19 Jan Long-Term Effects of Inhaled Budesonide for Bronchopulmonary Dysplasia

MedicalResearch.com Interview with:
Prof. Dr. Dirk Bassler, MSc
Head of Department, Professor of Neonatology
Department of Neonatology
University Hospital Zurich and University of Zurich
Zurich, Switzerland

MedicalResearch.com: What is the background for this study?

Response: Bronchopulmonary dysplasia (BPD), a form of lung disease, is the most common chronic complication of extremely preterm birth and represents a major threat to the short- and long-term health and development of affected infants. Only very few effective prophylactic or therapeutic drugs are available for this condition and some of them are associated with severe side effects. Systemic glucocorticoids are effective for the prevention of BPD but can increase the risk of neurodevelopmental impairment. Despite limited clinical evidence inhaled steroids are widely used around the world with the hope that through inhalation positive anti-inflammatory effects on the lungs can be augmented without leading to adverse effects on other organs, particularly the brain. We conducted this large randomized trial at 40 centers in 9 countries to study the short-term and long-term efficacy and safety of inhaled budesonide for the prevention of BPD in extremely preterm infants.

MedicalResearch.com: What are the main findings?

Response: We previously reported that inhaled budesonide is associated with a significantly lower risk of BPD than that with placebo. Now we are able to show that neurodevelopment among surviving infants at a corrected age of 18 to 22 months is not different between infants assigned to early treatment with inhaled budesonide and those assigned to placebo. Furthermore, our study shows that there is no difference between the budesonide group and the placebo group with respect to the composite outcome of death or neurodevelopmental disability.

However, our results suggest higher mortality with budesonide. The mortality finding is of nominal statistical significance but after conducting a detailed review of the causes of death and clinical course of all study infants who died, we found no plausible explanation for this difference.

MedicalResearch.com: What should readers take away from your report?

Response: Multiple studies indicate that a large number of preterm infants receive inhaled corticosteroids for the prevention or treatment of BPD in routine clinical care around the world. Despite their widespread use, inhaled glucocorticoids have been evaluated in only a few small and mostly short-term studies and there was a lack of data supporting or refusing this practice. This discrepancy prompted us to conduct the largest placebo-controlled randomized study of inhaled glucocorticoids for the prevention of BPD reported to date. Now we are able to show that inhaled budesonide decreases the risk of BPD without increasing the risk of neurodevelopmental impairment in survivors at 2 years. This is reassuring, considering the fact that the early administration of oral or intravenous glucocorticoids can compromise brain development. However, the mortality rate in our study was higher among those who received budesonide. There is no biologically plausible hypothesis to explain the seeming excess of deaths in treated infants and this finding may be attributed to chance. However, we can’t be sure about this assumption and neonatologists still need to carefully balance the risks of potentially increased mortality owing to early inhaled corticosteroids against those of decreased rates of BPD with no effect on neurodevelopment in survivors at 2 years of age.

MedicalResearch.com: What recommendations do you have for future research as a result of this work?

Response: Future studies should focus on subgroups of infants at highest risk of developing BPD, or with a pathophysiology that may most likely benefit from glucocorticoids. Furthermore, future research should include the design of appropriate aerosol delivery systems and the pharmacokinetics of inhaled glucocorticoids. There may be further advantages of using budesonide locally in a mixture together with surfactant, an approach that may lead to prolonged local antiinflammatory effects, a decreased risk of systemic adverse effects and a better calculability of the actual delivered dose.

MedicalResearch.com: Is there anything else you would like to add? 

Response:  I am indebted to physicians, nurses, psychometrists, psychologists, audiologists, our funders and all other staff who made this study possible; and most important, to the families and their children who participated in this trial.

Citations:

Long-Term Effects of Inhaled Budesonide for Bronchopulmonary Dysplasia

Dirk Bassler, M.D., Eric S. Shinwell, M.D., Mikko Hallman, M.D., Ph.D., Pierre-Henri Jarreau, M.D., Ph.D., Richard Plavka, M.D., Ph.D., Virgilio Carnielli, M.D., Christoph Meisner, Ph.D., Corinna Engel, Ph.D., Alexander Koch, M.D., Karen Kreutzer, M.D., Johannes N. van den Anker, M.D., Ph.D., Matthias Schwab, M.D., Henry L. Halliday, M.D., and Christian F. Poets, M.D., for the Neonatal European Study of Inhaled Steroids Trial Group^*

N Engl J Med 2018; 378:148-157January 11, 2018DOI: 10.1056/NEJMoa1708831

http://www.nejm.org/doi/full/10.1056/NEJMoa1708831

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Last Updated on January 19, 2018 by Marie Benz MD FAAD