lancet RM ARDS治疗进展

lancet Respiratory Medicine 六月号刊登了数篇与ARDS治疗有关的文献，兹介绍如下：

1. 角化细胞生长因子治疗ARDS的二期临床 Keratinocyte growth factor for the treatment of the acute respiratory distress syndrome (KARE): a randomised, double-blind, placebo-controlled phase 2 trial

http://www.thelancet.com/journals/lanres/article/PIIS2213-2600(17)30171-6/fulltext?rss=yes

背景：来自体外，动物和人体的肺损伤模型数据表明，角化细胞生长因子（KGF）可能对急性呼吸窘迫综合征（ARDS）有益。该试验的目的是调查KGF对ARDS患者的效果。

方法：我们在英国的两个重症监护病房中进行了双盲，分配隐蔽，随机，安慰剂对照的2期临床试验，纳入的患者符合美 - 欧联席会议的ARDS定义标准。患者通过计算机生成的随机化方案随机分配（1：1），根据部位以及因严重脓毒症需要血管加压药物的情况分入接受重组人类KGF（palifermin 60μg/ kg）或安慰剂（0.9％钠氯化物溶液）组，每日给药，最多6天。药物均对病人和研究人员遮盖。主要终点是第7天的氧合指数（OI）。分析是意向治疗。试验的国际标准随机对照试验注册号为ISRCTN95690673。

发现：2011年2月23日至2014年2月26日，368名患者符合入选标准。在招募的60例患者经随机化后29例患者接受KGF，31例接受安慰剂治疗。全部患者都被包括在主要结果的分析中。两组患者第7天OI均无显着性差异（KGF组平均62.3，SD 57.8），安慰剂组43±1 [33.5]，平均差异19·2,95 ％CI -5·6〜44·0，p = 0·13）。有趣的是，虽然并没有作为结局在先期定义，KGF组与安慰剂相比：中位非通气天数更少（KGF组1天[IQR 0至17]]与20天[13-22]安慰剂组;差异-8天，95％CI-17至-2; p = 0·0002），幸存者在第90天的平均通气时间较长（KGF组为16天[IQR 13-30] vs 11安慰剂组[8-16]日，差异6天，95％CI 2〜14; p = 0·002），28日死亡率高（9 [31％] vs 3 [10％]）风险比3·2，95％CI 1·0〜10·7，p = 0·054）。不良事件在KGF组比安慰剂组更为频繁（14对5事件;优势比4·9,95％CI 1·3〜20·3，p = 0·008）。经评估与KGF有关的两个不良事件是由于发热。

解释：KGF没有改善ARDS的生理或临床结局，可能对患者的健康有害。

Background Data from in-vitro, animal, and human lung injury models suggest that keratinocyte growth factor (KGF) might be beneficial in acute respiratory distress syndrome (ARDS). The objective of this trial was to investigate the effect of KGF in patients with ARDS.

Methods We did a double-blind, allocation concealed, randomised, placebo-controlled phase 2 trial in two intensive care units in the UK, involving patients fulfilling the American-European Consensus Conference Definition of ARDS. Patients were randomly assigned (1:1) by computer-generated randomisation schedule with variable block size stratified by site and presence of severe sepsis requiring vasopressors to receive either recombinant human KGF (palifermin 60 μg/kg) or placebo (0·9% sodium chloride solution) daily for a maximum of 6 days. Both patients and investigators were masked to treatment. The primary endpoint was oxygenation index (OI) at day 7. Analyses were by intention to treat. The trial is registered with International Standard Randomised Controlled Trial Registry, number ISRCTN95690673.

Findings Between Feb 23, 2011, and Feb 26, 2014, 368 patients were assessed for eligibility for inclusion in the trial. Of the 60 patients recruited, 29 patients were randomly assigned to receive KGF and 31 to placebo; all were included in the analysis of the primary outcome. There was no significant difference between the two groups in OI at day 7 (mean 62·3 [SD 57·8] in the KGF group, 43·1 [33·5] in the placebo group; mean difference 19·2, 95% CI −5·6 to 44·0, p=0·13). Of interest, although not defined as outcome measures a priori, the KGF group, compared with placebo, had fewer median ventilator-free days (1 day [IQR 0 to 17] in the KGF group vs 20 days [13–22] in the placebo group; difference −8 days, 95% CI −17 to −2; p=0·0002), a longer median duration of ventilation in survivors to day 90 (16 days [IQR 13–30] in the KGF group vs 11 days [8–16] in the placebo group; difference 6 days, 95% CI 2 to 14; p=0·002), and a higher mortality at 28 days (nine [31%] vs three [10%] deaths; risk ratio 3·2, 95% CI 1·0 to 10·7, p=0·054). Adverse events were more frequent in the KGF group than the placebo group (14 vs 5 events; odds ratio 4·9, 95% CI 1·3 to 20·3, p=0·008). The two adverse events assessed as related to KGF were due to pyrexia.

Interpretation KGF did not improve physiological or clinical outcomes in ARDS and might be harmful to patient health.

2. 综述：ARDS的临床试验 ：机遇与挑战 Clinical trials in acute respiratory distress syndrome: challenges and opportunities

http://www.thelancet.com/journals/lanres/article/PIIS2213-2600(17)30188-1/fulltext?rss=yes

今年是急性呼吸窘迫综合征（ARDS）被首次描述的50周年。从那时起，ARDS肺损伤的发病机理已经很多，重点是肺内皮和肺泡上皮的损伤机制。在治疗方面，主要的进展是通过6 mL/Kg理想体重的潮气量和平均气道压小于30 cm H2O的肺保护通气对ARDS死亡率的降低。在更严重的低氧血症ARDS患者中，神经肌肉阻滞和俯卧位定位进一步降低了死亡率，其机理可能是延长了肺保护通气的治疗效果。 ARDS患者的保守输液治疗增加了非通气天数。然而，缺乏成功的ARDS药物治疗成为当下的持续挑战。本文除了简要介绍以往在ARDS临床试验方面的经验，我们重点关注未来在改进临床试验设计以最大限度地发现有益的药物治疗的机遇。鉴于ARDS的异质性，以严重度和生物学为基础，针对ARDS患者的特定亚组要进行针对性治疗则需要富于预测性和并具有预后价值的策略。降低ARDS临床试验异质性的方法包括在进行2期和3期试验时应用生理学，放射学和生物学标准选择患者。另外，针对ARDS预防性的临床试验设计兴趣也在增多以在气管内插管之前开始对急性肺损伤患者进行早期治疗。我们还介绍了治疗ARDS的有前途的新方法，包括联合疗法，基于细胞的疗法和低风险的通用药物化合物，其已在其他临床疾病中获得常规临床使用。

Summary

This year is the 50th anniversary of the first description of acute respiratory distress syndrome (ARDS). Since then, much has been learned about the pathogenesis of lung injury in ARDS, with an emphasis on the mechanisms of injury to the lung endothelium and the alveolar epithelium. In terms of treatment, major progress has been made in reducing mortality from ARDS with lung-protective ventilation, using a tidal volume of 6 mL per kg of predicted bodyweight and a plateau airway pressure of less than 30 cm H2O. In more severely hypoxaemic patients with ARDS, neuromuscular blockade and prone positioning have further reduced mortality, probably by extending the therapeutic effects of lung protective ventilation. Fluid-conservative therapy has also increased ventilator-free days in patients with ARDS. The lack of success of pharmacological therapies for ARDS, however, presents a continued challenge in the field. In addition to presenting a brief summary of previous experience with clinical trials in ARDS, we focus in this Review on future opportunities to improve clinical trial design to maximise the likelihood of identifying beneficial pharmacological therapies. In view of the heterogeneity in ARDS, both prognostic and predictive enrichment strategies are needed that target therapies toward specific subgroups of patients with ARDS on the basis of both severity and biology. Approaches to reducing heterogeneity in ARDS clinical trials include using physiological, radiographic, and biological criteria to select patients for both phase 2 and 3 trials. Additionally, interest is growing in the design of preventive clinical trials in ARDS and to initiate early treatment of patients with acute lung injury before the need for endotracheal intubation. We also present promising new approaches to treating ARDS, including combination therapies, cell-based therapies, and generic pharmacological compounds with low-risk profiles that are already in routine clinical use for other clinical indications.

3. 综述：新的转化研究用于ARDS精准治疗 Novel translational approaches to the search for precision therapies for acute respiratory distress syndrome

http://www.thelancet.com/journals/lanres/article/PIIS2213-2600(17)30187-X/fulltext?rss=yes

在首次描述急性呼吸窘迫综合征（ARDS）的50年间，在确定综合征的危险因素和致病因子作用方面取得了实质性进展，并对ARDS患者血浆与支气管肺泡灌洗液中蛋白表达模式进行了划分。然而，尽管努力不少，ARDS的药物学选择仍然很少。常被提及的缺乏特定药物治疗的原因包括ARDS患者的异质性，药物差异反应的可能性以及错误靶点的可能性都被探讨过。应用分子生物学技术和生物信息学的进步已经为其他复杂的疾病（如心血管疾病或哮喘）带来了重大突破，特别是精准医学成为追求的典范——在其中生物标志物或基因表达模式能够提示患者对治疗反应。在本综述中，我们讨论了可以成为ARDS精准医学研究方法的生物和分析技术。

Summary

In the 50 years since acute respiratory distress syndrome (ARDS) was first described, substantial progress has been made in identifying the risk factors for and the pathogenic contributors to the syndrome and in characterising the protein expression patterns in plasma and bronchoalveolar lavage fluid from patients with ARDS. Despite this effort, however, pharmacological options for ARDS remain scarce. Frequently cited reasons for this absence of specific drug therapies include the heterogeneity of patients with ARDS, the potential for a differential response to drugs, and the possibility that the wrong targets have been studied. Advances in applied biomolecular technology and bioinformatics have enabled breakthroughs for other complex traits, such as cardiovascular disease or asthma, particularly when a precision medicine paradigm, wherein a biomarker or gene expression pattern indicates a patient's likelihood of responding to a treatment, has been pursued. In this Review, we consider the biological and analytical techniques that could facilitate a precision medicine approach for ARDS.

有趣的是以上三篇文章中，后两篇尚不能在Pubmed检索到。因此全文欠奉！

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