Chronic Sildenafil for Severe Diaphragmatic Hernia

慢性西地那非治疗严重膈疝

• 批准号: 7458992
• 负责人: ROBERTA L KELLER
• 金额: $ 12.04万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-29 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7458992
• 关键词: Age-Years; Alveolar; Blood Vessels; Cardiac Catheterization Procedures; Cardiopulmonary; Child; Chronic; Chronic lung disease; Clinic; Clinical; Clinical Trials; Congenital diaphragmatic hernia; Counseling; Cyclic GMP; Defect; Development; Diaphragmatic Hernia; Double-Blind Method; Endothelin-1; Evaluation; Experimental Models; Faculty; Growth; Growth and Development function; Health; Hypertension; Infant; Injury; Institution; Length of Stay; Live Birth; Lung; Measurement; Measures; Medical; Mentors; Morbidity - disease rate; Neonatal; Nitric Oxide; Nutrition Assessment; Operative Surgical Procedures; Outcome; Oxygen Therapy Care; Pathway interactions; Patients; Persistent Fetal Circulation Syndrome; Phase; Placebo Control; Placebos; Population; Positioning Attribute; Principal Investigator; Protocols documentation; Pulmonary Hypertension; Pulmonary Vascular Resistance; Randomized; Randomized Clinical Trials; Rate; Research; Research Personnel; Respiratory physiology; Rodent Model; Secondary to; Staging; Testing; Training; Vascular remodeling; Vascular resistance; Vasodilator Agents; attenuation; career; follow-up; improved; infancy; inhaled nitric oxide; inhibitor/antagonist; lung injury; lung vascular injury; member; mortality; phosphodiesterase V; postnatal; pressure; programs; response; sildenafil

DESCRIPTION (provided by applicant): Congenital diaphragmatic hernia (CDH) occurs 1 in 3000 live births. Infants born with severe CDH have poor lung function and persistent pulmonary hypertension of the newborn, secondary to pulmonary hypoplasia. These infants require aggressive, prolonged neonatal support. Postnatal lung growth is critical for long-term survival in severe CDH. However, measures required to support these infants may cause direct lung injury, impairing further growth. Normal alveolar development is dependent on normal microvascular growth. Therefore, in severe CDH, vascular injury may also impact postnatal lung growth and development. Experimental models of pulmonary hypertension (PH) demonstrate attenuation of abnormal pulmonary vascular remodeling with early manipulation of the nitric oxide (NO)-cyclic guanosine monophosphate pathway through administration of inhaled NO or phosphodiesterase-5 inhibitors. The local and systemic factors that result in abnormal postnatal lung and vascular growth, development, and remodeling in the CDH population are unknown. However, chronic PH and chronic lung disease are significant problems in this population, resulting in late mortality, extended neonatal hospital stays and prolonged supplemental oxygen therapy, which is associated with poor neurodevelopmental outcome in children with CDH. The aims of this study are 1) to evaluate pulmonary vascular function and reactivity in severe CDH in the subacute stage of illness; 2) to evaluate the effect of chronic sildenafil on pulmonary vascular function and reactivity in a randomized clinical trial; and 3) to compare 1 & 2 year health and neurodevelopmental outcomes in severe CDH after chronic sildenafil therapy in infancy. This project has the further aim of extending and developing the research expertise of the Principal Investigator, so that she may be positioned for an independent research career. This broad objective will be accomplished through completion of the scientific protocol, didactic training, and careful mentoring by successful senior faculty members at her institution.

描述（由申请人提供）： 先天性隔膜疝（CDH）发生在3000例活生生中。患有严重CDH的婴儿的肺功能较差和新生儿的持续性肺动脉高压，其继发于肺部发育不全。这些婴儿需要积极的，长时间的新生儿支持。产后肺的生长对于严重CDH的长期生存至关重要。但是，支持这些婴儿所需的措施可能会导致直接的肺损伤，从而损害进一步的生长。正常的牙槽发育取决于正常的微血管生长。因此，在严重的CDH中，血管损伤也可能影响产后肺的生长和发育。肺动脉高压（PH）的实验模型表明，通过施用INHALED NO或磷酸二酯酶-5抑制剂的施用，通过对一氧化氮（NO） - 环鸟苷单磷酸途径进行早期操纵，对异常肺血管重塑的衰减。 CDH种群中导致异常肺和血管生长，发育和重塑的局部和系统因素尚不清楚。然而，慢性pH和慢性肺部疾病在该人群中是重大问题，导致死亡率晚期，新生儿住院时间延长并延长了补充氧疗法，这与CDH儿童的神经发育结果不良有关。这项研究的目的是1）评估在疾病亚急性阶段严重CDH中肺血管功能和反应性； 2）在一项随机临床试验中评估慢性西地那非对肺血管功能和反应性的影响； 3）比较婴儿期慢性西地那非治疗后严重CDH的1＆2年健康和神经发育结果。该项目的进一步目的是扩展和发展主要研究者的研究专业知识，以便她可以将其定位为独立的研究职业。这一广泛的目标将通过完成科学方案，教学培训以及她机构成功的高级教师的仔细指导来实现。