A Randomized Trial of GM-CSF in Patients with ALI

尽管在重症监护病房护理和呼吸机管理方面取得了重大进展，但由急性肺损伤(ALL)和急性呼吸窘迫综合征(ARDS)引起的呼吸衰竭仍然是一个主要的健康问题，尽管医疗保健资源投入巨大，但死亡率约为30%。幸存者面临着生活质量的长期后果。需要新的治疗方法来提高早期存活率和减少这种综合征的长期后遗症。粒细胞巨噬细胞集落刺激因子(GMCSF)是一种存在于正常肺组织中的多功能细胞因子，在肺内稳态中起重要作用。GM-CSF具有独特的活动组合，使其成为理想的 ALI/ARDS的治疗干预。它是肺泡巨噬细胞正常成熟所必需的，对肺泡上皮细胞有很强的促进增殖和限制上皮细胞死亡的作用。这一应用的初步研究表明，GM-CSF可以保护小鼠免受急性肺损伤，降低对肺炎的易感性，并对急性肺损伤后的肺纤维化具有保护作用。在给人类患者注射重组人GM-CSF方面有丰富的经验；这种生物被FDA批准，在涉及危重患者的试验中获得了良好的耐受性。这一建议是基于这样一个假设，即应用GM-CSF将改善 ALI/ARDS患者。GM-CSF的随机、安慰剂对照试验(250微克/平方米/天×14天)将有5个特定目标。这些目标将决定GM-CSF治疗的效果：1)非机械通气天数(第1-28天)(本研究的主要终点)、死亡率、ICU住院率和呼吸机相关性肺炎的发生率；2)与呼吸衰竭相关的生理变量；3)肺泡上皮功能障碍的参数；4)ARDS患者肺泡巨噬细胞对宿主防御的功能；5)ARDS幸存者的生活质量和进展为纤维化。对于每个入选的患者，将收集临床参数(急性和晚期)和连续的支气管肺泡灌洗标本。 完成后，这些特定的目标将决定使用重组GM-CSF治疗是否会改善这些危重患者的预后，并将确定GM-CSF通过四种潜在机制中的哪一种发挥作用。

Despite significant progress in intensive care unit care and ventilator management, respiratory failure due to acute lung injury (ALl) and the acute respiratory distress syndrome (ARDS) remains a major health problem, with approximately >30% mortality despite enormous expenditure of health care resources. Survivors face long term consequences for quality of life. New therapies are needed both to improve early survival and to decrease long term sequelae of this syndrome. Granulocyte-macrophage colony stimulating factor (GMCSF) is a rnultifunctional cytokine that is present in the normal lung, with important roles in pulmonary homeostasis. GM-CSF has a distinctive combination of activities making it an ideal candidate for a therapeutic intervention in ALI/ARDS. It is essential for normal maturation of alveolar macrophages and has potent effects on alveolar epithelial cells, promoting proliferation and limiting epithelial cell death. Preliminary studies for this application demonstrate that GM-CSF can protect mice against acute lung injury, can decrease susceptibility to pneumonia, and is protective against pulmonary fibrosis following acute lung injury. There is extensive experience with the administration of recombinant human GM-CSF to human patients; this biological is approved by the FDA has been well-tolerated in trials involving critically ill patients. This proposal is based on the hypothesis that administration of GM-CSF will improve clinical outcomes for patients with ALI/ARDS. A randomized, placebo-controlled trial of GM-CSF (250 mcg/M2/day x 14 days) will be performed with 5 Specific Aims. These Aims will determine the effect of treatment with GM-CSF on: 1) days free of mechanical ventilation (days 1-28) (the primary endpoint of this study), mortality, ICU stay, and incidence of ventilator-associated pneumonia; 2) physiologic variables associated with respiratory failure; 3) parameters of alveolar epithelial dysfunction; 4) alveolar rnacrophage function for host defense in the context of ARDS; 5) quality of life and progression to fibrosis in survivors of ARDS. For each patient enrolled, clinical parameters (both acute and late) and serial bronchoalveolar lavage specimens will be collected. When completed, these Specific Aims will determine whether treatment with recombinant GM-CSF will improve outcome in these critically ill patients, and will determine through which of four potential mechanisms GM-CSF is acting.