• This presentation focuses on medication and prevention specifically as they relate
to children with asthma
Guidelines Update: An Overview of the Pathogenesis of Asthma
• ―Asthma is a chronic inflammatory disease of the airways that has created a
significant public health burden.‖
• Many cells and cellular elements, in particular, mast cells, eosinophils, T
lymphocytes, neutrophils, and epithelial cells, play a role in the inflammation
associated with asthma.
• In susceptible individuals, inflammation causes:
– Increased bronchial hyperresponsiveness to various stimuli
– Recurrent episodes of wheezing, breathlessness, chest tightness,
– Widespread, variable airflow obstruction that often is reversible
Asthma Predictive Index (API)
• The API was originally developed by Castro-Rodriguez et al based on data from
the Tucson Children’s Respiratory Study.
– A stringent index requires frequent wheezing in the first 3 years of life
plus 1 of 2 major criteria (parental diagnosis of asthma, diagnosis of
eczema in the child) or 2 of 3 minor criteria (diagnosis of allergic rhinitis
in the child, eosinophilia [ie, eosinophils 4% of the total white blood
cells], wheezing apart from colds).
– A loose index for the prediction of asthma requires any wheezing during
the first 3 years of life plus 1 of 2 major criteria or 2 of 3 minor criteria.
– Children with a positive loose index were up to 5.5 times more likely to
have active asthma between 6 and 13 years of age compared with children
with a negative loose index. Children with a positive stringent index were
up to 9.8 times more likely.
• The Prevention of Early Asthma in Kids (PEAK) criteria for a modified API
(mAPI) were adapted from the Tucson Children’s Respiratory Study’s original
tool and are more specific than the original API criteria.
– The mAPI criteria specifiy the frequency of wheezing as >3 exacerbations
of wheezing in the past 12 months or at least 1 physician-confirmed
– Additionally, the mAPI specifies allergic sensitization to 1 aeroallergen
among the major criteria and replaces allergic rhinitis as a minor criterion
with allergic sensitization to milk, egg, or peanuts.
• The PEAK study was designed to investigate the role of ICSs in preventing
persistent asthma in children with a positive mAPI.
When to Consider Long-term Treatment for Infants and Children
• Diagnosing asthma in infants and children can be clinically challenging.
• The NAEPP provides special considerations for when initiation of long-term
controller treatment should be considered for children 5 years and younger.
• Along with asthma symptoms and objective measures (if feasible), treatment
should be considered in the following situations:
– Positive API and more than 3 wheezing episodes lasting more than 1 day
and affecting sleep
– Consistent requirement for symptomatic treatment more than 2 times per
– Severe exacerbations less than 6 weeks apart requiring inhaled 2-
adrenergic agonist treatment more than every 4 hours for 24 hours
• When it has been determined that ICS therapy is necessary for the treatment of
asthma in children, several treatment options are available.
Stepwise Approach to Asthma Therapy for Children Aged 5 Years
• For all patients at all severity levels, step-up and step-down therapy should be
– Step down—review treatment every 1 to 6 months to determine if gradual
stepwise reduction in treatment is possible.
– Step up—consider if control is not maintained, after review of patient
medication technique, adherence, and environmental control.
– Gain control as quickly as possible; then, step down to the least
medication necessary to maintain control.
Advantages of Inhaled Therapy in Patients With Asthma
• The inhaled route for asthma medication delivery is generally preferred because
– Higher concentrations can be delivered more effectively to the airways
– Systemic side effects are avoided or minimized
– The onset of action of short-acting β2-adrenergic agonists (SABAs) is
substantially shorter when inhaled
• The National Asthma Education and Prevention Program (NAEPP) and the
American Academy of Allergy, Asthma and Immunology recommend the use of
inhaled therapies for patients with any severity of asthma.
• The NAEPP recommends the use of inhaled therapies for all severities of asthma
in patients of every age.
– Inhaled therapy is recommended for the long-term control and
prophylactic treatment of asthma (eg, ICSs, long-acting β2-adrenergic
agonists [LABAs]) and for the quick relief of asthma symptoms (SABAs).
Factors Affecting Inhaled Corticosteroid Delivery to the Lungs
• Patient acceptance of and adherence to the use of a particular inhalation device
and ability to properly use the device can affect medication delivery.
• The aerodynamic size of aerosolized drug particles emitted from an inhalation
device is one of the most important factors influencing lung deposition.
• Particle velocity also may affect lung deposition, with lower velocity emissions
reducing deposition in the oropharynx and optimizing drug delivery to the lungs.
• pMDIs, DPIs, and nebulizers are available for the delivery of inhaled asthma
• The inability to coordinate pMDI actuation and inhalation can result in high
aerosol deposition in the oropharynx and variability in lung delivery. The use of
spacers and holding chambers can help overcome this problem.
• A patient’s physical and cognitive abilities and willingness to use a particular
inhalation device should be considered when prescribing asthma therapy.
• Physical characteristics of a particular patient population may lead to less
effective drug delivery with specific inhalation devices. For example, dry-powder
inhalers may be less effective in very young children, and unmodified pMDIs
may be less effective in patients with arthritis.
• Inspiratory flow rate, upper airway anatomy, and degree of airway obstruction are
additional patient variables that influence drug deposition in the upper and lower
Challenges of Inhaled Therapies for Young Children
• Delivery of inhaled therapy to infants and young children is associated with
unique challenges due to anatomy, physiology, and cognitive development in this
• Because infants have small airways, it is likely that drug deposition will be
greatest in the upper and central airways; however, lower inspiratory volumes and
flows in infants may lessen drug impaction in the upper and central airways.
– High inspiratory flow rates (>30 L/min) can increase drug impaction in the
upper airways and reduce the lung deposition.
• A breathing pattern comprising slow inhalation coupled with breath holding can
improve lung deposition of medication administered via a pMDI.
• Infants and young children prefer nasal to mouth breathing; filtering of
aerosolized drug in the nose may reduce deposition in the lungs.
• Distress caused by the use of a face mask by infants and young children can lead
to breaking of the face mask seal or alteration in breathing pattern, both of which
may reduce the efficiency of lung deposition.
• Drug deposition studies demonstrate greatly reduced drug deposition in the lungs
of crying infants.
Aerosol Characteristics: Particle Size
• The MMAD of aerosolized particles should be <5 m; particles 1 to 5 m in
diameter are considered to be within the respirable range.
• Particles between 1 and 0.1 m are too large to diffuse significantly and too small
to be deposited by gravity in the airways. These particles remain suspended in the
airstream and are generally exhaled.
Correlation Between Particle Size and Thoracic Deposition
• This figure shows the percentage of aerosol deposited in the lungs, as a
percentage of total body deposition, versus volume median diameter of inhaled
aerosols for the studies listed.
• A correlation exists such that greater particle diameter correlates with reduced
Particle Velocity and Patient Breathing Requirements by Device
• This slide summarizes particle velocity and breathing techniques for the
nebulizer, DPI, and MDI.3
• Nebulizers generate particles at a slow velocity.
– The optimal breathing technique for use of a nebulizer involves slow tidal
breathing with occasional deep breaths, as well as use of a mouthpiece or
tightly fitting face mask.
– Use of nebulizers is less dependent on patient coordination or cooperation
than use of MDIs or DPIs.
• Particle delivery from DPIs is dependent on the patient’s inspiratory flow rate.
– Generally, a high inspiratory flow rate needs to be produced by the patient
to generate sufficient force to aerosolize the powder in the device.
– Children younger than 4 years may not be able to generate the inspiratory
force necessary to effectively use a DPI. Although some 4-year-old
children can use a DPI effectively, children
5 years and older are more likely to consistently produce a sufficient
• Compared with a DPI, particle delivery from a pMDI is less dependant on the
patient’s inspiratory flow.
– The optimal breathing technique for use of a pMDI is actuation during a
slow (30 L/min) deep inhalation, followed by a 10-second breath hold.
However, slow inhalation may be difficult.
– The high velocity of aerosol being emitted from a pMDI after actuation
makes it difficult to coordinate inhalation with device actuation; use of a
spacer can help to slow drug delivery.
• The optimal breathing technique for using each device should be taught to the
patient when the device is selected and reviewed regularly.
Inhalation Velocity Affects Lung Deposition With Nebulizer
• This slide demonstrates the effect of inspiratory flow rate on the distribution of
radiolabeled aerosol in the lungs of patients with asthma.
• In a study by Laube et al, 9 patients aged 23 to 36 years with a history of allergic
or exercise-induced asthma inhaled radiolabeled (99mTc sulfur) 0.9% buffered
saline aerosol administered by a No. 42 De Vilbiss at a rapid (60 L/min) or slow
(12 L/min) inspiratory flow rate on 2 study days.
• Aerosol distribution in the airways was quantified by gamma-camera scan.
• Methacholine challenge was performed after gamma scan; albuterol was
administered to reverse airway obstruction after each challenge.
• The amount of radiolabeled aerosol deposited in the trachea and lungs was
reduced in 6 of 9 patients during rapid versus slow inhalation, but mean values
were similar (5.1 3.0 L versus 5.2 2.3 L).
• As shown in the scans, rapid inspiration resulted in greater heterogeneity in lung
deposition and regions of higher-density labeling compared with slow inspiration.
• Rapid inhalation resulted in greater aerosol deposition in the inner lung and less
penetration to the lung periphery. The ratio of inner zone (large, central airways)
to outer zone (peripheral airways and alveoli) deposition was 2.91 0.51 during
rapid inhalation, compared with 1.84 0.30 during slow inspiration (P.001).
Examples of Delivery Devices for Inhaled Medications
• Types of delivery devices for inhaled medications include pMDIs, (with and
without holding chambers and spacers), DPIs (single capsules, multidose disks,
and multidose reservoirs), and nebulizers (jet and ultrasonic).
Types of Nebulizers
• There are 2 types of nebulizers currently available for use at home: jet nebulizers
and ultrasonic nebulizers. Jet nebulizer/compressor systems provide a simple way
to deliver inhaled medication to children and are the most common type of
• Some ICS preparations are suitable for oral inhalation use via a jet nebulizer
connected to an air compressor with an adequate airflow, equipped with a
mouthpiece or suitable face mask.
– Suspensions and highly viscous solutions decrease the propagation of
ultrasonic sound waves, thus decreasing effective output from ultrasonic
nebulizers.20 In addition, these devices only nebulize the water and not
the drug in a suspension; such devices may not be able to make a spray
from viscous drug solution and may damage certain drugs.
Jet Nebulizer: Description
• A jet nebulizer delivery system consists of a nebulizer and a source for
compressed air. Air flow to the nebulizer changes the medication solution to a
mist, which can be inhaled over 5 to 10 minutes.
• Nebulizers are recommended for use in infants and very young children, as well
as any patient unable to properly use an inhaler.
• Nebulized medications can be delivered via face mask to facilitate medication
delivery in very young children.
Some Advantages of Nebulizers
• Because their use depends less on coordination and cooperation than inhalers,
they are easy to use and can be used at any age.
• Administration of high drug doses is possible, including continuous nebulization.
• No chlorofluorocarbons are involved in the drug delivery mechanism.
• Nebulizers can be used with supplemental oxygen.
Some Disadvantages of Jet Nebulizers
• Jet nebulizers are less portable than inhalers; a power source and pressurized gas
source are required.
• Contamination is possible if the nebulizer components are not carefully cleaned.
• The treatment time for small-volume jet nebulizers is longer than that for inhalers.
However, ultrasonic nebulizers provide faster delivery than jet nebulizers.
• Output is device dependent, with substantial internebulizer and intranebulizer
output variances.3 Delivery may take 5 to 10 minutes or longer.
Technique for Optimal Nebulizer Use
• Maximizing the efficiency of aerosol delivery from a nebulizer involves slow
tidal breathing with occasional deep breaths, as well as use of a mouthpiece or
tightly fitting face mask.
Blow-By Technique Reduces Inhaled Drug Exposure
• The Sophia Anatomical Infant Nose–Throat (SAINT) model of the upper airway
of a 9-month-old, nose-breathing infant was coupled with a PARI COMPAS™
breath simulator to study the lung and throat deposition of Pulmicort Respules®
(budesonide inhalation suspension [BIS]) from several nebulizer–face mask
Advances in Nebulizer Technology
• Nebulizer technology continues to evolve, as evidenced by newer models that are
• The devices shown in this slide are compact, lightweight, portable, and battery-
Some Advantages of pMDIs
• Compared with most nebulizers, pMDIs are small and portable.
• pMDIs provide efficient dose-dose reproducibility, can be used quickly, and are at
least as effective as other delivery devices when used correctly.
• pMDIs (and DPIs) are less time consuming than nebulizer systems.
Some Disadvantages of pMDIs
• Because of the coordination of actuation and inhalation required to effectively use
pMDIs, they can be difficult for elderly and very young patients to use correctly.
– Elderly patients with physical (eg, decreased hand strength) and cognitive
decline may have problems with pMDI use.
– In children 5 years of age, pMDIs should be used with a spacer.
• Many patients use their pMDIs incorrectly.45 Improper technique, such as open
mouth versus closed mouth, affects dosing.
– The procedure for using a pMDI is difficult to teach, and even health care
providers are unclear about how to correctly use these devices.
– High aerosol velocity leads to deposition of 80% of the actuated dose in
the oropharynx. To reduce systemic absorption, mouthwashing is
Some Advantages of Valved Holding Chambers and Spacers
• Valved holding chambers and spacers
– Minimize the need for coordination between actuation of the pMDI and
– Slow the velocity of the aerosol, which decreases oropharyngeal
deposition to 5%-10%
– Although the terms are often used interchangeably, a spacer is an
extending device that allows the aerosol cloud to decelerate; whereas, a
holding chamber is a ―valved spacer allowing breathing from a standing
cloud of aerosol.‖
• Valved holding chambers and spacers, therefore, allow pMDIs to be used by
children (with closely fitted face masks), elderly patients, and handicapped
patients, as well as any patient who experiences difficulty using a pMDI.
Steps Performed Improperly: MDI + Holding Chamber
• The ability of children and adolescents to demonstrate proper technique when
using an MDI with or without a holding chamber (HC) and a peak flow meter
(PFM) was prospectively evaluated among children who presented to the
emergency department for an acute asthma exacerbation.
• A greater emphasis must be placed on teaching methods to optimize drug delivery
and to instruct patients about the importance of monitoring disease severity.
Appropriate Inhalation: Timing Affects Drug Availability
• Inappropriate use of a pMDI can affect drug delivery.
Some Advantages of DPIs
• Advantages of DPIs include
– Small size and portability enhance convenience
– Can be quickly administered (1-2 seconds)
– Less patient coordination required, compared with metered-dose inhalers,
because they are breath actuated
– Easy to use and teach
– Do not require propellants, which may harm the earth’s ozone layer
Some Disadvantages of DPIs
• The primary DPIs is the high rate of inhalation (60 L/min) required to use these
• The particle size and velocity of the drug aerosolized are related to the patient’s
rate of inhalation.
• Because of the high inspiratory flow rate required, use of DPIs may not be
suitable for children younger than 5 years; however, some 4-year-old children
may be able to use a DPI.
Percentage of Children With Peak Inspiratory Flow 50 L/min
• In a randomized, crossover study, Agertoft et al investigated the peak inspiratory
flow (PIF) rate generated by 198 children aged 3 to 15 years.
• In conclusion, drug delivery to a child with asthma varies with age, as well as the
Measures of Inhalation Device Efficiency
• Agents and devices that produce finer particles provide greater lung deposition
than those that produce larger particles.18
• Consistency in delivery of the dose from the device contributes to optimal
• A treatment cannot be optimally effective if administration issues or side effects
limit patient adherence.18
• Regardless of the device selected, the ultimate outcome of asthma treatment is the
achievement of therapeutic goals (eg, symptom relief).
Relevant Errors in Drug Delivery Device Use
• Kofman et al interviewed 150 children and parents about aerosolized drug
treatment after outpatient encounters at a hospital in Buenos Aires (4-5/2001).56
• The interview questionnaire covered parents’ knowledge about disease, utility of
treatment, and cleaning techniques for relevant delivery device. Children were
interviewed when appropriate.56
• A hands-on evaluation of inhalation technique also was performed. Patients using
DPIs had peak inspiratory flow checked.56
• Mistakes that could dramatically affect intrapulmonary drug deposition were
• Proper use for each device is outlined below56:
– Nebulizers – 81% demonstrated proper use.
– MDIs with spacer/holding chamber – 64% demonstrated proper use.
– DPIs – 42% demonstrated proper use.
Aerosol Characteristics Summary: Particle Size and Particle Velocity
• Both particle size and particle velocity affect aerosol deposition in the
• Particle size and velocity can be influenced by the inhalation device25,35 and
• Increasing the proportion of small to large particles will improve the therapeutic
index of an inhaled medication because there will be less impaction due to large
(>5 m) particles in the oropharynx and greater deposition of small particles in
the lower airways.19
• Although lung deposition is generally greater with particles <5 m, very small
particles (ie, with a mass median aerodynamic diameter of <1 m) may remain
suspended in the airstream, with the majority (80%) being exhaled.7
• At high speeds, large particles are more likely to deposit in the oropharynx.7
• Individual patient variables and capability should be considered when selecting
inhalation devices to ensure optimal lung deposition of aerosolized medications.
Thus, the device selected should be appropriate for the needs of the patient.
– While each device has its advantages and disadvantages for younger
children, nebulizers are easy to use and are faster than once believed (with
many models taking between 5-10 minutes).33,35
– pMDIs are difficult to teach, learn, and use consistently because of the
need to coordinate actuation with inhalation; use of a spacer facilitates
– DPIs are appropriate, however, for older children (5 years of age).6