Discussion
The objective of this trial was to compare the short-term tolerability
and efficacy of two different dose levels of aerosolized albuterol to
aerosolized saline placebo in very preterm infants with sBPD receiving
invasive mechanical ventilation. Relative to pre-treatment values,
albuterol and saline produced significant improvements in EF75. Both
dose levels of albuterol also led to modest but significant average
post-treatment reductions in peak inspiratory pressure and improvements
in minute ventilation. However, when using linear mixed effects models
to compare the relative change in outcome measures between albuterol and
aerosolized saline, there was no evidence of net benefit or harm with
either albuterol dose level for the primary outcome of EF75. The 2.5mg
dose of albuterol was more effective than saline placebo for the outcome
of post-treatment peak inspiratory pressure, but with a small average
net increase in heart rate. Collectively, these trial data suggest that
aerosolized albuterol and saline can positively affect respiratory
dynamics in ventilated very preterm infants with sBPD. A 2.5mg dose of
albuterol may provide a modest respiratory advantage over the other two
studied therapies, but clinicians should monitor changes in heart rate
if administering this dose.
To our knowledge, this is the first randomized, placebo controlled trial
to evaluate aerosolized bronchodilator therapy for the treatment of
established sBPD.
Prior trials have examined inhaled bronchodilators in ventilated preterm
infants at high risk of developing BPD13-18. Although
most of these studies used an alternative drug therapy or compared the
efficacy of different delivery devices rather than a placebo control,
they collectively show post-treatment improvements in respiratory
mechanics and oxygenation with inhaled bronchodilator therapy in
ventilated preterm infants13-18. More recently,
several observational studies have examined the use of aerosolized
albuterol in preterm infants with evolving or established
sBPD5,9,10,19. In a retrospective analysis of
pulmonary function testing (PFT) data, Morrow et al. assessed the
response to bronchodilator therapy in infants with evolving BPD using a
single breath occlusion technique19. Fifty-two percent
of infants studied had a reduction in respiratory system resistance of
10% or greater, 13% had a compliance reduction of <10%,
while 35% had no apparent response to bronchodilator
administration19. There were no significant
differences in respiratory system compliance measurements for any
infants19. Shepherd et al. also observed heterogeneity
in the bronchodilator responsiveness in a retrospective cohort of
infants with established sBPD, noting greater efficacy associated with
predominately obstructive rather than restrictive lung
disease9. Potentially consistent with the findings of
Morrow et al, our observation of a post-treatment reduction in PIP may
be the result of a reduction in pulmonary resistance with aerosolized
bronchodilator therapy.
We chose expiratory flow at 75% of the exhaled volume as the primary
means to assess bronchodilator responsiveness in this study population.
We hypothesized that relaxation of airway smooth muscle would increase
expiratory flow from 0 – 75% of the tidal volume and produce a net
increase in EF75 indicating a positive bronchodilatory effect. As a
secondary outcome, we examined changes in peak inspiratory pressure.
Since we did not change ventilator settings after aerosol
administration, we propose that peak inspiratory pressure during volume
guarantee ventilation is a reasonable surrogate measure of changes in
airway resistance. Of note, previous studies have used alternative
methods to assess bronchodilator responsiveness in infants and
children13,20-22. However, these methods require
manipulation and/or interruption of the ventilators settings and pattern
intern potentially changing the pulmonary mechanics from those of the
primary ventilator strategy. Measurement of tidal mechanics using
ventilator output signals requires a change in ventilator support to
constant flow without pressure regulation, and imposition of an
inspiratory hold in a passively ventilated
patient21,22. Other available methods require the use
of specialized equipment to perform brief
occlusions13,20. We purposely chose a measure that not
need specialized equipment or require a change to the patients’
mechanical ventilation settings. This enabled us to use an outcome
measure that could be easily reproduced in any NICU regardless of
research resources (equipment or personnel) and would not require
multiple disconnections of the ventilator circuitry which are typically
not well tolerated in this patient population.
The lack of an apparent benefit of albuterol relative to saline placebo
for our primary outcome of EF75 may be the result of a positive
treatment effect of normal saline. Prior studies have shown benefit with
aerosolized saline in conditions such as chronic obstructive pulmonary
disease and bronchiolitis23,24. Aerosolized saline may
increase hydration of the mucocillary bed, improve ciliary function and
mucous clearance, and thereby decrease airway
resistance25,26. The observed improvements in EF75
after nebulized saline suggest airway surface dehydration and resultant
ciliary dysfunction could exist in the sBDP population. Despite a
potential treatment effect, however, our use of normal saline a placebo
is consistent with multiple other randomized controlled trials of
bronchodilators24. Moreover, normal saline is present
in albuterol solutions used for nebulization. Thus, our use of normal
saline simply removed the active drug from the nebulized solution. An
alternative study design could employ a sham treatment without an actual
placebo. This may overcome the apparent treatment effects of aerosolized
saline, but could negatively impact the masking of clinicians and
investigators to the assigned therapy.
Traditionally at our facility, the dose of nebulized medications is
selected according to patient weight. However, this practice contradicts
to the results of aerosolization studies, which show that alveolar drug
delivery depends on breathing patterns and is largely independent of
patient weight27-29. High respiratory rates and small
tidal volumes effect deposition because less of the medication is drawn
into the lungs and the change in respiratory pattern as children age
into adults results in greater deposition of
medication27-29. This change in pattern of deposition
results in self-regulation of dose as breathing pattern changes.
Additionally, we commonly administer aerosolized medications through an
artificial airway during mechanical ventilation. In vitro studies of
this route of administration show that only 12% - 14% of the total
drug dose is delivered to the distal airways under these
conditions30,31.
There are several limitations to this study. First, this was a single
center trial and may not be generalizable to populations in other
centers. Although the number of enrolled infants was selected by an a
priori sample size estimation, the overall number of participants was
relatively small and larger studies are needed to confirm the study
findings. Lastly, the primary outcome utilized in this trial is not an
established indicator of bronchodilator response in mechanically
ventilated infants, but our secondary outcomes, including measurement of
PIP, have been used in prior studies of bronchodilator responsiveness in
mechanically ventilated subjects20,33,34.