Overall, 120 patients were expected, and 91 participated in the trial. One patient in each of the R0 and R2 groups withdrew from the trial after receiving treatment with atropine because of a heart rate of less than 50 beats/min during the trial. Additionally, two patients in the R3 group withdrew from the trial after receiving treatment with ephedrine for hypotension that occurred before pneumoperitoneum. Finally, each of the four groups, R0, R1, R2, and R3, obtained six crossover points from positive to negative or negative to positive. The cases used were 23, 20, 21, and 23, respectively (Figure 1).
The general information for the four groups of patients is shown in Table 1. There were no significant differences in age, BMI, basal MAP, HR, and ASA classification among the respective patients (P > 0.05). This indicates that the baseline data, such as age, did not act as a confounding factor (Table 1).
3.1 MACBAR comparison
The MACBAR measurement of the patients in each group is depicted in Figure 1, which illustrates the six crossing points of the positive and negative hemodynamic reactions after a pneumoperitoneum stimulation. The MACBAR values of sevoflurane in R0, R1, R2, and R3 groups were (2.46 ± 0.18)%, (2.18 ± 0.16)%, (1.81 ± 0.15)%, and (1.47 ± 0.18)%, respectively (as shown in Figure 2). The MACBAR values of sevoflurane in R1, R2, and R3 groups decreased by 11.4%, 26.4%, and 40.2%, respectively, and the difference was significant (P < 0.05). The EC95 (95% CI) values of sevoflurane were (2.34–2.55)%, (2.08–2.28)%, (1.72–1.90)%, and (1.36–1.59)% in groups R0, R1, R2, and R3, respectively (as shown in Table 2).
3.2 Secondary outcome
Compared with the R0 group, the differences in the corresponding HR and MAP were observed among the four groups at 1 and 3 min before pneumoperitoneum and 1 and 3 min after pneumoperitoneum. Remimazolam is a novel short-acting γ-aminobutyric acid (GABA) receptor agonist with no accumulation in long-term infusion, short half-life, inactive metabolites, and low occurrence of respiratory depression (10). It exhibits a rapid onset of action after intravenous injection, peaking at 15–30 min, with a terminal half-life of approximately 1 h. Although equilibration of the partial pressure of sevoflurane in alveolar and brain tissues is usually achieved in approximately 10–15 min, a preset end-tidal sevoflurane concentration was chosen to remain stable for at least 15 min. In this study, to adequately block the stress response during intubation and ensure hemodynamic stability during the tracheal intubation stage, the plasma target-controlled concentration of remifentanil was set at 3 ng/ml before intubation in all patients, and the concentration was adjusted to 1 ng/ml immediately after the end of intubation and was maintained for at least 15 min before the establishment of pneumoperitoneum (11). According to the pharmacokinetic and pharmacodynamic characteristics of remifentanil, the effector compartment equilibrium concentration was reached at the time of pneumoperitoneum, effectively reducing the interference of the experiments owing to individual differences. In the R1, R2, and R3 groups, where remimazolam was combined with a remifentanil plasma target concentration of 1 ng/ml, the MAP and HR were measured at 1 and 3 min before pneumoperitoneum, and 1 and 3 min after pneumoperitoneum were significantly lower than those of the R0 group. This observation may be related to the fact that remimazolam has a better sedative effect and a good synergistic effect with the analgesic remifentanil. In this study, it was found that when a remifentanil target-controlled infusion concentration of 1 ng/ml, inhalation of sevoflurane to maintain anesthesia, and remimazolam was pumped at 1 mg/kg/h, 1.5 mg/kg/h, and 2.0 mg/kg/h, the sevoflurane MACBAR value was reduced by 11.4%, 26.4%, and 40.2%, respectively. Therefore, when anesthesia is maintained using remimazolam in combination with remifentanil and sevoflurane simultaneously, the inhalation concentration of sevoflurane can be appropriately lowered to avoid excessively deep anesthesia (P < 0.05) (Table 3).
Comparing the basal values between groups, there was no significant difference in BIS values. However, after anesthesia induction, BIS values decreased significantly in the R0–R3 groups. When compared with the R3 group, the R0–R2 groups exhibited a decrease in BIS values before and after CO2 pneumoperitoneum at 1 min and 3 min (Figure 3).