1、临床研究复合瑞芬太尼时瑞马唑仑用于老年患者全膝关节置换术全麻镇静的半数有效剂量张卓施节娟马浩南余剑波DOI:1012089/jca202301008作者单位:300457天津市，泰达医院(天津大学泰达医院)麻醉科(张卓、施节娟、马浩南);天津医科大学南开临床学院麻醉科与危重症医学科(余剑波)通信作者:马浩南，Email:drhaonan 126com【摘要】目的采用序贯法测定复合瑞芬太尼时瑞马唑仑用于老年患者全膝关节置换术全麻镇静的半数有效剂量(ED50)。方法选择择期行单膝全膝关节置换术老年患者 29 例，男 13 例，女16 例，年龄65 岁，BMI30 kg/m2，ASA级。麻醉诱导后行
2、超声引导下股神经阻滞，麻醉维持采用瑞芬太尼 0.050.20 gkg1min1，顺式阿曲库铵 0.1 mgkg1h1和瑞马唑仑。根据预试验确定瑞马唑仑的起始剂量为 0.7 mgkg1h1，相邻浓度比值为 1 1.15，以出现镇静无效的前一例患者为第 1 例，按照序贯法确定下一例瑞马唑仑的维持剂量，若上一例镇静有效(BIS60、MAP波动幅度基础值的 20%且术后随访无术中知晓)，则下一例在上一例的给药剂量基础上降低一个梯度，反之任意一项指标不达标则为镇静无效，下一例给药剂量升高一个梯度，重复此过程直到出现第7 个拐点终止研究。采用概率单位 Probit 回归分析法计算瑞马唑仑的 ED50和 E
3、D95及其 95%可信区间(CI)。记录术中知晓、心动过缓、恶心呕吐等不良反应的发生情况。结果瑞马唑仑复合瑞芬太尼联合神经阻滞用于老年全膝关节置换术全麻镇静的 ED50为 0.539 mgkg1h1(95%CI 0.4690.604 mgkg1h1)，ED95为 0.681 mgkg1h1(95%CI 0.6111.136 mgkg1h1)。1 例术中出现窦性心动过缓，给予阿托品有效，1 例术后 4 h 出现恶心呕吐，无一例发生术中知晓和其他不良反应。结论复合瑞芬太尼时瑞马唑仑用于老年患者全膝关节置换术全麻镇静的 ED50为 0.539mgkg1h1。【关键词】瑞马唑仑;瑞芬太尼;股神经阻滞;
4、全膝关节置换术;半数有效剂量Median effective dose of remimazolam combined with remifentanil for general anesthesia sedation inelderly patients undergoing total knee arthroplastyZHANG Zhuo，SHI Jiejuan，MA Haonan，YUJianbo Department of Anesthesiology，Tianjin TEDA Hospital(TEDA Hospital of Tianjin University)，Tianjin
5、 300457，ChinaCorresponding author:MA Haonan，Email:drhaonan 126com【Abstract】ObjectiveTo determine the median effective dose(ED50)of remimazolam combinedwith remifentanil for general anesthesia sedation in elderly patients undergoing total knee arthroplasty by se-quential method MethodsTwenty-nine eld
6、erly patients undergoing unilater total knee arthroplasty wereselected，13 males and 16 females，aged 65 years，BMI 30 kg/m2，ASA physical status Afterinduction of general anesthesia，ultrasound-guided femoral nerve block was performed，and remifentanil0.050.20 gkg1min1and cis-atracurium 0.1 mgkg1h1were u
7、sed for general anesthesia ma-intenance The initial dose of remimazolam was determined to be 0.7 mgkg1h1according to the pre-liminary test，and the adjacent concentration ratio was 1 1.15，and the previous patient with ineffective se-dation was taken as the first case，the sequential method was used to
8、 determine the maintenance dose ofremimazolam for the next patient，if sedation was effective in the previous patient(BIS 60，MAP fluctua-tion amplitude 20%of the baseline value and no intraoperative awareness)，the next patient decreased agradient from the dose of the previous patient，otherwise，if the
9、 sedation was ineffective，and the dose of thenext patient would increase by a gradient This process was repeated until the seventh inflection point isreached to terminate the study ED50and ED95of remimazolam and the respective 95%confidence interval(CI)were calculated according to the regression ana
10、lysis of the Probit model The occurrence ofbradycardia，nausea and vomiting，intraoperative awareness and other adverse reactions were recordedesultsThe ED50of remimazolam combined with remifentanil combined with nerve block was 0.53993临床麻醉学杂志 2023 年 1 月第 39 卷第 1 期J Clin Anesthesiol，January 2023，Vol39
11、，No1mgkg1h1(95%CI 0.4690.604 mgkg1h1)for sedation of general anesthesia in senile totalknee replacement，and ED95was 0.681 mgkg1h1(95%CI 0.6111.136 mgkg1h1)One pa-tient had sinus bradycardia during the operation，and atropine was effective One patient had nausea andvomiting 4 hours after operation，non
12、e of the 29 patients had any intraoperative awareness，and the patientshad no obvious adverse reactions to anesthetic drugs ConclusionThe ED50of remimazolam combined withremifentanil combined was 0.539 mgkg1h1for the sedation of general anesthesia in elderly patientsundergoing total knee arthroplasty
13、【Key words】emimazolam;emifentanil;Femoral nerve block;Total knee arthroplasty;Medianeffective dose全膝关节置换术(total knee arthroplasty，TKA)自 20 世纪 70 年代以来被广泛应用，是目前治疗膝骨关节炎(osteoarthritis，OA)常见且有效的手段。OA 多发生于 65 岁以上的老年患者，且女性多于男性1。而老年患者常合并多系统疾病，对麻醉药敏感性较高，代谢较慢，易导致麻醉药蓄积甚至中毒，围术期常伴随着频繁的不良应激反应以及血流动力学的波动2，因此选择安全有效
14、的麻醉药至关重要。瑞马唑仑属于苯二氮类药物，该药起效快，代谢快，代谢产物活性低，药物间相互作用小，并可以通过氟马西尼逆转34。瑞马唑仑作为全麻的镇静催眠药具有良好的耐受性且其诱发低血压风险较低，尤其适用于血流动力学不稳定的患者5。然而，关于瑞马唑仑的剂量应用，临床尚缺乏系统报道。本研究拟测定瑞马唑仑复合瑞芬太尼用于老年患者 TKA 全麻维持剂量半数有效剂量(medianeffective dose，ED50)，为瑞马唑仑的临床用药提供参考。资料与方法一般资料本研究经医院伦理委员会批准 2021 伦审第(17)号，患者或家属均签署知情同意书。选择 2021 年 10 月 1 日至 2022 年
15、3 月 1日行单膝 TKA 老年患者，性别不限，年龄65 岁，BMI30 kg/m2，ASA级。排除标准:认知功能障碍，合并恶性肿瘤、肝肾功能不全、慢性阻塞性肺病(chronic obstructive pulmonary disease，COPD)、高血压级、支气管哮喘、电解质明显异常，凝血异常或穿刺部位感染，相关药物过敏史等禁忌，精神类疾病，吸毒史和/或酗酒史，术中出现难以纠正的低血压或心律失常。根据镇静是否有效将患者分为两组:镇静有效组(P 组)和镇静无效组(N 组)。麻醉方法患者术前常规禁食8 h，入室后监测BP、ECG、H、SpO2、BIS 等，并开放外周静脉，选取左桡动脉穿刺置管测
16、量 MAP。充分吸氧后进行全麻诱导，静脉注射瑞马唑仑 0.1 mg/kg、丙泊酚 2.0mg/kg、舒芬太尼 0.3 g/kg、顺式阿曲库铵 0.2mg/kg，药物起效后置入喉罩，行机械通气，设置FiO2100%，VT6 8 ml/kg，10 12 次/分，维持PETCO23545 mmHg。持续静脉泵注瑞芬太尼(批号:H20030197)0.05 0.20 gkg1min1、顺式阿曲库铵 0.1 mgkg1h1和瑞马唑仑(批号:H20190034)。置入喉罩后行超声引导下股神经阻滞，操作由同一名接受过专业培训的麻醉科医师完成。术中根据 H、MAP、BIS 等生命体征调整瑞芬太尼维持剂量，必要时调整瑞马唑仑的剂量。维持BIS 4060，MAP 波动幅度小于基础值的 20%。置入假体后停止泵注顺式阿曲库铵，手术缝皮时停止泵注瑞马唑仑和瑞芬太尼，待自主呼吸 VT200 ml后，静注新斯的明 0.04 mg/kg 和阿托品 0.01 mg/kg拮抗残余肌松，满足拔管指征后拔除喉罩。待生命体征 稳 定 后，连 接 电 子 静 脉 自 控 镇 痛(patientcontrolled intrav
