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.