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.