研究驗證Selepressin能否改善膿毒性休克預後
作者：
小柯機器人發布時間：2019/10/17 11:18:05
美國匹茲堡大學Derek C. Angus課題組的一項最新研究，分析了Selepressin與安慰劑對膿毒性休克患者無呼吸機和無血管加壓素天數的影響。相關論文發表在2019年10月15日出版的《美國醫學會雜誌》上。
去甲腎上腺素是治療膿毒性休克的一線血管加壓藥，但並非經常奏效，且有不容忽視的兒茶酚胺不良反應。選擇性血管加壓素V1a受體激動劑Selepressin是一種非兒茶酚胺類血管加壓藥，可減輕敗血症引起的血管舒張，血管滲漏和水腫，且副作用較少。
2015年7月至2017年8月，研究組在比利時、丹麥、法國、荷蘭和美國進行了一項適應性、2b/3期、隨機臨床試驗，共招募了868名膿毒性休克且需要劑量超過5μg/min的去甲腎上腺素進行治療的患者。將其隨機分組，其中585例隨機接受3種劑量Selepressin（開始輸注速率分別為1.7、2.5和3.5ng/kg/min）中的一種進行治療，283例接受安慰劑治療。
最終有817名患者完成了試驗。研究藥物的中位持續時間為37.8個小時。Selepressin組和安慰劑組中無需呼吸機和加壓素治療的時間分別為15.0天和14.5天，90天死亡率分別為40.6%和39.4%，無需腎臟替代治療的時間分別為18.5天和18.2天，無需住ICU的時間分別為12.6天和12.2天，差異均不顯著。兩組的不良事件主要包括心律失常、心肌缺血、腸繫膜缺血和外周缺血，但差異均無統計學意義。
總之，對於接受去甲腎上腺素治療的膿毒性休克患者，與安慰劑相比，使用Selepressin並不能在一個月內改善無加壓素和無呼吸機的天數。
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