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Chronic Sildenafil for Severe Diaphragmatic Hernia

慢性西地那非治疗严重膈疝

基本信息

批准号：
7646395
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
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-09-29 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7646395
关键词：
2 year old 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 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 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

项目摘要

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)：每3000名活产儿中就有1人患有先天性横隔疝(CDH)。重度CDH新生儿肺功能较差，继发肺发育不全，持续存在肺高压。这些婴儿需要积极的、长期的新生儿支持。出生后肺生长对重度CDH患者的长期生存至关重要。然而，支持这些婴儿所需的措施可能会导致直接的肺损伤，损害进一步的生长。正常的肺泡发育依赖于正常的微血管生长。因此，在重度CDH中，血管损伤也可能影响出生后肺的生长发育。肺动脉高压(PH)的实验模型显示，通过吸入NO或磷酸二酯酶-5抑制剂，早期操纵一氧化氮(NO)-环鸟苷一磷酸途径可减轻异常肺血管重构。导致CDH人群中出生后肺和血管生长、发育和重塑异常的局部和系统因素尚不清楚。然而，慢性肺高压和慢性肺部疾病是这一人群中的重要问题，导致晚期死亡、新生儿住院时间延长和补充氧疗时间延长，这与CDH儿童的神经发育预后不良有关。本研究的目的是：1)评估重症CDH在亚急性期的肺血管功能和反应性；2)在随机临床试验中评价慢性西地那非对肺血管功能和反应性的影响；3)比较重症CDH婴儿期慢性西地那非治疗后1~2年的健康和神经发育结果。该项目的另一个目的是扩大和发展首席调查员的研究专长，使她能够从事独立的研究工作。这一广泛的目标将通过完成科学规程、教学培训和她所在机构成功的资深教员的仔细指导来实现。