Abstract:

Objective　To determine the median and 95 percent effective doses (ED₅₀ and ED₉₅) of remimazolam combined with etomidate for general anesthesia induction by the biased coin design (BCD) method in two stages. Methods　One hundred and four patients taking general anesthesia by tracheal intubation at Affiliated Hospital of Guangdong Medical University from September 1, 2022 to October 31, 2023 were selected, and were divided in two stages (group S1 and group S2) for the BCD experiment; they were 18 - 64 years old. In group S1, the fixed dose of etomidate was set as 0.15 mg/kg; the first patient was given remimazolam 0.25 mg/kg; when the patient was not conscious, the score of alertness /sedation (OAA/S) ≤1, and bispectral index (BIS) ≤60, the patient was given sufentanil 0.4 μg/kg and atracurium 0.2 mg/kg; the ED₅₀ and ED₉₅ of remimazolam for the next patient were determined by the BCD method based on the situation of tracheal tube insertion in the previous patient. Similarly, the ED₅₀ of remimazolam was fixed in group S2, and the ED₅₀ and ED₉₅ of etomidate were measured. The cardiovascular response to tracheal intubation before induction (T0) and before (T1) and 1 (T2) and 3 min (T3) after intubation and the incidences of hypotension, bradycardia, muscle tremors, hiccup, injection pain, etc. were recorded.The repeated measurement analysis of variance, χ² test, and Fisher exact probability were applied. According to the dosage of medication, the effective dose and 95% confidence interval (CI) were calculated by the Probit probability unit method. Results　There were 52 cases in group S1, including 21 males and 31 females; they were (40.7±12.2) years old; their body mass index (BMI) was (22.8±3.1) kg/m²; there were 11 cases of grade Ⅰ and 41 cases of grade Ⅱ of American Society of Anesthesiologists (ASA). There were 52 cases in group S2, including 27 cases and 25 cases; they were (39.7±12.7) years old; their BMI was (22.4±2.8) kg/m²; there were 3 cases of grade Ⅰ and 49 cases of grade Ⅱ of ASA. When 0.15 mg/kg etomidate was used for the general anesthesia induction, the ED₅₀ and ED₉₅ of remimazolam required to prevent cardiovascular response to tracheal intubation were 0.253 mg/kg (95%CI 0.130-0.265 mg/kg) and 0.285 mg/kg (95%CI 0.276-0.352 mg/kg), respectively. The ED₅₀ and ED₉₅ of etomidate combined with remimazolam (0.25 mg/kg) required to prevent cardiovascular response to tracheal intubation were 0.191 mg/kg (95%CI 0.084-0.212 mg/kg) and 0.254 mg/kg (95%CI 0.234-0.413 mg/kg), respectively. There were no statistical differences in HR at T0, T1, T3 between the two groups (all P>0.05). The HR at T2 was higher than that at T0 (all P<0.05). The MAP's at T0 and T2 were higher than those at T1 and T3, with statistical differences (all P<0.05). The was no statistical difference in MAP between at T0 and T2 (all P>0.05). No bradycardia occurred in both groups. All the patients had successful intubation at one time. There were statistical differences in the incidences of injection pain and hiccup between group S1 and group S2 [17.3% (9/52) vs. 0 and 11.5% (6/52) vs. 0; both P<0.05]. There was no statistical difference in the incidences of muscle tremors and hypotension between the two groups (both P>0.05). Conclusion　Remimazolam combined with etomidate is safely and effective for endotracheal intubation in the 18 to 64 years old. The ED₅₀ and ED₉₅ of remimazolam can provide references for precision medication in clinic when it is combined with etomidate.

Key words:

Intubation, Biased coin design method, Remimazolam, Etomidate, Dose-response relationship, Effective dose

摘要：

目的　采用抛偏倚银币（BCD）法分阶段测定瑞马唑仑复合依托咪酯全麻诱导的半数有效剂量（ED₅₀）及95%有效剂量（ED₉₅）。方法　选取广东医科大学附属医院2022年9月1日至2023年10月31日收治的拟行气管插管全身麻醉手术患者104例，年龄18～64岁，分两个阶段（S1组和S2组）进行BCD法试验。S1组设定依托咪脂诱导剂量固定值为0.15 mg/kg，首例患者给予瑞马唑仑0.25 mg/kg，当患者麻醉后意识消失，警觉/镇静评分（OAA/S评分）≤1分且脑电双频指数（BIS）≤60时，给予顺阿曲库铵0.2 mg/kg和舒芬太尼0.4 μg/kg，根据患者气管插管后心血管反映情况，采用BCD法测定瑞马唑仑的ED₅₀、ED₉₅；同理，S2组固定瑞马唑仑ED₅₀剂量，测定依托咪酯的ED₅₀、ED₉₅。记录患者气管插管过程［麻醉诱导前（T0）、插管前（T1）、插管后1 min（T2）和插管后3 min（T3）］的心血管反应情况，记录给药后患者发生低血压、心动过缓、肌颤、呃逆及注射痛等不良反应情况。采用重复测量方差分析、χ²检验、Fisher精确概率，根据患者用药剂量，用Probit概率单位法计算有效剂量值及95%可信区间（CI）。结果　S1组试验患者52例，男21例，女31例，年龄（40.7±12.2）岁，体质量指数（BMI）为（22.8±3.1）kg /m²，美国麻醉医师协会（ASA）分级Ⅰ级11例，Ⅱ级41例；S2组试验患者52例，男27例，女25例，年龄（39.7±12.7）岁，BMI（22.4±2.8）kg /m²，ASA Ⅰ级3例，Ⅱ级49例。复合依托咪酯（0.15 mg/kg）全麻诱导时，瑞马唑仑抑制气管插管心血管反应的ED₅₀为0.253 mg/kg（95%CI 0.130～0.265 mg/kg），ED₉₅为0.285 mg/kg（95%CI 0.276～0.352 mg/kg）；复合瑞马唑仑（0.25 mg/kg）全麻诱导时，依托咪酯抑制气管插管心血管反应的ED₅₀为0.191 mg/kg（95%CI 0.084～0.212 mg/kg），ED₉₅为0.254 mg/kg（95%CI 0.234～0.413 mg/kg）。S1组及S2组T0、T1、T3时的心率（HR）比较差异均无统计学意义（均P>0.05）；与T0比较，T2时HR均加快（均P<0.05）；T0和T2时的平均动脉压（MAP）高于T1和T3时，差异均有统计学意义（均P<0.05）。T0和T2时的MAP差异均无统计学意义（均P>0.05）。两组患者均未发生心动过缓情况，均一次插管成功；S1组、S2组患者中注射痛［17.3%（9/52）比0］和呃逆［11.5%（6/52）比0］发生率比较，差异均有统计学意义（均P<0.05）；两组患者肌颤和低血压发生率差异均无统计学意义（均P>0.05）。结论　瑞马唑仑复合依托咪酯可安全有效用于18～64岁人群的全麻诱导，瑞马唑仑复合依托咪酯的ED₅₀和ED₉₅可为临床提供精准用药依据。

关键词:

气管插管, 抛偏倚银币法, 瑞马唑仑, 依托咪脂, 量效关系, 有效剂量