, sweating, etc.), the BIS value (maintained at a range of 40–60), and the overall condition of the patients. Cisatracurium was administered as a repeated bolus dose of 0.1–0.2 mg/kg. All patients were mechanically ventilated (tidal volume, 8 mL/kg; respiratory rate: 12 breaths/min; oxygen concentration: 60%; fresh gas flow: 2 L/min). Attending anesthetists adjusted for the drug and fluid administration. All episodes of hypotension (30% decrease in MAP from baseline) were treated with ephedrine boluses (5 mg) at the discretion of the anesthesia provider, and no other vasopressors were used during induction.

If signs of intraoperative awakening were detected, the infusion rate of propofol was adjusted to 10 mL/min for up to 1 min. If signs of awakening persisted, propofol was discontinued and replaced with sevoflurane.

All surgeries were performed according to clinical practice, and all drugs were discontinued at the end of surgery. All patients were transferred to the PACU for recovery. Muscle relaxant antagonists (neostigmine) were administered, if necessary.

2.4 Outcome measures

The primary outcome was the difference in MAP at tracheal intubation.

The secondary outcomes included vital signs, characteristics of anesthesia and surgery, and adverse effects during general anesthesia induction. NIBP was recorded at the following time points: 5 min before anesthesia (baseline), at LOR, at BIS ≤ 60, at intubation, and at 1 and 5 min after intubation. Heart rate, SpO₂, and BIS values were recorded at the following time points: 5 min before anesthesia, at LOR, at BIS ≤ 60, at intubation, and at 1 and 5 min after intubation. Respiratory rates were recorded 5 min before anesthesia, at LOR, and at BIS ≤ 60. The time from the onset of anesthesia induction to LOR and from the induction of anesthesia to BIS ≤ 60 were calculated. The administration of etomidate, remimazolam, and vasoactive drugs was recorded from the induction of anesthesia to LOR, at BIS ≤ 60, and at tracheal intubation. Numbers of ephedrine administration during induction, propofol administration, remifentanil administration and total crystalloid infusion volume were also recorded. Adverse effects such as injection pain, PIHO (≥30% decrease in MAP from baseline from the beginning of anesthesia induction to 5 min after intubation), hypertension (≥30% increase in MAP from baseline), shedding tears, myoclonus, hiccups, and awareness were recorded during anesthesia induction (defined from induction to 5 min after intubation). Bradycardia (<50 beats/min) and tachycardia (>100 beats/min) were recorded from the beginning of anesthesia to the end of surgery. Dysphoria, postoperative delirium, and postoperative nausea/vomiting (PONV) were recorded from the ending of surgery to 24 h after surgery.

2.5 Sample size calculation

The sample size was calculated using PASS (version 11.0; NCSS Statistical Software, Utah, United States). Our preliminary experiments showed that the MAP (means [standard deviation, SD]) was 84.0 (12) mmHg and 94.0 (24) mmHg at intubation under anesthesia with remimazolam and etomidate, respectively (unpublished). This calculation assumed a type-I error of 0.05. Based on this, 58 samples were required for each group (two-sample t-test power analysis; two-sided alpha = 5%, power = 80%). Considering the potential ineligibility and loss to follow-up, we increased the total sample size to 138 by 20%.

2.6 Statistical analysis

Continuous variables were initially tested for normality using a Kolmogorov–Smirnov test, and subsequently tested for equality of variances using a F test. Values with normal distribution and equal variance are expressed as means (SD), and values with non-normal distribution or with unequal variance are reported as medians (interquartile range [IQR]). Categorical variables are expressed as numbers (proportions). Absolute standardized difference (ASD) was determined to identify any imbalance in baseline characteristics, and an ASD value > 0.34 was regarded as an imbalance with a limited sample size (Austin, 2009). Serial continuous data, such as NIBP, heart rate, SpO₂ and categorical data BIS were compared using repeated-measures two-way analysis of variance (ANOVA) with Geisser–Greenhouse correction, followed by Bonferroni’s multiple comparison test. The baseline value of the outcomes was included as a covariate. The fixed effects were the group, time, and group × time interactions. Matching effects were used for the study patients. For a statistically significant interaction (p < 0.05), the data for the two groups were compared at each time point using Bonferroni’s multiple comparisons test (alpha = 0.05, with p values adjusted for multiple comparisons and significant if p < .05). For a statistically non-significant interaction (p > 0.05), the main effect of group was reported. Variables with non-normally distributed data, such as the characteristic of anesthesia and surgery, the administration of hypnotic, remifentanil, ephedrine and crystalloid infusion volume, were reported as median (IQR) and analyzed using the Mann–Whitney U test between the two groups. Other continuous data were compared using an unpaired t-test where appropriate. Categorical data, including incidence of PIHO, injection pain, hypertension, bradycardia, tachycardia, dysphoria, hiccups, delirium, PONV, shedding tears, myoclonus, awareness and numbers of using ephedrine were analyzed using Chi-square test (when < 20% cells have an expected count less than 5) or Fisher’s test (when ≥ 20% cells have an expected count less than 5, or at least one cell has an expected count less than 1) followed by Koopman asymptotic score, as appropriate. Statistical analyses were performed using GraphPad Prism 9.0 (Dotmatics, Boston, USA). A p-value of < 0.05 was considered statistically significant.

3 Results

One hundred and thirty-eight patients were assessed for eligibility (Figure 1; 15 November 2021–31 March 2022). Five patients were excluded from the analysis due to failure to meet the inclusion criteria (n = 3) or protocol violation (n = 2). Patient characteristics did not differ between the groups in terms of age, height, body weight, body mass index (BMI), sex, or ASA physical status (Table 1).

FIGURE 1

FIGURE 1. CONSORT diagram for the trial. CONSORT indicates Consolidated Standards for Reporting of Trials.

TABLE 1

TABLE 1. Demographic data in patients receiving etomidate or remimazolam for induction of anesthesia.

The primary outcomes are presented in Table 2. The MAP was higher in the etomidate group than in the remimazolam group at tracheal intubation (108 [22] mmHg vs. 83 [16] mmHg; mean difference, −26; 95% confidence interval [CI], −32 to −19; p < 0.0001).

TABLE 2

TABLE 2. MAP in patients receiving etomidate or remimazolam for induction of anesthesia (mmHg).

The MAP was higher in the etomidate group than in the remimazolam group at other time points during anesthesia induction (at LOR: 98 [13] mmHg vs. 91 [16] mmHg, mean difference, −7; 95% CI, −14 to −0.07; p = 0.0301; at BIS ≤ 60: 95 [13] mmHg vs. 86 [13] mmHg, mean difference, −9; 95% CI, −16 to −2; p = 0.0005; at 1 min after intubation: 105 [19] mmHg vs. 84 [16] mmHg, mean difference, −21; 95% CI, −28 to −14; p < 0.0001)); at 5 min after intubation, 93 [14] mmHg vs. 75 [14] mmHg, mean difference, −18; 95% CI, −26 to −11, p < 0.0001) (Table 2). Systolic blood pressure (SBP) and diastolic blood pressure (DBP) were higher in the etomidate group than in the remimazolam group at BIS ≤ 60, at tracheal intubation, at 1 min and 5 min after tracheal intubation (Figures 2A, B). The heart rate was higher in the etomidate group compared to the remimazolam group at tracheal intubation (p < 0.0001) and 1 min after tracheal intubation (p < 0.05) (Figure 2D). There was no significant difference in respiratory rate, SpO₂, or BIS between the two groups at the time points we designed (Figures 2C, E, F).

FIGURE 2

FIGURE 2. Changes of vital signs of patients receiving etomidate (circle) or remimazolam (inverted triangle) for induction of anesthesia. Data are displayed as means (SD) (A–E) or medians (IQR) (F). *p < 0.05, **p < 0.01, ****p < 0.0001, compared with remimazolam group. Data were compared using repeated-measures two-way analysis of variance (ANOVA) with Geisser-Greenhouse correction, followed by Bonferroni’s multiple comparisons test. Abbreviations: Eto, etomidate; Remi: remimazolam; SBP, systolic blood pressure; DBP, diastolic blood pressure; HR, heart rate; SpO₂, pulse oximetry; RR: respiratory rate; LOR: loss of responsiveness; BIS, bispectral index.

The characteristics of the anesthesia are shown in Table 3. The time from induction to LOR was shorter in the etomidate group (53 [40–66] s) than in the remimazolam group (69 [59–81] s) (p < 0.0001). The time from induction to BIS ≤ 60 was shorter in the etomidate group 85 [67–105] s) than in the remimazolam group (89 [77–124] s) (p = 0.1734). The patients’ condition warranted the administration of ephedrine more frequently in the remimazolam group (22%) than in the etomidate group (5%) (p = 0.0042) during anesthesia induction. The administration of propofol during anesthesia maintenance was lower in the remimazolam group than in the etomidate group (p = 0.0009). There was no significant difference in duration of anesthesia, duration of surgery, administration of remifentanil and crystalloid infusion between groups (p > 0.05).

TABLE 3

TABLE 3. Characteristic of anesthesia and surgery in patients receiving etomidate or remimazolam for induction of anesthesia.

All adverse events were classified as mild or moderate (Table 4). The most reported adverse events were PIHO, myoclonus, tachycardia, and hypertension. A significantly higher incidence of hypotension was observed in the remimazolam group (42%) than in the etomidate group (5%) during the induction period (p = 0.001). The incidence of myoclonus was particularly increased in the etomidate group (47%) than in the remimazolam group (0%) (p < 0.0001). The proportion of patients who developed tachycardia during anesthesia in the remimazolam group (16%) was lower than that in the etomidate group (35%) (p = 0.0148). No difference was found in the percentage of bradycardia in the remimazolam group (6%) and in the etomidate group (6%) (p > 0.9999). The proportion of patients who developed hypertension during anesthesia in the remimazolam group (0%) was lower than that in the etomidate group (9%) (p = 0.0133). There was no significant difference between the groups in the percentages of patients with injection pain, dysphoria, hiccups, and tear shedding. None of the patients in either group developed delirium, nausea, vomiting, or awareness symptoms. There were no serious adverse events, deaths, or discontinuations due to adverse events.

TABLE 4

TABLE 4. Incidence of adverse event in patients receiving etomidate or remimazolam for induction of anesthesia.

4 Discussion

To the best of our knowledge, the study is the first randomized controlled trial to compare the difference in MAP induced by remimazolam and etomidate in the presence of fentanyl at tracheal intubation. The main finding of our study was that the MAP was higher in the etomidate group than in the remimazolam group in the presence of fentanyl at tracheal intubation (Table 2). Additionally, heart rate was higher in the etomidate group compared to the remimazolam group at tracheal intubation. Patients in the remimazolam group had a higher incidence of PIHO, and the patients’ condition warranted the administration of ephedrine more frequently than in the etomidate group during anesthesia induction. Our results confirm our hypothesis that the MAP induced by remimazolam is lower than that induced by etomidate in the presence of fentanyl at tracheal intubation.

The distribution of volume, dynamic adjustments of cardiac output, and perfusion pressure rely on the preservation of adequate intravascular volume and autonomic nervous control system (Frandsen et al., 2022). General anesthesia is associated with cardiovascular depression and disruption of the autonomic nervous control system by anesthetic agents, which leads to redistribution of intravascular volume, thus resulting in PIHO. Etomidate is considered to be one of the most suitable anesthetic induction drugs because of its reliable sedation and hemodynamic stability (Aggarwal et al., 2016; Mohr et al., 2020; Dai et al., 2021). The lack of hemodynamic depression is a good characteristic of remimazolam (Doi et al., 2020a; Doi et al., 2020b; Zhu et al., 2021). The inhibitory effects of remimazolam on circulation are less than that of propofol (Chen et al., 2020; Chen et al., 2021; Zhang et al., 2021). Both etomidate and remimazolam are beneficial in patients with unstable hemodynamics. However, in our study, SBP, DBP and MAP was higher in the etomidate group than in the remimazolam group during anesthesia induction (Figure 2; Table 2). At intubation and 1 min after intubation, heart rate was significantly higher in etomidate group compared to the remimazolam group during anesthesia induction (Figure 2). The main reason for this may be the different mechanisms they work. GABA_ARs is a pentameric assembly of subunits drawn from multiple classes (α1-6, β1-3, γ1-3, δ1, and ε1), and is distributed throughout the brain (Whiting et al., 1995; Pirker et al., 2000). Positive allosteric modulation of GABA_ARs activity by general anesthetics represents a mechanism for central nervous system depression. Most general anesthetics are non-selective allosteric agonists of GABA_ARs. The etomidate binding site is formed by β and α subunits (Chiara et al., 2012). The ability of etomidate to modulate and activate GABA_ARs is dependent upon the β2-or β3-, but not β1 subunit (Belelli et al., 1997; Hill-Venning et al., 1997; Sanna et al., 1997). The β3-containing GABA_ARs mediates anesthesia induced by etomidate (Belelli et al., 1997; Jurd et al., 2003; Reynolds et al., 2003; O'Meara et al., 2004; Liao et al., 2005; Butovas et al., 2010; Amlong et al., 2016), β2-containing GABA_ARs contribute to the sedation induced by etomidate (Reynolds et al., 2003), and α5-containing GABA_ARs mediates the amnestic effects of etomidate (Cheng et al., 2006). These findings provide evidence that etomidate acts on different GABA_ARs subtypes, located in different neuronal circuits, to generate the multiple components of the anesthetic state. The benzodiazepine binding site is formed by the α and γ subunits, different from the binding site of other general anesthetics (Ernst et al., 2003; Ogris et al., 2004). It has been identified the GABA_ARs subtypes mediating specific aspects of the pharmacological spectrum of benzodiazepine too. For instance, the sedative and anterograde amnesic actions of diazepam is mediated by α1-containing GABA_ARs (Rudolph et al., 1999; McKernan et al., 2000), the anxiolytic action of diazepam is mediated by α2-containing GABA_ARs (Löw et al., 2000), whereas the myorelaxant action of diazepam is mediated by α2-,α3-and α5-containing GABA_ARs (Crestani et al., 2001; Crestani et al., 2002). Remimazolam, one of benzodiazepine intravenous anesthetics, is a high-affinity ligand for the benzodiazepine site on the GABA_ARs, showing similar activity between GABAA receptor subtypes (α1β2γ2, α2β2γ2, α3β2γ2, and α5β2γ2 subtypes) (Kilpatrick et al., 2007). We infer the different binding site and selectivity between etomidate and remimazolam may result in different hemodynamic changes. Another reason may be that etomidate does not significantly inhibit sympathetic tone and preserves autonomic reflexes (Ebert et al., 1992). It also acts as an agonist at the α2-adrenoceptors, in particular the α2B-adrenoreceptor responsible for the baroreflex (Paris et al., 2003; Rudolph and Antkowiak, 2004). Anesthetic induction doses of etomidate preserved cardiac index, systemic vascular resistance, and myocardial oxygen supply-to-demand ratio (Gooding and Corssen, 1977; Colvin et al., 1979; Gooding et al., 1979; Larsen et al., 1988; Brussel et al., 1989; Moller Petrun and Kamenik, 2013; Zgola et al., 2014). On the contrary, sedative and anesthetic doses of intravenous benzodiazepine induce a reduction of cardiac output, decrease the systemic vascular resistance and as a result of reduction in arterial blood pressure (Samuelson et al., 1981; Ruff and Reves, 1990). Remimazolam decreased autonomic nervous activity during anesthesia induction too (Hasegawa et al., 2022). Opioids showed synergistic effects with remimazolam in sedation, which decreased autonomic nervous activity (Zhou et al., 2021). Athough statistically different, it is possible that the different changes in NIBP observed in our study were not clinically relevant because we did not observe any serious complications. The duration and severity of PIHO was strongly associated acute kidney injury (Maheshwari et al., 2018). Routine therapy for maintaining hemodynamic stability included the use of different vasoactive drugs. The patients’ condition warranted more frequent administration of ephedrine, less propofol in the remimazolam group than that in the etomidate group (Table 3). One reason for this may be that we treated PIHO in a timely and effective manner, and the period of PIHO was too short to cause serious complications. Based on these results, we speculate that etomidate may be more beneficial for patients than remimazolam in the presence of fentanyl during the induction of anesthesia.

The onset time for etomidate was shorter than that for remimazolam (Table 3); however, only one injection speed was set for remimazolam and etomidate, and we could not exclude the possibility that the onset time depended on the injection speed. The proportion of patients who developed tachycardia and hypertension during anesthesia was higher in the etomidate group than in the remimazolam group. The incidence of etomidate-induced myoclonus was 47% (Table 4), which is consistent with previous reports (Schwarzkopf et al., 2003; Prakash et al., 2021). Myoclonus is not only bothersome but also increases the risk of vitreous prolapse in patients with open globe injury, pulmonary aspiration, and regurgitation in non-fasted patients (Van Keulen and Burton, 2003; Hüter et al., 2007). None of the patients in the remimazolam group developed myoclonus in our study. But whether remimazolam is more suitable for anesthesia induction than etomidate in patients with open-globe injury and non-fasted needs further study. PONV is a common phenomenon associated with etomidate use. Propofol has direct anti-emetic properties and can reduce PONV (Borgeat et al., 1992). In our study, PONV did not occur in the etomidate and remimazolam groups; however, we cannot directly conclude that remimazolam has anti-emetic properties unless the anti-emetic effect of propofol is excluded. Dysphoria, hiccups, and delirium were infrequent events in both groups.

Our study had some limitations. First, the external validity of the trial was weakened by the inclusion criteria of the patients and the single-center, single-blinded design. The study only included patients who underwent elective urological surgery. Therefore, our results may not be generalizable to patients undergoing other surgeries. All patients come from China. Further studies are needed to confirm our findings in other populations. Second, we did not assess some parameters related to cardiac function such as cardiac output or ejection fraction. Third, since only one injection rate of remimazolam was set, we could not get the most reasonable dose-effect relationship. Fourth, BIS is one of the most popular methods for monitoring the depth of anesthesia; however, the significance of using BIS to study remimazolam is not clear. Remimazolam has been shown to suppress BIS (Zhou et al., 2020). BIS monitoring was appropriate for assessing awareness signs during anesthesia with remimazolam (Sheng et al., 2020). Therefore, remimazolam and etomidate were administered in a near-equipotent fashion, maintaining a BIS value between 40 and 60 from induction to 5 min after intubation. If BIS is suitable for monitoring the anesthesia depth of remimazolam, its specific value requires further clinical data verification. Moreover, we did not record the duration of PIHO; therefore, we could not calculate the area under the hypotension-time curve. A higher incidence of PIHO does not necessarily indicate worse outcomes.

5 Conclusion

In conclusion, the MAP and heart rate was lower in the remimazolam group compared to the etomidate group in the presence of fentanyl at tracheal intubation. The incidence of PIHO was higher, and the patients’ condition warranted the administration of ephedrine more frequently in the remimazolam group compared to the etomidate group during anesthesia induction.

Data availability statement

The raw data supporting the conclusion of this article will be made available by the authors, without undue reservation.

Ethics statement

The studies involving human participants were reviewed and approved by The Medical Ethics Committee of the First Affiliated Hospital of Guangxi Medical University. The patients/participants provided their written informed consent to participate in this study.

Author contributions

Conceptualization: XfH and XhG. Methodology: XfH and XhG. Validation: XhG. Investigation: XfH, XfG, CZ, HL, and HyC. Resources: RL and YL. Formal analysis: CZ and HhC. Data curation and visualization: BX. Supervision: XhG. Funding acquisition: XhG. Writing–original draft: XfH and XhG. Writing–review and editing: All authors. Agree to and are accountable for all aspects of the work: All authors.

Funding

This study was supported by the Traditional Chinese medicine appropriate technology development and promotion project of Guangxi Zhuang Autonomous Region (No GZSY22-59), and the Natural Science Foundation of Guangxi Zhuang Autonomous Region (No 2022GXNSFAA035628).

Acknowledgments

The authors would like to thank Senior nurses Xiaomin Yang, Ying Li, Manli Miu, and Fei Yang (Department of Anesthesiology and Surgery, the First Affiliated Hospital of Guangxi Medical University) for preparing drugs and patients. The authors thank Editage for the English language editing.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

References

Aggarwal, S., Goyal, V. K., Chaturvedi, S. K., Mathur, V., Baj, B., and Kumar, A. (2016). A comparative study between propofol and etomidate in patients under general anesthesia. Braz J. Anesthesiol. 66 (3), 237–241. doi:10.1016/j.bjan.2016.02.010

PubMed Abstract | CrossRef Full Text | Google Scholar

Amlong, C. A., Perkins, M. G., Houle, T. T., Miller, K. W., and Pearce, R. A. (2016). Contrasting effects of the γ-aminobutyric acid type A receptor β3 subunit N265M mutation on loss of righting reflexes induced by etomidate and the novel anesthetic barbiturate R-mTFD-MPAB. Anesth. Analg. 123 (5), 1241–1246. doi:10.1213/ANE.0000000000001358

PubMed Abstract | CrossRef Full Text | Google Scholar

Austin, P. C. (2009). Balance diagnostics for comparing the distribution of baseline covariates between treatment groups in propensity-score matched samples. Stat. Med. 28 (25), 3083–3107. doi:10.1002/sim.3697

PubMed Abstract | CrossRef Full Text | Google Scholar

Belelli, D., Lambert, J. J., Peters, J. A., Wafford, K., and Whiting, P. J. (1997). The interaction of the general anesthetic etomidate with the gamma-aminobutyric acid type A receptor is influenced by a single amino acid. Proc. Natl. Acad. Sci. U. S. A. 94 (20), 11031–11036. doi:10.1073/pnas.94.20.11031

PubMed Abstract | CrossRef Full Text | Google Scholar

Bijker, J. B., Persoon, S., Peelen, L. M., Moons, K. G., Kalkman, C. J., Kappelle, L. J., et al. (2012). Intraoperative hypotension and perioperative ischemic stroke after general surgery: A nested case-control study. Anesthesiology 116 (3), 658–664. doi:10.1097/ALN.0b013e3182472320

PubMed Abstract | CrossRef Full Text | Google Scholar

Borgeat, A., Wilder-Smith, O. H., Saiah, M., and Rifat, K. (1992). Subhypnotic doses of propofol possess direct antiemetic properties. Anesth. Analg. 74 (4), 539–541. doi:10.1213/00000539-199204000-00013

PubMed Abstract | CrossRef Full Text | Google Scholar

Brussel, T., Theissen, J. L., Vigfusson, G., Lunkenheimer, P. P., Van Aken, H., and Lawin, P. (1989). Hemodynamic and cardiodynamic effects of propofol and etomidate: Negative inotropic properties of propofol. Anesth. Analg. 69 (1), 35–40. doi:10.1213/00000539-198907000-00007

PubMed Abstract | CrossRef Full Text | Google Scholar

Butovas, S., Rudolph, U., Jurd, R., Schwarz, C., and Antkowiak, B. (2010). Activity patterns in the prefrontal cortex and hippocampus during and after awakening from etomidate anesthesia. Anesthesiology 113 (1), 48–57. doi:10.1097/ALN.0b013e3181dc1db7

PubMed Abstract | CrossRef Full Text | Google Scholar

Chen, S. H., Yuan, T. M., Zhang, J., Bai, H., Tian, M., Pan, C. X., et al. (2021). Remimazolam tosilate in upper gastrointestinal endoscopy: A multicenter, randomized, non-inferiority, phase III trial. J. Gastroenterol. Hepatol. 36 (2), 474–481. doi:10.1111/jgh.15188

PubMed Abstract | CrossRef Full Text | Google Scholar

Chen, S., Wang, J., Xu, X., Huang, Y., Xue, S., Wu, A., et al. (2020). The efficacy and safety of remimazolam tosylate versus propofol in patients undergoing colonoscopy: A multicentered, randomized, positive-controlled, phase III clinical trial. Am. J. Transl. Res. 12 (8), 4594–4603.

PubMed Abstract | Google Scholar

Cheng, V. Y., Martin, L. J., Elliott, E. M., Kim, J. H., Mount, H. T., Taverna, F. A., et al. (2006). Alpha5GABAA receptors mediate the amnestic but not sedative-hypnotic effects of the general anesthetic etomidate. J. Neurosci. 26 (14), 3713–3720. doi:10.1523/JNEUROSCI.5024-05.2006

PubMed Abstract | CrossRef Full Text | Google Scholar

Chiara, D. C., Dostalova, Z., Jayakar, S. S., Zhou, X., Miller, K. W., and Cohen, J. B. (2012). Mapping general anesthetic binding site(s) in human α1β3 γ-aminobutyric acid type A receptors with [³H]TDBzl-etomidate, a photoreactive etomidate analogue. Biochemistry 51 (4), 836–847. doi:10.1021/bi201772m

PubMed Abstract | CrossRef Full Text | Google Scholar

Colvin, M. P., Savege, T. M., Newland, P. E., Weaver, E. J., Waters, A. F., Brookes, J. M., et al. (1979). Cardiorespiratory changes following induction of anaesthesia with etomidate in patients with cardiac disease. Br. J. Anaesth. 51 (6), 551–556. doi:10.1093/bja/51.6.551

PubMed Abstract | CrossRef Full Text | Google Scholar

Crestani, F., Keist, R., Fritschy, J. M., Benke, D., Vogt, K., Prut, L., et al. (2002). Trace fear conditioning involves hippocampal alpha5 GABA(A) receptors. Proc. Natl. Acad. Sci. U. S. A. 99 (13), 8980–8985. doi:10.1073/pnas.142288699

PubMed Abstract | CrossRef Full Text | Google Scholar

Crestani, F., Low, K., Keist, R., Mandelli, M., Mohler, H., and Rudolph, U. (2001). Molecular targets for the myorelaxant action of diazepam. Mol. Pharmacol. 59 (3), 442–445. doi:10.1124/mol.59.3.442

PubMed Abstract | CrossRef Full Text | Google Scholar

Dai, Z. L., Cai, X. T., Gao, W. L., Lin, M., Lin, J., Jiang, Y. X., et al. (2021). Etomidate vs propofol in coronary heart disease patients undergoing major noncardiac surgery: A randomized clinical trial. World J. Clin. Cases 9 (6), 1293–1303. doi:10.12998/wjcc.v9.i6.1293

PubMed Abstract | CrossRef Full Text | Google Scholar

Doi, M., Hirata, N., Suzuki, T., Morisaki, H., Morimatsu, H., and Sakamoto, A. (2020a). Safety and efficacy of remimazolam in induction and maintenance of general anesthesia in high-risk surgical patients (ASA class III): Results of a multicenter, randomized, double-blind, parallel-group comparative trial. J. Anesth. 34 (4), 491–501. doi:10.1007/s00540-020-02776-w

PubMed Abstract | CrossRef Full Text | Google Scholar

Doi, M., Morita, K., Takeda, J., Sakamoto, A., Yamakage, M., and Suzuki, T. (2020b). Efficacy and safety of remimazolam versus propofol for general anesthesia: A multicenter, single-blind, randomized, parallel-group, phase IIb/III trial. J. Anesth. 34 (4), 543–553. doi:10.1007/s00540-020-02788-6

PubMed Abstract | CrossRef Full Text | Google Scholar

Ebert, T. J., Muzi, M., Berens, R., Goff, D., and Kampine, J. P. (1992). Sympathetic responses to induction of anesthesia in humans with propofol or etomidate. Anesthesiology 76 (5), 725–733. doi:10.1097/00000542-199205000-00010

PubMed Abstract | CrossRef Full Text | Google Scholar

Ernst, M., Brauchart, D., Boresch, S., and Sieghart, W. (2003). Comparative modeling of GABA(A) receptors: Limits, insights, future developments. Neuroscience 119 (4), 933–943. doi:10.1016/s0306-4522(03)00288-4

PubMed Abstract | CrossRef Full Text | Google Scholar

Frandsen, M. N., Mehlsen, J., Bang Foss, N., and Kehlet, H. (2022). Pre-operative autonomic nervous system function - a missing link for post-induction hypotension? Anaesthesia 77 (2), 139–142. doi:10.1111/anae.15546

PubMed Abstract | CrossRef Full Text | Google Scholar

Gooding, J. M., and Corssen, G. (1977). Effect of etomidate on the cardiovascular system. Anesth. Analg. 56 (5), 717–719. doi:10.1213/00000539-197709000-00021

PubMed Abstract | CrossRef Full Text | Google Scholar

Gooding, J. M., Weng, J. T., Smith, R. A., Berninger, G. T., and Kirby, R. R. (1979). Cardiovascular and pulmonary responses following etomidate induction of anesthesia in patients with demonstrated cardiac disease. Anesth. Analg. 58 (1), 40–41. doi:10.1213/00000539-197901000-00016

PubMed Abstract | CrossRef Full Text | Google Scholar

Green, R. S., and Butler, M. B. (2016). Postintubation hypotension in general anesthesia: A retrospective analysis. J. Intensive Care Med. 31 (10), 667–675. doi:10.1177/0885066615597198

PubMed Abstract | CrossRef Full Text | Google Scholar

Hasegawa, G., Hirata, N., Yoshikawa, Y., and Yamakage, M. (2022). Differential effects of remimazolam and propofol on heart rate variability during anesthesia induction. J. Anesth. 36 (2), 239–245. doi:10.1007/s00540-022-03037-8

PubMed Abstract | CrossRef Full Text | Google Scholar

Hill-Venning, C., Belelli, D., Peters, J. A., and Lambert, J. J. (1997). Subunit-dependent interaction of the general anaesthetic etomidate with the gamma-aminobutyric acid type A receptor. Br. J. Pharmacol. 120 (5), 749–756. doi:10.1038/sj.bjp.0700927

PubMed Abstract | CrossRef Full Text | Google Scholar

Hüter, L., Schreiber, T., Gugel, M., and Schwarzkopf, K. (2007). Low-dose intravenous midazolam reduces etomidate-induced myoclonus: A prospective, randomized study in patients undergoing elective cardioversion. Anesth. Analg. 105 (5), 1298–1302. doi:10.1213/01.ane.0000287248.25610.c0

PubMed Abstract | CrossRef Full Text | Google Scholar

Jurd, R., Arras, M., Lambert, S., Drexler, B., Siegwart, R., Crestani, F., et al. (2003). General anesthetic actions in vivo strongly attenuated by a point mutation in the GABA(A) receptor beta3 subunit. FASEB J. 17 (2), 250–252. doi:10.1096/fj.02-0611fje

PubMed Abstract | CrossRef Full Text | Google Scholar

Kilpatrick, G. J., Mcintyre, M. S., Cox, R. F., Stafford, J. A., Pacofsky, G. J., Lovell, G. G., et al. (2007). CNS 7056: A novel ultra-short-acting benzodiazepine. Anesthesiology 107 (1), 60–66. doi:10.1097/01.anes.0000267503.85085.c0

PubMed Abstract | CrossRef Full Text | Google Scholar

Krzych, L. J., Pluta, M. P., Putowski, Z., and Czok, M. (2020). Investigating association between intraoperative hypotension and postoperative neurocognitive disorders in non-cardiac surgery: A comprehensive Review. J. Clin. Med. 9 (10), 3183. doi:10.3390/jcm9103183

PubMed Abstract | CrossRef Full Text | Google Scholar

Larsen, R., Rathgeber, J., Bagdahn, A., Lange, H., and Rieke, H. (1988). Effects of propofol on cardiovascular dynamics and coronary blood flow in geriatric patients. A comparison with etomidate. Anaesthesia 43, 25–31. doi:10.1111/j.1365-2044.1988.tb09064.x

PubMed Abstract | CrossRef Full Text | Google Scholar

Liao, M., Sonner, J. M., Husain, S. S., Miller, K. W., Jurd, R., Rudolph, U., et al. (2005). R (+) etomidate and the photoactivable R (+) azietomidate have comparable anesthetic activity in wild-type mice and comparably decreased activity in mice with a N265M point mutation in the gamma-aminobutyric acid receptor beta3 subunit. Anesth. Analg. 101 (1), 131–135. doi:10.1213/01.ANE.0000153011.64764.6F

PubMed Abstract | CrossRef Full Text | Google Scholar

Löw, K., Crestani, F., Keist, R., Benke, D., Brunig, I., Benson, J. A., et al. (2000). Molecular and neuronal substrate for the selective attenuation of anxiety. Science 290 (5489), 131–134. doi:10.1126/science.290.5489.131

PubMed Abstract | CrossRef Full Text | Google Scholar

Maheshwari, K., Turan, A., Mao, G., Yang, D., Niazi, A. K., Agarwal, D., et al. (2018). The association of hypotension during non-cardiac surgery, before and after skin incision, with postoperative acute kidney injury: A retrospective cohort analysis. Anaesthesia 73 (10), 1223–1228. doi:10.1111/anae.14416

PubMed Abstract | CrossRef Full Text | Google Scholar

Mckernan, R. M., Rosahl, T. W., Reynolds, D. S., Sur, C., Wafford, K. A., Atack, J. R., et al. (2000). Sedative but not anxiolytic properties of benzodiazepines are mediated by the GABA(A) receptor alpha1 subtype. Nat. Neurosci. 3 (6), 587–592. doi:10.1038/75761

PubMed Abstract | CrossRef Full Text | Google Scholar

Mohr, N. M., Pape, S. G., Runde, D., Kaji, A. H., Walls, R. M., and Brown, C. A. (2020). Etomidate use is associated with less hypotension than ketamine for emergency department sepsis intubations: A near cohort study. Acad. Emerg. Med. 27 (11), 1140–1149. doi:10.1111/acem.14070

PubMed Abstract | CrossRef Full Text | Google Scholar

Moller Petrun, A., and Kamenik, M. (2013). Bispectral index-guided induction of general anaesthesia in patients undergoing major abdominal surgery using propofol or etomidate: A double-blind, randomized, clinical trial. Br. J. Anaesth. 110 (3), 388–396. doi:10.1093/bja/aes416

PubMed Abstract | CrossRef Full Text | Google Scholar

Nakayama, J., Ogihara, T., Yajima, R., Innami, Y., and Ouchi, T. (2021). Anesthetic management of super-elderly patients with remimazolam: A report of two cases. JA Clin. Rep. 7 (1), 71. doi:10.1186/s40981-021-00474-4

PubMed Abstract | CrossRef Full Text | Google Scholar

O'meara, G. F., Newman, R. J., Fradley, R. L., Dawson, G. R., and Reynolds, D. S. (2004). The GABA-A beta3 subunit mediates anaesthesia induced by etomidate. Neuroreport 15 (10), 1653–1656. doi:10.1097/01.wnr.0000134842.56131.fe

PubMed Abstract | CrossRef Full Text | Google Scholar

Ogris, W., Poltl, A., Hauer, B., Ernst, M., Oberto, A., Wulff, P., et al. (2004). Affinity of various benzodiazepine site ligands in mice with a point mutation in the GABA(A) receptor gamma2 subunit. Biochem. Pharmacol. 68 (8), 1621–1629. doi:10.1016/j.bcp.2004.07.020

PubMed Abstract | CrossRef Full Text | Google Scholar

Paris, A., Philipp, M., Tonner, P. H., Steinfath, M., Lohse, M., Scholz, J., et al. (2003). Activation of alpha 2B-adrenoceptors mediates the cardiovascular effects of etomidate. Anesthesiology 99 (4), 889–895. doi:10.1097/00000542-200310000-00022

PubMed Abstract | CrossRef Full Text | Google Scholar

Pirker, S., Schwarzer, C., Wieselthaler, A., Sieghart, W., and Sperk, G. (2000). GABA(A) receptors: Immunocytochemical distribution of 13 subunits in the adult rat brain. Neuroscience 101 (4), 815–850. doi:10.1016/s0306-4522(00)00442-5

PubMed Abstract | CrossRef Full Text | Google Scholar

Prakash, S., Mullick, P., Virmani, P., Talwar, V., and Singh, R. (2021). Effect of pre-treatment with a combination of fentanyl and midazolam for prevention of etomidate-induced myoclonus. Turk J. Anaesthesiol. Reanim. 49 (1), 11–17. doi:10.5152/TJAR.2019.90248

PubMed Abstract | CrossRef Full Text | Google Scholar

Rex, D. K., Bhandari, R., Lorch, D. G., Meyers, M., Schippers, F., and Bernstein, D. (2021). Safety and efficacy of remimazolam in high risk colonoscopy: A randomized trial. Dig. Liver Dis. 53 (1), 94–101. doi:10.1016/j.dld.2020.10.039

PubMed Abstract | CrossRef Full Text | Google Scholar

Reynolds, D. S., Rosahl, T. W., Cirone, J., O'meara, G. F., Haythornthwaite, A., Newman, R. J., et al. (2003). Sedation and anesthesia mediated by distinct GABA(A) receptor isoforms. J. Neurosci. 23 (24), 8608–8617. doi:10.1523/JNEUROSCI.23-24-08608.2003

PubMed Abstract | CrossRef Full Text | Google Scholar

Rudolph, U., and Antkowiak, B. (2004). Molecular and neuronal substrates for general anaesthetics. Nat. Rev. Neurosci. 5 (9), 709–720. doi:10.1038/nrn1496

PubMed Abstract | CrossRef Full Text | Google Scholar

Rudolph, U., Crestani, F., Benke, D., Brunig, I., Benson, J. A., Fritschy, J. M., et al. (1999). Benzodiazepine actions mediated by specific gamma-aminobutyric acid(A) receptor subtypes. Nature 401 (6755), 796–800. doi:10.1038/44579

PubMed Abstract | CrossRef Full Text | Google Scholar

Ruff, R., and Reves, J. G. (1990). Hemodynamic effects of a lorazepam-fentanyl anesthetic induction for coronary artery bypass surgery. J. Cardiothorac. Anesth. 4 (3), 314–317. doi:10.1016/0888-6296(90)90037-g

PubMed Abstract | CrossRef Full Text | Google Scholar

Samuelson, P. N., Reves, J. G., Kouchoukos, N. T., Smith, L. R., and Dole, K. M. (1981). Hemodynamic responses to anesthetic induction with midazolam or diazepam in patients with ischemic heart disease. Anesth. Analg. 60 (11), 802–809. doi:10.1213/00000539-198111000-00007

PubMed Abstract | CrossRef Full Text | Google Scholar

Sanna, E., Murgia, A., Casula, A., and Biggio, G. (1997). Differential subunit dependence of the actions of the general anesthetics alphaxalone and etomidate at gamma-aminobutyric acid type A receptors expressed in Xenopus laevis oocytes. Mol. Pharmacol. 51 (3), 484–490.

PubMed Abstract | Google Scholar

Schwarzkopf, K. R., Hueter, L., Simon, M., and Fritz, H. G. (2003). Midazolam pretreatment reduces etomidate-induced myoclonic movements. Anaesth. Intensive Care 31 (1), 18–20. doi:10.1177/0310057X0303100103

PubMed Abstract | CrossRef Full Text | Google Scholar

Sheng, X. Y., Liang, Y., Yang, X. Y., Li, L. E., Ye, X., Zhao, X., et al. (2020). Safety, pharmacokinetic and pharmacodynamic properties of single ascending dose and continuous infusion of remimazolam besylate in healthy Chinese volunteers. Eur. J. Clin. Pharmacol. 76 (3), 383–391. doi:10.1007/s00228-019-02800-3

PubMed Abstract | CrossRef Full Text | Google Scholar

Van Keulen, S. G., and Burton, J. H. (2003). Myoclonus associated with etomidate for ED procedural sedation and analgesia. Am. J. Emerg. Med. 21 (7), 556–558. doi:10.1016/j.ajem.2003.08.004

PubMed Abstract | CrossRef Full Text | Google Scholar

Walsh, M., Devereaux, P. J., Garg, A. X., Kurz, A., Turan, A., Rodseth, R. N., et al. (2013). Relationship between intraoperative mean arterial pressure and clinical outcomes after noncardiac surgery: Toward an empirical definition of hypotension. Anesthesiology 119 (3), 507–515. doi:10.1097/ALN.0b013e3182a10e26

PubMed Abstract | CrossRef Full Text | Google Scholar

Whiting, P. J., Mckernan, R. M., and Wafford, K. A. (1995). Structure and pharmacology of vertebrate GABAA receptor subtypes. Int. Rev. Neurobiol. 38, 95–138. doi:10.1016/s0074-7742(08)60525-5

PubMed Abstract | CrossRef Full Text | Google Scholar

Zgola, K., Kulakowski, P., Czepiel, A., Swiatkowski, M., Makowska, E., Blachnio, E., et al. (2014). Haemodynamic effects of etomidate, propofol and electrical shock in patients undergoing implantable cardioverter-defibrillator testing. Kardiol. Pol. 72 (8), 707–715. doi:10.5603/KP.a2014.0086

PubMed Abstract | CrossRef Full Text | Google Scholar

Zhang, X., Li, S., and Liu, J. (2021). Efficacy and safety of remimazolam besylate versus propofol during hysteroscopy: Single-centre randomized controlled trial. BMC Anesthesiol. 21 (1), 156. doi:10.1186/s12871-021-01373-y

PubMed Abstract | CrossRef Full Text | Google Scholar

Zhou, J., Curd, L., Lohmer, L. R. L., Delpratt, N., Ossig, J., Schippers, F., et al. (2021). A population pharmacodynamic Markov mixed-effects model for determining remimazolam-induced sedation when co-administered with fentanyl in procedural sedation. Clin. Transl. Sci. 14 (4), 1554–1565. doi:10.1111/cts.13023

PubMed Abstract | CrossRef Full Text | Google Scholar

Zhou, J., Leonowens, C., Ivaturi, V. D., Lohmer, L. L., Curd, L., Ossig, J., et al. (2020). Population pharmacokinetic/pharmacodynamic modeling for remimazolam in the induction and maintenance of general anesthesia in healthy subjects and in surgical subjects. J. Clin. Anesth. 66, 109899. doi:10.1016/j.jclinane.2020.109899

PubMed Abstract | CrossRef Full Text | Google Scholar

Zhu, X., Wang, H., Yuan, S., Li, Y., Jia, Y., Zhang, Z., et al. (2021). Efficacy and safety of remimazolam in endoscopic sedation-A systematic Review and meta-analysis. Front. Med. (Lausanne) 8, 655042. doi:10.3389/fmed.2021.655042

PubMed Abstract | CrossRef Full Text | Google Scholar