Influence of Postnatal Glucocorticoid use on Structure and Function of the Fetal Diaphragm.
Preterm birth is the leading cause of mortality and morbidity in the newborn. While advances in medicine and technology have significantly improved the survival rate of premature infants, associated morbidity has not decreased. Due to the immaturity of their respiratory system, infants that are born premature are at increased risk of developing respiratory distress. As the diaphragm is the major respiratory muscle, it is critically important for the establishment of spontaneous unsupported breathing. However, like the lung, the preterm diaphragm is structurally and functionally immature at birth. The preterm diaphragm produces lower transdiaphragmatic twitch pressures, has reduced antioxidant capacity and a lower proportion of fatigue-resistant oxidative fibres than that of mature infants. In addition, the increased work of breathing and exposure to in utero inflammation are likely to contribute to the development of respiratory distress and necessitate the use of mechanical ventilator support.
Postnatal glucocorticoids produce short term improvements in pulmonary function and therefore, are frequently used to facilitate weaning off mechanical ventilation. Dexamethasone is the most commonly used postnatal glucocorticoid, however its use is associated with serious side effects including adverse long-term neurodevelopmental outcomes. In adult skeletal muscle Dexamethasone reduces protein synthesis and increases protein breakdown. If Dexamethasone has similar effects on the fetal diaphragm, then the beneficial effects of Dexamethasone treatment on lung function may be compromised by diaphragm dysfunction.Therefore, there is an urgent need to evaluate the cost-benefit ratio for postnatal glucocorticoid use in preterm infants. To date, the effect of postnatal glucocorticoid administration on the development and function of the fetal diaphragm is unknown.
The main objective of this project is to determine the effect of the clinically relevant, postnatal glucocorticoid administration on the structure and function of the fetal and newborn diaphragm.
Why my research is important
Premature birth, defined as birth at less than 37 weeks gestation, is the leading cause of morbidity and mortality in the newborn. The world health organisation (WHO) estimated over 1 million babies died due to complications associated with premature birth in 2013. Despite advances in medicine and technology, the rate of premature birth is increasing in almost every country with reliable data (‘Born too soon: The Global action report on Preterm Birth).
Due to the immaturity of their respiratory system, infants that are born premature often require mechanical ventilator support. However, this creates a ‘catch-22’ situation, while mechanical ventilation is vital for the survival of the infant, it causes ventilator induced lung injury and diaphragm dysfunction. Postnatal steroids have been used since the 1980s to facilitate weaning the preterm infant from mechanical ventilation. Despite their long term use, we still don’t know when and how to use postnatal steroids in the preterm infant. In order to successfully wean preterm infants from mechanical ventilation, and reduce the severity of associated respiratory illness, it is vital that the effect of postnatal glucocorticoids treatment on the primary respiratory muscle, the diaphragm, is evaluated. This project will, for the first time, investigate the effects of postnatal glucocorticoid administration on the structure and function of the fetal diaphragm. These findings may be useful in a neonatal clinical setting to improve cardiorespiratory disease in preterm infants, thereby providing the potential for a healthier start to life.