Division of Nephrology, Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, NM, USA.
Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, NM, USA.
Trials. 2024 Mar 12;25(1):182. doi: 10.1186/s13063-024-07995-0.
Data to support the use of specific vasopressors in septic shock are limited. Since angiotensin II (AT2) was approved by the Food and Drug Administration in 2017, multiple mechanistically distinct vasopressors are available to treat septic shock, but minimal data exist regarding which patients are most likely to benefit from each agent. Renin and dipeptidyl peptidase 3 (DPP3) are components of the renin-angiotensin-aldosterone system which have been shown to outperform lactate in predicting sepsis prognosis, and preliminary data suggest they could prove useful as biomarkers to guide AT2 use in septic shock.
The DARK-Sepsis trial is an investigator-initiated industry-funded, open-label, single-center randomized controlled trial of the use of AT2 versus standard of care (SOC) vasopressor therapy in patients admitted to the intensive care unit (ICU) with vasodilatory shock requiring norepinephrine ≥ 0.1 mcg/kg/min. In both groups, a series of renin and DPP3 levels will be obtained over the first 24 h of treatment with AT2 or SOC. The primary study outcome will be the ability of these biomarkers to predict response to vasopressor therapy, as measured by change in total norepinephrine equivalent dose of vasopressors at 3 h post-drug initiation or the equivalent timepoint in the SOC arm. To determine if the ability to predict vasopressor response is specific to AT2 therapy, the primary analysis will be the ability of baseline renin and DPP3 levels to predict vasopressor response adjusted for treatment arm (AT2 versus control) and Sequential Organ Failure Assessment (SOFA) scores. Secondary outcomes will include rates of acute kidney injury, need for mechanical ventilation and kidney replacement therapy, lengths of stay in the ICU and hospital, ICU and hospital mortality, and rates of prespecified adverse events.
With an armamentarium of mechanistically distinct vasopressor agents now available, sub-phenotyping patients using biomarkers has the potential to improve septic shock outcomes by enabling treatment of the correct patient with the correct vasopressor at the correct time. However, this approach requires validation in a large definitive multicenter trial. The data generated through the DARK-Sepsis study will prove crucial to the optimal design and patient enrichment of such a pivotal trial.
ClinicalTrials.gov NCT05824767. Registered on April 24, 2023.
目前用于脓毒性休克的特定血管加压药的数据有限。自 2017 年血管紧张素 II（AT2）被食品和药物管理局批准以来，有多种机制不同的血管加压药可用于治疗脓毒性休克，但关于哪种患者最有可能从每种药物中获益的数据很少。肾素和二肽基肽酶 3（DPP3）是肾素-血管紧张素-醛固酮系统的组成部分，已被证明在预测脓毒症预后方面优于乳酸盐，初步数据表明它们可能作为生物标志物有用，以指导 AT2 在脓毒性休克中的使用。
DARK-Sepsis 试验是一项由研究者发起、工业资助的、开放性、单中心随机对照试验，比较 AT2 与标准治疗（SOC）血管加压药治疗在因需要去甲肾上腺素≥0.1 mcg/kg/min 而接受血管扩张性休克且入住重症监护病房（ICU）的患者中的应用。在两组中，将在接受 AT2 或 SOC 治疗的前 24 小时内获得一系列肾素和 DPP3 水平。主要研究结局是这些生物标志物预测血管加压药治疗反应的能力，通过药物起始后 3 小时或 SOC 组等效时间点的总去甲肾上腺素等效剂量的变化来衡量。为了确定预测血管加压药反应的能力是否特定于 AT2 治疗，主要分析将是调整治疗臂（AT2 与对照）和序贯器官衰竭评估（SOFA）评分的基础肾素和 DPP3 水平预测血管加压药反应的能力。次要结局包括急性肾损伤、机械通气和肾脏替代治疗的需要、ICU 和医院的住院时间、ICU 和医院死亡率以及预定不良事件的发生率。
目前有多种机制不同的血管加压药，使用生物标志物对患者进行亚表型分型有可能通过在正确的时间为正确的患者提供正确的血管加压药来改善脓毒性休克结局。然而，这种方法需要在大型、明确的多中心试验中得到验证。通过 DARK-Sepsis 研究生成的数据对于此类关键试验的最佳设计和患者富集将至关重要。
ClinicalTrials.gov NCT05824767。注册于 2023 年 4 月 24 日。
