Download Trends in Nebulizer Therapy

Reference Section
Trends in Nebulizer Therapy
a report by
F r é d é r i c F L i t t l e , M D , and M a r t i n J o y c e - B r a d y , M D
Assistant Professor of Medicine and Associate Professor of Medicine, Department of Medicine, Boston University
Frédéric F Little, MD
Martin Joyce-Brady, MD
Frédéric F Little, MD, is an Assistant
Professor in the Department of
Medicine at Boston University.
He attends in the Medical Intensive
Care Unit and on the Pulmonary
Consultation Service at Boston
University Medical Center. His
out-patient activity is concentrated
on the Adult Asthma Center and
Allergy Clinics. Dr Little’s
longstanding interest and research
efforts are focused on examining the
nature of airway inflammation in
asthma. He is working with several
transgenic mouse lines to investigate
factors that regulate and dampen
the allergic airway response.
Martin Joyce-Brady, MD, is Associate
Professor in the Department of
Medicine at Boston University. He
attends in the Medical Intensive
Care Unit and on the Pulmonary
Consultation Service at Boston
University Medical Center. He is also
the Director of the Pulmonary Care
Unit and Respiratory Therapy at
Radius Specialty Hospital-Boston.
Dr Joyce-Brady’s bench research
interest is the role of glutathione
and glutathione metabolism in
antioxidant defense during perinatal
lung development and injury.
1
Since the advent of nebulizer therapy in 1859 in
France,1 nebulizers have been used to treat a range of
pulmonary diseases in pediatric and adult populations,
including asthma, chronic obstructive pulmonary
disease (COPD), and cystic fibrosis (CF).The expansion
of nebulizer therapy in the mid to late 20th century for
common respiratory diseases has been followed by a
focus on use for more specific indications and certain
new applications.2
The introduction of metered-dose inhalers (MDIs) in
the 1950s allowed portable patient-actuated drug
delivery in the home with markedly decreased waste.
Since then, many studies have shown that MDIs have
similar clinical efficacy to nebulizers for many
pulmonary therapies if used correctly.3–6 In addition,
newer devices (such as dry powder inhalers (DPI))
have mitigated some of the variability in drug
delivery attributable to patient technique.7
The need for durable medical equipment in the home
and hospital has furthered the trend away from
nebulizer use; however, several newer indications for
nebulizer treatment, both disease- and drug-specific,
predict that the need for nebulizer therapy remains. In
addition, nebulizers generate continuous and
consistent small particle sizes deliverable to the distal
lung that are of directly controllable (and, if necessary,
large) total quantities.
This concise article provides a summary of the current
applications of nebulizer therapy and comparison with
alternate drug delivery systems for pulmonary
diseases. It also reviews general features of aerosol
generation and output by nebulizers—comparison of
detailed technical specifications of the range of
commercially available nebulizers is beyond the scope
of this article. In addition, the discussion will be
limited to use of jet nebulizers, despite understanding
that ultrasonic nebulizers may have specific
compound-/drug-specific applications. Jet nebulizer
use is more prevalent, and engineering improvements
over the past 15 years have led to their comparable
performance with ultrasonic devices.8 Delivery of
nebulized agents for systemic non-pulmonary
conditions will not be discussed.
Characteristics of Nebulized Aerosols
Nebulizers are essentially atomizers with a
continuous source of compressed air.8 When passed
through a small aperture (venturi)—as a consequence
of the Bernoulli principle—high-velocity air
produces primary aerosolized particles of a broad
range of diameters (1–500µm). A non-obstructive
baffle above the jet captures larger particles that
condense and return to the reservoir for
reatomization; small particles (1–5µm) evade the
baffle for inhalation. Conventionally, particle size
available for inhalation is expressed as mass median
diameter (MMD) or closely related mass median
aerodynamic diameter (MMAD), and size range is
expressed as geometric standard deviation (GSD) of
particle size. The former is the aerosolized particle
diameter that divides the total mass of aerosol (versus
size distribution).This is more therapeutically relevant
as it determines the mass (or dose) of aerosolized drug
at or below a certain particle size, rather than the
median particle size.
The therapeutic operational characteristics of various
aerosol delivery devices are therefore the total
amount of drug exiting a device for inhalation and
proportion by mass of drug aerosolized in particles of
a certain size or less. In general, particles larger than
10µm in diameter deposit primarily proximal to the
airways, 5–10µm in the large airways, and 1–5µm in
the distal airways and alveoli. Particles smaller than
1µm have poor deposition and are largely exhaled.
While there is a broad range of commercially
available nebulizers, most have a MMD of 4–6µm.8
Based on empirical modeling, this results in
approximately 30% and 70% of total lung deposition
to the central and peripheral airways, respectively.9
This highlights one of two advantages of nebulizer
therapy compared with pressurized MDIs (pMDI)
and DPI: the absence of variability in MMAD/fineparticle fraction due to patient/MDI timing or
inspiratory flow rate. In addition, nebulizers on the
whole permit delivery of a larger total dose of drug
due to their continuous operation and, in some cases,
related to specific drug characteristics, e.g. antibiotics
in CF. This is balanced by the inherent increase in
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Trends in Nebulizer Therapy
waste from continuous nebulizer therapy. This is
particularly relevant for expensive medications and
has been partially mitigated by nebulizers that
function in a breath-actuated mode.
Nebulizer Use in Specific
Pulmonary Disorders
Asthma and COPD in Adults
Inhalational delivery of drugs for reactive airways
disease in adults is a staple of current therapeutic
management, whether the reactivity results from a
reversible cause such as asthma or a typically
irreversible cause such as COPD. The advantages of
direct delivery to the airway, including rapid onset of a
therapeutic effect, reduced drug dose need, and
limitation of systemic side effects, far outweigh those of
any enteral or parenteral route of administration. A
continual effort is now expended on improving the
inhalational drug delivery device and the duration of
drug action.7,10 The nebulizer may have a longer history
of usage but, in the patient with stable disease, the
advantages offered by pMDI or DPI devices in terms
of portability, simplicity of components, and
independence from a power source are compelling,
especially when the objectives include patient mobility
and independence.
Comparative studies in stable patient populations
consistently show that pMDI and DPI devices are as
effective as nebulizers, with a clear advantage in cost
savings.3,5 Overall risk benefit should also include the
potential for infection if nebulizer components are
not properly stored and maintained, even in the acute
hospital setting.11 This has led most reviewers to favor
pMDI or DPI devices over nebulizers to deliver betaagonist,
anticholinergic
and
corticosteroid
medications in these patient populations.6 One caveat
for pMDI and DPI devices is the need for repeated
re-assessment and education on proper technique.12
In the elderly patient, the potential benefits of pMDI
and DPI may become limited by the difficulty of
triggering the device and coordinating triggering
with inhalation.13 Some of these issues can be
overcome with spacer devices, but in the stable
and sessile individual a nebulizer does offer an
alternative choice. 14
In unstable patient populations with acute
exacerbations of reactive airways disease, studies
repeatedly show that outcomes of lung function, such
as an increase in forced expiratory volume in one
second (FEV1) or peak flow, or subsequent admission
to hospital, are comparable between nebulizer and
pMDI or DPI delivery devices.15 Again, the major
caveat here is the need for patient education on proper
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pMDI technique, even in the acute setting. In the
emergency department setting, the passive nature of
the nebulized delivery method, along with patient
respiration at tidal volume (VT), may be easier to
employ. This is clearly a matter of preference for both
the healthcare team, from the point of view of staffing
requirements, and the patient, for that ‘sense of relief ’.
Some patients express a preference for nebulized drug
delivery due to disease severity or difficulty with
pMDI/DPI coordination.16 Even policies to switch
from nebulizers to pMDI in a large medical center
have met with limited success, despite equal
effectiveness.17 This protracted attachment to nebulizers
resembles that of intermittent positive pressure
breathing (IPPB) in the past.18 It is proposed that
nebulizer therapy will continue to be available to
asthma and COPD patients as a viable and prevalent
alternative to pMDI and clinical performance
instrument (CPI) therapy.
A s t h m a i n I n f a n t s a n d Yo u n g C h i l d r e n
As alluded to earlier, pMDI and DPI efficacy is limited
by patient factors, particularly timing and inspiratory
flow rate, respectively. Due to these factors, lung
deposition with these devices is variable in children
younger than four years. In young children, efficient
lung deposition requires both small (MMAD <3µm)
and relatively monodisperse (GSD <1.3µm)
particles.19 In this population, these requirements are
best met with nebulizer therapy.20 For both
bronchodilators and inhaled corticosteroids (ICSs),
this mode is the delivery device of choice, particularly
in children who have more severe asthma and are
younger than three years. In light of the well
documented increase in asthma incidences in the US
(particularly in urban settings),21,22 it is anticipated that
the need for nebulizer therapy to treat asthma in
children and infants will increase slightly over the next
decade. The dependence on exclusive nebulizer use is
partially mitigated by improvement in DPI and pMDI
devices as well as improved inhaled fine-particle
fraction with spacer use.
Cystic Fibrosis
CF is a congenital defect in mucosal chloride transport
that affects infants, children, and young adults with a
range of lung disease progression and resultant need for
drug therapy.23 The hallmarks of CF lung disease are early
colonization with opportunistic pathogens, episodic
infectious exacerbations leading to progressive
bronchiectasis, and chronic airflow obstruction/
hyperresponsiveness, all contributing to progressive
respiratory insufficiency. Due to the age range of patients
(especially including children <4 years), chronic airflow
obstruction, infection with complex antibiotic resistance
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Reference Section
patterns, and well-described increased drug clearance and
volumes of distribution, nebulizer therapy remains a
mainstay of CF treatment.24
In individuals with advanced lung disease and young
children, where reliable inspiratory flow rates to ensure
adequate pulmonary drug delivery from pMDIs/DPIs
are difficult to achieve, nebulizer therapy is the most
effective means of administering bronchodilators
(albuterol/salbutamol and metaproterenol) and passive
assistance of mucociliary clearance (physiological
saline). Specific drug treatments are only available by
nebulizer, primarily due to specifics of drug
formulation and physical characteristics.25 Both inhaled
tobramycin (Tobi®) and recombinant dornase alpha
(DNAse) (Pulmozyme®) are US Food and Drug
Administration (FDA)-approved for routine treatment
of bronchiectasis in CF. Both of these drugs also require
high total inhaled masses for efficacy—which further
explains why their successful application depends on
nebulizer administration.
Several other antibiotics are given to CF patients by
nebulizer in ‘off-label’ indications, including
gentamicin, ceftazidime, and colistin. In light of the
stable incidence and markedly improved life
expectancy of CF, it is likely that a number of
nebulized drugs that are given off-label for CF lung
disease will acquire FDA-improved formulations and
indications. However, it is worth noting that pMDIs
with appropriate spacer devices are being used in more
younger children, and there is also concern among CF
clinicians over the risk of nebulizer hardware,
paraphernalia, and solutions becoming colonized with
Pseudomonas species.26 Overall, it is proposed that
nebulizer therapy in CF will increase slightly in the
coming decade.
AIDS
The AIDS epidemic heralded the emergence of
previously rarely seen opportunistic pulmonary
infections as well as new patterns of infection from
typical pulmonary pathogens. Pneumocystis
pneumonia (PcP; previous determined etiology:
P. carinii, recently renamed P. jirovecii) is an
opportunistic pneumonia with minimal proximal
airway involvement.27 Early in the epidemic, the
mainstay of primary and secondary prophylaxis
against PcP in susceptible individuals had been daily
oral trimethoprim/sulfamethoxazole or monthly
aerosolized pentamidine.
As other options for prophylaxis have been defined
and treatment for HIV infection has revolutionized
AIDS care, few individuals receive aerosolized
pentamidine for PcP prophylaxis. However, it retains
its indication and is noteworthy as efficacy depends
on distal lung delivery of high drug mass that is only
deliverable by nebulizer, especially one which has low
MMAD (1.5µm) with small GSD. Despite the small
market for this specific indication, it is likely that new
indications, with similar lung delivery requirements as
pentamidine, will emerge for both systemic and
pulmonary diseases.
Summary
The authors believe that nebulizer therapy for
pulmonary diseases retains a solid position for the
future but speculate that the maintained market for
nebulized drugs (and their nebulizers) will be as much
attributable to specialty drugs that have specific niches
and nebulizer compound synergy requirements (e.g.
Respirgard II® and pentamidine) as increasing
underlying disease prevalence.
Currently, there are several drugs that are only
deliverable by nebulizer. This opportunity is balanced
by improved aerosol characteristics (MMAD and GSD)
of recently formulated DPIs and hydrofluoroalkane
(HFA) pMDIs for highly prevalent respiratory
medicines. Finally, experimental applications of
nebulizer therapy (e.g. delivery of complex molecules
for gene therapy of CF and pulmonary hypertension
(PH), surfactant treatment for respiratory distress
syndrome of the newborn,1 and antioxidant treatment
for emphysema) provide opportunity for both unique
and readily accessible modes of drug delivery.The latter
plays a particular role in drug discovery and clinical
trials that mitigate engineering and development of a
delivery device. ■
References
3
1. Barry P W, “The future of nebulization”, Respir Care (2002);47: pp. 1,459–1,469.
2. Muers M F, “Overview of nebuliser treatment”, Thorax (1997);52(suppl. 2): pp. S25–S30.
3. Leversha A M, Campanella S G, Aickin R P, Asher M I, “Costs and effectiveness of spacer versus nebulizer in young children
with moderate and severe acute asthma”, J. Pediatr. (2000);136: pp. 497–502.
4. Schuh S, Johnson D W, Stephens D et al., “Comparison of albuterol delivered by a metered dose inhaler with spacer versus a
nebulizer in children with mild acute asthma”, J. Pediatr. (1999);135: pp. 22–27.
5. Mandelberg A, Chen E, Noviski N, Priel I E, “Nebulized wet aerosol treatment in emergency department—is it essential?
B U S I N E S S B R I E F I N G : U S R E S P I R A T O RY C A R E 2 0 0 6
Trends in Nebulizer Therapy
Comparison with large spacer device for metered-dose inhaler”, Chest (1997);112: pp. 1,501–1,505.
6. Brocklebank D, Ram F, Wright J et al., “Comparison of the effectiveness of inhaler devices in asthma and chronic obstructive
airways disease: a systematic review of the literature”, Health Technol. Assess. (2001);5: pp. 1–149.
7. Byron P R, “Drug delivery devices: issues in drug development”, Proc. Am.Thorac. Soc. (2004);1: pp. 321–328.
8. O’Callaghan C, Barry P W, “The science of nebulised drug delivery”, Thorax (1997);52(suppl. 2): pp. S31–S44.
9. Rudolph G, Kobrich R, Stahlhofen W, “Modelling and algebraic formulation of regional aerosol deposition in man”, J. Aerosol.
Sci. (1990);21(suppl. 1): pp. S306–S406.
10. Pavia D,“Efficacy and safety of inhalation therapy in chronic obstructive pulmonary disease and asthma”, Respirology (1997);
Suppl 1: pp. S5–10.
11. Schultsz C, Meester H H, Kranenburg A M et al., “Ultra-sonic nebulizers as a potential source of methicillin-resistant
Staphylococcus aureus causing an outbreak in a university tertiary care hospital”, J. Hosp. Infect. (2003);55: pp. 269–275.
12. Seeto L, Lim S, “Asthma and COPD. Inhalation therapy—clarity or confusion?”, Aust. Fam. Physician (2001);30:
pp. 557–561.
13. Connolly M J, “Inhaler technique of elderly patients: comparison of metered-dose inhalers and large volume spacer devices”, Age
Ageing (1995);24: pp. 190–192.
14. Labrune S, Chinet T, Huchon G, “Inhaled therapy in asthma: metered-dose inhaler experience”, Monaldi Arch. Chest. Dis.
(1994);49: pp. 254–257.
15. Shortall S P, Blum J, Oldenburg F A, et al.,“Treatment of patients hospitalized for exacerbations of chronic obstructive pulmonary
disease: comparison of an oral/metered-dose inhaler regimen and an intravenous/nebulizer regimen”, Respir. Care (2002);47:
pp. 154–158.
16. Dolovich M B, Ahrens R C, Hess D R et al., “Device selection and outcomes of aerosol therapy: Evidence-based guidelines:
American College of Chest Physicians/American College of Asthma, Allergy, and Immunology”, Chest (2005);127:
pp. 335–371.
17. Hendeles L, Hatton R C, Coons T J, Carlson L, “Automatic replacement of albuterol nebulizer therapy by metered-dose inhaler
and valved holding chamber”, Am. J. Health Syst. Pharm. (2005);62: pp. 1,053–1,061.
18. Duffy S Q, Farley D E,“The protracted demise of medical technology.The case of intermittent positive pressure breathing”, Med.
Care (1992);30: pp. 718–736.
19. Janssens H M, De Jongste J C, Hop W C,Tiddens H A,“Extra-fine particles improve lung delivery of inhaled steroids in infants:
a study in an upper airway model”, Chest (2003);123: pp. 2,083–2,088.
20. Schuepp K G, Straub D, Moller A,Wildhaber J H,“Deposition of aerosols in infants and children”, J.Aerosol. Med. (2004);17:
pp. 153–156.
21. Eagan T M, Brogger J C, Eide G E, Bakke P S,“The incidence of adult asthma: a review”, Int. J.Tuberc. Lung Dis. (2005);9:
pp. 603–612.
22. Brisbon N, Plumb J, Brawer R, Paxman D, “The asthma and obesity epidemics: the role played by the built environment—a
public health perspective”, J. Allergy Clin. Immunol. (2005);115: pp. 1,024–1,028.
23. Davis P B, Drumm M, Konstan M W, “Cystic fibrosis”, Am. J. Respir. Crit. Care Med. (1996);154: pp. 1,229–1,256.
24. Garcia-Contreras L, Hickey A J,“Pharmaceutical and biotechnological aerosols for cystic fibrosis therapy”, Adv. Drug Deliv. Rev.
(2002);54: pp. 1,491–1,504.
25. Kuhn R J, “Formulation of aerosolized therapeutics”, Chest (2001);120: pp. 94S–98S.
26. Ordóñez C, Children’s Hospital, Boston, personal communication.
27. Thomas C F, Jr, Limper A H, “Pneumocystis pneumonia”, N. Engl. J. Med. (2004);350: pp. 2,487–2,498.
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