Abraham E, Park Y C, Covington P, Conrad S A, Schwartz M
University of Colorado, Department of Medicine, Denver, USA.
Crit Care Med. 1996 Jan;24(1):10-5. doi: 10.1097/00003246-199601000-00005.
To evaluate the safety and efficacy of liposomal prostaglandin E1 (TLC C-53) in the treatment of patients with the acute respiratory distress syndrome (ARDS).
Randomized, prospective, multicenter, double-blind, placebo-controlled, phase II clinical trial.
Eight community and university-affiliated hospitals in the United States.
Twenty-five patients with ARDS.
Patients were prospectively randomized in an unbalanced ratio within each site to receive either TLC C-53 (n = 17) or placebo (n = 8). Study drug was infused intravenously over 60 mins every 6 hrs for a 7-day period, starting at a dose of 0.15 micrograms/kg/hr. The dose was increased every 12 hrs until the maximal dose (3.6 micrograms/kg/hr) was attained, intolerance to further increases developed, or invasive monitoring was discontinued. Patients received standard, aggressive, medical/surgical care throughout the trial.
Outcome measurements were Pao2/FI0(2), dynamic pulmonary compliance, ventilator dependence on day 8, and 28-day all-cause mortality rate. At baseline, the distribution of variables describing Lung Injury Scores, Acute Physiology and Chronic Health Evaluation II scores, Pao2/FI0(2), pulmonary compliance, and time from onset of ARDS to first dose of study drug was similar between patients in the TLC C-53 and placebo treatment groups. On day 8, all eight patients given placebo required mechanical ventilation, while eight of 17 patients given TLC C-53 were healthy enough to be removed from the ventilator (p = .03). Improvement in PaO2/FIO2 during the initial 8-day study period was greater in patients receiving TLC C-53. This trend achieved statistical significance on day 3, when the increase in PaO2/FIO2 from baseline was 82.5 +/- 14.6 in the TLC C-53 group compared with 28.3 +/- 22.1 in the placebo group (p = .05). By day 8, lung compliance also increased from baseline significantly more in TLC C-53 patients than in placebo patients (5.7 +/- 1.7 vs -1.5 +/- 1.8 mL/cm H2O; p = .01). The 28-day mortality rate was 6% (1/17 patients) in the TLC C-53 group and 25% (2/8 patients) in the placebo group (p = .23). Drug-related adverse events were reported in 82% of the patients receiving TLC C-53 compared with 38% of the placebo group, with half of the adverse events in the TLC C-53 group being localized infusion site irritation. TLC C-53 was hemodynamically well tolerated, with transient hypotension occurring in three patients.
In patients with ARDS, TLC C-53 was associated with improved oxygenation, increased lung compliance, and decreased ventilator dependency.
评估脂质体前列腺素E1（TLC C - 53）治疗急性呼吸窘迫综合征（ARDS）患者的安全性和有效性。
随机、前瞻性、多中心、双盲、安慰剂对照的II期临床试验。
美国八家社区及大学附属医院。
25例ARDS患者。
患者在各研究地点按不均衡比例进行前瞻性随机分组，分别接受TLC C - 53（n = 17）或安慰剂（n = 8）治疗。研究药物每6小时静脉输注60分钟，共7天，起始剂量为0.15微克/千克/小时。每12小时增加一次剂量，直至达到最大剂量（3.6微克/千克/小时）、出现进一步增加剂量不耐受情况或停止有创监测。在整个试验过程中，患者接受标准、积极的内科/外科治疗。
观察指标包括动脉血氧分压/吸入氧分数值（Pao2/FI0(2)）、动态肺顺应性、第8天的呼吸机依赖情况以及28天全因死亡率。基线时，TLC C - 53治疗组和安慰剂治疗组患者在描述肺损伤评分、急性生理与慢性健康状况评分II、Pao2/FI0(2)、肺顺应性以及从ARDS发病到首次给予研究药物的时间等变量分布相似。第8天，所有8例接受安慰剂治疗的患者均需机械通气，而17例接受TLC C - 53治疗的患者中有8例身体状况良好可撤机（p = 0.03）。在最初8天的研究期间，接受TLC C - 53治疗的患者PaO2/FIO2改善更明显。这一趋势在第3天达到统计学意义，此时TLC C - 53组PaO2/FIO2较基线增加82.5±14.6，而安慰剂组为28.3±22.1（p = 0.05）。到第8天，TLC C - 53组患者肺顺应性较基线的增加也显著高于安慰剂组患者（5.7±1.7 vs -1.5±1.8 mL/cm H2O；p = 0.01）。TLC C - 53组28天死亡率为6%（1/17例患者），安慰剂组为25%（2/8例患者）（p = 0.23）。接受TLC C - 53治疗的患者中82%报告有药物相关不良事件，而安慰剂组为38%，TLC C - 53组不良事件半数为局部输注部位刺激。TLC C - 53在血流动力学方面耐受性良好，3例患者出现短暂性低血压。
在ARDS患者中，TLC C - 53与氧合改善、肺顺应性增加及呼吸机依赖减少相关。
