Dead Space and Inhaled Nitric Oxide in Pediatric Acute Respiratory Distress Syndrome

PROJECT SUMMARY Mortality remains high (20%) for the 8,000 US children each year that develop pediatric acute respiratory distress syndrome (ARDS). No pharmacologic therapies have been identified that decrease the mortality risk from ARDS. This is likely due to underlying biologic heterogeneity among patients with ARDS that may result in

some benefiting from a therapy whereas others are harmed, limiting the ability to find effective therapies in clinical trials of general cohorts. Inflammatory phenotypes have been described in ARDS that may help identify underlying biologic differences contributing to heterogeneity in treatment effect. However, these phenotypes

cannot currently be identified in real-time. There is an urgent need for easily available markers to identify clinically relevant heterogeneity in patients with ARDS. Markers of dead space may be promising for this purpose. Dead space is area of the lung that receive ventilation without perfusion and reflects abnormal

pulmonary perfusion (microvascular dysfunction, low cardiac output) and alveolar overdistension. With routine patient monitoring data (time-based capnography, blood gases), dead space can be estimated with the end tidal alveolar dead space fraction (AVDSf). We have found in single-center studies that AVDSf is more strongly

associated with mortality risk than are markers of the severity of hypoxemia (oxygenation index [OI]) in early pediatric ARDS. Dead space may also be an attractive marker for identifying heterogeneity of treatment effect for therapies such as inhaled Nitric Oxide (iNO) that target pulmonary perfusion. iNO is a selective pulmonary

vasodilator, with additional anti-inflammatory and anticoagulation effects, that is commonly used off-label for refractory hypoxemia in ARDS. But almost all clinical trials of iNO therapy have failed to demonstrate a benefit when enrolling general cohorts of patients or selecting patients based on severity of hypoxemia. One small

pediatric trial found higher extracorporeal membrane oxygenation free survival suggesting the potential for some subgroups to benefit from iNO therapy. Our preliminary data suggest that iNO therapy decreases the AVDSf associated mortality risk and that a decline in AVDSf with iNO therapy is associated with improving

plasma markers of microvascular dysfunction. Our central hypotheses are that the routinely available AVDSf is more strongly tied to mortality risk than OI and that AVDSf is an important marker of heterogeneity in the iNO treatment effect in patients with ARDS. These hypotheses will be tested through the following Specific Aims:

1) validate AVDSf for risk stratification of mortality in pediatric ARDS 2) determine if there is heterogeneity in treatment effect for iNO defined by AVDSf, and 3) detect the association between AVDSf and microvascular dysfunction trajectory and whether iNO therapy modifies the association. Demonstrating that AVDSf

outperforms OI for mortality risk stratification in patients with ARDS and that AVDSf may identify the patients most likely to benefit from iNO therapy, has the potential to be frameshifting for future clinical trials of ARDS interventions, including those of iNO therapy.