Recombinant platelet-activating factor acetylhydrolase to prevent acute respiratory distress syndrome and mortality in severe sepsis: Phase IIb, multicenter, randomized, placebo-controlled, clinical trial
Recombinant platelet-activating factor acetylhydrolase to prevent acute respiratory distress syndrome and mortality in severe sepsis: Phase IIb, multicenter, randomized, placebo-controlled, clinical trial
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DOI：
10.1097/01.ccm.0000063267.79824.db
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发表时间：
2003-06-01
影响因子：
8.8
通讯作者：
Pribble, J
中科院分区：
文献类型：
--
作者：
Schuster, DP;Metzler, M;Pribble, J
目的：血小板活化因子(PAF)在严重脓毒症和急性呼吸窘迫综合征的发病机制中起重要作用。PAF的调节途径之一是通过PAF乙酰水解酶(PAF-AH)降解为非活性代谢物lyso-PAF。由于脓毒症患者的天然PAF-AH浓度降低的报道，本研究旨在确定在严重脓毒症发作后使用重组人PAF-AH(rPAF-AH，Pafase)治疗是否安全，以及是否降低急性呼吸窘迫综合征的发生率和28天全因死亡率。设计：一项前瞻性、随机、双盲、安慰剂对照的多中心试验。背景：33个位于美国的内科和外科重症监护病房。患者：共127名严重脓毒症患者，但没有明确的急性呼吸窘迫综合征。随机分组发生在严重脓毒症发病后12小时内。然后，患者分别接受1.0 mg/kg rPAF-AH(n=45)、5.0 mg/kg rPAF-AH(n=39)或安慰剂(n=43)静脉注射，每日1次，连续5天。测量和主要结果，三组患者的人口学和基线临床特征相似，不同之处在于使用1.0 mg/kg rPAF-AH的患者严重脓毒症的呼吸道感染发生率显著升高。没有与治疗相关的死亡，接受rPAF-AH治疗的患者和接受安慰剂治疗的患者总体不良事件发生率相似。三组间急性呼吸窘迫综合征的发生率无显著差异。然而，28天的全因死亡率在1.0 mg/kg rPAF-AH组为21%，在5.0 mg/kg rPAF-AH组为28%，在安慰剂组为44%(总体卡方p=0.07；1.0 mg/kg rPAF-AH与安慰剂相比，p=0.03)。与安慰剂组相比，1.0 mg/kg rPAF-AH组的多器官功能障碍也有减轻的趋势(p=.11)。结论：本研究结果表明，rPAF-AH耐受性良好，应作为一种潜在的新疗法来降低严重脓毒症患者的死亡率。
Objective: Platelet-activating factor (PAF) is a potent proinflammatory mediator implicated in the pathogenesis of both severe sepsis and acute respiratory distress syndrome. One of the regulatory pathways for PAF involves degradation to the inactive metabolite lyso-PAF by the enzyme PAF acetylhydrolase (PAF-AH). Because reduced concentrations of the natural form of PAF-AH have been reported in septic patients, the present study was conducted to determine whether treatment with recombinant human PAF-AH (rPAF-AH, Pafase) was safe when administered after the onset of severe sepsis and whether it decreases the prevalence of acute respiratory distress syndrome and 28-day all-cause mortality.Design: A prospective, randomized, double-blind, placebo-controlled, multicenter trial.Setting: Thirty-three medical and surgical intensive care units located in the United States.Patients: A total of 127 patients with severe sepsis, but without established acute respiratory distress syndrome, were enrolled in the study. Randomization occurred within 12 hrs of the onset of severe sepsis. Patients then received 1.0 mg/kg rPAF-AH (n = 45), 5.0 mg/kg rPAF-AH (n = 39), or placebo (n = 43) administered intravenously, once daily, for five consecutive days.Measurements and Main Results., Demographic and baseline clinical characteristics of the three treatment groups were similar, except for a significantly higher prevalence of respiratory tract infections as the cause of severe sepsis in patients treated with 1.0 mg/kg rPAF-AH. There were no treatment-related deaths, and the overall prevalence of adverse events was similar among rPAF-AH-treated and placebo-treated patients. There were no significant differences in the prevalence of acute respiratory distress syndrome among the three treatment groups. However, 28-day all-cause mortality was 21% in the 1.0 mg/kg rPAF-AH group, 28% in the 5.0 mg/kg rPAF-AH group, and 44% in the placebo group (overall chi-square p = .07; 1.0 mg/kg rPAF-AH vs. placebo, p = .03). A trend toward reduced multiple organ dysfunction also was observed in the 1.0 mg/kg rPAF-AH group compared with the placebo group (p = .11).Conclusion: The results from this study indicate that rPAF-AH was well tolerated and should be pursued as a potential new treatment to decrease mortality in patients with severe sepsis.