Educational Aims
The reader will come to appreciate how aerosol drug delivery to children depends on:
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Selecting the right device,
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Selecting the right interface,
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Educating the patient and parents effectively
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Optimizing patient adherence to therapy in children.
Summary
Pulmonary drug delivery is complex due to several challenges including disease-, patient-, and clinicians-related factors. Although many inhaled medications are available in aerosol medicine, delivering aerosolized medications to patients requires effective disease management. There is a large gap in the knowledge of clinicians who select and provide instructions for the correct use of aerosol devices. Since improper device selection, incorrect inhaler technique, and poor patient adherence to prescribed medications may result in inadequate disease control, individualized aerosol medicine is essential for effective disease management and control. The components of individualized aerosol medicine include: (1) Selecting the right device, (2) Selecting the right interface, (3) Educating the patient effectively, and (4) Increasing patient adherence to therapy. This paper reviews each of these components and provides recommendations to integrate the device and interface into the patient for better clinical outcomes.
Introduction
Aerosolized medications offer many advantages in the treatment of pulmonary diseases yet delivering them to patients is a challenge and it is difficult to achieve disease control in many patients . Barriers to effective aerosol therapy are significant. Non-uniform pulmonary diseases and conditions generating purulent secretions in the airways or laryngospasms limit the aerosol drug delivery to the lungs . However, Health Care Providers [HCP] may be unfamiliar with the correct use of aerosol devices , or have inadequate time to train patients in clinical settings. Patients/parents often need more extensive education than feasible during office visits and there may be no single HCP primarily responsible for patient education and assessment of the inhalation technique.
The correct use of aerosol devices requires the patient’s proper mastery . The importance of correct inhaler technique remains a challenge in a variety of patient populations . For instance, children possess different psychomotor skills than adults. Their airway size, respiratory rate, inspiratory flow, breathing pattern, and lung volume change over time which impacts their ability to use the aerosol device correctly . Since most inhaled drugs are tested in adults, care must be taken to determine the best device and appropriate dose in children. Also, patients’ diseases and comorbidities were associated with errors in the inhaler technique . Critical errors in the inhaler technique may increase emergency department visits and hospital admissions . While all aerosol devices have been tested in clinical efficacy studies, researchers provide rigorous inhaler technique training and require demonstration of proficiency in these studies, which is not the case with HCPs training patients in real life.
There is no single aerosol device on the market that meets the needs of all children; therefore, it is essential to individualize aerosol therapy and integrate the device and interface into the patient. In addition to choosing the right drug for the patient, it is the specialist’s responsibility to choose the right aerosol device with the appropriate interface . However, 90% of HCPs give more importance to the medication than the device to administer medications to patients . Since improper device and interface selection, as well as incorrect inhaler technique, may cause poor disease control, individualized aerosol medicine may be beneficial to disease management and control. Individualized aerosol medicine has four essential components: (1) Selecting the right device, (2) Selecting the right interface, (3) Educating the patient effectively, and (4) Increasing patient adherence to prescribed medication.
Device selection in spontaneously breathing children
Over the last century, the variety of marketed aerosol devices and medications to treat patients has greatly expanded . The evolution of delivery devices has advanced with the availability of new technologies and the development of therapeutic molecules primarily targeted at facilitating increased levels of patient adherence and compliance. From a drug perspective, treatments have evolved from short durations of action to longer durations of action , reducing the requirement for multiple doses each day to once a day is associated with better compliance and higher sales. While aerosol devices utilizing single-dose capsules for a single drug are still marketed, they have been largely eclipsed by multidose devices delivering 2–3 active molecules (including a bronchodilator, antimuscarinic, and a steroid) with a once-a-day dosing and monthly replacement .
Device technology reflects both engineering and pharmaceutical advances which continue with rapid innovation; however, the adoption of new technology is slow for the industry to use to develop better products, and seemingly even slower for clinicians to adopt once available. While there are multiple technologies currently in development, clinician choices are largely limited to the approved drug and devices available to their practice .
A range of aerosol devices is available on the market that has different features, characteristics, operating, cleaning, and maintenance requirements that should be considered for the effective treatment of patients with pulmonary disease . These include pressurized metered-dose inhalers (pMDIs), dry powder inhalers (DPIs), soft mist inhalers (SMIs), and nebulizers; each with attributes that may affect device selection in children. ( Fig. 1 ).
SMI
The SMI technology was initially developed in the 1980s for use and the Respimat™ persevered to commercial success worldwide. A mechanical spring action pressurizes the device, and manual triggering releases a small particle, low force plume over a 1–1.5 s period for inspiration, combining to have less upper airway deposition and greater lung doses. The devices are small and not dependent on specific inspiratory flow generated by the patient if inspiration continues from the beginning to past the end of the aerosol plume generated. Dose per actuation ranges from 10 to 15 mcl, with most drugs administered with 1–3 breaths .
pMDI
Since their introduction to the market in the 1950s, the pMDI technology has undergone incremental changes. The introduction of dose counter technology is perhaps the most important change in pMDIs, providing quantification of how many doses remain at the end of the device’s life. Advances in device use monitoring and patient tracking systems have the potential for impacting physician awareness of patient usage patterns. The pMDI actuation requires hand-breath coordination. The dose per actuation is between 80 and 200 mcl, with most drugs administered with 1–4 actuations .
DPI
The DPI technology integrates the formulation, the metering system, and the aerosol dispersion features. The difficulty of dispersing micronized dry powders has been recognized since modern DPIs were developed in the 1960s. Small particles coalesce and do not readily disperse into an aerosol, so they were blended and loosely bound to larger (50–100 µm) lactose particles. DPIs are all active devices, which require the patient to generate sufficient energy and inspiratory flow to disperse the micronized particles from the lactose. In early DPIs, only 20% of the micronized drug was inhaled, while 80% would deposit in the back of the pharynx. Early DPIs used capsules filled with formulation for a single breath. The individual capsule was placed in the inhaler, a mechanism to puncture the capsule, allowing the force of patient inhalation to dispense and disaggregate the powder. The patient would dispose of the used capsule and insert the next capsule for repeated breaths up to the prescribed dose. The introduction of devices such as cyclone classifiers allowed a device-driven approach to disperse micronized particles opening the possibility for relatively high dose delivery of antimicrobials, as required to treat infectious diseases. The powder is drawn from a metering blister built into the device through a cyclone classifier such that only respirable particles can pass into the airstream to the patient in the form of a simple disposable inhaler. DPI using powder cakes in which a twist of the dial scrapes a dose into the chamber, and other forms of powder dispensing reservoirs provided multidose convenience beyond managing individual capsules . Regulatory approval and commercialization of Advair®/Seretide® were one of the most significant developments combining two drug formulations filled into blister packs in a device design that allowed 60 doses in a single disposable device. DPIs can now range from mid to high payloads, typically intended to be administered in less than 5 breaths.
The DPI “automatically” coordinates drug delivery with an inhalation that provides the energy to extract and disperse the inhaled dose. However, the patient must inhale at a sufficiently high-pressure drop/flow rate to ensure the dose is adequately delivered. The patients’ flow rates depend on the inhaler resistance and the pressure drops a patient can produce. Consequently, pressure drop not inhaled flow rate is the more appropriate metric for the efficient operation of a DPI .
Nebulizers
As one of the earliest aerosol devices, jet nebulizers (JNs) are driven by compressed gas to generate and suspend small drops of liquid (solutions or suspensions) in gas to be inhaled by the patient. Unlike inhalers, nebulizers may operate with a variety of liquids. The particle size depends on the pressure generated by the gas flow through the device. The inhaled dose depends on the proportion of inspiratory time to the total breathing cycle. Generated aerosol not inhaled is lost to the ambient air, reducing the inhaled dose to 5–12% of the total dose. Residual volumes left in the device at the end of therapy range from 0.8 to 1.2 mL, a problem with unit dose medications ranging from 1 to 3 mL. Due to a large amount of residual drug and the open reservoirs that directly attach to mouthpieces and masks, JNs have a risk of contamination and pathogen proliferation between treatments. Consequently, rinsing, air drying, sterilizing, or replacing nebulizers between treatments are recommended .
The performance variability of nebulizers ranges from 3 to 15%. When drugs are approved based on clinical trials with nebulizers, the label of the drug specifies which nebulizers were used and, directed users to only use the “approved” nebulizer. It is important to prescribe these specific nebulizers to be used with those prescriptions.
The ultrasonic nebulizers (UNs) use a piezo-ceramic disk, vibrating at 1.3 mHz, to create a standing wave in the medication producing high-output small particle aerosol. These devices generate considerable heat and are not recommended for suspensions such as budesonide®. Large-volume devices are used in clinics for sputum inductions, while small handheld devices are marketed for ambulatory care. The piezo element requires cleaning for reliable operation. One drug/device is the pulse UNs distributed with Tyvaso™ for the treatment of pulmonary hypertension, in which each dose is based on the prescribed number of breaths.
The development of the vibrating mesh nebulizers (VMNs) was described as the most significant improvement in nebulizer technology since the 1990s due to their relatively high output aerosols, in precise ranges, with low residual (1.1–0.3 mL) and no driving or diluting gas flow. The VMN technologies were developed over decades, and their applications range from very small (individual micro-grams, Treprostinil, Iloprost) to large (hundreds of milligrams, Tobramycin) doses of drug delivered. The most commonly used VMNs are the eFlow (Pari), and iNeb (Philips) for ambulatory patients and Aerogen Solo (Aerogen Ltd) for the acute care setting.
Device selection
Device selection in spontaneously breathing children is dependent upon drug-, device-, and patient-related factors . Drug-related factors include the therapeutic aims of the drug, the availability of the formulation with specific aerosol devices, and the combination of treatments prescribed. Device-related factors consist of decisions made by the manufacturer to commercialize a formulation with a specific device design used in clinical trials to establish drug safety and efficacy before regulatory approval . Pharmaceutical companies tend to offer their formulations in proprietary aerosol delivery systems, which may result in patients being prescribed multiple drugs available in different inhalers from various companies. This can lead to some confusion for the patient, as each device has different instructions for use and maintenance. For example, many DPIs require rapid inhalation, while a slower inspiratory flow is needed for the correct use of pMDIs. Confusion about these inspiratory patterns can result in reducing inhaled doses while using both devices. A goal for device selection is to minimize the “Device Dementia” precipitated by the need to properly use this wide variation in devices .
Age, physical and cognitive ability, and socio-economic status of patients, as well as patient preference, are patient-related factors that should be considered during device selection. If the medication is available only as a DPI, clinicians are compelled to choose that DPI for aerosol therapy with that specific drug. If a drug can be delivered with nebulizers and inhalers, clinicians should select a device based on the patient’s needs, ability to afford the medication, as well both physical and cognitive abilities including the patient/parent’s preference. When more than one fit-for-purpose inhaled medication is prescribed, it is highly desirable to use the same device with each medication or to select a combination of formulations in a single device.
Aerosol therapy is prescribed for patients with acute and chronic diseases such as asthma . Virtually none of these commercial devices are specifically designed for administration to neonates, infants, or toddlers . This may eliminate device choices that cannot be actuated by the child or incorporates an interface that they cannot use or tolerate .
It is important to choose an aerosol device that is affordable with the least out-of-pocket expense for the patient. When possible, an easy-to-operate device with good reliability and durability, which does not require extensive maintenance and cleaning is preferred . Failure to clean nebulizers after each use is common and improper cleaning may result in reduced device performance and increased risk of bio-contamination.
In summary, device selection should be less based on the individual technology or even molecule, but properly matching the device to the needs of the specific patient. Evidence-based reviews concluded that the various devices properly used for the delivery of bronchodilators and steroids are equally efficacious. Consequently, when selecting an aerosol device for children, clinicians should consider device/drug availability; clinical setting; patient age and the availability to use the selected device correctly; device use with multiple medications; cost and reimbursement; drug administration time; convenience in both outpatient and inpatient settings; and physician and patient/parent preference . Table 1 includes a comparison of the advantages and disadvantages of available devices as well as recommendations about each device.
| Devices | Advantages | Disadvantages | Recommendations |
|---|---|---|---|
| pMDI | Inhaler designed for specific drug formulation. Multidose convenience. Compact and Portable. Easy to use. Short treatment times. | Limited drug/device combination Expensive. Requires hand-breath coordination. Requires low inspiratory flow. Breath-hold recommended. Small payload per actuation. | The most common aerosol device. Use it in patients with good hand-breath coordination. Combine it with a VHC in children and patients without good hand-breath coordination. Train patients about the effective use of pMDI. |
| SMI | Inhaler designed for specific drug formulation. Multi-dose convenience Portable and easy to use. Short treatment times. Less oropharyngeal deposition than other inhalers. Actuation emits aerosol up to 1.5 s. | Requires hand-breath coordination. Expensive. Limited to patients > 5 yo. Small payload < 15 mcl/actuation. | Higher efficiency aerosol device. Use with VHC in infants, toddlers, and children with hand-breath coordination problems. Train patients about the effective use of SMI. |
| DPI | Breath-actuated. No hand-breath coordination. Compact and portable. Increased drug deposition in capsule or device. Less risk of drug contamination. Short treatment times. No propellant is required. | A high inspiratory flow is required. High oropharyngeal deposition. Dose affected by humidity. Breath-hold recommended. Proprietary devices specific to drug. Great variety of device designs across DPIs. Can lead to “device dementia.” If the patient exhales into DPI inhaled dose can be reduced. | Not recommended for children < 5 years. Screen patients to assure they can generate adequate flow. Do NOT use single-dose DPIs in patients with manual dexterity. Do NOT use it in patients with physical & cognitive impairments. Train patients about the effective use of DPI. |
| Nebulizer | Used with a range of suspensions and solutions. Limited drug/device combinations. Easy to use. No hand-breath coordination is required. Used with patients of all ages. The larger payload of drugs. | More complicated setup. Single unit dose for treatment. Drug was added to the nebulizer. Cleaning is required after use. Variability in dose efficiency across designs. Longer treatment times. Larger payload per treatment. | Often used for the youngest and oldest patients. Use it in patients with physical and cognitive impairments. Consider regular vs prn treatments. |
Interface selection in spontaneously breathing children
The aerosol interface is defined as the device between the aerosol generator and the patient that enables the delivery of the aerosolized medication. Using a patient interface that can effectively enhance aerosol delivery in children is important as children may be unable to effectively inhale the aerosol. Also, distress and crying severely limit aerosol delivery. Therefore, it is essential to review each interface and make recommendations for using specific interfaces in children of different ages, abilities, and disease severities ( Table 2 ).
| Interface | Definition | Advantages | Disadvantages | Recommendations |
|---|---|---|---|---|
| Blow-by | Lack of interface, aerosol blown directly onto infant’s face. | Less invasive Improved patient tolerance. | Inefficient drug delivery. | It should never be used due to lack of efficacy. |
| Headbox | Enclosed chamber that delivers aerosols; secure seal and nebulizer inlet on the back panel. | Decreased patient distress. | Suboptimal drug delivery. | Preferably not used, unless patient <4 years is significantly intolerant of facemask/mouthpiece/HFNC. |
| Facemask | Interface overlying mouth and nose secured by strap. | Provides efficient method of direct drug delivery for children unable to use a mouthpiece. | Less drug delivery compared to the mouthpiece. Caregiver variability in accurate usage. | Preferred option for infants and children who cannot form mouthpiece seal. |
| Mouthpiece | Apparatus around which a mouth seal can be performed to inhale the medication. | Enhanced drug delivery. Improved clinical effectiveness. | Not suitable for young children who cannot form mouthpiece seal or for those with physical deformities. | Preferred option for children who can form mouthpiece seal. |
| HFNC | Dual nasal prong tubing inserted into the nares that directly deliver aerosols with high or low flow O2. | Improved tolerability compared to facemasks. Reduced aerosol loss. | Dose varies with gas flow. More invasive. | Preferred option for children receiving HFNC and unable to tolerate interruption of oxygen for aerosol administration. |
Blow-By
In the concept of “blow-by” delivery, there is no patient interface. Rather, the JN blows the aerosol directly onto the child’s face. Blow-by has been used because it is non-invasive and thought to be more comfortable for the child (usually an infant). However, a controlled, slow inhalation followed by a breath hold is necessary to target airways by maximizing lung deposition and minimizing upper airway deposition but this is not consistent with the erratic respiration of an upset infant . Thus, there is the temptation to use ineffective blow-by aerosol administration. The National Asthma Education and Prevention Program specifically discourages the use of blow-by delivery .
Headboxes (Hoods)
Headboxes (also known as hoods) are enclosed chambers used to deliver oxygen or aerosols, with the most effective designs consisting of a secure seal and nebulizer inlet on the back panel . A notable historical example is the use of Ribavirin, an RSV antiviral, with the small particle aerosol generator-2 , which delivered the aerosol using flexible tubing attached to an oxygen hood to allow young children to passively inhale the antiviral. However, its use has been discontinued due to its limited efficacy . There have been novel developments to headboxes, made of clear Perspex, a circular dome 30 cm × 25 cm, 3 cm vents, and a 22 mm nebulizer outlet. Scintigraphic scans of lung aerosol distribution did not show significant differences between the hood and facemask, but the custom hood decreased patient distress and increased parental preference . However, in vitro models show that the headbox delivers a lower inhaled dose of medication compared to facemasks . Ultimately, these devices can be a more convenient and comfortable way to provide aerosolized medications to infants and young children but are likely to be less effective compared to other interfaces.
Mouthpieces
Mouthpiece size and shape can affect particle loss in the device and oral cavity. Increasing the size of the mouthpiece may make it more difficult for young children to make an effective seal on a large mouthpiece leading to higher oral cavity deposition . Second-generation mouthpiece designs, one with an increased cross-sectional area and another with a perforated wall have considered these characteristics to decrease mouthpiece particle deposition . The mouthpieces of some DPIs are designed to allow for large particles to disaggregate. The Turbuhaler DPI has a mouthpiece inlet shaped in a rotating double helix to generate a turbulent, swirl-like flow. While this design effectively disaggregates and disperses larger particles, eddy simulation studies have shown that this swirling flow is uneven, favoring one side of the mouth with asymmetric particle deposition . The pMDI can be used alone but is often attached to a spacer or valved holding chamber (VHC), a chamber with a one-way valve outlet, with either a mouthpiece or mask. Secure and comfortable masks can be an important interface for VHCs .
Compared to facemasks, mouthpieces have the advantage of greater airway medication delivery . When facemasks were compared to mouthpieces using constant-output nebulization, mouthpieces had a higher inhaled mass of budesonide than a facemask . There was also an increase in FEV 1 and FVC when mouthpieces were compared to facemasks . While 4% more drug was delivered to the lungs with a mouthpiece than mask (22.5% vs 18.1%, respectively) peripheral lung deposition was higher in 7 out of 10 children with the facemask . However, using a mouthpiece requires the patient to have the ability to seal their mouth on the mouthpiece and coordinate to inhale the dispensed medication. Infants, for example, cannot form a mouthpiece seal and inhale on command, making mouthpieces an ineffective interface for this population. Anatomical differences also exist in premature infants that limit drug deposition, including larger tongue size and higher position of the larynx, which can alter the flow of aerosols . Furthermore, patients with craniofacial deformities, such as those with cleft lip and palate, or patients that simply cannot provide the aperture necessary for mouthpiece usage limits the mouthpiece’s generalizability as an interface.
Facemasks
Facemasks overlying the nose and mouth are one of the oldest interfaces used for children. They allow for medications to be inhaled by young children who are unable to use a mouthpiece . Infants and young children can use facemasks attached to a VHC when they are unable to form an effective mouthpiece seal . Facemask design has considerable effects on medication delivery. A balance must be struck between a mask that is too rigid, preventing the creation of a successful seal, versus overly yielding, allowing for air leakage . The AeroChamber and Hans Rudolph masks had the most effective seals, determined by the increased ventilation and thus decreased leak compared to other commercially available masks like the NebuChamber and BabyHaler . Force-dependent decreases in dead space volume are more pronounced with increased mask flexibility, demonstrating the importance of face-mask seal in drug delivery . This, in combination with Everard’s work , was postulated to be due to the increased flexibility of these masks compared to their poorer-performing counterparts . A redesigned mask for the NebuChamber made of flexible material with decreased dead space and a round rolled soft edge enhanced aerosol delivery in vitro by 30% due to its improved seal .
Even with improved facemask designs, variability can be produced by leaks. A model of the infant’s upper airway was used to show that increased facemask leak size decreased the dose delivered to the lungs . Caregiver education in applying a tight facemask seal is important since significant variability in facemask application occurs. Thus, aerosol dose delivery can differ even with individualized coaching regarding proper seal formation .
The facemask has undergone further improvements to address the problems associated with poor fit. A computerized analysis of infants’ faces and commercial inhalers was used to develop masks that minimized dead space . The contour of the SootherMask ( Fig. 2 ) in particular has been theorized to provide more efficient drug delivery as it accounts for the shape of the facial surface more effectively to reduce the effects of dead space . It also contains a built-in pacifier that may improve interface tolerance and create a better seal as the infant sucks on the pacifier .
