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. Trial Registration ClinicalTrials.gov Identifier: NCT02508649.

中文翻译：

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Selepressin 与安慰剂对感染性休克患者无呼吸机和无血管加压药天数的影响

重要性 去甲肾上腺素是脓毒性休克的一线升压药，但并不总是有效，并且具有重要的儿茶酚胺能副作用。Selepressin 是一种选择性加压素 V1a 受体激动剂，是一种非儿茶酚胺能血管加压剂，可减轻脓毒症引起的血管舒张、血管渗漏和水肿，副作用较少。目的检测selepressin是否能改善感染性休克的预后。设计、设置和参与者 一项适应性 2b/3 期随机临床试验包括 2 个部分，其中包括成人患者 (n = 868)，感染性休克需要超过 5 μg/min 的去甲肾上腺素。第 1 部分使用贝叶斯算法来调整随机化概率以替代 selepressin 给药方案，并触发过渡到第 2 部分，该部分将比较表现最佳的方案与安慰剂。该试验于 2015 年 7 月至 2017 年 8 月在比利时、丹麦、法国、荷兰和美国的 63 家医院进行，随访于 2018 年 5 月完成。起始输注速率为 1.7、2.5 和 3.5 ng/kg/min；n = 585) 或安慰剂 (n = 283)，均根据血流动力学参数滴定连续输注。主要结果和措施 主要终点是开始研究药物后 30 天内（死亡分配为零天）内无呼吸机和血管加压药的天数。关键的次要终点是 90 天死亡率、无肾脏替代治疗天数和无 ICU 天数。结果 在 868 名随机患者中，828 名接受了研究药物治疗（平均年龄 66.3 岁；341 名 [41.2%] 女性）并构成主要分析队列，其中 562 人接受了 3 种 Selepressin 方案中的 1 种，266 人接受安慰剂，817 人（98.7%）完成了试验。该试验在第 1 部分结束时因无效而停止。中位研究药物持续时间为 37.8 小时（IQR，17.8-72.4）。主要终点（无呼吸机和无血管加压药的天数：15.0 vs 14.5，selepressin 组和安慰剂组；差异，0.6 [95% CI，-1.3 至 2.4]；P = .30）或关键终点没有显着差异次要终点（90 天死亡率，40.6% vs 39.4%；差异，1.1% [95% CI，-6.5% 至 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 至 2.6]；P = .85；无 ICU 天数：12.6 对 12.2；差异，0.5 [95% CI，-1.2 至 2.2]；P = .41）。不良事件发生率包括心律失常（27.9% 对 25.2% 的患者）、心脏缺血（6.6% 对 5.6%）、肠系膜缺血（3. 2% 对 2.6%）和外周缺血（2.3% 对 2.3%）。结论和相关性 在接受去甲肾上腺素治疗的感染性休克患者中，与安慰剂相比，使用 selepressin 并没有改善 30 天内无血管加压药和无呼吸机的天数。需要进一步的研究来评估 selepressin 在感染性休克中其他以患者为中心的结果的潜在作用。试验注册 ClinicalTrials.gov 标识符：NCT02508649。需要进一步的研究来评估 selepressin 在感染性休克中其他以患者为中心的结果的潜在作用。试验注册 ClinicalTrials.gov 标识符：NCT02508649。需要进一步的研究来评估 selepressin 在感染性休克中其他以患者为中心的结果的潜在作用。试验注册 ClinicalTrials.gov 标识符：NCT02508649。