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

项目摘要 每年有超过170亿美元用于神经损伤儿童的医疗保健 （NI）。这些高成本的主要驱动因素是吸入性肺炎， 住院、更高的紧急住院和显著的死亡率。长期以来，人们一直认为， 肺炎是由反流的酸性胃内容物吸入引起的，因此应该用酸治疗。 抑制和抗反流手术然而，这些疗法不仅未能减少 吸入性肺炎的发展，但也可能加速肺部疾病的发展， 通过改变呼吸消化微生物组，在酸抑制的情况下，或通过阻碍 食管流出或延迟胃动力，在抗反流手术的情况下。食管胃底 运动障碍是特别令人关注的，因为它们引起流体停滞， 化学和微生物组成。如果这些改变的食管和胃内容物被吸出， 疾病可能会恶化。但问题仍然存在：哪些特定的运动异常导致液体淤滞， 这些异常使NI儿童更容易发生吸入性肺炎？哪些组件 是否预示着更糟糕的临床结果纠正运动障碍是否会改善临床结局？ 本研究将在现有文献的基础上，提出以下假设：（1） 不同的食管和胃动力模式导致食管和胃内容物的停滞;（2）这 停滞改变了食管和胃液的微生物和化学环境;（3）停滞的胃和 食管内容物在抽吸时会引起可测量的微生物组和炎症变化， 易患吸入性肺炎;（4）食管和胃的治疗 运动障碍改善了与吸气相关的症状，并导致食管和胃肠道的可测量变化。 胃动力障碍首先，使用纵向队列研究设计，研究人员将确定哪些独特的 食管和胃动力模式引起淤滞，并预测吸入性肺炎的发展， 孩子们与你其次，使用随机、盲法交叉设计，研究者将测试是否 普卢卡必利是一种5 HT 4激动剂，可改善与吸气相关的症状以及食管和胃的运动。 这项研究将：1）在医学上解决一个常见的和昂贵的问题，吸入性肺炎， 弱势人群;（2）超越GERD，寻求一种新的、范式转变的病理生理学 机制、动力障碍、吸入性肺炎的潜在发展;（3）进展超过标准 测试不仅包括运动参数，还包括微生物组和化学后果， 动力障碍;和（4）为吸入症状提供创新的治疗干预， 健康成果和降低弱势群体的医疗保健费用。最终，这项研究可以 用于设计额外的新型治疗动力干预措施来治疗食管外症状。

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.