Chawla Lakhmir S, Russell James A, Bagshaw Sean M, Shaw Andrew D, Goldstein Stuart L, Fink Mitchell P, Tidmarsh George F
Department of Medicine, Veterans Affairs Medical Center, Washington, DC, USA.
Department of Medicine, University of British Columbia, Vancouver, BC, Canada.
Crit Care Resusc. 2017 Mar;19(1):43-49.
Catecholamine-resistant hypotension (CRH) is characterised by inadequate response to standard doses of vasopressors, and increased mortality. Our Angiotensin II for the Treatment of High-Output Shock 3 (ATHOS-3) trial compares the efficacy and safety of angiotensin II (ANGII) versus placebo in CRH.
DESIGN, SETTING AND PARTICIPANTS: A phase III, multicentre, randomised, placebo-controlled trial of LJPC-501 (synthetic ANGII) for CRH in up to 120 intensive care units. We have set a target of 300 critically ill patients with CRH receiving standard-of-care (SOC) vasopressor therapy (ie, catecholamine dose > 0.2 µg/kg/min for 6-48 hours to maintain a mean arterial pressure [MAP] of 55-70 mmHg). Calculation of a norepinephrine-equivalent vasopressor dose is critical to determining patient eligibility, as ANGII will supplement ongoing vasopressor therapy.
Stable patients will be randomised 1:1 to SOC vasopressor plus continuous intravenous infusion of ANGII or placebo for 48 hours, with an aim of achieving MAP of 75 mmHg for the first 3 hours. ANGII (initiated at 20 ng/ kg/min) will be titrated according to pre-specified guidelines until 48 hours, with patients followed until Day 7. Frequent vital sign and haemodynamic monitoring will support ANGII titration, safety monitoring and efficacy assessments.
The primary efficacy endpoint is MAP ≥ 75 mmHg or an increase of ≥ 10 mmHg at treatment Hour 3. Secondary endpoints include change in total and cardiovascular Sequential Organ Failure Assessment scores over 48 hours, and safety data.
Our study will investigate the utility of adding ANGII to current SOC vasopressor options to increase the efficacy and safety of CRH therapy.
儿茶酚胺抵抗性低血压（CRH）的特征是对标准剂量血管升压药反应不足，且死亡率增加。我们的血管紧张素II治疗高输出量休克3（ATHOS-3）试验比较了血管紧张素II（ANGII）与安慰剂在CRH中的疗效和安全性。
设计、地点和参与者：一项III期、多中心、随机、安慰剂对照试验，在多达120个重症监护病房中使用LJPC-501（合成ANGII）治疗CRH。我们设定了一个目标，即300例患有CRH的重症患者接受标准治疗（SOC）血管升压药治疗（即儿茶酚胺剂量>0.2μg/kg/分钟，持续6 - 48小时，以维持平均动脉压[MAP]为55 - 70 mmHg）。计算去甲肾上腺素等效血管升压药剂量对于确定患者入选资格至关重要，因为ANGII将补充正在进行的血管升压药治疗。
病情稳定的患者将按1:1随机分配，接受SOC血管升压药加持续静脉输注ANGII或安慰剂治疗48小时，目标是在最初3小时内使MAP达到75 mmHg。ANGII（起始剂量为20 ng/kg/分钟）将根据预先指定的指南进行滴定，持续48小时，对患者进行随访直至第7天。频繁的生命体征和血流动力学监测将支持ANGII滴定、安全性监测和疗效评估。
主要疗效终点是治疗第3小时MAP≥75 mmHg或升高≥10 mmHg。次要终点包括48小时内总序贯器官衰竭评估评分和心血管序贯器官衰竭评估评分的变化，以及安全性数据。
我们的研究将探讨在当前SOC血管升压药选择中添加ANGII以提高CRH治疗的疗效和安全性的效用。
