Advances in Clinical Medicine
Vol.
12
No.
06
(
2022
), Article ID:
52455
,
5
pages
10.12677/ACM.2022.126759
瑞马唑仑用于全身麻醉诱导与维持的研究进展
闫锦威1,吴馨婷1,杨靖梅1,王学军2*
1青海大学研究生院,青海 西宁
2青海红十字医院麻醉科,青海 西宁
收稿日期:2022年5月13日;录用日期:2022年6月1日;发布日期:2022年6月15日
摘要
作为一种新型的超短效苯二氮卓类药物,瑞马唑仑起效迅速,代谢不依赖肝、肾功能,对呼吸和循环的抑制作用小,且具备特异性拮抗药物氟马西尼。相关临床研究证明瑞马唑仑在全身麻醉诱导和维持方面具备广阔的临床应用前景。但是,其有效性及安全性需要进一步的临床研究来证实。
关键词
瑞马唑仑,全身麻醉诱导与维持
Research Progress of Remimazolam in Induction and Maintenance of General Anesthesia
Jingwei Yan1, Xinting Wu1, Jingmei Yang1, Xuejun Wang2*
1Graduate School of Qinghai University, Xining Qinghai
2Qinghai Red Cross Hospital Anesthesiology, Xining Qinghai
Received: May 13th, 2022; accepted: Jun. 1st, 2022; published: Jun. 15th, 2022
ABSTRACT
As a new type of ultra-short-acting benzodiazepine, remimazolam has rapid onset of action, independent of liver and kidney function, little inhibitory of respiration and circulation, and has a specific antagonist, flumazenil. Relevant clinical studies have proved that remimazolam has a broad clinical application prospect in induction and maintenance of general anesthesia. However, further clinical studies are required to confirm its efficacy and safety.
Keywords:Remimazolam, Induction and Maintenance of General Anesthesia
Copyright © 2022 by author(s) and Hans Publishers Inc.
This work is licensed under the Creative Commons Attribution International License (CC BY 4.0).
http://creativecommons.org/licenses/by/4.0/
1. 引言
瑞马唑仑(CNS7056)是在苯二氮卓类药物咪达唑仑的分子结构基础上引入一个可以代谢的丙酸甲酯侧链从而产生的一种新型的超短效麻醉镇静药物,作用于γ-氨基丁酸A型受体(GABAA),使氯离子顺浓度梯度差进入细胞内,引起神经细胞的膜电位增大而产生超极化作用,导致细胞兴奋性下降,从而抑制神经元的活动,产生麻醉作用 [1]。目前,用于临床麻醉诱导与维持的静脉镇静药物主要有丙泊酚和咪达唑仑,这两种催眠剂都存在缺点,在安全性和麻醉效率方面都有改善的空间。与咪达唑仑相比,瑞马唑仑能迅速转变为一种非活性代谢产物(CNS7054),起效迅速且不易蓄积;与丙泊酚相比,瑞马唑仑不易引起心血管抑制、呼吸抑制和注射疼痛 [2]。
2. 药代动力学特点
2.1. 吸收
目前所开发用于临床的瑞马唑仑均为静脉剂型,可满足绝大部分的临床需要,但对于一些特殊情况,静脉给药并不总是完全适用的。口服给药时,瑞马唑仑从胃肠道系统完全吸收,但快速广泛的首过消除效应导致其口服生物利用度极低,Pesic等 [3] 在健康志愿者身上所做的实验表明,瑞马唑仑口服给药时的生物利用度仅有1.2%~2.2%,几乎没有镇静作用,口服给药并不是一个合适的替代给药途径。通过随机对照临床试验,Pesic等发现了另一种潜在的替代途径。鼻内给予粉剂10~40 mg时,瑞马唑仑的生物利用度可达到50%,消除半衰期为0.7~1.2 h。虽然目前所用的瑞马唑仑剂型在鼻内给药时会引起鼻腔的不适和疼痛,但是这种替代途径仍然具备一定的临床潜力 [4]。
2.2. 分布
瑞马唑仑静脉注射后与血浆蛋白(主要是白蛋白)结合率为91%,药代动力学与剂量呈线性关系 [5] [6]。Schüttler [7] [8] 在给健康男性志愿者静脉持续输注瑞马唑仑时发现其血浆浓度可由三室模型描述,最大血药浓度时间为[1 min],具有较小的稳态分布容积[(35.4 ± 4.2) L],较短的平均停留时间[0.51 h],较高的清除率[(1.15 ± 0.12) L/min]以及较短的终末半衰期[(70 ± 10) min]。
2.3. 代谢
瑞马唑仑是一种以酯类结构为基础的超短效药物,在体内被非特异性酯酶(羧酸酯酶1)快速水解为唑仑丙酸(CNS7054)和甲醇,CNS7054对GABAA受体的亲和力仅为瑞马唑仑的1/400,几乎不具备药物活性,从而使得瑞马唑仑起效及失效都非常迅速,可提供可控的镇静和麻醉效果 [5] [6]。并且,羧酸酯酶1在体内广泛分布,在肝脏、胆囊和肺中均高度表达,使得瑞马唑仑的代谢并不依赖肝肾功能 [9] [10]。
2.4. 排泄
99.7%的瑞马唑仑在体内被羧酸酯酶1快速水解为CNS7054,其中绝大部分24小时内经尿液排出体外,少部分进一步氧化或经葡萄糖醛酸化后排泄 [11]。
3. 全身麻醉诱导与维持的研究进展
3.1. 非劣效性
为了证明瑞马唑仑和丙泊酚在外科患者全麻诱导和维持中的非劣效性,Doi [12] 等进行了一项多中心、单盲、随机、对照的IIb/III期临床试验,该实验中375名患者分别使用低剂量的瑞马唑仑(n = 158, 6 mg∙kg−1∙h−1)、高剂量的瑞马唑仑(n = 156, 12 mg∙kg−1∙h−1)和丙泊酚(n = 77, 2 mg∙kg−1)进行全身麻醉的诱导和维持。在该实验中,瑞马唑仑的非劣效性得到证实[95%置信区间(−0.0487; 0.0250)],瑞马唑仑组不良反应发生率(39.3%, 42.7%)明显低于丙泊酚组(61.3%),瑞马唑仑组患者血压下降程度(20.0%, 24.0%)也明显低于丙泊酚组(49.3%),注射痛仅发生在丙泊酚组(18.7%),两组瑞马唑仑患者均未发生。Doi等人的研究表明两种剂量的瑞马唑仑与丙泊酚相比均无劣效性,且不良反应发生率更低,对血流动力学的影响也更小,这表明瑞马唑仑在全身麻醉诱导和维持方面具有广泛的临床应用前景。
3.2. 安全性
为进一步研究瑞马唑仑在高危手术患者(ASAIII级)全身麻醉诱导和维持中的有效性和安全性,Doi [13] 等进行了另外一项多中心、双盲、随机、平行组比较实验。67名ASA III级患者依照麻醉诱导剂量分为低剂量组(n = 33, 6 mg∙kg−1∙h−1)和高剂量组(n = 34, 12 mg∙kg−1∙h−1),术中均以瑞马唑仑2 mg∙kg−1∙h−1维持。两组患者100%的镇静有效率表明瑞马唑仑具有可靠的麻醉诱导效果,两组患者BIS值相似,介于45.0~68.0之间,表明瑞马唑仑能产生足够的镇静深度。除低剂量组患者意识消失时间明显长于高剂量组外,两组患者血压下降发生率、恢复情况、不良事件或药物不良反应发生率及严重程度均无统计学差异。两种剂量瑞马唑仑在高危手术患者的麻醉诱导与维持过程中均安全有效,对患者的血流动力学影响也较小,这表明对于危重患者,两组剂量的瑞马唑仑均具备可靠的临床应用效果。
3.3. 可逆性
氟马西尼作为苯二氮卓类药物的拮抗剂,已被证明可逆转或预防瑞马唑仑的作用 [14]。夏晨 [15] 等人的研究表明,患者在接受瑞马唑仑后的一小时内存在中度短期的精神运动障碍效应,而氟马西尼可以有效的消除瑞马唑仑的这些残余效应。在一项对接受结肠镜检查的志愿者的研究表明,氟马西尼可以完全逆转瑞马唑仑的镇静作用,使受试者迅速恢复到完全警觉状态 [16]。Yoshida等 [17] 使用氟马西尼联合瑞马唑仑来精确控制镇静水平,在开颅手术中唤醒患者,这为需要清醒开颅的手术患者的全身麻醉提供了新的途径。
4. 小结与展望
瑞马唑仑于2020年1月率先在日本被批准用于麻醉诱导与维持 [18]。目前,苯磺酸瑞马唑仑在我国已被批准用于全身麻醉诱导与维持。作为一种新型的苯二氮卓类麻醉药物,瑞马唑仑起效迅速,代谢不依赖肝肾功能,早期报告的临床数据表明,瑞马唑仑具有良好的疗效和安全性,具备优越的血流动力学稳定性,值得注意的是,瑞马唑仑还具备特异性拮抗剂氟马西尼 [19] [20]。瑞马唑仑的这些药物特点,使得理论上瑞马唑仑在全身麻醉诱导与维持的应用方面具备广阔的临床应用前景。然而,为了获得广泛的应用,还需要更多的临床研究来证明瑞马唑仑的安全性、有效性,潜在的不良反应以及与阿片类镇痛药的相互作用等方面也需要更多的临床研究来发现。
文章引用
闫锦威,吴馨婷,杨靖梅,王学军. 瑞马唑仑用于全身麻醉诱导与维持的研究进展
Research Progress of Remimazolam in Induction and Maintenance of General An-esthesia[J]. 临床医学进展, 2022, 12(06): 5245-5249. https://doi.org/10.12677/ACM.2022.126759
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NOTES
*通讯作者。