Inhaled AP301 for treatment of pulmonary edema in mechanically ventilated patients with acute respiratory distress syndrome: a phase IIa randomized placebo-controlled trial
Inhaled AP301 for treatment of pulmonary edema in mechanically ventilated patients with acute respiratory distress syndrome: a phase IIa randomized placebo-controlled trial
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DOI：
10.1186/s13054-017-1795-x
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发表时间：
2017-07-27
期刊：
影响因子：
15.1
通讯作者：
Ullrich, Roman
中科院分区：
文献类型：
--
作者：
Krenn, Katharina;Lucas, Rudolf;Ullrich, Roman
背景资料：高渗透性肺水肿是急性呼吸窘迫综合征（ARDS）的标志，常伴有肺泡液体清除率（AFC）受损。AP 301通过激活肺泡上皮细胞上的上皮钠通道（ENaCs）增强AFC，我们研究了其对机械通气患者ARDS的血管外肺水指数（EVLWI）的影响。方法：40例成人ARDS机械通气患者被纳入一项随机、双盲、安慰剂对照试验，以验证概念。患者接受吸入性AP 301（n = 20）或安慰剂（0.9% NaCl; n = 20）治疗，每日两次，持续7天。通过热稀释法（PiCCO（R））测量EVLWI，并使用非参数Mann-Whitney U检验比较治疗组。在AP 301组和安慰剂组之间，从筛选至第7天EVLWI的平均基线校正变化无差异（p = 0.196）。治疗组之间的PaO 2/FiO 2比值、通气压力、Murray肺损伤评分或28天死亡率没有差异。根据疾病严重程度进行的探索性亚组分析显示，与安慰剂相比，吸入AP 301的初始序贯器官衰竭评估（SOFA）评分>= 11的患者7天内EVLWI（p = 0.04）和通气压（p < 0.05）降低，但接受AP 301的SOFA评分= 11的患者未降低。这些结果提示在未来的临床试验中进一步证实吸入AP 301治疗ARDS患者的肺水肿。
Background: High-permeability pulmonary edema is a hallmark of acute respiratory distress syndrome (ARDS) and is frequently accompanied by impaired alveolar fluid clearance (AFC). AP301 enhances AFC by activating epithelial sodium channels (ENaCs) on alveolar epithelial cells, and we investigated its effect on extravascular lung water index (EVLWI) in mechanically ventilated patients with ARDS.Methods: Forty adult mechanically ventilated patients with ARDS were included in a randomized, double-blind, placebo-controlled trial for proof of concept. Patients were treated with inhaled AP301 (n = 20) or placebo (0.9% NaCl; n = 20) twice daily for 7 days. EVLWI was measured by thermodilution (PiCCO (R)), and treatment groups were compared using the nonparametric Mann-Whitney U test.Results: AP301 inhalation was well tolerated. No differences in mean baseline-adjusted change in EVLWI from screening to day 7 were found between the AP301 and placebo group (p = 0.196). There was no difference in the PaO2/FiO(2) ratio, ventilation pressures, Murray lung injury score, or 28-day mortality between the treatment groups. An exploratory subgroup analysis according to severity of illness showed reductions in EVLWI (p = 0.04) and ventilation pressures (p < 0.05) over 7 days in patients with initial sequential organ failure assessment (SOFA) scores >= 11 inhaling AP301 versus placebo, but not in patients with SOFA scores = 11 receiving AP301. These results suggest further confirmation in future clinical trials of inhaled AP301 for treatment of pulmonary edema in patients with ARDS.