Alveolar Dead Space and New or Progressive MODS

肺泡死腔和新的或进展性 MODS

基本信息

批准号：
10740810
负责人：
Anoopindar Bhalla
金额：
$ 17.65万
依托单位：
CHILDREN'S HOSPITAL OF LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10740810
关键词：
Acute respiratory failure Address Admission activity Alveolar Alveolus Ancillary Study Angiopoietin-2 Biological Markers Blood Vessels Blood gas Blood specimen COVID-19 patient Capnography Cardiovascular system Child Child Mortality Clinical Clinical Data Clinical Markers Clinical Trials Coagulation Process Collection Complement Critical Care Critical Illness Critically ill children Data Data Collection Defect Development Early identification Endothelium Enrollment Functional disorder Funding Inflammation Intensive Care Units Intervention Lung Measurement Measures Mechanical ventilation Methods Microvascular Dysfunction Monitor Morbidity - disease rate Multiple Organ Failure National Institute of Child Health and Human Development Organ Outcome Pathway interactions Perfusion Phase Physiological Plasma Plasminogen Activator Inhibitor 1 Protein C Protocols documentation Randomized Recovery Research Resources Risk Sampling Sepsis Shunt Device Surrogate Markers Syndrome TFPI Testing Thrombomodulin Time United States National Institutes of Health Work acute hypoxemic respiratory failure cadherin 5 clinical translation cohort high risk improved indexing longitudinal analysis lung injury mortality mortality risk prevent prognostic receptor for advanced glycation endproducts repository secondary analysis standard care systemic inflammatory response translational study ventilation von Willebrand Factor

项目摘要

PROJECT SUMMARY Multiple organ dysfunction syndrome (MODS) is common at the time of intensive care unit (ICU) admission in children (25%). While MODS resolves or stabilizes in some, others develop either new or progressive multiple organ dysfunction (NPMODS) during ICU management. Those that develop NPMODS are at twice the risk of mortality than children with MODS alone. NPMODS is thought to develop in part due to on-going dysregulated systemic inflammation and microvascular (endothelial and coagulation) dysfunction. There are currently no bedside clinical methods to easily detect children with microvascular dysfunction or high NPMODS risk. Alveolar dead space (DS) is a physiologic marker of alveoli that receive ventilation without perfusion reflecting pulmonary microvascular dysfunction. It is easily measured using routinely available clinical data (blood gas, capnography) in any invasively mechanically ventilated child. Alveolar DS may be an early marker of systemic microvascular dysfunction. Elevated alveolar DS is associated with mortality independent of oxygenation defect or cardiovascular dysfunction in critically ill mechanically ventilated children. This suggests the relationship between alveolar DS and mortality is not explained by the degree of intrapulmonary shunt or cardiovascular dysfunction. Furthermore, in our preliminary data, elevated alveolar DS, microvascular dysfunction markers, and NPMODS are all associated. As >70% of critically ill children with NPMODS are invasively mechanically ventilated, alveolar DS has potential as an early clinical marker of systemic microvascular dysfunction and high NPMODS risk. Our central hypothesis to be tested in this proposal is that children with elevated alveolar DS will be at higher risk of developing NPMODS and that this relationship is related primarily to pathways of microvascular dysfunction. Our primary research aims are to 1) identify the relationship between alveolar DS and NPMODS after adjusting for oxygenation defect and cardiovascular dysfunction and 2) to identify the relationship between markers of microvascular dysfunction (receptor for advanced glycation end-products, von Willebrand factor, angiopoietin-2, claudin-5, vascular endothelial cadherin, thrombomodulin, plasminogen activator inhibitor-1, tissue factor pathway inhibitor, protein C) and NPMODS and alveolar DS. If alveolar DS is associated with NPMODS, we will then determine if alveolar DS is a surrogate marker of the systemic microvascular dysfunction associated with NPMODS risk. To address the research aims, we will leverage a cohort of mechanically ventilated critically ill children at high risk for NPMODS (40% have developed NPMODS to-date) enrolled in an NIH-funded clinical trial. This cohort has routine longitudinal collection of plasma samples and alveolar DS measurements. The potential outcome of this line of research is to significantly improve prognostic and predictive enrichment of clinical trials in children targeting microvascular dysfunction and reduction of NPMODS.

项目概要多器官功能障碍综合征（MODS）在重症监护病房（ICU）入院时很常见儿童（25%）。虽然 MODS 在某些疾病中得到解决或稳定，但其他疾病则发展出新的或渐进的多重疾病 ICU 管理期间的器官功能障碍（NPMODS）。那些患有 NPMODS 的人面临两倍的风险死亡率高于仅患有 MODS 的儿童。 NPMODS 被认为部分是由于持续失调所致全身炎症和微血管（内皮和凝血）功能障碍。目前没有床边临床方法可轻松检测患有微血管功能障碍或高 NPMODS 风险的儿童。肺泡死腔（DS）是接受通气但无灌注的肺泡的生理标志肺微血管功能障碍。使用常规可用的临床数据（血气、二氧化碳图）适用于任何有创机械通气的儿童。肺泡 DS 可能是系统性病变的早期标志物微血管功能障碍。肺泡 DS 升高与死亡率相关，与氧合无关重症机械通气儿童的缺陷或心血管功能障碍。这表明肺泡 DS 与死亡率之间的关系不能用肺内分流或肺内分流的程度来解释心血管功能障碍。此外，在我们的初步数据中，肺泡 DS 升高、微血管功能障碍标志物和 NPMODS 均相关。由于 >70% 患有 NPMODS 的危重儿童有创机械通气时，肺泡 DS 有潜力作为全身性呼吸衰竭的早期临床标志物微血管功能障碍和高 NPMODS 风险。我们在本提案中要测试的中心假设是肺泡 DS 升高的儿童患 NPMODS 的风险较高，并且这种关系是主要与微血管功能障碍的途径有关。我们的主要研究目标是 1) 确定调整氧合缺陷和心血管后肺泡 DS 和 NPMODS 之间的关系功能障碍和2）确定微血管功能障碍标志物（受体）之间的关系晚期糖基化终末产物、血管性血友病因子、血管生成素-2、claudin-5、血管内皮细胞钙粘蛋白、血栓调节蛋白、纤溶酶原激活剂抑制剂-1、组织因子途径抑制剂、蛋白 C) 和 NPMODS 和肺泡 DS。如果肺泡 DS 与 NPMODS 相关，我们将确定肺泡 DS 是否为与 NPMODS 风险相关的全身微血管功能障碍的替代标志物。为了解决为了研究目标，我们将利用一组机械通气危重儿童的高风险 NPMODS（迄今为止 40% 已发展为 NPMODS）参加了 NIH 资助的临床试验。这个队列有血浆样本的常规纵向采集和肺泡 DS 测量。的潜在结果这一系列研究旨在显着改善儿童临床试验的预后和预测丰富性针对微血管功能障碍和减少 NPMODS。