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Delivery of Aerosolized Bronchodilators by High-Flow Nasal Cannula
During COPD Exacerbation
Nicola
´s Colaianni-Alfonso, Ronan MacLoughlin, Ariel Espada, Yasmine Saa, Mariano Techera,
Ada Toledo, Guillermo Montiel, and Mauro Castro-Sayat
BACKGROUND: Bronchodilator delivery via a high-flow nasal cannula (HFNC) has generated
great interest in recent years. The efficacy of in-line vibrating mesh nebulizers with an HFNC
during COPD exacerbation is limited. The aim of this study was to evaluate the clinical response
of subjects with COPD exacerbation who require bronchodilator therapy (anticholinergic and
b-agonist) by using a vibrating mesh nebulizer in line with an HFNC. METHODS: This was a
prospective single-center study performed in a respiratory intermediate care unit that enrolled
patients with a diagnosis of COPD exacerbation who required noninvasive ventilation on admis-
sion. All the subjects underwent noninvasive ventilation breaks with an HFNC. After clinical
stability, pulmonary function tests were performed to assess changes in FEV
1
and clinical pa-
rameters before and after bronchodilation by using a vibrating mesh nebulizer in line with an
HFNC. RESULTS: Forty-six patients with COPD exacerbation were admitted. Five patients who
did not use noninvasive ventilation and 10 patients who did not receive bronchodilator treatment
with a vibrating mesh nebulizer were excluded. Thirty-one were selected, but 1 subject was sec-
ondarily excluded due to loss of data. Finally, 30 subjects were included. The primary outcome
was spirometric changes in FEV
1
. The mean 6SD FEV
1
before receiving bronchodilator treat-
ment by using a vibrating mesh nebulizer in line with an HFNC was 0.74 60.10 L, and, after
receiving treatment, the mean 6SD FEV
1
changed to 0.88 60.12 L (P<.001). Similarly, the
mean 6SD FVC increased from 1.75 60.54 L to 2.13 60.63 L (P<.001). Considerable differ-
ences were observed in breathing frequency and heart rate after receiving bronchodilator treat-
ment. No relevant changes were observed in the Borg scale or S
pO
2
after treatment. The mean
clinical stability recorded was 4 d. CONCLUSIONS: In the subjects with COPD exacerbation,
bronchodilator treatment by using a vibrating mesh nebulizer in line with an HFNC showed a
mild but significant improvement in FEV
1
and FVC. In addition, a decrease in breathing fre-
quency was observed, which suggests a reduction in loads imposed by dynamic hyperinflation.
Key words: COPD; high-flow nasal cannula oxygen; nebulization; aerosol; respiratory function tests.
[Respir Care 0;0(0):1–.© 2023 Daedalus Enterprises]
Introduction
One in 10 adults in the world’s population has COPD,
which causes some 3.2 million deaths a year and has become
1 of the 3 most common causes of death worldwide.
1,2
The
main burden of COPD mortality is seen in low- and middle-
income countries.
3
Bronchodilator therapy is currently the
main pharmacological treatment, and noninvasive ventila-
tion (NIV) is an effective and evidence-based therapeutic
tool in patients with COPD exacerbation.
4,5
High-flow nasal
cannula (HFNC) has gained popularity in recent years and
has been proposed as an alternative in patients with COPD
exacerbation for breaks in or intolerance to NIV.
6
In subjects
with COPD exacerbation, HFNC has been shown to reduce
PaCO2levels,
7,8
breathing frequency, and decrease work of
breathing, similar to NIV.
9
An HFNC delivers a heated and humidified air–oxygen
mixture to the patient, with FIO2that ranges from 0.21 to
1.0 and a flow up to 60 L/min through a large-bore nasal
cannula.
10
The use of an in-line vibrating mesh nebulizer
during HFNC therapy is a relatively novel combination;
vibrating mesh nebulizers do not alter the flow or FIO2
delivered by an HFNC because no oxygen source is
required for operation.
11
Clinical studies in subjects with
stable COPD have demonstrated a satisfactory bronchodila-
tor response by an HFNC with no significant differences
RESPIRATORY CARE VOL NO1
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compared with a jet nebulizer.
12,13
Using noninvasive pul-
monary function tests (PFT), the aim of this study was to
evaluate the clinical response of subjects with COPD exac-
erbation who received bronchodilator therapy (anticholiner-
gic and
b
-agonist) via a vibrating mesh nebulizer in line
with an HFNC.
Methods
Study Design
This was a prospective single-center study. Institutional
review board reviewed the protocol and authorized prospec-
tive data collection (code register 2263). Informed written
consent was obtained from all the subjects before inclusion
in the study.
Subjects
Patients with a previous diagnosis of COPD who were
admitted to the respiratory intermediate care unit within the
Hospital de Agudos Juan A. Ferna
´ndez with COPD exacer-
bation and required NIV for acute hypercapnic respiratory
failure (pH #7.35, with a PaCO2$45 mm Hg)
5
were
selected for the study. Underlying COPD could be docu-
mented by spirometry and defined by an FEV
1
/FVC <
0.70
14
or, alternatively, highly suspected underlying COPD.
Subjects with suspected underlying COPD without previ-
ous spirometry should have a history of smoking and em-
physema on chest radiograph or computed tomography
scan without other reasons for respiratory acidosis.
Exclusion criteria were the following: inability to cooper-
ate, inability to perform PFTs, unstable hemodynamics
(blood pressure <90 mm Hg, auricular fibrillation), a his-
tory of asthma, cystic fibrosis, morbid obesity (body mass
index >40 kg/m
2
) thoracic deformities, previous known
hypersensitivity to salbutamol, or pregnancy. All the subjects
in this study received bronchodilators via a vibrating mesh
nebulizer in line with NIV from admission until clinical sta-
bilization, NIV breaks were performed with an HFNC.
Measurements were performed once subjects met the stabilty
criteria. Frequency <35 breaths/min, Glasgow coma scale
score of 15 points, the need for intermittent NIV <6h,and
the need for #4 sessions of bronchodilators per day.
Interventions
After a $6-h washout period without bronchodilator
nebulization, the subjects were treated with bronchodilator
therapy by using a vibrating mesh nebulizer in line with an
HFNC.
HFNC
HFNC therapy was administered via Airvo2 (Fisher &
Paykel, Auckland, New Zealand) through nasal prongs
QUICK LOOK
Current knowledge
The high-flow nasal cannula has gained importance in
patients with COPD exacerbation due to its well-described
physiologic and clinical effects, in addition to being a com-
fortable and easy-to-use interface. This device can be an al-
ternative to noninvasive ventilation in case of intolerance
or as an alternative during noninvasive ventilation breaks.
The use of bronchodilators is a mainstay in the treatment
of COPD. However, the efficacy of bronchodilator therapy
by using high-flow nasal cannula has not been studied in
detail.
What this article adds to our knowledge
This study in subjects with severe COPD exacerbation
demonstrated a positive response to bronchodilator
therapy with vibrating mesh nebulizers in line with
high-flow nasal cannula. This bronchodilator effect
was related to a substantial improvement in the sub-
jects’ pulmonary function tests and clinical variables.
Therefore, the application of bronchodilators in line
with vibrating mesh nebulizers and high-flow nasal
cannula is possible without interrupting respiratory
treatment, and no adverse events were observed during
bronchodilator therapy.
Mr Colaianni-Alfonso, Mr Espada, Ms Saa, Mr Techera, Dr Toledo,
Dr Montiel, and Mr Castro-Sayat are affiliated with the Respiratory
Intermediate Care Unit, Hospital General de Agudos Juan A. Ferna
´ndez,
Ciudad Auto
´noma de Buenos Aires, Argentina. Dr MacLoughlin is affili-
ated with the Research and Development, Science and Emerging
Technologies, Aerogen Ltd, Galway, Ireland. Dr MacLoughlin is affili-
ated with the School of Pharmacy and Biomolecular Sciences, Royal
College of Surgeons in Ireland, Dublin, Ireland. Dr MacLoughlin is
affiliated with the School of Pharmacy and Pharmaceutical Sciences,
Trinity College, Dublin, Ireland.
The study location was Hospital Juan A. Ferna
´ndez, Respiratory Inter-
mediate Care Unit, Ciudad Auto
´noma Buenos Aires, Argentina.
No funding was received to assist with preparation of this manuscript.
Dr MacLoughlin is an employee of Aerogen Limited. The other authors
have disclosed no conflicts of interest.
Correspondence: Nicolas Colaianni-Alfonso, Respiratory Intermediate
Care Unit, Hospital Juan A. Ferna
´ndez, Av. Cervin
˜o 3356, C1425 Ciudad
Auto
´noma Buenos Aires, Argentina. E-mail: nicolkf@gmail.com.
DOI: 10.4187/respcare.10614
AEROSOLIZED BRONCHODILATORS BY HFNC
2R
ESPIRATORY CARE VOL NO
RESPIRATORY CARE Paper in Press. Published on April 11, 2023 as DOI: 10.4187/respcare.10614
Copyright (C) 2023 Daedalus Enterprises ePub ahead of print papers have been peer-reviewed, accepted for publication, copy edited
and proofread. However, this version may differ from the final published version in the online and print editions of RESPIRATORY CARE
by using a medium-sized cannula, with a gas flow of 30
L/min, which allowed 100% relative humidity at 34C,
and FIO2to maintain SpO2of 88%–92%.
Nebulization
Nebulizer placement was as follows: according to the
manufacturer’s recommendations, the nebulizer was placed
in the outlet of the humidifier for Airvo2 (with Airvo2 neb-
ulizer adapter designed specifically for the Aerogen Solo).
Medication was salbutamol (2.5 mg) and ipratropium bro-
mide (0.5 mg) were provided through the vibrating mesh
nebulizer (Aerogen Solo nebulizer and Aerogen Pro-X con-
troller, Aerogen Galway, Ireland). The session was set at
30 min, and the complete delivery of bronchodilators was
confirmed.
Data Collection
Demographic data were collected on admission to the re-
spiratory intermediate care unit in conjunction with clinical
parameters and laboratory blood test. Clinical parame-
ters were measured before performing PFTs; dyspnea
was assessed by using the Borg scale, which ranges
from 0 to 10 points, with a higher score indicating maxi-
mum dyspnea. All PFTs were performed by using a
spirometer (Spirolab III, MIR, Rome, Italy) before
bronchodilator therapy and 60 min after bronchodilator
therapy through the vibrating mesh nebulizer in line
with an HFNC. For the performance of the PFTs, the
HFNC was removed; for each test, 2 measurements of
FEV
1
and FVC were performed, and the best of them
was recorded. The spirometry procedure was performed
by following the American Thoracic Society/European
Respiratory Society guidelines
14
for standardization of
PFT.
Patients with COPD
exacerbation treated in the
respiratory intermediate care unit
46
No NIV at admission
5
Required NIV and
bronchodilators at admission
41
Patients received
bronchodilators via pMDI or jet
nebulizer
10
Met inclusion
criteria
31
Excluded for data loss: 1
Subjects enrolled and
analyzed
30
Fig. 1. Flow chart. NIV ¼noninvasive ventilation; pMDI ¼pressur-
ized metered-dose inhaler.
Table 1. Demographic and Baseline Characteristics of Subjects with
COPD Exacerbation Admitted to Respiratory Intermediate Care Unit
(N¼30)
Characteristic Result
Variable
Age, y 73 610
Men/women, n22/8
Body mass index, kg/m
2
28 66
Active smoking, n(%) 8 (27)
Domiciliary oxygen, n(%) 5 (17)
Domiciliary NIV, n(%) 7 (23)
GOLD classification, n(%)
I0
II 0
III 7 (23)
IV 23 (77)
At admission
Frequency, breaths/min 29 62
Heart rate, beats/min 89 69
SpO2,% 9064
NIV setting
Inspiratory pressure, cm H
2
O1262
PEEP, cm H
2
O761
FIO20.4 60.1
Laboratory blood test
Arterial pH 7.32 60.1
PaCO2,mmHg 55610
PaO2,mmHg 6269
HCO
3
, mmol/L 30 65
Long-acting muscarinic antagonist, n(%) 22 (73)
Long-acting
b
2
-agonist, n(%) 21 (70)
Oral or intravenous corticosteroids, n(%) 16 (60)
At clinical stability
Frequency, breaths/min 25 61
Heart rate, beats/min 83 610
SpO2,% 9162
Days until clinical stability 4 61
Data are presented as mean 6SD unless otherwise noted.
NIV ¼noninvasive ventilation
GOLD ¼Global Initiative for Chronic Obstructive Lung Disease
AEROSOLIZED BRONCHODILATORS BY HFNC
RESPIRATORY CARE VOL NO3
RESPIRATORY CARE Paper in Press. Published on April 11, 2023 as DOI: 10.4187/respcare.10614
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and proofread. However, this version may differ from the final published version in the online and print editions of RESPIRATORY CARE
Outcomes
The primary outcome was change in FEV
1
after broncho-
dilator therapy via a vibrating mesh nebulizer in line with an
HFNC. Secondary outcomes included FVC changes and
clinical parameters (breathing frequency, heart rate, SpO2)
and dyspnea (Borg scale).
Statistical Analysis
Continuous variables are presented as mean and SD (if
data were normally distributed) and median and interquartile
range (IQR) values (if data were not normally distributed).
Categorical variables were described as frequency rates and
percentages. Means for continuous variables were compared
by paired ttests or analysis of variance test. Proportions of
categorical variables were compared by using the chi-square
test or Fisher exact test. P<.05 was considered statistically
significant. The statistical analysis was performed by using
R Studio (Version 1.3.1093, R Foundation for Statistical
Computing, Vienna, Austria).
Results
Forty-six patients with COPD exacerbation were admitted.
Five patients who did not use NIV at admission and 10
patients who did not receive bronchodilator treatment with a
vibrating mesh nebulizer were excluded. Thirty one were
selected, but one subject was secondarily excluded due to loss
of data in the system. Finally, 30 subjects were included from
September 2021 to July 2022 (Fig. 1). There were 23 subjects
with severe COPD classification according to GOLD (Global
Initiative for Chronic Obstructive Lung Disease) (Table 1).
The primary outcome was spirometric changes in FEV
1
.
The mean 6SD FEV
1
before receiving bronchodilator treat-
ment when using a vibrating mesh nebulizer in line with an
HFNC was 0.74 60.10 L and after receiving treatment the
mean 6SD FEV
1
changedto0.8860.12 L (P<.001)
(Table 1). The FEV
1
increased in 83% of the subjects (25 of
the 30 subjects). Secondary outcome measures included
FVC and clinical parameters. Similarly, mean 6SD FVC
increased from 1.75 60.54 L to 2.13 60.63 L (P<.001).
The FVC increased in 83% (25 of the 30 subjects).
Significant differences were observed in breathing frequency
and heart rate after receiving bronchodilator treatment
through a vibrating mesh nebulizer in line with an HFNC
(Table 1) (P<.001). No significant changes were observed
in Borg scale and SpO2after treatment (Table 2). The mean
6SD clinical stability recorded was 4 60.92 d. When
PFTs were performed 60 min after aerosol therapy, the pre-
set HFNC flow was restored and complete uninterrupted
delivery of the dose by using the vibrating mesh nebulizer
was noted for all aerosol therapy sessions, and no alarms
were noted on the Airvo2 machine.
Discussion
In this single-center study, the subjects with COPD exac-
erbation showed improvement in FEV
1
and FVC after
receiving bronchodilator therapy by using a vibrating mesh
nebulizer in line with an HFNC, which suggests a positive
bronchodilator effect. Physiologic effects of HFNC are well
described in the literature; the application of an HFNC can
facilitate the elimination of CO
2
by elevated gas flows.
10,15
This promotes the flushing of anatomic dead space of the
upper airway, and the CPAP effect could contribute to
decrease the work of breathing caused by expiratory air flow
obstruction by compensating for intrinsic PEEP.
16,17
A recent
study was able to confirm these physiologic effects by prov-
ing a reduction in inspiratory effort and neuroventilatory
drive in stable and COPD exacerbation subjects.
16,18,19
For these reasons, we consider it an attractive combination
to perform aerosol therapy through a vibrating mesh nebu-
lizer in line with an HFNC. A common albeit suboptimal
Table 2. Changes in Pulmonary Function Tests and Clinical Parameters Before and After Bronchodilator Therapy
Variables
Before Vibrating Mesh Nebulizer
Bronchodilator Treatment In Line
With HFNC
After Vibrating Mesh Nebulizer
Bronchodilator Treatment In Line
With HFNC
P
FEV
1
, L 0.74 60.10 0.88 60.12 <.001
FVC, L 1.75 60.54 2.13 60.63 <.001
Frequency, breaths/min 25 612361<.001
Heart rate, beats/min 83 610 88 69<.001
SpO2,% 91629162 .48
Dyspnea (Borg scale), points 2 60.3 2 60.3 >.99
Flow setting, L/m 45 610 30 60 N/A
FIO20.3 60.1 0.3 60.1 N/A
Data are presented as mean 6SD.
HFNC ¼high-flow nasal cannula
N/A ¼not applicable
AEROSOLIZED BRONCHODILATORS BY HFNC
4R
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and proofread. However, this version may differ from the final published version in the online and print editions of RESPIRATORY CARE
practice includes positioning a nebulizer face mask over the
nasal cannula during therapy. This setup considerably
reduces the amount of aerosol being inhaled by the patient
and, in some cases, reduces it to as low as 1% of the nomi-
nal dose placed in the nebulizer for adults, and lower still in
newborn and pediatric patients, with levels reported to be
between 0.1% and 0.93% of the nominal dose.
17,20
The opti-
mal configuration for nebulization through the HFNC system
has been shown to be placement dry side of the humidifier
and with gas flow as low as possible but at a level that can be
tolerated by the patient.
21
Previous studies administered aero-
sol to subjects at a gas flow that did not exceed 30
L/min.
12,22
However, we decreased the gas flow to 30 L/min
to facilitate optimal concurrent bronchodilator therapy. All
the subjects tolerated the decrease in flow without adverse
events. Further, this is in line with international clinical prac-
tice, in which it is reported that, during 30% of aerosol ther-
apy sessions, HFNC gas flow is reduced.
23
FEV
1
and FVC are both known to be reliable parameters
for measurement of expiratory air flow obstruction and vol-
ume retention, and have been demonstrated to be easily re-
producible in a large proportion of subjects when obtained
by trained specialists.
24
In our study, the usual criteria for
reversibility (ie, 12% increase and/or 200 mL) were not
reached. Our data are similar to those reported by Beuvon
et al,
25
in which they performed bronchodilation with salbu-
tamol via a vibrating mesh nebulizer in line with an HFNC,
FEV
1
showed changes of 9.5% in their study population.
Our study showed 13.7% changes in FEV
1
in a population
with mostly severe (GOLD IV) COPD. Reminiac et al
12
showed a >16% increase in FEV
1
when using a vibrating
mesh nebulizer in line with an HFNC in subjects with stable
asthma and COPD.
A recent study indicates that the prevalence of bronchodila-
tor reversibility in subjects with COPD was only 17% when
these usual criteria were met.
26
However, a 5%–10% change
in FEV
1
from baseline values is considered clinically relevant,
whereas a change of <3% has been considered not to be clini-
cally relevant.
27
Therefore, a slight increase in FEV
1
may
result in a reduction in residual volume and delay in the onset
of dynamic hyperinflation during tachypnea.
28,29
Of note,
those 3 studies also made use of an HFNC system with a
vibrating mesh nebulizer, and the temperature, flow, and can-
nula size used were the same as that described herein.
12,22,25
We reported increased FVC after bronchodilator nebulization,
which could be considered a consequence of a reduction in
lung hyperinflation.
30,31
In fact, there is a certain group of
patients in whom bronchodilation can induce changes in FVC
rather than FEV
1
. This has been associated with the effect of
airway inflation due to loss of elastic recoil or to spatial com-
petition.
31
The first limitation of our study was the small num-
ber of subjects and, second, only 2 spirometric measurements
were performed to avoid subject fatigue.
Conclusions
In subjects with COPD exacerbation, bronchodilator
treatment by using a vibrating mesh nebulizer in line with
an HFNC showed a mild but substantial improvement in
FEV
1
and FVC. In addition, a decrease in breathing
frequency was observed, which suggests a reduction in
dynamic hyperinflation.
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