The impact of upper gastrointestinal dysmotility on aspiration-associated aerodigestive disorders in children

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PROJECT SUMMARY More than $17 billion dollars are spent per year on health care for children with neurologic impairment (NI). The main driver of these high costs is aspiration pneumonias, which cause lengthy and repeated hospitalizations, higher acuity hospitalizations, and significant mortality. The dogma has long been that these pneumonias are caused by aspiration of refluxed acidic gastric contents and thus should be treated with acid suppression and anti-reflux surgeries. However, these therapies not only have failed to reduce the development of aspiration pneumonias, but also may hasten the development of lung disease by increasing pneumonia risk by altering the aerodigestive microbiome, in the case of acid suppression, or by obstructing esophageal outflow or delaying gastric motility, in the case of anti-reflux surgery. Esophageal and gastric dysmotility are particularly concerning because they cause fluid stagnation with secondary changes in chemical and microbial composition. If these altered esophageal and gastric contents are aspirated, lung disease likely ensues. But questions remain: Which specific motility abnormalities result in fluid stasis and do these abnormalities predispose children with NI to more frequent aspiration pneumonias? Which components of static fluid portend worse clinical outcomes? Will correcting the dysmotility improve clinical outcomes? The proposed research will build on the current literature by addressing the following hypotheses: (1) distinct esophageal and gastric motility patterns result in stasis of esophageal and gastric contents; (2) this stasis alters the microbial and chemical milieu of esophageal and gastric fluids; (3) the stagnant gastric and esophageal contents, when aspirated, cause measurable microbiome and inflammatory changes that predispose patients to developing aspiration pneumonias; and (4) treatment of esophageal and gastric dysmotility improves aspiration-related symptoms and results in measurable changes in esophageal and gastric dysmotility. First, using a longitudinal cohort study design, the investigators will determine which unique esophageal and gastric motility patterns cause stasis and predict the development of aspiration pneumonias in children with NI. Second, using a randomized, blinded crossover design, investigators will test whether prucalopride, a 5HT4 agonist, improves both aspiration-related symptoms and esophageal and gastric motility. This research will: 1) attack a common and costly problem, aspiration pneumonias, in a medically vulnerable population; (2) move beyond GERD to pursue a novel, paradigm-shifting pathophysiologic mechanism, dysmotility, underlying development of aspiration pneumonias; (3) progress beyond standard testing to include not only motility parameters, but also the microbiome and chemical consequences of dysmotility; and (4) offer an innovative therapeutic intervention for aspiration symptoms that may improve health outcomes and reduce health care costs in a vulnerable population. Ultimately, this research can be used to devise additional novel therapeutic motility interventions to treat extraesophageal symptoms.