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

项目总结 每年有超过170亿美元用于神经功能障碍儿童的医疗保健 (NI)。这些高成本的主要驱动因素是吸入性肺炎，它会导致漫长和反复的 住院，更高的敏感度住院，和显著的死亡率。长期以来，人们一直认为这些 肺炎是由吸入反流的酸性胃内容物引起的，因此应该用酸治疗。 抑制和抗反流手术。然而，这些疗法不仅没有减少 吸入性肺炎的发展，但也可能加速肺部疾病的发展 通过改变空气中的消化微生物群，在抑酸的情况下，或通过阻碍肺炎的风险 食道流出或延缓胃动力，在抗反流手术的情况下。食道和胃 运动障碍尤其令人担忧，因为它们会导致体液停滞，继发于 化学和微生物组成。如果这些改变的食道和胃内容物被吸入，肺 疾病很可能随之而来。但问题仍然存在：哪些特定的运动异常会导致液体停滞和 这些异常使NI儿童容易患上更频繁的吸入性肺炎？哪些组件 静止液的减少预示着更糟糕的临床结果？纠正运动障碍会改善临床结果吗？ 拟议的研究将建立在现有文献的基础上，解决以下假设：(1) 不同的食道和胃运动模式导致食道和胃内容物停滞；(2)这 瘀血改变食管液和胃液的微生物和化学环境；(3)胃和胃的停滞 当吸入食道内容物时，会引起可测量的微生物群和炎性变化， 易患吸入性肺炎；及(4)食道及胃病的治疗 运动障碍改善吸入相关症状并导致可测量的食道和 胃动力障碍。首先，使用纵向队列研究设计，研究人员将确定哪种独特的 食道和胃动力模式导致瘀血并预测吸入性肺炎的发展 感染新城疫的儿童。其次，使用随机、盲目交叉设计，调查人员将测试 普鲁卡必利是一种5HT4激动剂，可以改善吸入相关症状以及食道和胃动力。 这项研究将：1)解决一种常见且代价高昂的问题，吸入性肺炎，在医学上 弱势群体；(2)超越GERD，追求一种新的、改变范式的病理生理学 吸入性肺炎的发病机制、动力障碍、潜在发展；(3)进展超出标准 测试不仅包括运动性参数，还包括微生物组和化学后果 运动障碍；以及(4)为可能改善的吸入症状提供创新的治疗干预 改善弱势群体的健康状况，降低医疗保健成本。最终，这项研究可以 用于设计额外的治疗运动干预措施来治疗食道外症状。

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.