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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23HL079922-05
Application #
7646395
Study Section
Special Emphasis Panel (ZHL1-CSR-Q (F3))
Program Officer
Colombini-Hatch, Sandra
Project Start
2005-09-29
Project End
2011-06-30
Budget Start
2009-07-01
Budget End
2011-06-30
Support Year
5
Fiscal Year
2009
Total Cost
$120,410
Indirect Cost
Name
University of California San Francisco
Department
Pediatrics
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Radman, Monique; Mack, Ricardo; Barnoya, Joaquin et al. (2014) The effect of preoperative nutritional status on postoperative outcomes in children undergoing surgery for congenital heart defects in San Francisco (UCSF) and Guatemala City (UNICAR). J Thorac Cardiovasc Surg 147:442-50
Amirnovin, Rambod; Keller, Roberta L; Herrera, Christina et al. (2013) B-type natriuretic peptide levels predict outcomes in infants undergoing cardiac surgery in a lesion-dependent fashion. J Thorac Cardiovasc Surg 145:1279-87
Keller, Roberta L; Merrill, Jeffrey D; Black, Dennis M et al. (2012) Late administration of surfactant replacement therapy increases surfactant protein-B content: a randomized pilot study. Pediatr Res 72:613-9
Keller, Roberta L; Tacy, Theresa A; Hendricks-Munoz, Karen et al. (2010) Congenital diaphragmatic hernia: endothelin-1, pulmonary hypertension, and disease severity. Am J Respir Crit Care Med 182:555-61
Hsu, Jong-Hau; Oishi, Peter E; Keller, Roberta L et al. (2008) Perioperative B-type natriuretic peptide levels predict outcome after bidirectional cavopulmonary anastomosis and total cavopulmonary connection. J Thorac Cardiovasc Surg 135:746-53
Chikovani, Omar; Hsu, Jong-Hau; Keller, Roberta et al. (2007) B-type natriuretic peptide levels predict outcomes for children on extracorporeal life support after cardiac surgery. J Thorac Cardiovasc Surg 134:1179-87
Keller, Roberta L (2007) Antenatal and postnatal lung and vascular anatomic and functional studies in congenital diaphragmatic hernia: implications for clinical management. Am J Med Genet C Semin Med Genet 145C:184-200
Keller, Roberta L; Moore, Phillip; Teitel, David et al. (2006) Abnormal vascular tone in infants and children with lung hypoplasia: Findings from cardiac catheterization and the response to chronic therapy. Pediatr Crit Care Med 7:589-94