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 ...