【罂粟摘要】在阿片类药物引起的呼吸抑制中非典型三环类抗抑郁药噻奈普汀对通气的影响

在阿片类药物引起的呼吸抑制中非典型三环类抗抑郁药噻奈普汀对通气的影响

贵州医科大学    麻醉与心脏电生理课题组

翻译：胡廷菊       编辑：宋雨婷     审校：曹莹

背景

动物实验数据表明，抗抑郁药α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体调节剂噻奈普汀能够预防阿片类药物引起呼吸抑制。本试验假设口服或静脉注射噻奈普汀可以有效预防或抵消阿片类药物引起的呼吸抑制。

方法

本试验包括两项研究，采用了随机、双盲、安慰剂对照、交叉设计。首先，口服噻奈普汀（37.5mg、50mg和100mg剂量，8名受试者）进行预处理后，观察阿芬太尼诱导时的呼吸抑制（阿芬太尼靶浓度，100ng/ml）。主要结局指标为呼气末二氧化碳分压推测值为55mmHg（V_E55）时的通气情况。在15名志愿者中依次增加噻奈普汀（噻奈普汀目标血药浓度400、1000、1500和2000ng/ml，每次注射超过15min），观察其对瑞芬太尼引起的呼吸抑制的作用。在等碳酸值时测量通气量（基线通气20±2 l/min）。主要观察指标为噻奈普汀与安慰剂输注60min内的分钟通气量。

结果

安慰剂预处理后，使用阿芬太尼，V_E55降至13.7(95% CI，8.6-18.8）l/min，口服50mg噻奈普汀预处理后，V_E55降至17.9（10.2-25.7）l/min（治疗组间均差4.2（-11.5-3.0）l/min，P = 0.070）。静脉注射噻奈普汀（目标血浆浓度为500ng/ml至2000ng/ml）1小时后无呼吸兴奋作用，且加重了瑞芬太尼引起的呼吸抑制：噻奈普汀9.6±0.8 l/min，安慰剂15.0±0.9 l/min；均差，5.3 l/min；95% CI，2.5-8.2 l/min；P = 0.001。

结论

口服或静脉使用噻奈普汀无呼吸性兴奋作用。静脉注射噻奈普汀（血药浓度达500ng/ml至2000ng/ml）加重了瑞芬太尼引起的呼吸抑制。

原始文献来源

Algera H, van der Schrier R, Cavalla D, van Velzen M, Roozekrans M, McMorn A, Snape M, Horrigan JP, Evans S, Kiernan B, Sarton E, Olofsen E, Niesters M, Dahan A. Respiratory Effects of the Atypical Tricyclic Antidepressant Tianeptine in Human Models of Opioid-induced Respiratory Depression. Anesthesiology. 2022 Oct 1;137(4):446-458.

英文原文

Respiratory Effects of the Atypical Tricyclic Antidepressant Tianeptine in Human Models of Opioid-induced Respiratory Depression

Background:Animal data suggest that the antidepressant and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor modulator tianeptine is able to prevent opioid-induced respiratory depression. The hypothesis was that oral or intravenous tianeptine can effectively prevent or counteract opioid-induced respiratory depression in humans.

Methods: Healthy male and female volunteers participated in two studies that had a randomized, double blind, placebo-controlled, crossover design. First, oral tianeptine (37.5-, 50-, and 100-mg doses with 8 subjects) pretreatment followed by induction of alfentanil-induced respiratory depression (alfentanil target concentration, 100 ng/ml) was tested. Primary endpoint was ventilation at an extrapolated end-tidal carbon dioxide concentration of 55 mmHg (VE 55). Next, the ability of four subsequent and increasing infusions of intravenous tianeptine (target tianeptine plasma concentrations 400, 1,000, 1,500, and 2,000 ng/ml, each given over 15min) to counteract remifentanil-induced respiratory depression was determined in 15 volunteers. Ventilation was measured at isohypercpania (baseline ventilation 20±2 l/min). The primary endpoint was minute ventilation during the 60min of tianeptine versus placebo infusion.

Results: Alfentanil reduced VE ̇ 55 to 13.7 (95% CI, 8.6 to 18.8) l/min after placebo pretreatment and to 17.9 (10.2 to 25.7) l/min after 50-mg tianeptine pretreatment (mean difference between treatments 4.2 (–11.5 to 3.0) l/min, P = 0.070). Intravenous tianeptine in the measured concentration range of 500 to 2,000 ng/ml did not stimulate ventilation but instead worsened remifentanil-induced respiratory depression: tianeptine, 9.6±0.8 l/min versus placebo 15.0±0.9 l/min; mean difference, 5.3 l/min; 95% CI, 2.5 to 8.2 l/min; P = 0.001, after 1 h of treatment.

Conclusions:Neither oral nor intravenous tianeptine were respiratory stimulants. Intravenous tianeptine over the concentration range of 500 to 2000 ng/ml worsened respiratory depression induced by remifentanil.