Alveolar Dead Space and New or Progressive MODS

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.

Grant Number: 1R03HD110889-01A1
NIH Institute/Center: NIH
Principal Investigator: Anoopindar Bhalla