美国匹兹堡大学Derek C. Angus课题组的一项最新研究，分析了Selepressin与安慰剂对脓毒性休克患者无呼吸机和无血管加压素天数的影响。相关论文发表在2019年10月15日出版的《美国医学会杂志》上。

去甲肾上腺素是治疗脓毒性休克的一线血管加压药，但并非经常奏效，且有不容忽视的儿茶酚胺不良反应。选择性血管加压素V1a受体激动剂Selepressin是一种非儿茶酚胺类血管加压药，可减轻败血症引起的血管舒张，血管渗漏和水肿，且副作用较少。 

2015年7月至2017年8月，研究组在比利时、丹麦、法国、荷兰和美国进行了一项适应性、2b/3期、随机临床试验，共招募了868名脓毒性休克且需要剂量超过5μg/min的去甲肾上腺素进行治疗的患者。将其随机分组，其中585例随机接受3种剂量Selepressin（开始输注速率分别为1.7、2.5和3.5ng/kg/min）中的一种进行治疗，283例接受安慰剂治疗。

最终有817名患者完成了试验。研究药物的中位持续时间为37.8个小时。Selepressin组和安慰剂组中无需呼吸机和加压素治疗的时间分别为15.0天和14.5天，90天死亡率分别为40.6%和39.4%，无需肾脏替代治疗的时间分别为18.5天和18.2天，无需住ICU的时间分别为12.6天和12.2天，差异均不显著。两组的不良事件主要包括心律失常、心肌缺血、肠系膜缺血和外周缺血，但差异均无统计学意义。

总之，对于接受去甲肾上腺素治疗的脓毒性休克患者，与安慰剂相比，使用Selepressin并不能在一个月内改善无加压素和无呼吸机的天数。

附：英文原文

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

Author: Pierre-Francois Laterre, Scott M. Berry, Allan Blemings, Jan E. Carlsen, Bruno Franois, Todd Graves, Karsten Jacobsen, Roger J. Lewis, Steven M. Opal, Anders Perner, Peter Pickkers, James A. Russell, Nis A. Windelv, Donald M. Yealy, Pierre Asfar, Morten H. Bestle, Grégoire Muller, Cédric Bruel, Nolle Brulé, Johan Decruyenaere, Alain-Michel Dive, Thierry Dugernier, Kenneth Krell, Jean-Yves Lefrant, Bruno Megarbane, Emmanuelle Mercier, Jean-Paul Mira, Jean-Pierre Quenot, Bodil Steen Rasmussen, Hans-Christian Thorsen-Meyer, Margot Vander Laenen, Marianne Lauridsen Vang, Philippe Vignon, Isabelle Vinatier, Sine Wichmann, Xavier Wittebole, Anne Louise Kjlbye, Derek C. Angus

Issue&Volume: 2019/10/15

Abstract: 

Importance  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.

Objective  To test whether selepressin improves outcome in septic shock.

Design, Setting, and Participants  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.

Interventions  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.

Main Outcomes and Measures  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.

Results  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%).

Conclusions and Relevance  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.

DOI: 10.1001/jama.2019.14607

Source: https://jamanetwork.com/journals/jama/article-abstract/2752580