Discussion:
In this retrospective cohort study, the incidence of BPD was compared before and after a significant clinical practice change of less surfactant administration and less invasive mechanical ventilation using four different definitions of BPD. In contrast to other studies that have either looked at a practice change or assessed differences in BPD incidence based on multiple definitions, our study simultaneously assessed a practice change in the context of all currently available BPD definitions [20-22]. Additionally, this study investigated an isolated practice change of less delivery room intubation and surfactant instillation in two consecutive time periods, in contrast to other studies that have evaluated multiple practice changes in multiple centers over time[20-22]. This makes our research data interpretable and more generalizable in comparison to recently published studies examining similar questions.
Our practice change followed from institutional participation in the SUPPORT trial and the results of other trials where less surfactant was administered within the first 24 hours of life due to increased use of non-invasive ventilation [7, 23]. Prior to 2014, the majority of premature neonates born at less than 28 weeks gestation were intubated and given surfactant in the delivery room or within the first 24 hours of life. More recently, very premature neonates received a trial of non-invasive ventilation with intubation, mechanical ventilation, and surfactant administration reserved for neonates who failed to adequately respond. Despite this change, there was no effect on the incidence of BPD or death, or the composite outcome of death or BPD across varying definitions. Additionally, we did not find a difference in the incidence and severity of BPD between Epochs 1 and 2 despite fewer males, C-sections, multiple gestations, maternal chorioamnionitis, and less intubation and surfactant administration in Epoch 2, situations and characteristics expected to decrease BPD incidence [15-18, 24-26].
There are likely multiple explanations for the findings. Our population is also notable for high rates of prenatal steroid course, which may have also impacted incidence of BPD in both Epochs. Second, with a limited sample size, genetic predispositions could have accounted for BPD propensity among subjects with twin studies demonstrating that genetic factors may explain up to 80% of the variance in susceptibility to moderate/severe BPD [27]. Also, genome-wide sequencing studies have identified potential variants and novel molecular pathways that are linked to increased risk of developing BPD [28, 29]. Third, while surfactant improves respiratory status in RDS, it has not been shown to impact the incidence of BPD which occurs months after surfactant administration [30]. Fourth, the existence of different BPD phenotypes (e.g. pulmonary hypertension) [27, 31, 32] were not addressed in the current study. Fifth, prior to 2010, we began incorporating the RAM Cannula interface for non-invasive ventilation in the ELGAN population as an alternative when skin breakdown was imminent. Thus, multiple different interfaces (including Fisher & Paykel FlexiTrunk mask and prongs) with varying abilities to deliver pressure were utilized in our unit during the study period. Interestingly, we identified an increased use of postnatal steroid use (DART protocol reference) in Epoch 2. It is important to note that postnatal steroids were administered at more mature post-conceptional ages, so that the same clinical scenarios that drove the diagnosis of BPD likely drove the use of postnatal steroid use (inability to wean ventilator support and oxygen need). As a result, this was determined to be an association in our study and cause-and-effect or lack thereof, could not be discerned. Lastly, examination of moderate/severe BPD in Epochs 1 and 2 illustrate a significant increase in CPAP utilization and decreased mechanical ventilation which may indicate a negative impact of CPAP on lung development. This is consistent findings of Doyle et al who found that neonates receiving non-invasive ventilation for more than 30 days had more airway obstruction when tested at 8 years of age [9]. This study questioned whether less invasive respiratory support is actually beneficial long-term.
Another important finding from our study is demonstrating the wide variability using the four definitions of BPD (Table 4). While inconsistency across definitions is not surprising, it is very concerning because it highlights the lack of specificity among current BPD definitions despite being applied within a single institution. As a result, BPD pharmaceutical development has been hampered, as most clinical trials have shown no impact, most likely due to the outcome measures chosen and not the drug/biologic itself. It also highlights the inability to compare BPD outcomes from different trials or studies that do not use the same BPD definition. Our data supports the currently evolving strategy adopted by researchers, sponsors, and the Food and Drug Administration, which is to assess for direct evidence of chronic respiratory morbidity (e.g. hospital admissions, wheezing/coughing from asthma, use of respiratory medications) at one year corrected age–a more accurate and a clinically meaningful outcome for parents, families, and regulators [36].
While our data are consistent with that of COIN, SUPPORT, and CURPAP randomized trials, our patient population represents a more recent cross-section of patients exposed to the more current respiratory care practices [6, 7, 33]. Additionally, strengths of our study include a large sample size with an abrupt change in practice patterns along with comparisons of outcomes across four current BPD definitions.
A further unique aspect of our population in both Epochs is the large percentage of inborn infants and the ability to follow infants for prolonged periods to use the applications of the different definitions (ie the 40 wk definition). Despite this regionalization and uniformity of care in both Epochs, once again the incidence of BPD remained relatively constant.
In summary, BPD is a clinically meaningful outcome as it potentially designates infants who require closer pulmonary follow-up and because it can impact long-term pulmonary and neurodevelopmental outcomes. However, the wide variability in the incidence of BPD in our data reflects the difficulty with using these definitions to optimally plan postnatal follow-up and there remains no consensus that these current definitions represent the most appropriate clinical or research outcome measure [34] [35]. It is essential to identify predictive criteria early in postnatal life and standardize a BPD definition to develop the next generation of novel therapies. Identifying appropriate, at-risk infants for researchers and continuing to better understand BPD phenotypes and the pathophysiology of acute and chronic lung injury will ultimately enable clinicians to change the course of prematurity-related respiratory outcomes.
Abbreviations: BPD- Bronchopulmonary Dysplasia, PMA – Postmenstrual Age, VON – Vermont Oxford Network, NIH - National Institutes of Health, NRN - Neonatal Research Network, CPAP - Continuous Positive Airway Pressure, non-invasive positive pressure ventilation.
Acknowledgements: We would like to thank Jamon Foster and Ariel Scalise for assistance with data collection and Samantha Kumarasena and Andrea Clapp with data organization. We would also like to thank Drs. Turcu, Jassar, and Brazauskas for their valuable input during the course of the research and Janis Breeze who assisted with data analysis.