Feasibility Study of A Comparison of Minimally Invasive Surfactant Application Techniques in Preterm Infants

1. The Need for a Trial What is the problem to be addressed? Respiratory distress syndrome (RDS) is a major clinical challenge affecting 60% of babies born before 30 weeks gestation and significantly contributes to mortality and morbidity in very preterm infants, including chronic lung disease and bronchopulmonary dysplasia. Given that the immature lungs of these tiny infants are developmentally deficient in surfactant, exogenous surfactant administration might be beneficial to prevent pulmonary atelectasis. The traditional method in preterm infants is via endotracheal tube accompanied by mechanical ventilation using positive pressure. The latter predisposes to permanent lung injury.This study seeks to assess the feasibility of conducting a large-scale clinical trial to compare two minimally invasive methods of surfactant administration to very low birth weight preterm infants. As such a comparative study has not been reported, the proposed study is a pilot trial to test the feasibility of the study design and to gather preliminary data on the comparison of two methods of surfactant administration. Results from this study will inform the design of a larger clinical trial including appropriate power calculation.

Current management of lung disease in preterm infants RDS significantly contributes to mortality and morbidity in very preterm infants and is, itself, a major determinant of chronic lung disease (CLD) in the premature infant. One of the most common causes of RDS is surfactant deficiency; therefore, exogenous surfactant is frequently used for the treatment of RDS of the preterm infant. Endogenous surfactant is typically produced by alveolar cells type II and this substance, among other functions, decreases and modulates the surface tension in the small gas exchanging units of the lung, the alveoli.1 It has been shown that surfactant treatment is more effective when used within first hours of life rather than later as rescue therapy. The traditional method of surfactant administration is via an endotracheal tube where the infant is intubated and mechanically ventilated, with the latter often resulting in a pulmonary inflammatory response. This response is known to be a significant contributor to the development of CLD which is the main pulmonary morbidity, both in the short and long term, associated with premature birth, thus traditionally supporting the need for mechanical ventilation in a highly vulnerable phase of lung development. Despite advances in management of respiratory distress, about 30% of infants born under < 1,000 g still develop CLD - defined as an oxygen need at 36 weeks postmenstrual age. Some of these infants develop severe lung disease requiring ventilation and/or supplemental oxygen for months or years. Significant contributors to this adverse long term outcome of premature birth are oxidant - and ventilation mediated injury and inflammation, leading to disrupted alveolarization and septation of the lungs.

One well established therapy to prevent RDS is antenatal administration of steroids to mothers with imminent preterm birth for induction of lung maturation, a treatment that has resulted in significant improved outcome following preterm birth. This treatment results in improved neonatal lung compliance with fewer infants requiring exogenous surfactant therapy.7 The increasing use of this intervention has led to more infants not necessarily requiring postnatal surfactant and thus reduced need for mechanical ventilation, which allows to manage even extreme low birth weight infants with non-invasive pressure support as CPAP (continuous positive airway pressure) to establish functional residual capacity.

Postnatal non-invasive respiratory support using continuous positive airway pressure (CPAP) has been shown to be effective in reducing lung damage in several studies, especially when initiated during the immediate postnatal adaptation period. This results in fewer days of ventilation and a trend towards a lower risk of CLD, when compared to intubated and mechanically ventilated controls. However, the number of infants who are started on CPAP but who ultimately require intubation for the administration of exogenous surfactant within the first 72 hours remains high in the extremely low birth weight category. Usually CPAP failure is due to unremitting RDS requiring surfactant therapy. There is evidence that failing CPAP therapy, defined as need for intubation within 72 hours of postnatal age, is associated with adverse outcome in infants between 25 to 28 weeks gestation with a higher risk of CLD, death or CLD and necrotizing enterocolitis. In the same trial infants between 29 and 32 weeks of gestation failing CPAP were at higher risk of pneumothorax.

In current clinical practice neonatologists are faced with the quandary of avoiding mechanical positive pressure ventilation, but with the knowledge that surfactant treatment is more effective in earlier phases of RDS, and that CPAP failure could lead to higher risk of an adverse outcome. Hence efforts have been made to develop non-invasive strategies of surfactant application to take advantage of the high efficacy of this treatment and to decrease duration of mechanical ventilation and subsequent lung injury. To date, all attempts to produce an effective surfactant for nebulization have been unsuccessful.