Respiratory distress syndrome (RDS), caused by surfactant deficiency, is the leading cause of mortality and morbidity in preterm infants. Intratracheal instillation, the only approved means of surfactant delivery, requires endotracheal intubation and mechanical ventilation with their attendant risks. Interventions that decrease need for intubation and mechanical ventilation (MV) like noninvasive ventilation (NIV) including nasal continuous positive airway pressure, high flow nasal cannula or nasal intermittent mandatory ventilation are increasingly being used for initial respiratory support in preterm neonates with RDS to improve outcomes. However, the use of NIV not only averts the need for intubation and mechanical ventilation, but also delays surfactant administration. Therefore, aerosolized surfactant delivered during NIV is expected to be an innovative and promising concept for the treatment of RDS by retaining the advantages of early surfactant with alveolar recruitment while obviating the risks of intubation and mechanical ventilation. The investigators'overall hypothesis is that treatment of RDS with aerosolized surfactant in preterm infants undergoing NIV is safe and feasible and will result in short-term improvement in oxygenation and ventilation thus leading to a decrease in need for intensive care support, complications of prematurity, duration of hospitalization and health care costs. The objective of this proposal is to perform a single-center, unblinded, Phase 1/2, randomized clinical trial of aerosolized surfactant for the treatment of RDS in preterm neonates undergoing NIV. The investigators will achieve this objective by addressing the following Specific Aims:
Specific Aim 1 : Evaluate safety and feasibility of aerosolized surfactant generated with two nebulizers approved for use in neonates - the MiniHeart Lo-Flo jet &the AeroNeb Solo vibrating mesh nebulizer. Safety will be evaluated by monitoring cardiorespiratory parameters, blockage of NIV circuit, nasal trauma scores &cerebral oxygenation. Feasibility will be assessed in terms of tolerance by both the infant &clinical caregivers.
Specific Aim 2 : Determine the optimal dilution and dose of aerosolized surfactant for treatment of RDS in preterm neonates undergoing NIV. Infants will be randomized to 2 doses and 2 dilutions of aerosolized surfactant resulting in 4 dosing schedules.
Specific Aim 3 : Evaluate short term efficacy of aerosolized surfactant as assessed by need for intubation and MV in the first 72 hours of life. Efficacy of aerosol delivery will also be assessed by change in surfactant activity in gastric aspirates after aerosolized surfactant. Additional secondary efficacy measures include respiratory severity score, diagnosis of patent ductus arteriosus, need for blood transfusions, postnatal growth, duration of respiratory support, length of hospital stay, incidence of complications of prematurity and death.

Public Health Relevance

The lungs of infants born too early are lacking in a substance that helps keeps the lungs open. This leads to signs of breathing difficulty soon after birth and this condition is called Respiratory Distress Syndrome (RDS). To treat this problem, physicians administer commercially available surfactant through a tube in the airway and a breathing machine. This treatment has improved survival in preterm infants but can cause damage to the immature lungs that may lead to long term lung disease and breathing problems. The need for more gentle and less invasive methods of delivering surfactant to preterm infants has led us to propose the use of surfactant as a breathing treatment (aerosol). Aerosols of surfactant can be administered even without a breathing machine and have the potential for dramatically changing outcomes for these vulnerable infants thus leading to decreased need for intensive care and healthcare costs. Since a large proportion of preterm infants treated with aerosolized surfactant may avoid the need for a tube in their airway and assistance with a breathing machine, they will have less damage to the lung from the breathing machine in addition to lung disease of prematurity. Lung injury resulting from immature lungs, exposure to oxygen and breathing machines is a strong risk factor for other complications of prematurity like chronic lung disease, feeding problems, bleeding in the brain and other brain injury. Avoidance for the need of assistance with a breathing machine will thus decrease complications of prematurity resulting in shorter hospital stay with significant cost savings. The ability to give surfactant as an aerosol will also allow parents to bond with their infant much more easily than if an infant were receiving support with a breathing machine. The proposed study will determine if it is practical to administer surfactant as an aerosol for the treatment of lung disease of prematurity. Should this study look promising, the resulting data will be used to design a larger clinical trial to compare this novel method with existing methods for treatment of RDS. Results of such a trial would help us to understand the best way to administer surfactant to preterm infants and thus help doctors to better care for tiny infants at risk of lung disease.

National Institute of Health (NIH)
Food and Drug Administration (FDA)
Research Project (R01)
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Wayne State University
Schools of Medicine
United States
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