In patients with reversible obstructive pulmonary disease, away from an exacerbation, albuterol delivered by vibrating mesh nebulization through an NHF circuit appeared non-inferior to standard facial mask jet nebulization in terms of FEV
1 increase. This was in part due to a small but a significant increase in FEV
1 due to NHF without the addition of bronchodilator nebulization. To the best of our knowledge, this is the first controlled study in adults documenting clinical efficacy of nebulization within an NHF circuit adequately controlling for all confounding factors. These results have important clinical implications. As the use of NHF is expanding, physicians will increasingly be faced with patients undergoing NHF and requiring inhaled bronchodilator therapy [
23]. Given the lack of controlled data, interrupting NHF therapy to deliver the inhaled medication may currently be the preferred option; these results show that albuterol can be delivered within the NHF circuit with the same efficacy and tolerance avoiding cumbersome equipment switches. These results are in line with the study of Bräunlich et al. who used a homecare NHF device to deliver a combination of albuterol and ipratropium bromide placing a jet nebulizer close to the nasal cannula but lacked a control group without nebulization [
24]. Of note, positioning the nebulizer close to the nasal cannula may be suboptimal, as it favours aerosol deposition in the cannula. This deposition reduces drug delivery to the patient but was also associated with aerosol nasal dripping which may impact patients’ comfort [
11]. Our results provide controlled evidence supporting the observation made by Morgan et al. of efficient albuterol delivery after nebulization within a NHF circuit set-up similar to the present one among children with acute bronchiolitis [
18].
Effects of NHF without bronchodilator nebulization on pulmonary function tests are of complex interpretation. We observed a statistically significant increase in FEV
1 after Control-NHF, albeit modest in magnitude (median increase of 50 mL and 3%, values below validated thresholds to define reversibility [
19]); this result supports the hypothesis of an NHF-induced bronchodilation. Interestingly, 20% of the patients showed significant increases in FEV
1 after Control-NHF meeting guideline criteria for airflow obstruction reversibility without having received a bronchodilator. Of note, FEV
1 was measured after interruption of NHF in patients breathing spontaneously unlike other physiological studies which observed an increase in lung volumes measured during NHF therapy [
25]. This may also explain the lack of association between flow limitation and FEV
1 increase after Control-NHF. Plethysmography-measured lung volumes were not significantly affected by NHF in the present study. One can speculate on potential mechanism such as positive airway pressure and improved mucus hydration during the 30-min NHF session leading to the significant increase in FEV
1 once the therapy is interrupted. Indeed, improved mucus clearance may lead to improved lung mechanics; however, no major cough and expectoration was observed among the included patients. NHF may also induce changes in respiratory pattern potentially leading to higher tidal volume and eventually to deeper inspiration during spirometry manoeuvres. Such mechanisms will need to be investigated in the future, particularly given the ongoing studies evaluating NHF among patients suffering obstructive pulmonary disease. This study has important limitations. Only stable patients were included; thus, extrapolation to the acute care setting of unstable decompensated patients warrants evaluation. Results cannot be extrapolated to other pharmacological classes, as the favourable results observe here in terms of nebulization efficiency during NHF are due in part to the large therapeutic index of albuterol [
26]. Deposition studies performed in humans suggest other drugs like antibiotics are unlike effective when inhaled through an NHF circuit [
17]. Clinical efficacy studies are required in intensive care unit, emergency department and pulmonology ward patients. Two different nebulizers were used in the study. We aimed to compare usual practice (facial mask jet nebulization) to the new modality of NHF-nebulization using a vibrating mesh nebulizer. Jet nebulization within the NHF circuit, albeit feasible, comes with important limitations as the gas driving the nebulizer interferes with the NHF oxygen content, humidity and temperature. Vibrating mesh facial mask nebulization is currently of uncommon practice. Thus, the potential limit of using different nebulizers represents a pragmatic choice favouring clinical applicability of the results. Using jet nebulization in combination with nasal high-flow therapy would need further evaluation. Of note, the study did not comprise a condition of sham jet nebulization to delineate individual effect of beta-2-adrenergic agonist nebulization per se. Only one NHF setting (temperature, flow rate, cannula size) and one dose of albuterol were evaluated clinically. However, results in other conditions, tested in the bench study, can give indications of potential dose adjustments, in case of nebulization with higher flow rates for example. The significantly improved delivery observed in vitro with non-humidified settings allows for new innovation in NHF devices to improve combined inhaled drug delivery.
In conclusion, the present work shows that albuterol vibrating mesh nebulization within an NHF circuit induces similar FEV1 increases and patient comfort and tolerance compared to standard facial mask jet nebulization and can be implemented in clinical practice. Beyond pharmacologically induced bronchodilation, NHF by itself may induce a small but significant increase in FEV1 which deserves further evaluation.