Persistent pulmonary hypertension of the newborn (PPHN) is associated with significant morbidity and mortality. Current management strategies include mechanical ventilation and inhaled nitric oxide therapy (iNO). iNO therapy has proven to be a safe and effective treatment for term newborns with PPHN, however, in randomized, controlled trials, approximately 40% of newborns still required treatment with extracorporeal membrane oxygenation (ECMO) because of the failure of INO therapy to cause sustained improvement in oxygenation. There are investigational adjuvant therapies that have the potential to cause selective pulmonary vasodilation and/or enhance the response to inhaled NO, such as the type 5 specific phosphodiesterase inhibitor sildenafil. Although enteral administration of sildenafil has been reported in newborns with PPHN, variable absorption in critically ill patients limits its application. We have recently completed a dose response/PK study using intravenous sildenafil (IVS) in infants with PPHN demonstrating that it is well tolerated and associated with marked improvements in oxygenation. We hypothesize that IVS will acutely reduce pulmonary artery pressure and improve oxygenation in near-term and term newborns with PPHN, thus reducing the need for rescue therapy with INO and/or ECMO. To test this hypothesis, we have designed a randomized, controlled, masked trial of IV sildenafil treatment In 50 near-term and term newborns with PPHN to be conducted at 5 clinical sites. This trial is designed to provide estimates for event rates (including mortality, ECMO utilization, and acute changes in pulmonary hypertension and gas exchange) that will guide power analysis for a larger, multicenter, randomized controlled trial of IVS in this population Specific Aim #1) To determine the acute changes in the physiological outcome measures of pulmonary artery pressure and gas exchange during treatment with IVS.
Specific Aim#2 : To determine the incidence of treatment failure (i.e. need for INO/ECMO) between the control and IVS treatment groups. In response to the RFA, the clinical trial will be augmented by 2 ancillary laboratory studies to be conducted at the University of Colorado and Northwestern University.

Public Health Relevance

In response to the RFA, we are proposing this phase II clinical therapeutic trial as a novel intervention for a severe lung disease affecting newborns. We are targeting physiological variables (as well as a treatment failure outcome measure) to generate event rates to provide proof of concept for this therapy that we believe has high potential for modifying current treatment strategies.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project--Cooperative Agreements (U01)
Project #
1U01HL102235-01A1
Application #
8020254
Study Section
Special Emphasis Panel (ZHL1-CSR-H (S1))
Program Officer
Blaisdell, Carol J
Project Start
2010-09-17
Project End
2013-03-31
Budget Start
2010-09-17
Budget End
2013-03-31
Support Year
1
Fiscal Year
2010
Total Cost
$1,293,473
Indirect Cost
Name
University of Colorado Denver
Department
Pediatrics
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
Acker, Shannon N; Seedorf, Gregory J; Abman, Steven H et al. (2015) Altered pulmonary artery endothelial-smooth muscle cell interactions in experimental congenital diaphragmatic hernia. Pediatr Res 77:511-9
Mourani, Peter M; Abman, Steven H (2015) Pulmonary Hypertension and Vascular Abnormalities in Bronchopulmonary Dysplasia. Clin Perinatol 42:839-55
Baker, Christopher D; Abman, Steven H (2015) Impaired pulmonary vascular development in bronchopulmonary dysplasia. Neonatology 107:344-51
Acker, Shannon N; Seedorf, Gregory J; Abman, Steven H et al. (2013) Pulmonary artery endothelial cell dysfunction and decreased populations of highly proliferative endothelial cells in experimental congenital diaphragmatic hernia. Am J Physiol Lung Cell Mol Physiol 305:L943-52
Steinhorn, Robin H; Kinsella, John P; Abman, Steven H (2013) Beyond pulmonary hypertension: sildenafil for chronic lung disease of prematurity. Am J Respir Cell Mol Biol 48:iii-v
Lakshminrusimha, Satyan; Steinhorn, Robin H (2013) Inodilators in nitric oxide resistant persistent pulmonary hypertension of the newborn. Pediatr Crit Care Med 14:107-9
Mourani, Peter M; Abman, Steven H (2013) Pulmonary vascular disease in bronchopulmonary dysplasia: pulmonary hypertension and beyond. Curr Opin Pediatr 25:329-37
Steinhorn, Robin H (2012) Pharmacotherapy for pulmonary hypertension. Pediatr Clin North Am 59:1129-46
Porta, Nicolas F M; Steinhorn, Robin H (2012) Pulmonary vasodilator therapy in the NICU: inhaled nitric oxide, sildenafil, and other pulmonary vasodilating agents. Clin Perinatol 39:149-64
Bishop, Naomi B; Stankiewicz, Pawel; Steinhorn, Robin H (2011) Alveolar capillary dysplasia. Am J Respir Crit Care Med 184:172-9