Pathophysiology of Childhood Obstructive Sleep Apnea

描述(由申请人提供)：阻塞性睡眠呼吸暂停综合征(OSAS)是儿科人群中常见的发病率原因。该建议将整合对上呼吸道神经运动控制(UA)和UA结构的研究，以便对同一个体中OSAS的所有病理生理危险因素进行全面评估，并将这一知识应用于高危儿科患者。该提案的重点是肥胖在青春期过渡期的影响。总体假设是，当个体获得结构性负荷并伴有UA神经运动功能潜在损害时，OSAS就会发生。这将是一项1：1：1匹配的病例-双对照研究，具有互补的干预成分。尿酸反射将通过测量睡眠状态下的尿酸压力-流量反应与低张状态下的尿酸反应以及对高碳酸血症的尿酸反应之间的差异来确定。UA的大小和结构将通过MRI确定。在目标1中，我们将通过进行一项横断面病例对照研究来确定UA反射对呼吸暂停低通气指数(AHI)的贡献，该研究将比较(I)无鼾症、BMI匹配的肥胖对照组和(Ii)非肥胖、非鼾症对照组。我们假设，与肥胖对照组相比，患有阻塞性睡眠呼吸暂停综合征的肥胖青少年的尿酸反射将减少，而肥胖对照组的尿酸反射将比非肥胖对照组更强。在目标2A中，我们将确定结构性UA收窄对AHI的贡献。我们假设，与肥胖对照组相比，患有阻塞性睡眠呼吸暂停综合征的肥胖青少年的UA会更窄。在目标2B中，我们将确定导致上呼吸道狭窄的最重要的结构性因素。我们假设扁桃体组织和脂肪组织的区域分布是青少年UA大小的主要决定因素。在目标3中，我们将确定减肥对OSAS的影响。在目标3A中，我们将确定体重减轻程度是否与AHI的变化相关。我们假设体重下降得越多，AHI下降的幅度就越大。在AIM 3B中，我们将确定体重减轻后AHI的降低是否主要是由于UA反射的改变或UA大小的改变。我们假设，体重减轻后AHI的改善主要是由于UA大小的增加，而不是UA反射的改变。在目标3C中，我们将确定体重减轻对尿酸结构的影响。我们假设，体重减轻将主要导致咽旁脂肪垫大小的减少，但也可能影响舌头和软腭的大小。这些研究将有助于阐明肥胖青少年阻塞性睡眠呼吸暂停综合征的病理生理学机制，最终改善对这种疾病的治疗。 公共卫生相关性：目前美国的肥胖流行正在导致青少年阻塞性睡眠呼吸暂停综合征(OSAS)的患病率不断上升。这项研究将有助于阐明青少年OSAS的原因，并确定减肥在改善这些原因方面的有效性。

DESCRIPTION (provided by applicant): The obstructive sleep apnea syndrome (OSAS) is a common cause of morbidity in the pediatric population This proposal will integrate studies of neuromotor control of the upper airway (UA) and UA structure in order to provide a comprehensive assessment of all pathophysiologic risk factors for OSAS in the same individual, and to apply this knowledge to high risk pediatric patients. The proposal focuses on the effects of obesity during the transitional period of adolescence. The overall hypothesis is that OSAS develops when a structural load is acquired by an individual with an underlying impairment of UA neuromotor function. This will be a 1:1:1 matched case-dual control study with a complementary interventional component. UA reflexes will be determined by measuring the difference between the UA pressure-flow response during sleep in the activated vs the hypotonic state, and the UA response to hypercapnia. UA size and structure will be determined using MRI. In Aim 1, we will determine the contribution of UA reflexes to the apnea hypopnea index (AHI) by conducting a cross-sectional, case control study that will compare obese, adolescent cases with OSAS to (i) non-snoring, BMI-matched obese controls and to (ii) non-obese, non-snoring controls. We hypothesize that UA reflexes will be decreased in obese adolescents with OSAS compared to obese controls, and that UA reflexes will be greater in obese controls than in non-obese controls. In Aim 2A, we will determine the contribution of structural UA narrowing to the AHI. We hypothesize that the UA will be narrower in obese adolescents with OSAS compared to obese controls. In Aim 2B, we will identify the most important structural factors leading to upper airway narrowing. We hypothesize that adenotonsillar tissue and regional distribution of adipose tissue are the prime determinants of UA size in adolescents. In Aim 3, we will determine the effects of weight loss on OSAS. In Aim 3A, we will determine whether the degree of weight loss correlates with the change in AHI. We hypothesize that the greater the weight loss, the greater the fall in AHI. In Aim 3B, we will determine whether the decrease in AHI following weight loss is due primarily to a change in UA reflexes or a change in UA size. We hypothesize that the improvement in AHI following weight loss is due primarily to an increase in UA size rather than to a change in UA reflexes. In Aim 3C, we will determine the effect of weight loss on UA structure. We hypothesize that weight loss will result primarily in a decrease in the size of the parapharyngeal fat pads, but may also affect tongue and soft palate size. These studies will help elucidate the pathophysiology of OSAS in obese adolescents, ultimately resulting in improved management of this disease. PUBLIC HEALTH RELEVANCE: The current obesity epidemic in the United States is resulting in an increasing prevalence of the obstructive sleep apnea syndrome (OSAS) in adolescents. This study will help elucidate of the causes of OSAS in teenagers, and determine the effectiveness of weight loss in ameliorating these causative factors.