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[JAMA在线发表]:Selepressin与安慰剂对感染性休克患者无机械及无升压药天数的影响
2019年10月07日 时讯速递, 进展交流 暂无评论

Original Investigation Caring for the Critically Ill PatientOctober 2, 2019

Effect of Selepressin vs Placebo on Ventilator- and Vasopressor-Free Days in Patients With Septic Shock: The SEPSIS-ACT Randomized Clinical Trial

Pierre-Francois Laterre, Scott M. Berry, Allan Blemings, et al

JAMA. Published online October 2, 2019. doi:10.1001/jama.2019.14607

Importance 背景

Norepinephrine, the first-line vasopressor for septic shock, is not always effective and has important catecholaminergic adverse effects. Selepressin, a selective vasopressin V1a receptor agonist, is a noncatecholaminergic vasopressor that may mitigate sepsis-induced vasodilatation, vascular leakage, and edema, with fewer adverse effects.

去甲肾上腺素是治疗感染性休克的一线升压药物,但并非总是有效,且具有儿茶酚胺类药物重要的副作用。Selepressin是一种选择性血管加压素V1a受体激动剂。作为一种非儿茶酚胺类升压药物,Selepressin能够缓解脓毒症诱发的血管扩张、血管渗漏及水肿,且副作用更少。

Objective 目的

To test whether selepressin improves outcome in septic shock.

验证Selepressin能否改善感染性休克的预后

Design, Setting, and Participants 试验实际,场景及研究对象

An adaptive phase 2b/3 randomized clinical trial comprising 2 parts that included adult patients (n = 868) with septic shock requiring more than 5 μg/min of norepinephrine. Part 1 used a Bayesian algorithm to adjust randomization probabilities to alternative selepressin dosing regimens and to trigger transition to part 2, which would compare the best-performing regimen with placebo. The trial was conducted between July 2015 and August 2017 in 63 hospitals in Belgium, Denmark, France, the Netherlands, and the United States, and follow-up was completed by May 2018.

这是一项包括两个部分的调整设计2b/3期随机临床试验,纳入需要去甲肾上腺素剂量超过5 μg/min的成年感染性休克患者(n = 868)。第一部分采用Bayesian算法调整随机分配至不同selepressin剂量的概率,并据此启动第二部分,即将最佳剂量组与安慰剂进行比较。试验于2015年7月至2017年8月间在比利时、丹麦、法国荷兰和美国的63所医院进行,随访于2018年5月终止。

Interventions 干预措施

Random assignment to 1 of 3 dosing regimens of selepressin (starting infusion rates of 1.7, 2.5, and 3.5 ng/kg/min; n = 585) or to placebo (n = 283), all administered as continuous infusions titrated according to hemodynamic parameters.

随机分至selepressin三个剂量组(起始输注剂量分别为1.7, 2.5, 和 3.5 ng/kg/min; n = 585) 或安慰剂 (n = 283),所有研究药物均持续输注,根据血流动力学参数情况调整剂量。

Main Outcomes and Measures 主要预后指标

Primary end point was ventilator- and vasopressor-free days within 30 days (deaths assigned zero days) of commencing study drug. Key secondary end points were 90-day mortality, kidney replacement therapy–free days, and ICU-free days.

主要预后终点为开始使用研究药物30天内无机械通气且无升压药物天数(死亡患者这一指标为0天)。关键的次要预后终点为90天病死率,无肾脏替代治疗天数,以及非ICU住院天数。

Results 结果

Among 868 randomized patients, 828 received study drug (mean age, 66.3 years; 341 [41.2%] women) and comprised the primary analysis cohort, of whom 562 received 1 of 3 selepressin regimens, 266 received placebo, and 817 (98.7%) completed the trial. The trial was stopped for futility at the end of part 1. Median study drug duration was 37.8 hours (IQR, 17.8-72.4). There were no significant differences in the primary end point (ventilator- and vasopressor-free days: 15.0 vs 14.5 in the selepressin and placebo groups; difference, 0.6 [95% CI, −1.3 to 2.4]; P = .30) or key secondary end points (90-day mortality, 40.6% vs 39.4%; difference, 1.1% [95% CI, −6.5% to 8.8%]; P = .77; kidney replacement therapy–free days: 18.5 vs 18.2; difference, 0.3 [95% CI, −2.1 to 2.6]; P = .85; ICU-free days: 12.6 vs 12.2; difference, 0.5 [95% CI, −1.2 to 2.2]; P = .41). Adverse event rates included cardiac arrhythmias (27.9% vs 25.2% of patients), cardiac ischemia (6.6% vs 5.6%), mesenteric ischemia (3.2% vs 2.6%), and peripheral ischemia (2.3% vs 2.3%).

共有 868 名患者接受随机分组,828 名患者接受研究药物(平均年龄, 66.3 岁; 341 [41.2%] 名女性) 作为主要分析队列,其中 562 名患者使用selepressin三种剂量中的一种,266 名患者使用安慰剂,817 名患者 (98.7%) 完成试验。在第一部分结束时试验因无效终止。研究药物使用中位时间为37.8 小时 (IQR, 17.8-72.4)。主要预后终点无显著差异 (无机械通气且无升压药物天数: selepressin组15.0 vs 安慰剂组14.5; 差异, 0.6 [95% CI, −1.3 to 2.4]; P = .30),关键次要终点也没有差异 (90天病死率, 40.6% vs 39.4%; 差异, 1.1% [95% CI, −6.5% to 8.8%]; P = .77; 无肾脏替代治疗天数: 18.5 vs 18.2; 差异, 0.3 [95% CI, −2.1 to 2.6]; P = .85; 非ICU住院天数: 12.6 vs 12.2; 差异, 0.5 [95% CI, −1.2 to 2.2]; P = .41)。不良事件包括心律失常(27.9% vs 25.2%),心肌缺血(6.6% vs 5.6%),肠系膜缺血 (3.2% vs 2.6%)及外周缺血(2.3% vs 2.3%)。

Conclusions and Relevance 结论与意义

Among patients with septic shock receiving norepinephrine, administration of selepressin, compared with placebo, did not result in improvement in vasopressor- and ventilator-free days within 30 days. Further research would be needed to evaluate the potential role of selepressin for other patient-centered outcomes in septic shock.

对于使用去甲肾上腺素的感染性休克患者,与安慰剂相比,使用selepressin不能改善30天内无升压药物及无机械通气天数。需要进一步研究评价selepressin对感染性休克患者其他预后指标的作用。

Trial Registration 试验注册

ClinicalTrials.gov Identifier: NCT02508649

评论[仅代表个人观点]

  • 包括本项研究在内的多项随机对照试验表明,用另外一种升压药物替代现有的去甲肾上腺素,并不能改善感染性休克患者的临床结局
  • 当然,血管紧张素II还没有做3期临床试验。但是,根据现有结果,这将会是一个有阳性结果的临床试验吗?
  • 多年前,VASST研究发表后,Joseph Parrillo述评中的一段话仍然是正确的:与其讨论使用哪种升压药物能够改善结局,不如说使用升压药物的时机更为关键。

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