Review Drug Delivery

Vibrating Mesh Nebulisers – Can Greater

Drug Delivery to the Airways and Lungs
Improve Respiratory Outcomes?
Stephan Ehrmann
Médecine Intensive Réanimation, Réseau CRICS-TRIGGERSEP, Centre Hospitalier Régional et Universitaire de Tours, INSERM U1100, Centre
d’Études des Pathologies Respiratoires, Tours, France
DOI: https://doi.org/10.17925/ERPD.2018.4.1.33

A
erosols are an increasingly important mode of delivery of drugs, particularly bronchodilators, for the treatment of respiratory diseases,
notably asthma and chronic obstructive pulmonary disease. The most common type of nebuliser is the jet nebuliser (JN); they have
been in use for more than a century but these devices can be cumbersome to use and may sometimes deliver insufficient amounts
of drug. A more recent development in aerosol therapy is the vibrating mesh nebuliser (VMN) which is very user friendly and is more efficient
than the JNs due to an extremely low residual volume. Scintigraphy images from studies of volunteer subjects using radio-labelled aerosol
treatment show that VMN-generated aerosols deliver more drug to patients in a shorter period of time than JN-generated aerosols. Various
bench, animal model and small clinical studies have shown that VMNs are more efficient than JNs in drug delivery, potentially improving
clinical outcomes. These studies have included various breathing circuits used in mechanical ventilation (MV), non-invasive ventilation,
high-flow nasal cannula systems and devices for spontaneously breathing patients. The efficiency of drug delivery was affected by factors
including the position of the nebuliser in the circuit and humidity. Some studies have shown potential substantial savings by hospitals
in the cost of MV treatments after switching from metered dose inhalers to VMNs. VMNs have also been shown to be effective for the
administration of inhaled antibiotics, corticosteroids and other drugs. Larger studies of the effects of VMNs on patient outcomes are needed
but they are likely to be an increasingly important means of administering therapies to a burgeoning population with respiratory disease.

Keywords Aerosol administration of drug therapies is a well-established and

Vibrating mesh nebuliser, inhaled medication, respiratory disease, increasingly important delivery method for patients with acute or
chronic obstructive pulmonary disease, asthma chronic respiratory conditions, especially for those receiving critical
care. Aerosol therapies are now given to one-quarter of critically ill
Disclosure: Stephan Ehrmann has given presentations, acted as
a consultant or received honoraria from: Aerogen, La Diffusion patients and one-fifth of ventilated patients, and they are widely used
Technique Française, Fisher & Paykel and Baxter. in chronic respiratory conditions, particularly chronic obstructive
Review Process: Double-blind peer review. pulmonary disease (COPD) and asthma.1–5 Additionally, nebulisers are
Acknowledgements: Medical writing support, including preparation widely used for patients with cystic fibrosis (CF) in both hospital and
of the drafts under the guidance of the author, was provided by James
Gilbart of Touch Medical Media and funded by Aerogen. home settings.6,7
Compliance with Ethics: This study involves a review of the literature and did
not involve any studies with human or animal subject performed by the author. A number of factors affect aerosol delivery including lung anatomy
Authorship: The named author meets the International Committee in relation to airway geometry and branching and narrowing of the
of Medical Journal Editors (ICMJE) criteria for authorship of this
manuscript, takes responsibility for the integrity of the work as a whole, airways.8 Mucociliary clearance mechanisms and humidity can also
and has given final approval for the version to be published. impede the inhalation of drugs.9 Additionally, factors associated with
Open Access: This article is published under the Creative Commons
the type of ventilation, including tidal volume, inspiratory time and
Attribution Noncommercial License, which permits any non-commercial
use, distribution, adaptation and reproduction provided the original author(s) duty cycle, inspiratory flow, waveform and bias flow can affect aerosol
and source are given appropriate credit. © The Author(s) 2018.
deposition.10 The lung offers an attractive site for delivery as it has a large
Received: 3 November 2017
surface area and thin epithelium which permits rapid drug absorption.
Accepted: 3 January 2018
Drug delivery through the lung is also a non-invasive route for drug
Citation: European Respiratory & Pulmonary Diseases. 2018;4(1):33–43
administration.9 When levels of drug absorption into the circulation are
Corresponding Author: Stephan Ehrmann, Médecine Intensive Réanimation, Réseau
CRICS-TRIGGERSEP, Centre Hospitalier Régional et Universitaire de Tours, INSERM U1100, low, administration through inhalation is associated with fewer side
Centre d’Études des Pathologies Respiratoires, Tours, France. effects than systemic administration. If, however, there is large and
E: [email protected] Twitter: stephanehrmann
rapid absorption there can be more side effects. This painless delivery
Support: The publication of this article was supported by Aerogen. can provide a more rapid onset of action, have a higher therapeutic
The views and opinions expressed in the article are those of index and achieve higher pulmonary tissue concentrations than many
the author and not necessarily those of Aerogen.
systemically administered drugs.8 This is particularly important in the
treatment of pulmonary infections.

Aerosols of drugs introduced to the breathing circuit need to be created

efficiently with minimal drug wastage. The size of aerosol droplet
should be consistent and small enough to facilitate airway penetration
so that a high proportion of the dose is deposited into lung tissues.9,11,12

TOUC H MED ICA L MEDIA Print Publication Date: 5 September 2018 33

Review Drug Delivery

Jet nebulisers (JNs) have been used to administer drugs for around (MV), non-invasive ventilation (NIV) and high-flow oxygen nasal cannula
150 years and are widely accepted. Aerosol droplet size for JNs, however, ventilation (HFNC); its utility has been demonstrated in various clinical
can be inconsistent and often there is incomplete nebulisation of the studies.30,31,38–41 Other VMN devices include the NEBU-TEC® M-neb®
dose in the nebuliser reservoir. This results in variability of the actual (NEBU-TEC International med. Produkte Eike Kern GmbH, Elsenfeld,
dose delivered to the airways and lungs, which is a key factor affecting Germany), which is also used in MV but there is currently little information
therapeutic response and is important when administering drugs such supporting its clinical use. VMN technology is also successfully used to
as antibiotics; for example, an imaging study reported that only 3% of generate aerosols in handheld nebuliser devices such as the PARI eFlow
the dose placed in the nebuliser actually reached the ventilated patient’s (PARI Medical Limited, West Byfleet, Surrey, UK) and the Aerogen® Ultra
lungs in the specific conditions studied.13 (Aerogen, Dangan, Galway, Ireland) (Table 1).42–45

The increasing prevalence of COPD and asthma is creating substantial VMNs have a number of further advantages over JNs especially when
healthcare burdens and is diminishing quality-of-life worldwide.14–17 used with MV systems. Some VMNs can remain in the circuit for up to
These diseases impose high treatment costs where escalation of 28 days with no influence on the gas flow when delivering nebulised
hospital care is required and there are consequent economic effects drugs.1,46,47 VMNs do not alter air flows or pressures in the circuit and
resulting from disability and incapacity.17–22 The World Health Organisation require less frequent intervention from medical staff.1,47 JNs require
(WHO) estimates that 65 million people have COPD and believe it to switching in and out of an MV circuit every 24 hours, which can be time
be the current fifth leading cause of death, expecting it to rise to the consuming. Such processes can also be hazardous since there is a risk
third leading cause by 2030.23 Asthma exerts a significant burden in all of lung derecruitment in sicker patients, after which re-establishing
territories in all age groups; it is estimated to affect between 235 and airflows can take time and opening the circuit can create opportunities
334 million people worldwide and this prevalence is rising.24,25 Although for introducing infection leading to pneumonia.48 Reduced need for
the prevalence of CF is much lower, the associated lung disease requires intervention from nursing staff and reduced infection risk have the
chronic treatment which places a serious burden on patients, carers and potential to reduce costs of treating patients on MV.49 Delivery of some
healthcare systems. Treatments for COPD, asthma and CF during acute viscous drugs, suspensions and solutions prone to crystallisation on
disease exacerbations are therefore of critical importance. drying can sometimes clog the pores of VMNs. This can usually be
avoided by nebulising a few drops of normal saline at the end of the
Efficient nebulisers and inhalers have the potential to improve cost nebulisation period to clear the pores. There is also some variability in
effectiveness of treatments through shorter treatments and reduced VMN output and nebulisation times, but this has limited practical impact
drug wastage.26–29 Newer high-performance aerosol delivery such in the hospital setting. In spontaneous breathers there is a requirement
as vibrating mesh nebulisers (VMNs) are a vital means of rapidly to disassemble the VMN from its valved adapter to allow it to air dry
administering medications such as bronchodilators, steroids and between uses. Although more efficient, VMNs are generally more
antibiotics. These maximise drug delivery with low residual volumes and expensive than JNs, but in the intensive care unit (ICU) setting a VMN can
some early data suggest that they may improve clinical outcomes more be used for up to 28 days in a single patient.
than other, less efficient aerosol generators.30,31 Early retrospective data
support this and also suggest that efficient nebulisers and inhalers may Another type of aerosol generator is the ultrasonic nebuliser (UN). These
reduce hospital admission rates and reduce the drug dosage needed were first developed in the 1960s and are also used to treat airway
for patients requiring bronchodilators in emergency departments. This diseases. These nebulisers have a piezoelectric crystal that vibrates at
results in improved patient throughput in busy acute care settings. The high frequencies (1–3 MHz) in a liquid to form an aerosol.50 These devices
use of such treatments has the potential to rapidly improve a patient’s are small, easy to use, require no air compressor, have quiet operation
condition and may improve long-term outcomes.5,12,32,33 and, like VMNs, are more efficient aerosol generators than the JNs. UNs
are mostly used for the administration of hypertonic saline but can also
This review examines the evidence supporting the use of VMN devices be used for the delivery of inhaled medications.51 The main disadvantage
and their current and potential roles in delivering drug therapy to patients of UNs is that heat is generated in the process of producing aerosol;
with respiratory disease. this can break down complex proteins in some inhaled medications. In
addition, UNs are not recommended for administration of suspensions
The vibrating mesh nebuliser such as Pulmicort® (budesonide).1 They are therefore unsuitable for
The VMN consists of recently developed aerosol technology that administration of suspensions and proteins. They are also unable to
improves the delivery of aerosolised drugs to the lungs. The device create aerosols from viscous solutions and have a large residual volume.
has a very different design to conventional jet nebulisers. The key Both UNs and VMNs have controllers that drive them, but the UN’s
component is a central aperture plate that is perforated with precisely controller is bulkier and heavier. The UN has a reservoir that is positioned
formed holes. A piezo ring vibrates the aperture plate which acts as a below the ventilator circuit whereby contaminated fluids in the circuit
micro-pump drawing liquid through the holes to generate consistently can more readily enter the nebulizer.1 Some comparative in vitro studies
sized fine particles of 1–5 µm diameter.12,34 This size of particle is have shown that UNs have a fast delivery but can have poorer efficiency
advantageous because particles of 5–10 µm diameter will not penetrate and produce larger particles than VMNs.29,50,52,53
beyond the larger lung airways.35
Vibrating mesh nebulisers used with
VMNs produce a low velocity aerosol which minimises ‘rainout’ mechanical ventilation
(condensation of drug-containing solutions) in the circuit and upper MV is used for the most seriously ill and critical patients, but more
airways thereby optimising drug deposition. They generate no heat recently there has been a general trend towards less invasive means
and so maintain drug integrity.34,36,37 Several different VMN systems are of ventilatory support for many such patients.54–56 Aerosol therapy is
available.12,34 One example is the Aerogen® Solo (Aerogen, Dangan, frequently introduced into mechanical breathing circuits and is used by
Galway, Ireland), which can be used during mechanical ventilation over 95% of intensivists, mostly for bronchodilator, antibiotic and steroid

34 EUR OP EAN R ES P I R ATORY & P UL M ONA RY D ISE A SE S

 Vibrating Mesh Nebulisers – Improving Respiratory Outcomes

Table 1: Vibrating mesh nebuliser systems currently available

Nebuliser system Use as a Use in Device Advantages and use in studies

portable breathing
handheld circuits for
device mechanical
ventilation
Omron Micro Air
®
+ - A small-sized nebuliser, with quiet operation and tubeless and cordless
Nebulizer NE-U22V design. A piezoelectric crystal vibrates at a high frequency when an electrical
(and NE-U03): current is applied. Efficient aerosol delivery with fine particle fraction produces
battery-operated42 a low velocity aerosol. The device has a low residual volume and delivers most
medications. No diluent is needed.
PARI eFlow rapid nebulizer + - A highly-efficient nebuliser producing aerosols with a high fine particle fraction.
system: small, portable, Patient compliance is improved due to the short treatment time. The device
battery-operated device is powered by battery or external electrical supply, and is controlled using an
with silent operation43 external controller. The device is quiet while running, suitable for the delivery of
most medications, easy to clean and can be disinfected or autoclaved.

Aerogen Solo
® 44
- + The Aerogen Solo has a piezo ring that vibrates the aperture plate at a rate
of 128,000 per second. Each aperture acts as a micro pump, drawing liquid
through a cone-shaped hole resulting in up to 7.7 billion precise, consistently
sized fine particles of 1–5 µm every minute. Particles sized 5–10 µm will
not penetrate beyond the larger lung airways. The nebuliser operates with
ventilated and non-ventilated patients (coupled with the Aerogen® Ultra; see
below). The device is economical and a single patient can use Aerogen Solo
for up to 28 days. It does not heat or degrade medication and so is suitable for
solutions, suspensions, proteins and peptides. The device has a low residual
volume. Aerogen Solo is currently the only standalone, single-patient mesh
device commercially available for use in mechanically ventilated patients. It
is powered by an external controller for 30-minute or 6-hour durations, or for
continuous use.
Aerogen® Ultra45 + - Aerogen Ultra is a valved holding chamber for use with Aerogen Solo
in patients with spontaneous breathing. It has an ergonomic valved
mouthpiece controlling air flow, maximising aerosol delivery. It can be used
with standard or valved face masks. Supplementary oxygen can be delivered
with the aerosol.

administration,51,57–59 and less frequently for anticoagulants, diuretics, Figure 1: Comparison of salbutamol levels captured at
mucoactive agents, prostacyclins and surfactants.46 the end of an endotracheal tube using a model ventilator
circuit with four different nebuliser systems at two different
One recent in vitro study compared the performance of four different positions (ventilator column or Y-piece before humidifier)
nebulisers; the SideStream® Disposable JN (Philips Healthcare Limited,
Guildford, Surrey, UK), the Multisonic® InfraControl UN (Flores medical 30

GmbH, Probstzella, Germany), the Aerogen® Pro VMN and the Aerogen® 25
captured at end of ETT

Solo VMN (Aerogen, Dangan, Galway, Ireland) to deliver salbutamol in

% Salbutamol dose

a model MV system.52 The UN was the fastest system to nebulise the 20

dose; the JN was the slowest. Solution temperatures increased with the 15
JN and UN, but decreased with the VMNs. Osmolarity increased with
the JN and UN, but was stable with the VMNs. Salbutamol delivery was 10

2.3- and 1.6-fold higher with the VMNs and UN, respectively, compared 5
with the JN. In addition, particle size was significantly greater with the UN
0
(mean mass distribution: JN: 5.00 ± 0.36 µm, UN: 5.80 ± 0.07 µm, VMNs:
or

ce

or

ce

or

ce

or

ce
at

at

at

at
ie

ie

ie

ie

5.14 ± 0.54 µm (Aerogen Pro) and 4.60 ± 0.54 µm (Aerogen Solo); p<0.01
til

til

til

til
p

p
Y-

Y-

Y-

Y-
n

n
Ve

Ve

Ve

Ve

for UN versus VMN (Aerogen Pro). Overall, the VMNs and the UN were Aerogen® Solo Manquet Hudson Salter 8900
more efficient than the JN, but the VMNs did not heat the drug and Vibrating Mesh Ultrasonic Updraft II Opti-Neb Jet
Nebuliser Nebuliser Jet Nebuliser Nebuliser
produced a substantially higher respirable fraction.
Total dose of salbutamol was 2.5 mg in each case. ETT = endotracheal tube. Modified
with permission from Berlinski and Willis, 2013.61
Several bench and imaging studies have demonstrated suitability of
VMN technology for use in MV circuits and improved drug delivery of
aerosolised solutions.52,60–63 These investigations generally showed that Berlinski and Willis showed that a VMN delivers ninefold more aerosol
aerosol devices are more efficient when placed at the ventilator or dose compared with a JN during simulated mechanical ventilation.61 A
humidifier and less efficient at or near the Y-piece when bias flow was further bench study using both paediatric and adult breathing model
present (Figure 1).61 systems showed that nebuliser placement prior to the humidifier

E UROPEAN RESPIRATORY & P U LMO N A RY D IS E A S E S 35

Review Drug Delivery

Figure 2: Vibrating mesh nebuliser aerosols delivered via pressure support ventilation and volume-controlled ventilation.
A: Penetration index; B: Right/left lung deposition ratio. C: Scintigraphic images of aerosol lung deposition

Pressure support ventilation Volume-controlled ventilation

A Right lung Left lung Right lung Left lung

1.5 1.5
Penetration index

Penetration index
1.0 1.0

0.5
0.5

1 2 3 4 5 6 7 8 1 2 3 4 5 6 7 8 9
Patient Patient

B
12 12

10 10
R/L lung deposition ratio

R/L lung deposition ratio

8 8

6 6

4 4

2 2

0 0
1 2 3 4 5 6 7 8 1 2 3 4 5 6 7 8 9
Patient Patient

Reproduced with permission from Dugernier et al., 2016.39

increased drug delivery to a greater extent with a VMN than with a JN The performance of VMNs have also been demonstrated in animal
and that higher bias flow reduced drug delivery.64 In both model systems models. One example used a macaque model of a neonate and compared
drug delivery with the VMN was two- to fourfold greater than with the JN a JN (Misty-Neb [CareFusion, San Diego, CA, US]) with a VMN (Aerogen
at all positions (p<0.05). Pro [Aerogen, Dangan, Galway, Ireland]). This study used scintigraphy
to demonstrate that 0.5% and 12.6% of 99mTc-diethylenetriamine
A randomised, controlled study compared the in vivo impact of two pentaacetic acid (DTPA) was delivered to the lungs using the JN and VMN,
ventilation modalities – pressure support versus volume-controlled resepectively.65 This and other studies indicated that the advantages of
ventilation – on lung dose of a radiolabelled aerosol administered with VMN are mainly driven through lower residual volumes.
a VMN during invasive mechanical ventilation and was measured using
scintigraphy.39 The study enrolled postoperative neurosurgery patients who Early clinical data suggest that the higher drug deposition associated
were mechanically ventilated with healthy lung function and found that with VMNs can improve pulmonary mechanics. One study included
controlling the ventilatory pattern in volume control mode was associated 25 children (aged 1–18 years) with respiratory failure (the majority had
with higher lung deposition compared with spontaneous ventilation postoperative respiratory failure with pulmonary oedema) who were
in pressure support mode (15.1% versus 10.5%; p<0.05) (Figure 2). treated with salbutamol delivered by VMN.66 At baseline, functional
These levels of deposition are considerably higher than the deposition of residual capacity was only 53.0% of that predicted. After aerosolised
3.0% observed with standard JNs.13 Lung dose and the site of deposition salbutamol, functional residual capacity increased by 18.3% (p=0.008).
were highly variable among patients with both ventilation modes. The authors concluded that in infants and children, salbutamol

36 EUR OP EAN R ES P I R ATORY & P UL M ONA RY D ISE A SE S

 Vibrating Mesh Nebulisers – Improving Respiratory Outcomes

Table 2: Cost effectiveness studies conducted in the United States comparing vibrating mesh nebulisers with metered
dose inhalers in mechanically ventilated patients

Study reference and design Comparison Cost savings Other effects

Retrospective study of patients Cost of pMDI (1-year period) switched to Net cost savings of $208,828 Patients were considered to respond more
receiving MV in one US hospital68 VMN (Aerogen Solo; 1-year period) for with VMN favourably with a VMN, but had more
bronchodilator administration in patients medication side effects, possibly due to
receiving MV over 2 consecutive years greater exposure to medication
Retrospective study in one US Financial impact of MDI conversion to Extrapolated total cost saving No difference in end-user satisfaction,
hospital (1,242 beds) using EHR VMN (Aerogen Solo) for bronchodilator of $146,806 in the first year and ventilator days, length of stay or rates of
data69 administration in patients receiving MV $257,963 in subsequent years ventilator-acquired pneumonia
during 3-month periods before and with VMN
after switching
Survey of 13 high-utilisation US Cost savings on switching from pMDIs Pharmacy savings of $226,000 Among respiratory therapists, 69% were
hospitals45 to VMN (Aerogen Solo) for delivery of (3.4% of total drug costs) very satisfied with the VMN; 83% chose
bronchodilator drugs to patients in acute with VMNs VMN over JNs or pMDIs as the best aerosol
care receiving MV over a 6-month period delivery method
Survey of a US hospital (part of a Financial impact of transition from MDI to Saving per patient after transition Respiratory staff satisfaction; process
105 hospital system)70 VMNs (Aerogen) in patients receiving MV to VMNs of $145. Potential changes can be implemented at other
(1 year receiving each type) system-wide annual cost savings hospitals, initiated by the multidisciplinary
of $1,740,000 team; no additional pressure in circuit;
ventilator checks can be performed
during administration

EHR = electronic health records; JN = jet nebuliser; MV = mechanical ventilation; pMDI = pressurised metered dose inhaler; VMN = vibrating mesh nebuliser.

aerosolised by VMN might favourably enhance pulmonary mechanics Vibrating mesh nebulisers used with
and thereby represent a novel strategy for lung recruitment in children non-invasive ventilation
with respiratory failure. Non-invasive ventilation (NIV) is increasingly used as a less invasive
option when MV can be avoided. NIV can be associated with lower
Several studies in the US have demonstrated substantial cost savings morbidity than MV and reduces the risk of VAP.73–75 Some patients
when switching from pressurised metered dose inhaler (pMDI) to VMN with severe COPD receive intermittent NIV in the homecare
administration of drug treatments during MV. This effect is partly due to setting.76,77 A variety of bench studies have demonstrated the
the relatively higher costs of pMDIs in the US.67 In these studies, switching use of VMNs during NIV using simulated breathing patterns.78–81
from pMDIs to VMNs resulted in projected cost savings of approximately One such NIV model compared terbutaline aerosol generated
$150,000 to over $1.7 million per year depending on the numbers of by VMN and a JN. The VMN produced aerosols that contained
hospitals involved. In some of these studies, the savings were made significantly more drug than the JN and this difference was more
in parallel with improved patient and/or medical staff satisfaction over marked when the nebuliser was positioned before the leak port
pMDI aerosol administration (Table 2).49,68–70 Little information on cost in the ventilation circuit (p<0.001 for VMN versus JN and p<0.001
savings associated with VMN use with mechanical or other ventilator for position comparison).78 Another bench study using a face
types in Europe is currently available. model/respiration simulator showed that the proportion of drug
(99mTc-salbutamol) inhaled via aerosol using a VMN was substantially
Lung infections are a serious risk in patients with respiratory disease, greater than with a JN for three different NIV settings (VMN:
particularly in those receiving MV, and they can be difficult to treat.7 14.3–15.4% versus JN: 3.6–7.2%; p=0.004–0.094).79 A comparison of
VMNs in combination with MV have been successfully used to deliver a VMN, JN and pMDI used in an NIV model showed that the VMN
antibiotic aerosol treatments directly to the lung in several studies. In was superior in terms of salbutamol delivery (p<0.001) and that
one study of 165 patients with ventilator-acquired pneumonia (VAP), placing each nebuliser before the leak port provided the best drug
treatment with aerosolised colistin from a VMN (Aerogen Pro). achieved delivery (p<0.001).81
cure rates of 66% in patients with antibiotic-sensitive Pseudomonas
aeruginosa or Acinetobacter baumannii infections and 67% with An NIV in vitro study compared the performance of three VMNs
multidrug resistant infections of these bacteria.71 This efficacy was non- (Aerogen Pro, Aerogen Solo, and NIVO® [Philips UK Ltd, Guildford,
inferior to intravenous treatments with β-lactams, aminoglycosides or Surrey, UK]), one JN (Sidestream), and one UN (Servo Ultra Nebulizer
quinolones for treating VAP. A similar study that included 149 critically ill 145 [Siemens-Elema AB, Solna, Sweden]) coupled with a single-limb
adults found that VMN-aerosolised colistin achieved a clinical cure rate of bilevel ventilator in the delivery of amikacin.29 When the nebuliser
67.1% in P. aeruginosa and A. baumannii infections compared with 72.0% was positioned before the exhalation port in the circuit, the VMN
receiving intravenous colistin (p=0.59).72 The aerosol-treated patients delivered the highest inhaled dose (p<0.001), the JN showed the
also had significantly lower incidence of acute renal failure (p=0.004), highest expiratory wasted dose (p<0.001) and UN had the highest
shorter time to bacterial eradication (p=0.023) and earlier weaning from total lost dose (p<0.001). When the nebulisers were placed after the
the ventilator (gain of 5 ventilator-free days). In an international survey exhalation port, however, the VMN showed the highest expiratory
of aerosol therapies administered during mechanical ventilation,51 80% wasted dose. The authors concluded that UNs are not recommended
of 854 analysed responses had a positive opinion of nebulised colistin in this NIV application and that the VMNs were the most efficient
and 30% reported using nebulised antibiotics at least every other month. provided they were placed before the exhalation port.

E UROPEAN RESPIRATORY & P U LMO N A RY D IS E A S E S 37

Review Drug Delivery

Clinical evidence supporting the use of VMNs with NIV in respiratory levels to adult patients. In some cases, however, it may be necessary to
disease is, as yet, limited. In a crossover study, 10 healthy volunteers decrease flow to deliver a meaningful dose of bronchodilator in severe
received 99mTc-DTPA aerosol treatment via VMN or JN connected to bronchospasm; with VMNs the duration of nebulisation is shorter than
an NIV circuit using a facemask. Radioactive counts and scintigraphy with JNs keeping times of lower flow to a minimum.
images showed that healthy subjects received greater than threefold
more radioactive drug during VMN treatment than during JN treatment.82 In an interim analysis of an ongoing, randomised, crossover clinical
This evidence indicates that there is potential for VMN devices to be study, 13 adult patients with respiratory failure received a nebulised
used in combination with NIV as successfully as with other ventilation bronchodilator via a VMN through HFNC, via a standard JN and
approaches, but larger comparative trials are needed. facemask or just HFNC with sham nebulisation (no drug). HFNC was
operated with a low airflow of 30 L/min.41 The absolute and relative
Vibrating mesh nebulisers used with high-flow changes in forced expiratory volume in one second (FEV1) were: for
oxygen through nasal cannulas HFNC/VMN: 330 ml, +17%; for standard facemask/JN: 350 ml, +18%
Therapy with high-flow oxygen through nasal cannulas may offer an and for HFNC and sham nebulisation: 40 ml, +2%. This interim analysis
alternative to MV and NIV in some patients. A number of different bench suggests that at 30 L/min airflow, the HFNC/VMN treatment was non-
studies have demonstrated VMN aerosol medication delivery via HFNCs inferior to standard facemask/JN treatment and that both were greatly
and explored the optimal position of the nebuliser in the circuit.11,83–86 superior to HFNC with sham treatment.
A model HFNC system with a VMN placed on the patient side of a
humidifier found that cannula output ranged from 8.45–26.90% of Additional evidence supporting the use of VMNs with HFNC was
the loaded dose depending on the variable flow rates.11 The median provided by a case series of five infants with asthma and bronchiolitis
particle sizes generated were 4.2 ± 0.4 µm for adult cannulas and due to rhinovirus or enterovirus infection who were initially treated
3.8 ± 0.5 µm for paediatric cannulas. A study with a model paediatric with bronchodilators via JN and standard facemask, and then switched
breathing circuit showed that when using a VMN with a HFNC, decreasing to HFNC with VMN.88 Following treatment with HFNC and VMN the
the flow of oxygen or heliox (helium and oxygen) from 6 L/min to infants became markedly less agitated than with the JN and facemask,
3 L/min increased salbutamol lung deposition delivery twofold or suggesting that HFNC with VMN was clinically better tolerated, possibly
greater (p=0.028 and 0.002, respectively).83 At 6 L/min drug deposition preventing them from escalating to more invasive respiratory support.
was twofold or greater with heliox than with oxygen (p=0.01). A Mean heart rate was also substantially higher at 187 beats per minute
further in vitro study using three different HFNC systems found that a for HFNC/VMN compared with 138 beats per minute for facemask/JN
10 L/min air flow provided the best drug delivery.84 At 30 L/min and administration. The authors believed that this reflected greater delivery
50 L/min the size of the cannula made a significant difference (p<0.001). of drug using HFNC/VMN.
A study modelling HFNC with a VMN or JN in adults showed similar
findings in that more drug (salbutamol) was delivered to the lungs with Vibrating mesh nebulisers in spontaneously
an air flow of 30 L/min rather than 45 L/min or 60 L/min. This delivery breathing patients
was not affected by high inspiratory flows as would be seen during VMNs have been used to generate aerosolised drug delivery in many
respiratory distress.85 This study also found that the most efficient spontaneously breathing patients with respiratory difficulties.3,89,90
position of the nebuliser was before the humidifier allowing greater The use of VMNs in this indication is supported by a range of bench
drug delivery beyond the nose and pharynx. studies that have demonstrated their advantages over JNs in terms of
drug deposition.
Despite the improved efficiency of VMNs compared with JNs used in
HFNC, the total proportion of drug nebulised with HFNC is lower than Hickin et al.28 compared the dose and rate of drug delivery of a VMN
with other ventilator methods. A recent scintigraphy study included with a standard JN fitted to a standard face mask in a breathing model
six healthy subjects and compared lung deposition using 99mTc-DTPA simulating a normal patient and one having a COPD exacerbation.
(4 mCi/4 ml) administered via a VMN (Aerogen Solo) or a JN (Opti-Mist The VMN delivered salbutamol at a significantly higher rate than the
Plus [ConvaTec Limited, Deeside, Flintshire, UK]) via an HFNC (Optiflow™ JN (257.9 µg/min versus 11.9 µg/min) in simulated healthy patients
[Fisher & Paykel Healthcare Limited, Auckland, New Zealand]).38 In the (p=0.008). In simulated COPD, these figures were 109.8 µg/min and
specific conditions of the study, with a flow rate of 30 L/min, lung 8.5 µg/min (p=0.005) meaning that nebulisation time was almost
deposition was 3.6% of the nominal dose with the VMN compared halved. Furthermore, the VMN delivered nearly eight times the dose of
with 1.0% for the JN. Both nebulisers were associated with substantial salbutamol to the carina compared with the JN; less than 1% of the
deposition in the single limb circuit, the humidification chamber and the original dose remained in the VMN reservoir (residual) compared with
nasal cannula (58.2% versus 19.2%; p<0.05) and in the upper respiratory over 40% in the JN reservoir (p<0.001).
tract, especially in the nasal cavity (17.6% versus 8.6%; p<0.05).
Ari et al. conducted performance comparisons of JNs and VMNs using
A further study of VMN used in a HFNC system in 23 healthy adult different interfaces in simulated spontaneously breathing adults and
volunteers confirmed effective delivery of 99mTc-DTPA.87 Scintigraphy children.90 Drug delivery was shown to be greater for the VMN than JN
images showed the greatest deposition occurred at 10 L/min compared when using a mouthpiece (15.4% versus 7.7% of nominal dose) or a
with 30 L/min or 50 L/min, and that there was a strong inverse valved mask (15.2% versus 8.6%), but was similar when using an aerosol
correlation between lung deposition and air flow in both heated and mask (7.5% versus 6.8%).
unheated conditions (r2= -0.008 and -0.597, respectively). Overall,
aerosol administration via HFNC was seen to be a viable option for Another model study investigated the risk of exposing carers and
delivering clinically relevant doses to the lung. It should be stressed bystanders to aerosols as a result of leakage from facemasks and filtered
that in the acute setting, physicians use more than 50 L/min or mouthpieces used in combination with JNs. Simulated patient models
60 L/min to provide positive pressure and increase oxygen saturation showed that this risk is lower with VMNs than other aerosol devices due

38 EUR OP EAN R ES P I R ATORY & P UL M ONA RY D ISE A SE S

 Vibrating Mesh Nebulisers – Improving Respiratory Outcomes

Figure 3: Scintigraphic images from two studies of lung deposition comparing a vibrating mesh nebuliser with a jet
nebuliser in spontaneously breathing healthy subjects

Vibrating Mesh Nebuliser Jet Nebuliser

A: Reproduced with permission from Alcoforado et al., 2015.92 B: Reproduced with permission from Dugernier et al., 2017.93

to the fact they generate lower velocity aerosols.91 Such exposure risk is 30 patients with an acute exacerbation of COPD were treated with a
also decreased with a valved mask and mouthpiece. single bronchodilator dose (2.5 mg salbutamol/0.5 mg ipratropium
bromide) using a VMN (Aerogen Ultra) or a JN (Hudson Micro Mist
In a scintigraphy study, spontaneously breathing healthy volunteer [Teleflex Medical Europe Limited, Athlone, Ireland]).30 The VMN group
subjects (n=6) were treated with radio-aerosol (99mTc-DTPA) via a VMN demonstrated a significant improvement over JN in forced vital capacity
(Aerogen Solo plus Aerogen Ultra) or a JN (NS, São Paulo, Brazil).92 The VMN (p<0.05) and a greater volume response to bronchodilators with clinically
achieved pulmonary deposition with four to six times greater efficiency significant increases in inspiratory capacity (>10% of predicted) and a
compared with a JN (22.8% versus 4.5% of dose delivered to the lungs; clinically significant reduction in residual volume (>300 ml). There was
p=0.004). The JN also had a much greater residual volume resulting in also a significant improvement in the Borg breathlessness score from
lower drug delivery to the subject (Figure 3A). Further evidence of VMN baseline with the VMN, with a trend to significance between the two
efficiency comes from an imaging study with a crossover design that nebulisers (p=0.08). The authors concluded that since exacerbation
included six healthy male subjects. Single-photon emission computed recovery has been associated with increases in respirable lung volume,
tomography (SPECT-CT) was used to determine lung penetration of it is possible that greater bronchodilator delivery with VMNs may hasten
99m
Tc-DTPA that was administered via a VMN (Aerogen Ultra) or a JN (Opti- exacerbation recovery, although this has yet to be explored.
Mist Plus).93 Pulmonary aerosol deposition from SPECT-CT analysis was
six times greater with the VMN compared with JN (34.1% versus 5.2%; Additional evidence showing the advantages of VMNs in spontaneously
p<0.001) (Figure 3B). However, aerosol penetration expressed as the breathing patients came from a retrospective analysis of a large body
three-dimensional normalised ratio of the outer and inner regions of the of emergency department patient data (n=1,594), which compared
lungs was similar between the VMN and JN. the efficacy of VMN (n=879) (Aerogen Ultra) with JNs (n=715) (brand of
JN not specified) in the administration of a bronchodilator (salbutamol)
VMNs have also shown efficacy in the administration of bronchodilators (Figure 4).31 Patients receiving JN treatment were 1.7 times more likely
to spontaneously breathing patients with COPD. In a pilot study, to be admitted to hospital than those receiving treatment with a VMN

E UROPEAN RESPIRATORY & P U LMO N A RY D IS E A S E S 39

Review Drug Delivery

Figure 4: A: Admission rates; B: Discharge rates; C: Length of hospital stay in patients (n=1,594) receiving bronchodilator
treatments via vibrating mesh nebulisers or jet nebulisers

A When compared to the Jet Neb group, B When compared to the Jet Neb group, C 37 minute median reduction in LOS
admission rates are 32% lower with VMN discharges are 30% higher with VMN per patient with the VMN vs. Jet Neb
p=0.0001
p<0.05
50 80 6
p<0.05
5
40
60
% Admission rates

% Discharge rates
4

LOS (Hours)
30
40 3 Median=
41.4% Median= 4.79 hours
20
56.1% 2 4.17 hours
28.1% 43%
20
10
1
n=199 n=362 n=397 n=378 n=720 n=882
0 0 0
VMN Jet Neb VMN Jet Neb VMN Jet Neb
All Age Groups All Age Groups All Age Groups

Jet Neb = jet nebuliser; LOS = length of stay; VMN = vibrating mesh nebuliser. Reproduced with permission from Dunne et al., 2016.31

Figure 5: Bronchodilator (salbutamol) doses required by eFlow device with 300 mg tobramycin/5 ml via a PARI LC Plus device.95
patients (n=1,594) receiving therapy via a vibrating mesh The 170 mg tobramycin/1.7 ml treatment produced higher area under
nebuliser or a jet nebuliser the curve (AUC) and maximum concentration (Cmax) values but a lower
systemic burden and shorter inhalation times, making it a favourable
Vibrating Mesh Nebuliser Jet Nebuliser option for patients with CF. In a further crossover study of 29 patients
400 mg with CF and chronic P. aeruginosa infection, tobramycin inhalation
1%
solution was administered via a VMN (PARI eFlow) once daily for 8 weeks,
5 mg then twice daily for 8 weeks.96 The AUC0–90min ratio at 8 weeks and mean
15%
>7.5 mg FEV1 did not differ markedly between the treatments and no nephrotoxic
23%
or audiological side effects were noted. This indicated that both once-
2.5 mg
47% and twice-daily tobramycin inhalation solution aerosol dosing achieves
effective drug levels and both are tolerable. Overall, these studies
5 mg indicate that VMN-nebulised antibiotics have considerable potential for
2.5 mg 29%
85% the routine administration of antibiotics in CF.

Breath-enhanced/actuated nebulisers (BANs) are important frequently

Salbutamol dose was significantly lower with vibrating mesh nebuliser than jet used aerosol generators in the treatment of spontaneously breathing
nebuliser; p<0.001. Reproduced with permission from Dunne et al., 2016.31
patients. In a recent spontaneously breathing model study, a BAN
(AeroEclipse® [Monaghan Medical Corporation, Plattsburgh, NY, US]) was
compared with a VMN (Aerogen Solo plus Ultra).97 The VMN delivered
(p<0.001). Patients receiving VMN treatment had significant reductions in two- to threefold greater drug dose than the BAN, with lower residual
median length of emergency department stay (-13%) and were 1.3 times volume left in the VMN. Clinical investigations of BANs include a
more likely to be discharged than those receiving JN treatment (p<0.001).31 randomised controlled study by Sabato et al.98 In 149 spontaneously
The VMN group used less total drug (p<0.05) with a 75% reduction of breathing paediatric patients with asthma in the emergency department,
maximum salbutamol dose administered (20 mg to 5 mg) (Figure 5).31 bronchodilator administration was compared using either a small volume
standard JN (SVN), a large volume JN (LVN) or a BAN (AeroEclipse®).
In patients with CF, pulmonary infection is a persistent risk and cause Length of stay in the emergency department was not reduced; however,
of significant morbidity and mortality.7 VMNs in handheld devices have patients in the BAN group showed a greater improvement in clinical
been used in several pharmacokinetic studies to investigate antibiotic asthma score, respiratory rate and a significantly lower admission rate
administration, particularly tobramycin, to treat P. aeruginosa and (38% versus 57%; p=0.03). In an editorial review of this article, Ari and
other Gram-negative bacterial infections in spontaneously breathing Fink identified a few confounding factors between the groups (SVN
patients. One open-label, crossover study of 27 patients with CF versus LVN versus BAN).98,99 The authors concluded that the method of
and pulmonary P. aeruginosa infection investigated tobramycin delivering the bronchodilator could have impacted on the outcomes of
(300 mg/4 ml) administrated via the PARI eFlow VMN nebuliser or the the study.
PARI LC Plus (a ‘breath-enhanced’ nebuliser for home use that uses a
valve system to enhance delivery in a similar manner to the Aerogen Discussion and future directions
Ultra). The VMNs produced similar pharmacokinetic profiles in plasma The evidence discussed above indicates that in both in vitro systems
and sputum, but with shorter nebulisation times for the PARI eFlow and patient studies investigating various ventilation modalities, VMNs
device.94 A similar crossover study of 58 patients with CF and pulmonary showed greater efficiency in delivering drugs to lung tissues than JNs,
P. aeruginosa infection compared 170 mg tobramycin/1.7 ml via an pMDIs or UNs. This has the potential to improve patient outcomes;

40 EUR OP EAN R ES P I R ATORY & P UL M ONA RY D ISE A SE S

 Vibrating Mesh Nebulisers – Improving Respiratory Outcomes

however, few randomised controlled trials studying patient outcomes antibiotics for difficult to treat respiratory infections such as VAP or
have been published to date.3,12,47,100–2 VMN administration is applicable to community-acquired pneumonia,71,72,105 or chronic and acute
adult use but the efficiency and size of the aerosol particles also make pulmonary infections in CF,7,101 has increased substantially over recent
it suitable for paediatric use where penetrating very small airways can years. This is driven by the possibility of achieving higher antibiotic
be an issue.39,58,82,101,103 While much of the evidence justifying VMN aerosol concentrations in the infected tissue while keeping systemic blood
administration comes from studies that use handheld or portable devices, levels low and potentially improving the therapeutic index. This is
there are indications that the devices have considerable potential for important especially when some of the antibiotics required to treat
routine use in breathing circuits for patients in respiratory distress. multidrug resistant infections have serious systemic toxicity, but also
given the concerns around antibiotic resistance and the need to
Compared to JNs, the key advantages of VMNs include: shorter control the doses of these powerful drugs.7,106
treatment times; lower residual volumes (<0.1 ml for 3.0 ml dose)
resulting in less drug wastage and higher amounts of drug being There are many publications outlining the use of VMNs for delivery of
delivered to patients; and the possibility to nebulise small volumes of heparin for pulmonary inflammation in ventilated patients,32 antifungals
drug. VMNs can be used with most medications for inhalation. They do for invasive aspergillosis,107–109 furosemide for COPD exacerbations,
not heat or degrade medications so they are suitable for most solutions, surfactant for neonates, prostacyclins for pulmonary hypertension,
suspensions, proteins and peptides.1,34 In mechanically ventilated bronchopulmonary dysplasia and breathlessness in lung cancer,33,110,111
patients, the extended time that VMNs can be left in place in the circuit and the administration of insulin to patients with diabetes.112–114 However,
reduces the need for manipulation, making it possible to refill medication many of these drugs are not approved for inhalation or are not specifically
without breaking the circuit. Ventilator parameters are therefore not approved for inhalation with a VMN and are off label. Further clinical
disturbed and there is potentially lower risk of introducing infection.94,104 studies are needed to better support the use of VMNs in this wider range
Clinical trials are required to confirm the patient outcomes related to of indications.
these factors.
A notable development in VMN systems in recent years has been the
The recent pilot study by Cushen et al.,30 suggested that utilising VMN to appearance of the so-called ‘smart nebulisers’ such as the I-neb Adaptive
improve the delivery of bronchodilators to the airways of patients with Aerosol Delivery (AAD) System (Philips Healthcare Limited, Guildford,
acute exacerbations of COPD may improve lung volumes. However, this Surrey, UK).115–117 These systems have the potential to improve nebuliser
was only a single dose study and a multiple dose study would be needed efficiency by adapting delivery in response to the patient’s breathing
to determine whether the improvements in lung volume and symptom pattern. Smart nebulisers also have internet connectivity providing
score can result in shorter durations of acute exacerbations. This could feedback to the patient and healthcare professionals via a smart phone
be important in terms of shortening hospital admissions for patients for monitoring adherence, patient condition and device performance.
with COPD and the consequent impact on healthcare costs, but also in The high cost of the I-neb AAD System is a potential downside. It is only
potentially impacting the progressive lung damage caused by severe for use in spontaneously breathing patients and can’t be used during
COPD exacerbations. mechanical ventilation.116

The recent retrospective analysis of 1,594 patients by Dunne et al.31 Respiratory conditions including COPD, asthma and CF impose
also suggested that in patients requiring nebulised bronchodilators it increasingly serious health burdens on worldwide populations and
may be possible to reduce hospital admissions and length of stay in VMN technology has the potential to improve aerosol treatments
the emergency department. The latter might be due to more efficient for these diseases. Bench models and imaging data confirm the high
drug delivery to the airways but could also be due to shorter treatment efficiency of VMNs to deliver drug to the lungs and airways across all
times. If these results can be confirmed in randomised, controlled ventilation modalities. Early clinical studies, especially in spontaneous
clinical trials this would suggest substantial hospital savings from breathing patients, may suggest that increased bronchodilator
reduced hospital admissions and improved patient throughput in often delivery to the airways and lungs could improve clinical outcomes
overcrowded emergency departments. Several studies in the US49,68–70 in terms of shortening treatment times and potentially reducing
have demonstrated notable savings in drug costs when using VMNs as hospital admissions and duration of exacerbations, but much larger
opposed to MDIs in the intensive care setting but, as yet, there is little randomised studies are needed to confirm this. There are many
evidence available on cost savings from studies on other nebuliser types ongoing antibiotic delivery studies which will report in the coming
or from studies conducted in Europe or elsewhere where the costs of years. Delivering more drug to the airways and lungs, therefore,
MDIs are much lower. has the potential to more rapidly and cost-effectively resolve acute
exacerbations of respiratory disease than is currently possible and
In addition to bronchodilators, VMNs are also used for the may positively impact outcomes in an increasing population of
administration of a variety of other treatments. The nebulisation of patients worldwide.

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