Mechanical Ventilation Management, New or Progressive MODS, and Post-ICU Morbidity in Pediatric ARDS

项目总结 理论基础：大多数儿童患有儿童急性呼吸窘迫综合征(PARDS)，这是一种严重的肺部疾病 受伤，需要机械通风。在患有ARDS的成年人中，破坏性的机械通气做法增加 死亡率，主要归因于新的或进行性的多器官功能障碍综合征的发展 (NPMODS)。儿科研究没有发现类似的一致的机械通气关联 实践和死亡率。NPMODS是死亡率的一个可行的替代结果，在Pards中， 有很强的生物学可信度，与损伤性机械通风有关，并可能改善 儿童机械通风相关危害的识别。在采用中介之前 结果NPMODS，由于大多数儿童存活下来，确定两者之间的联系是至关重要的 NPMODS和ICU后发病率。研究：通过这个职业发展奖，Anoopindar Bhala博士， 作为一名儿科强化医生，他试图了解呼吸机管理、NPMODS和 患有PARDS的儿童的ICU后发病率。研究将利用基础设施和资源 肺保护性通气策略的II期随机对照试验，纳入276名患有PARDS的儿童 并由巴拉博士的共同导师领导(PI：Khemani，NHLBI R01 HL134666，REDvent.)。中心假设是 创伤性机械通气导致NPMODS，而NPMODS又与ICU后相关 患有PARDS儿童的发病率。这些假设将通过以下具体目标进行检验：1) 确定肺保护性通风策略是否可以预防帕德患者的NPMODS；2)确定生理学 PARDS中与NPMODS相关的损伤性通风机制(包括评估 经肺压力)；3)表征NPMODS与ICU后发病率之间的关系 (与健康相关的生活质量、功能状态和肺状态)。职业发展： 通过完成拟议的研究、更多的职业发展培训活动，以及 在多学科指导下，巴拉医生将在1)儿科临床试验原则方面学习关键技能；2) 先进的研究设计和生物统计学；3)儿童ICU后结局的评估。获取这些信息 对于巴拉博士领导精心设计的危重儿童临床试验的长期职业目标来说，技能至关重要。 与世界一流的呼吸生理学、生物统计学和长期护理专家组成的指导团队 结果以及临床试验将支持她的这些努力。影响：这项研究将提供 关于损伤性机械通气、NPMODS和ICU后相关性的关键信息 发病率以指导未来的PARDS临床试验。此外，通过职业发展培训和 生成的数据，巴拉博士将处于有利地位，成功竞争R01资金，并成为 领导儿科机械通气临床试验的独立研究员。

PROJECT SUMMARY Rationale: Most children with pediatric acute respiratory distress syndrome (PARDS), a severe form of lung injury, require mechanical ventilation. In adults with ARDS, injurious mechanical ventilation practices increase mortality, primarily attributed to the development of new or progressive multiple organ dysfunction syndrome (NPMODS). Pediatric studies have not found similar consistent associations between mechanical ventilation practices and mortality. NPMODS is a feasible alternative outcome to mortality, which is low in PARDS, that has strong biological plausibility for association with injurious mechanical ventilation and may improve identification of mechanical ventilation associated harm in children. Before adoption of the intermediary outcome NPMODS, as most children survive PARDS, it is crucial to characterize the association between NPMODS and post-ICU morbidity. Research: Through this career development award, Dr. Anoopindar Bhalla, a pediatric intensivist, seeks to understand the associations between ventilator management, NPMODS, and post-ICU morbidity in children with PARDS. The research will leverage the infrastructure and resources of a Phase II randomized controlled trial on a lung-protective ventilation strategy enrolling 276 children with PARDS and led by Dr. Bhalla’s co-mentor (PI: Khemani, NHLBI R01 HL134666, REDvent). The central hypothesis is that injurious mechanical ventilation leads to NPMODS and, in turn, NPMODS is associated with post-ICU morbidity in children with PARDS. These hypotheses will be tested through the following Specific Aims: 1) Determine whether a lung-protective ventilation strategy prevents NPMODS in PARDS; 2) Identify physiologic mechanisms of injurious ventilation which are associated with NPMODS in PARDS (including assessment of transpulmonary pressures); 3) Characterize the association between NPMODS and post-ICU morbidity (health-related quality of life, functional status, and pulmonary status) in PARDS. Career Development: Through completion of the proposed research, additional career development training activities, and multidisciplinary mentorship, Dr. Bhalla will learn key skills in 1) the principles of pediatric clinical trials; 2) advanced study design and biostatistics; 3) the assessment of post-ICU outcomes in children. Acquiring these skills is critical for Dr. Bhalla’s long-term career goal to lead well-designed clinical trials in critically ill children. The assembled mentorship team with world-class experts in respiratory physiology, biostatistics, and long-term outcomes as well as clinical trials, will support her in these endeavors. Impact: This research will provide crucial information on the associations between injurious mechanical ventilation, NPMODS, and post-ICU morbidity to guide future PARDS clinical trials. Furthermore, through the career development training and generated data, Dr. Bhalla will be well-positioned to successfully compete for R01 funding and become an independent investigator leading pediatric mechanical ventilation clinical trials.