Supplemental oxygen strategies in children with bronchopulmonary dysplasia (BPD) after the neonatal intensive care unit: the SOS BPD study.

Extreme preterm birth leads to an arrest in lung and pulmonary vascular
development which may result in bronchopulmonary dysplasia (BPD). BPD is a
chronic lung disease that leads not only to life-long respiratory issues, but
also to adverse cardiovascular and neurodevelopmental outcomes. Moreover, the
impact on parents of taking care of a child with BPD can be significant,with
increased stress, low sleep quality and depressive symptoms, all having an
impact on their quality of life. In the Netherlands, BPD affects approximately
500 infants each year, of whom two thirds have the moderate to severe form of
the disease, which means that they are still oxygen-dependent at 36 weeks
postmenstrual age (PMA).

The main treatment for BPD is supplemental oxygen. Several randomised
controlled trials have assessed a liberal versus a restricted use of
supplemental oxygen in extreme preterm infants in the first weeks of life on
major outcomes such as death, development of BPD or retinopathy of prematurity,
and neurodevelopment. However, no study has ever examined the optimal oxygen
saturation (SpO2) target that should be obtained by supplemental oxygen in
children with established BPD after 36 weeks PMA. This target may be different
from the established SpO2 targets in the first weeks of life, as at 36 weeks
PMA vulnerability to oxidative stress (and e.g. development of retinopathy of
prematurity) has most probably decreased. Moreover, alveolar growth only starts
from approximately 34 weeks of gestation, announcing a new era in lung growth.

Due to the lack of studies, the Dutch BPD guideline refrains from any
recommendations on SpO2 targets in children with established BPD. This has
resulted in wide practice variability between hospitals in lower SpO2 targets,
with most hospitals accepting a lower SpO2 limit of 90%. However, this limit
may be too low, because, according to a number of observational studies,
supplemental oxygen may decrease respiratory symptoms, prevent pulmonary
hypertension, be beneficial for neurodevelopment and improve weight gain if BPD
is present. Importantly, in children with BPD, body weight during infancy has
been positively associated with the amount of normal lung tissue as assessed
with CT scans, and better lung growth is related to increased lung function in
later life. Furthermore, poor weight gain is associated with increased
vulnerability to infections and supplementary oxygen may reduce the risk for
nosocomial infections and consequently for re-hospitalisation. On the other
hand, hyperoxia (e.g. too much oxygen) may result in increased levels of
reactive oxygen species and subsequent oxidative damage. This may negatively
influence lung development but also the development of other organs such as the
eyes and the brain. In short, too little oxygen may have detrimental effects on
preterm children with BPD, while too much oxygen should also be avoided, and it
is unknown where this balance lies between too little and too much oxygen.

The objective of this study is to determine the optimal lower oxygen saturation
target in children with moderate-severe BPD, i.e. children who are
oxygen-dependent at 36 weeks PMA.

This is a multi-centre randomised controlled, open study in children with
moderate-severe BPD from 36 weeks PMA onwards with two parallel arms:
1. weaning of supplemental oxygen based on SpO2 lower limit >= 95%
2. weaning of supplemental oxygen based on SpO2 lower limit >= 90%.

This is a non-blinded study because we considered it not feasible to blind
parents and treating physicians for SpO2, as supplemental oxygen will be weaned
based on SpO2. Study duration for each patient will be one year with three
visits: at inclusion and at 6 and 12 months corrected age.
Setting of the study: patients will be included between 36 and 38 weeks PMA,
when they are still admitted on the NICU or post-IC-high care units. Follow up
will be alongside neonatal follow up pathways at outpatient clinics.

Besides from the two saturation targets, there are no other interventions.

The burden associated with participation is minimal. As long as the children
are on respiratory support, we ask the parents or physician to download a
saturation profile from the pulse oximeter (which is already used for the child
because of the respiratory support) and send it to us. This saturation profile
will be done once a week when at home or twice a week when admitted.
Children will attend their regular check-ups in the outpatient clinic. We ask
the parents to fill in a questionnaire a few times.
Only if it is part of routine follow up, we will look at CT-scans,
echocardiography or multiple breath wash-out (MBW).

The risk associated with participation is minimal. The intervention (= higher
oxygen saturation target) will probably lead to better outcomes. Hyperoxia can
potentially lead to lung damage and retinopathy of prematurity. However, the
risk of these morbidities is considerably lower for children at the age of 36
weeks postmenstrual age than before this age. Potentially, the children in de
controle group (i.e. lower oxygen saturation target) will grow less and show
more work of breathing.