Acute Respiratory Distress Network (ARDSNet) Studies 01 and 03 Lower Versus Higher Tidal Volume, Ketoconazole Treatment and Lisofylline Treatment (ARMA/KARMA/LARMA) (ARDSNet-ARMA/KARMA/LARMA-BioLINCC)

Data Access NOTE: Please refer to the “Authorized Access” section below for information about how access to the data from this accession differs from many other dbGaP accessions. Biospecimens Access to Biospecimens is through the NHLBI Biologic Specimen and Data Repository Information Coordinating Center (BioLINCC). Biospecimens from ARDSNet-ARMA/KARMA/LARMA include plasma, serum and urine. Please note that use of biospecimens in genetic research is subject to a tiered consent. Objectives The ARDS Network is a consortium of clinical centers and a coordinating center to design and test novel therapies for the treatment of Acute Lung Injury (ALI) and Acute Respiratory Distress Syndrome (ARDS). The primary objective of the KARMA trial was to investigate the efficacy and safety of Ketoconazole and Respiratory Management in the treatment of ALI and ARDS. The Ketoconazole arm of the study was later stopped due to an inability to show efficacy. Participants continued to be randomized to the respiratory management arms of the study (ARMA), which compared two ventilator strategies: a tidal volume of 6 mL/kg versus 12 mL/kg. The LARMA phase of the study investigated the efficacy of Lisofylline and Respiratory Management. Background Participants suffering from ARDS are extremely ill, require mechanical ventilation and, despite improvements in medical care and technology, had a mortality rate as high as 50 percent. An excessive inflammatory response is characteristic of ALI of which ARDS represents the most severe end of the pathophysiologic spectrum. The inflammatory response includes increased numbers of neutrophils activated to produce cytokines, proteases, and reactive oxygen intermediates. Pulmonary injury may also be enhanced by alveolar and tissue macrophages as a producer of vasoactive substances, neutrophil chemoattractants, and procoagulant substances. Ketoconazole, a synthetic antifungal imidazole, also has anti-inflammatory activities and may inhibit neutrophil recruitment via several different pathways known to be involved in the development of ALI and ARDS. Lisofylline causes a marked decrease in the circulating levels of the major oxidizable species of free fatty acids and also inhibits proinflammatory intracellular signaling. Mechanical ventilation in participants with ALI and ARDS have traditionally used tidal volumes of 10 to 15 ml per kilogram of body weight. These large tidal volumes are often necessary to achieve normal partial pressure of arterial carbon dioxide and pH, but may induce inflammatory responses through disruption of pulmonary epithelium and endothelium. Mechanical ventilation at lower tidal volumes may reduce injurious lung stretch and decrease the inflammatory response. Participants The Ketoconazole and Lisofylline trials were designed as 2 x 2 factorials and included 220 participants in each trial. A total of 860 participants were randomized into the ventilator management trial. Participants enrolled in the Lisofylline or Ketoconozole studies had to be concurrently enrolled in the ventilator management study and were first randomized into a ventilator strategy and then to drug or placebo. Conclusions Ketoconazole was found to be safe but did not reduce mortality, duration of mechanical ventilation, or improve lung function. Lisofylline was also found to be safe and to have no beneficial effect for participants with ALI or ARDS. Ventilation at lower tidal volumes resulted in reduced mortality and an increase in the number of days without ventilator support. (PMIDs: 10789668, 11902249, 10793162). ]]>
Inclusion Criteria:Participants were recruited from hospitals at the 10 University centers of the ARDS Network and were eligible if: they were in an ICU and required positive pressure ventilation, had acute onset of significantly impaired oxygenation (PaO2 to FIO2 300), bilateral infiltrates consistent with pulmonary edema, no clinical evidence of left atrial hypertension, were enrolled within 36 hours of developing these criteria. Exclusion Criteria:age less than 18, participation in other clinical trials within the previous 30 days, pregnancy, increased intracranial pressure, neurologic conditions that could impair weaning from ventilator support, chronic respiratory disease, sickle cell disease, burns covering more than 30% of body surface area, bone or marrow transplant history, comorbid irreversible conditions with a six month mortality rate of at least 50 percent.]]>

数据访问说明：请参阅下文“授权访问”章节，了解本收录数据集与多数其他基因型和表型数据库（Database of Genotypes and Phenotypes, dbGaP）收录数据集的访问方式差异。
生物样本访问：需通过美国国立心肺血液研究所（National Heart, Lung, and Blood Institute, NHLBI）生物样本与数据资源库信息协调中心（BioLINCC）进行。ARDSNet-ARMA/KARMA/LARMA研究的生物样本涵盖血浆、血清与尿液。请注意，将生物样本用于基因研究需遵守分层知情同意要求。

试验目标
急性呼吸窘迫综合征临床研究网络（ARDS Network）是由多家临床中心与协调中心组成的联盟，旨在设计并测试用于治疗急性肺损伤（ALI）与急性呼吸窘迫综合征（ARDS）的新型疗法。KARMA试验的核心目标为评估酮康唑（Ketoconazole）联合呼吸管理方案治疗ALI与ARDS的疗效与安全性。本研究的酮康唑组后续因未观察到明确疗效而提前终止。后续受试者仍被随机分配至本研究的呼吸管理组（ARMA），该组对比了两种机械通气策略：潮气量6mL/kg与12mL/kg。本研究的LARMA阶段则评估了利司呋喃（Lisofylline）联合呼吸管理的疗效。

试验背景
罹患ARDS的受试者病情危重，需接受机械通气治疗；尽管当前医疗护理与技术水平已有提升，其病死率仍高达50%。过度炎症反应是ALI的典型病理特征，而ARDS正是ALI病理生理谱中最为严重的阶段。此类炎症反应表现为活化中性粒细胞数量增加，进而分泌细胞因子、蛋白酶与活性氧中间产物。肺泡巨噬细胞与组织巨噬细胞可产生血管活性物质、中性粒细胞趋化因子与促凝物质，进一步加重肺损伤。酮康唑作为合成咪唑类抗真菌药物，同时具备抗炎活性，可通过多种已知参与ALI与ARDS发病的通路抑制中性粒细胞募集。利司呋喃可显著降低循环中主要可氧化游离脂肪酸的水平，同时抑制促炎细胞内信号通路。传统机械通气方案对ALI与ARDS患者多采用10~15mL/kg体重的潮气量，此类大潮气量虽常可实现动脉二氧化碳分压与pH的正常化，但可通过破坏肺上皮与内皮细胞诱发炎症反应。采用低潮气量的机械通气策略可减少肺组织损伤性牵拉，降低炎症反应程度。

临床试验受试者
酮康唑与利司呋喃试验均采用2×2析因设计，每项试验纳入220名受试者。另有共计860名受试者被随机分配至通气管理试验。参与利司呋喃或酮康唑临床试验的受试者需同时纳入通气管理研究，即首先被随机分配至通气策略组，随后再被分配至药物组或安慰剂组。

试验结论
研究结果显示，酮康唑安全性良好，但未能降低病死率、缩短机械通气时长或改善肺功能。利司呋喃同样安全性良好，但对ALI或ARDS患者无明确获益。采用低潮气量通气可降低患者病死率，并延长无需机械通气支持的天数。（PMIDs：10789668、11902249、10793162）

纳入标准
受试者从ARDS Network旗下10所大学附属医院的重症监护室（ICU）招募，符合以下全部条件者可入组：处于ICU并需接受正压通气；急性起病，氧合功能显著受损（动脉血氧分压与吸入氧浓度比值PaO₂/FiO₂ ≤ 300）；双侧肺部浸润影符合肺水肿表现；无左心房高压的临床证据；符合上述入组标准后36小时内完成入组。

排除标准
年龄小于18岁；入组前30天内参与过其他临床试验；妊娠；颅内压升高；存在可能影响呼吸机脱机的神经系统疾病；慢性呼吸系统疾病；镰状细胞病；体表烧伤面积超过30%；有骨髓或实体器官移植史；合并存在6个月内病死率≥50%的不可逆并发症。