Response to Bronchodilators Administered via Different Nebulizers in Patients With COPD Exacerbation

Abstract

BACKGROUND:

The recommended treatment of COPD exacerbations includes administration of short-acting bronchodilators that act to reverse bronchoconstriction, restore lung volumes, and relieve breathlessness. In vitro studies demonstrate vibrating mesh nebulizers (VMNs) provide greater drug delivery to the airway compared to standard small-volume nebulizers (SVNs). We examined whether the physiological and symptom response to nebulized bronchodilators during a COPD exacerbation differed between these 2 modes of bronchodilator delivery.

METHODS:

Subjects hospitalized with a COPD exacerbation participated in a comparative clinical effectiveness study of 2 methods of nebulization. Using block randomization, 32 participants in this open-label trial were administered salbutamol 2.5 mg/ipratropium bromide 0.5 mg via vibrating mesh (VMN group, n = 16) or small-volume jet nebulizer (SVN group, n = 16) on one occasion. Spirometry, body plethysmography, and impulse oscillometry were performed and Borg breathlessness scores recorded pre bronchodilator and at 1 h post bronchodilator.

RESULTS:

Baseline demographics were comparable between groups. Mean FEV₁ was 48% predicted. Significant changes in lung volumes and airway impedance were seen in both groups. Inspiratory capacity (IC) increased by 0.27 ± 0.20 L and 0.21 ± 0.20 L in the VMN and SVN group, respectively, between group difference P = .40. FVC increased in the VMN group by 0.41 ± 0.40 L compared to 0.19 ± 0.20 L with SVN, between group difference P = .053; and residual volume (RV) decreased by 0.36 ± 0.80 L and 0.16 ± 0.50 L in the VMN and SVN group, respectively, between group difference P = .41. The VMN group had a significant reduction in Borg breathlessness score, P = .034.

CONCLUSIONS:

Greater improvement in symptoms, and larger absolute change in FVC, was observed in response to equivalent doses of standard bronchodilators administered by VMN, compared to SVN, but no substantial difference in change in IC.

Introduction

COPD is a chronic inflammatory disease of the airways. The World Health Organization estimates that 64 million people worldwide have a diagnosis of COPD. Progressive airway narrowing arises from long-term exposure to noxious fumes and gases, most commonly cigarette smoke, often in genetically susceptible individuals.¹ Dyspnea, resulting from expiratory air-flow limitation, is the cardinal clinical symptom in COPD and is accompanied by chronic cough and sputum production. Exacerbations of the disease occur, often due to a viral or bacterial trigger.^2,3 An abrupt increase in air-flow resistance ensues due to mucus hypersecretion and bronchial plugging within the small airways. This leads to a worsening of expiratory flow limitation and an increase in end-expiratory lung volume (EELV), and thus lung hyperinflation, with resultant worsening dyspnea³. In severe cases, subjects with a COPD exacerbation require admission to hospital for treatment.

Short-acting bronchodilators are a mainstay of the treatment of COPD exacerbations.^1,4 Bronchodilation, by inhaled β₂ agonists and anti-muscarinic agents both alone or in combination, acts to increase airway caliber, thus reducing obstruction to expiratory flow, facilitating restoration of resting lung volumes, and improving symptoms. Physiologically, this manifests as improvement in FEV₁ and in measures of lung volume including FVC, inspiratory capacity (IC), and residual volume (RV).^5–9

Whereas either nebulizer or metered-dose inhaler with spacer can be used for the delivery of bronchodilators in COPD, nebulization is usually the preferred and most convenient mode of bronchodilator delivery in acutely unwell subjects.¹ The most commonly used nebulizer in the hospital setting is the small-volume nebulizer (SVN).¹⁰ Conventional SVN consists of a chamber into which the solution to be nebulized is placed. Compressed air or gas, often oxygen, is passed continuously through a narrow feeding tube in the center of the chamber and aerosolizes the solution, which can then be inhaled through a mouthpiece or face mask. Due to continuous aerosolization, up to 50% can be wasted during expiration;¹¹ and this may be exacerbated in the acutely obstructed, tachypneic subject.

In recent years, devices using novel nebulization technologies such as vibrating mesh have become widely available. Vibrating mesh nebulizers (VMNs) consist of a small, perforated aperture plate (mesh) surrounded by a vibrational element that, when electrical energy is applied, draws liquid through each of the apertures within the mesh, producing an aerosol. Studies have demonstrated superior deposition of aerosol within the lung following mesh nebulization compared to SVN in mechanically ventilated subjects with COPD,¹² simulated mechanically ventilated subjects,¹³ healthy volunteers delivered via noninvasive ventilation (NIV),¹⁴ and using a COPD lung model.¹⁵ A previous study demonstrated reduced emergency department (ED) stay and a reduction in hospital admission, and overall decreased cumulative dose of short-acting bronchodilators, with VMN delivery compared to SVN in the acute ED setting. However, the treatment effect by diagnostic group (ie, COPD or asthma) was not determined.¹⁶ In mechanically ventilated subjects with asthma, a trend to reduced ICU stay was observed when bronchodilators were delivered via VMN over pressurized metered-dose inhaler with AeroChamber or SVN.¹⁷

Fifty-one percent of ED presentations with COPD exacerbations require admission to hospital for treatment.¹⁸ The heterogenous nature of COPD exacerbations and individual responses to treatment result in variable hospital lengths of stay.¹⁹ The potential benefit of bronchodilator delivery via VMN versus SVN, and the physiological mechanism underlying any response, in a self-ventilating cohort hospitalized for treatment of a COPD exacerbation has not been explored.

The aim of this proof-of-concept study was to test the hypothesis that since in vitro VMN provides superior drug delivery compared to standard oxygen-driven SVN then in vivo this device may yield a greater clinical response to bronchodilation in subjects with COPD. Clinical bronchodilator response was determined by measuring changes in lung volumes, spirometry, and in subject-reported symptoms.

QUICK LOOK.

Current knowledge

Inhaled bronchodilators are a key component of COPD exacerbation management. Vibrating mesh nebulizer (VMN) technologies have been shown to improve bronchodilator delivery to the airway in lung models compared to standard jet nebulization. The clinical benefits of these devices in spontaneously breathing hospitalized subjects during a COPD exacerbation have not been explored.

What this paper contributes to our knowledge

In spontaneously breathing subjects hospitalized with a COPD exacerbation, delivery of an equivalent dose of bronchodilator medications via VMN provided greater symptom reduction compared to small-volume nebulizer. A larger FVC response to bronchodilator therapy was observed with VMN but no significant difference in change in inspiratory capacity. Varying the method of bronchodilator delivery may have a clinically relevant impact in COPD exacerbations.

Methods

This was a prospective, open-label randomized trial carried out at Beaumont Hospital, Dublin, Ireland, between February–August 2016. The study was sponsored by Aerogen, Galway, Ireland. The study was designed independently by the principal investigator. Subject recruitment, test procedures, data analysis, and data interpretation were all carried out by the Royal College of Surgeons in Ireland research and statistics teams without any input from the sponsor. Ethical approval was obtained from the Beaumont Hospital Ethics Committee. The study was registered at ClinicalTrials.gov, NCT02686086, before any subjects were enrolled. The study was registered and designed as a pilot study; it was anticipated that the results of the study would inform a larger body of work aimed at understanding how stay and rate of hospitalization due to COPD exacerbations may be reduced.²⁰

Subjects admitted to the hospital with a COPD exacerbation, as diagnosed by the admitting physician, and within the first week of hospital admission were approached to participate in the study by the research team. Only subjects prescribed regular nebulized bronchodilators as part of their acute medical care and without contraindication to salbutamol 2.5 mg plus ipratropium bromide 0.5 mg were approached to participate. All subjects were receiving these bronchodilators through an oxygen-driven SVN, Hudson Micro Mist (Teleflex, Wayne, Pennsylvania), in line with local hospital policy. All subjects had a known diagnosis of COPD with a post-bronchodilator FEV₁/FVC of < 0.70 and FEV₁ of < 80% predicted (Global Initiative for Chronic Obstructive Lung Disease [GOLD] stage 2–4).¹ Subjects with COPD with any other concurrent acute medical cause for admission, such as decompensated heart failure or respiratory sepsis, were excluded. Those with significant confusion, resulting in an inability to follow commands, or those who were clinically unstable were not recruited. Clinical instability was defined as significant hypoxemia (oxygen saturations < 88% on room air and no previous history of resting hypoxemia), hypotension (systolic blood pressure < 90 mm Hg), significant tachycardia (heart rate > 120 beats/min), tachypnea (breathing frequency > 22 breaths/min), or presence of respiratory acidosis. Any subject whose spirometry technique was deemed poor or non-reproducible on previous studies was excluded. On recruitment, written informed consent was obtained.

All tests were carried out at the same time each day, between 0630 and 0800 in the morning, in the pulmonary function unit. Prior to testing, all short-acting inhaled and nebulized therapy was withheld for at least 5 h (12 h in the case of long-acting bronchodilators). Pre- and post-bronchodilator testing was carried out in the pulmonary function laboratory with a trained respiratory scientist. Subjects were randomized to use either a VMN, Aerogen Ultra (Aerogen, Galway, Ireland), VMN group; or an oxygen-driven SVN, Hudson Micro Mist, as per our institution's standard of care, SVN group, using computer-generated block randomization that was allocated post subject recruitment. Subjects were blinded to their allocated group up to the time of bronchodilator administration. Each subject received nebulized salbutamol 2.5 mg and ipratropium 0.5 mg (Combivent UDV, Boehringer Ingelheim, Ingelheim, Germany) immediately after the first set of pulmonary function measurements. Medication was administered in the pulmonary function unit by the research team. One h post administration, all tests were repeated.

Subjects completed spirometry, body plethysmography (Vmax Encore pulmonary function testing system, Vyaire Medical, Mettawa, Illinois), and impulse oscillometry (IOS) (Jaegar MasterScreen IOS, Vyaire Medical) in accordance with American Thoracic Society (ATS)/European Respiratory Society criteria.^21–23 The sequence of testing pre and post bronchodilator was consistent for all subjects. The best of 3 spirometry measurements and relaxed vital capacity (VC) measurements were recorded.²¹ Mean functional residual capacity (FRC) and corresponding mean expiratory reserve volume measurements were calculated, from which the RV and total lung capacity (TLC) were derived.²² The mean of IC volume and IOS measurements were used in accordance with recommended guidelines.^22,23 Subjects scored their level of dyspnea on the Borg Breathlessness Scale²⁴ before each set of measurements. Mean daily heart rate for the day prior to and on the day of the study, for each study arm, was calculated and compared.

The primary outcome was the change in EELV post–nebulized bronchodilator as measured by the absolute change in IC. IC is an indirect measure of EELV and lung hyperinflation.^25,26 Decreases in IC have been shown to correlate well with the onset of dyspnea and exercise limitation in COPD,²⁶ with improvements in these parameters occurring as the IC increases.^8,9,27,28

Secondary outcome measures included changes in spirometry (FEV₁, FVC, forced expiratory flow at 25–75% FVC, FEV₁/FVC; and body plethysmography–derived measurements TLC, FRC, RV, and slow VC), in respiratory reactance (X5) and resistance (R5 and R20) as measured by IOS, and change in Borg breathlessness score.

Data are presented as mean ± SD or median (interquartile range) unless otherwise stated. Normality of data was confirmed graphically using histogram and statistically by Shapiro-Wilk test. Comparison of baseline demographic data between nebulizer groups was performed using unpaired t test, Wilcoxon rank-sum test, or chi-square test where appropriate. Within-group changes in all measured parameters were assessed using paired t test. Between-group comparisons of the pre- to post-bronchodilator difference in outcome measures were analyzed using unpaired Student t test. Between-group differences in these measurements are reported as mean (95% CI). Statistical significance was set at P < .05. Statistical analysis was performed using Stata v.13.1 (StataCorp, College Station, Texas).

Results

Thirty-eight subjects were screened to participate in the study, and 32 subjects consented to and completed the study. Reasons for non-recruitment are shown in the consort diagram in Figure 1. Sixteen subjects were randomized to the VMN arm and 16 to the SVN arm. There were complete pre- and post-bronchodilator spirometry data available for all participants. Acceptable lung volume measurements from body plethysmography were achieved by all but 2 subjects, one from each group. IOS measurements were available for 31 subjects.

Fig. 1.

Flow chart.

Baseline demographics are shown in Table 1. The mean age of participants was 71 ± 8.1 y. All participants had GOLD stage 2–4 COPD with a mean FEV₁ of 1.2 ± 0.5 L, 48 ± 18% predicted. The median time from the day of admission to the day of testing was 5 ± 4d. There was no significant difference in the baseline characteristics between groups, in their pre-bronchodilator pulmonary function measurements or symptom scores, or in the timing of study procedures (Table 1).

Table 1.

Baseline Demographics

There was substantial variability in individual subject responses to bronchodilator across both groups (VMN and SVN) as shown in Table 2. On average, both groups achieved significant within-group changes in IC, P < .01. IC increased 0.27 ± 0.20 L in the VMN group and 0.21 ± 0.20 L in the SVN group (Figure 2 and Table 3), between-group difference 0.06 (95% CI −0.09 to 0.22) L, P = .40. RV and FRC decreased, and VC increased, in all groups post bronchodilator (Figure 2 and Table 3). RV and FRC reduced by 0.36 ± 0.80 L and 0.23 ± 0.60 L in the VMN group and by 0.16 ± 0.50 L and 0.12 ± 0.50 L, respectively, in the SVN group. Both groups achieved significant within-group improvements in mean VC of 0.34 ± 0.50 L for the VMN group and 0.26 ± 0.30 L for the SVN group, P ≤ .01 for both comparisons. For all lung volume measures, the absolute improvement was greater in the VMN group; however, there was no statistically significant difference over that achieved with the SVN. The overall change in TLC was the same in both groups at 0.04 ± 0.80 L VMN and 0.05 ± 0.60 L SVN.

Table 2.

Individual Study Subject Post-Bronchodilator Changes in Mean Inspiratory Capacity, FVC, and Residual Volume

Fig. 2.

Lung volume response to nebulized bronchodilator. Mean (SD) changes in absolute values of FVC, inspiratory capacity (IC), and residual volume (RV) post bronchodilator for each group are shown. There was a significant improvement in post-bronchodilator FVC and IC values within each group, P < .01.** The improvement in FVC among the vibrating mesh nebulizer (VMN) group was not significantly greater than that achieved by the small-volume nebulizer (SVN) group, P = .053. There was no significant difference in IC change between groups. Absolute RV reduced post bronchodilator in each group (VMN group 0.36 [0.80] L, SVN group 0.16 [0.50] L) with no statistically significant change. IC = inspiratory capacity; RV = residual volume; VMN = vibrating mesh nebulizer; SVN = small-volume nebulizer.

Table 3.

Paired Pre- and Post-Bronchodilator Results for Spirometry, Lung Volumes, and Respiratory Impedance Measurements for Each Group

Pre- and post-bronchodilator values for both FEV₁ and FVC and the differences achieved for both the VMN and SVN groups are shown in Table 3. FEV₁ increased significantly by 0.17 ± 0.20 L, 20%, and 0.13 ± 0.10 L, 18%, within VMN and SVN groups, respectively, with no significant difference between the 2 groups. Differences were observed in the absolute and percentage increase in FVC between the groups; the VMN group achieved an absolute improvement in FVC of 0.41 (0.40) L, 21%, compared to a 0.19 ± 0.20 L, 10%, improvement within the SVN group, P = .053 (Figure 2). Neither group demonstrated any significant within-group change in FEV₁/FVC. Within- and between-group changes in respiratory reactance are shown on Table 3. Total and peripheral resistance decreased significantly in both groups while reactance increased. There was no significant difference in recorded changes between nebulizer groups.

The VMN group recorded a significant improvement in the Borg breathlessness score pre and post bronchodilator. Borg score decreased in this group from a mean of 4.0 ± 2.8 pre bronchodilator to 3.3 ± 2.5 post bronchodilator, P = .034. In the SVN group, Borg breathlessness score decreased by 0.1 ± 0.8, P = .63. There was no significant difference in mean daily heart rate in the day preceding and day of testing in either group.

Discussion

This study assessed the bronchodilator response to a standard dose of a combination bronchodilator administered to a cohort of subjects with a COPD exacerbation. Two different delivery systems, a VMN and SVN, were compared. Both groups of subjects demonstrated a positive response to the medication, with significant increases in measures of lung volume, in keeping with the known effect of bronchodilators in subjects with COPD.^5,6 A substantial difference in IC change between the VMN and SVN group was not demonstrated. The absolute change in FVC post-bronchodilator was > 200 mL (11%) greater in the VMN group than the SVN group but not statistically significant, P = .053. There was no significant difference between changes in other lung volume and spirometry measurements or in markers of respiratory impedance (as measured using IOS) between the 2 groups. The absolute and percentage improvements were, however, greater in the VMN group across all the studied parameters. A significant improvement in Borg breathlessness score was recorded post bronchodilator in the VMN group.

Newton et al²⁹ have previously characterized bronchodilator response in COPD in terms of flow response and volume response. Flow response was that in which FEV₁ increased by > 12% and ≥ 200 mL in accordance with ATS reversibility criteria.³⁰ Volume response incorporated the effect on FVC, RV, and IC. An increase in FVC of > 12% and ≥ 200 mL; a 10% increase in predicted IC or 200 mL; or a 20% decrease in predicted RV, an estimated 300–500 mL change, were deemed indicative of significant volume change.²⁹ Volume responses are more reflective of the changes in lung mechanics that occur during COPD exacerbations, particularly the development of lung hyperinflation, which is responsible for the onset of dyspnea.^25,26,29,31 For this reason, we chose IC, an indirect measure of lung hyperinflation, as our primary outcome measure.³² As an exacerbation recovers, symptom resolution is coupled with significant reductions in EELV, an increase in IC and FVC, and a subsequent increase in FEV_1.^8,9,28

Whereas our cohort demonstrated significant percentage improvements in flow, the absolute improvement in FEV₁ did not exceed the threshold for bronchodilator responsiveness of 200 mL in either group. Further, despite high percentage improvements in FEV₁ of 20% (VMN) and 18% (SVN), the FEV₁/FVC remained unchanged. This suggests that the post-bronchodilator improvements in FEV₁ resulted from an increase in expired volume due to reductions in air trapping and not solely due to changes in airway caliber. This was true of both the VMN and the SVN groups. The VMN group achieved greater absolute improvements in FVC, RV, and in IC, with both FVC and RV change meeting the threshold for a significant post-bronchodilator volume response.^29,30 In the VMN group, FVC increased by a mean of 410 mL (21%); and RV decreased by 360 mL compared to 190 mL (10%) and 160 mL in the SVN group, respectively.

Individual subject responses to nebulized bronchodilator varied substantially. We did not explore the reasons. However, the degree of variability in physiological measurements seen in this study is in keeping with that observed in other physiological studies of COPD exacerbations^8,33 and may reflect the heterogeneous nature of COPD itself and of COPD exacerbations.

The VMN group had a significant reduction in post-bronchodilator breathlessness score. Dyspnea in COPD, both during exercise and exacerbation, correlates to changes in lung volume and improves in parallel with reducing lung hyperinflation.^8,9,26,28,34 Hence, it is likely that the observed changes in Borg score are reflective of the greater improvement in lung volume in this group.

Whereas this was a small-scale study, examining physiological and symptom changes following bronchodilator nebulization at only one point during a COPD exacerbation, it is plausible that the use of mesh nebulizers could increase bronchodilator response. In previous studies, VMNs have demonstrated superior deposition of aerosol in the lungs, meaning a greater penetration of active drug into the smaller airways, which are a major site of obstruction in COPD.^14,35 Comparative studies have shown that VMNs also provide a higher dose for inhalation, over 12.0% versus 1.5% for SVNs, and leave smaller RVs than SVNs, thereby making a higher concentration of active drug available for inhalation.³⁶ The use of a valved adapter combined with a mouthpiece also reduces the risk of significant aerosol wasting during exhalation, one of the major disadvantages of SVNs.¹¹ Interestingly, a study conducted using valved mask or reservoir interfaces with the SVN found that whereas the inhaled mass from the SVN increased, delivery efficiency was less than that obtained with a VMN, suggesting that use of a valved interface alone does not account for observed improvements in drug delivery.³⁶ As the focus of this study was to examine the clinical response to different methods of bronchodilator delivery, the exact dose of bronchodilator delivered to the subject was not measured. It is possible that comparable improvements in lung physiology and symptoms could be achieved with SVN by increasing the dose of bronchodilator administered.

This is one of the first studies directly comparing VMN to SVN in spontaneously breathing subjects with COPD in a clinical setting. All participants had moderate to severe COPD with a severe exacerbation of their disease that necessitated hospital admission. Both study groups were well matched with regard to baseline demographics, pre-bronchodilator lung function, and time from onset of exacerbation to testing. Studies in subjects with COPD exacerbations requiring treatment with NIV have reported similar results.³⁷ Our study number was small, and the results should be interpreted in that context; however, the results do form a basis for further studies in this area.

A major disadvantage of vibrating mesh technology is cost. At the time of this study, the VMN device used cost in the region of €10 ($11) more per person/week than the SVN used. The results of this pilot study will inform a larger study to determine whether the continued use of a VMN during a COPD exacerbation results in shorter recovery time or shorter length of hospital stay.

Limitations

This study only examined bronchodilator response to one dose of combined ipratropium bromide/salbutamol and on one occasion during the course of the hospital admission. Medical management of the exacerbation was directed by the subject's admitting physician and not directed by the research team. Whereas we only approached subjects who were already prescribed dual short-acting bronchodilators as part of their hospital medical care to participate in the study, there may have been between-subject variations in the other COPD exacerbation treatments they received. The SVN used in this study is that currently employed by our institution, and our results cannot be generalized to all SVNs. All subjects were required to attend the pulmonary function laboratory for measurements; therefore, those subjects with acute type 2 respiratory failure and requiring NIV were not included. The average stay at time of study procedures was 5 d. It is possible that greater bronchodilator response may have been observed earlier in the course of the exacerbation. However, the timing of measurements was comparable to Avdeev et al³⁷ in their study of nebulized bronchodilator response in mechanically ventilated subjects with COPD. Additionally, several studies have demonstrated that physiological improvements indicative of exacerbation recovery are evident at 42 d⁹ and 60 d⁸ post exacerbation onset. Despite differences in the absolute change in volumes post bronchodilator in the VMN and SVN group, statistical significance was not reached.

Conclusions

In a cohort of subjects hospitalized with a COPD exacerbation, improved symptoms and a larger absolute increase in FVC were observed when equivalent doses of bronchodilators were delivered via VMN compared to SVN. Substantial differences in IC change were not detected. Further larger studies are needed to determine the clinical impact of VMNs on COPD care.