|Vol.10 No. 1|
Editors: Dr. KY Wong
Drs. Daniel KK Ng, PY Chow, YY Lam
Department of Paediatrics, Kwong Wah Hospital
Aerosolized medications are becoming more popular. This form of direct administration of medications to target organs has been shown to be effective and possibly reduce unwanted systemic side effects. Dr Ng and his colleagues reviewed the basic principles behind the use of various devices for respiratory diseases, which are extremely useful and practical.
Delivery of medications directly to the respiratory tract for respiratory diseases has been an attractive idea as it would minimize the systemic effects of the medications. For intubated patients , it could be achieved simply by administering the medications through endotracheal tubes, e.g. surfactant, adrenaline. In most other situations, the first step would be the provision of the medications in a form that could be inhaled by spontaneously breathing individuals. The principles of aerosol generation and delivery to the lungs are reviewed.
Aerosol is a suspension of liquid or solid particles between 0.001 and 100 microns in a carrier gas. For treatment of pulmonary diseases, the effective range of particle sizes is 1 to 10 microns. In general, only 10% to 20% of a given dose of aerosolized medication actually reaches the lower respiratory tract. Mass median aerodynamic diameter (MMAD) is the most commonly used parameter to describe the median diameter of the population of aerosol particles. MMAD is defined as the particle size below which lies 50% of the mass of the aerosol particles. Particles of size greater than 15 microns are deposited in the mouth, while those greater than 10 microns would be deposited in the nose - ideal for treatment of nasal diseases. Particles of size between 5 and 10 microns are deposited in the first six generations of the bronchial tree, and are ideal for treatment of croup. (Note: There are 23 generations of bronchial tree. The two main stem bronchi represent the 1st generation and the alveolar sac the last.) Those between 2-5 microns are deposited in the last six generations of bronchial tree, ideal for treatment of asthma. Those particles between 0.8 and 3 microns are deposited in the lung parenchyma, ideal for prophylaxis against Pseudomonas. Deposition of medications also depends on lung volume, inspiratory time, flowrate, end-inspiratory pause, and routes of breathing (nasal or oral).
These refer to devices that suspend liquid particles in a carrier gas, either room air or oxygen at different concentrations. Ultrasonic nebulizers are electrically powered devices operating on the piezoelectric principle. The oscillator converts electrical energy into acoustic energy, hence the term ultrasonic. The acoustic energy shatters the solution into suspension of particles that are drawn into the lungs during inspiration using room air as carrier gas. The frequency of oscillation decides the MMAD of the aerosolized particles, with higher frequencies producing smaller particles. Frequencies greater than 1 MHz are needed to produce MMAD of less than 8 microns. Its main advantages are its handy size and rapid rate of nebulization (1-2 ml /min.) (Figure 1).
Figure 1. Ultrasonic nebulizers.
Small volume nebulizer (SVN) refers to small reservoir, gas-powered aerosol generator (Figure 2). Its output flowrate is around 0.25-1 ml/min. This longer administration time allows a dose to be delivered over a few minutes. Hence, a single ineffective breath will not jeopardise the efficacy of drug delivery during treatment. SVN does not work well if the volume of medications is below a minimal volume, i.e. dead volume. With the presence of this dead volume, the actual volume of drug nebulized is usually reduced to 35% to 60% of the total volume. The dead volume varies with different brands of nebulizers, usually from 0.5 to 1 ml. This volume decreases with vigorous shaking of the SVN. The optimal treatment time is recommended to be around 5 minutes. Compliance would become a problem if the treatment time exceeds the recommended range. The actual treatment time depends on the fill volume and the flow rate. The usual recommended fill volume is 3 to 5 ml while the usual flow rate is 10 L/min. At this flow rate, the time for nebulization of 3 to 5 ml of medications would be 5 to 10 minutes. Types of solution would also affect the nebulization time. Quoted calculations refer to common bronchodilator solutions. For other medications, modification may be needed in view of different physical characteristics, e.g. viscosities. For example, a higher flow of 12 L/min is required for gentamicin nebulization. In ideal settings, 3-10 % of the nebulized medication reaches intra-thoracic airways (Figure 2).
Figure 2. Small volume nebulizer.
Small particle aerosol generator (SPAG) is a large-volume reservoir (300 ml) nebulizer that allows continuous or a longer period of nebulization (Figure 3). It operates on a jet-shearing principle. It has been used for administration of ribavirin in case of severe Respiratory Syncytial Virus bronchiolitis, and salbutamol (0.3mg/kg/hour) for life-threatening asthma.
Figure 3. SPAG (small particle aerosol generator).
Medications are micronized powder either suspended in a liquid propellant or dissolved in a mixture of solvent, usually ethanol. The pressure within the canister is around 400 kPa. Each dose is contained in a small chamber, i.e. the metered dose, within the canister. It is released under pressure when the nozzle is opened. The liquid propellant rapidly expands and vaporizes, and the exit velocity reaches 100 km/hour. This rapid process shatters the medication into an aerosol. As a result of the ban on use of chloroflurocarbons (CFC), new propellants are used. These include hydroflurocarbons (HFCs) and hydrofluoroalkanes (HFAs). These new kinds of propellants are found to be as good or even better than CFC. As a result, the active drug dose is re-adjusted to account for the higher level of respirable particles. It is important to shake the canister to ensure even distribution of the medications. Otherwise, a higher or lower dosage of medications will be delivered, depending on whether the medication is lighter or heavier than the propellant. It should also be noted that rapid firing of successive doses, e.g. 4 puffs in 4 seconds, leads to significant reduction in dose output. It is advised to space out successive puffs by a few seconds.
Breath-actuated MDIs, e.g. Autohaler (3M), Easi-Breathe (IVAX) are developed to overcome the problem of hand-breathing incoordination. This is the device of choice for MDIs in the absence of spacers. After the device has been primed, an inspiratory flow of around 22 to 26 L/min can be generated with one metered dose.
Figure 4. Cross section diagram of metered dose inhaler1
Spacers are designed to hold the aerosol cloud and this obviates the need for immediate inhalation upon actuation. It also increases the proportion of medications in the respirable range and decreases the direct deposition of the high-speed particles onto the oropharynx. Systemic effects would be minimized. The volumes of spacers range from 70 ml to 750 ml. It is generally recommended to give the smaller volume holding chambers for infants and toddlers. Spacers are made of polycarbonate, plastic or metal. For non-metallic spacers, static charge will decrease availability of aerosols. Washing the spacers with detergent and allowing drip dry can decrease the static charge. Caregiver should ensure tidal breathing for 5 times whilst the spacer is applied to the face either by face mask or mouth piece. Breath holding is not necessary. If more than one puff is given, it should be given one at a time followed by tidal breathing. In ideal setting, 10% of medication reaches the intra-thoracic airway with MDI-spacers.
All DPIs are breath-actuated devices and inspiratory flow of between 40 of 60 L/min is necessary to create an aerosol. If the inspiratory flow rate is too high, significant extra-pulmonary deposition would occur. Hence, it is important to coach the children on the appropriate flow with an inspiratory flow meter. One of the main benefits of DPIs is the absence of propellants - that implies the absence of 'cold freon effect'. The latter refers to reflex cough or cessation of inspiration upon impact of the cold puff on the pharynx. It is now the device of choice for children over the age of six.
Delivery of medications to the lungs by inhalation is an attractive mode of treatment as it decreases systemic effects and allows a higher dose to be given. Aerosol generation is a key component in the process of drug delivery. A clear understanding of this process allows medical practitioners to choose the most appropriate device for treatment of different diseases.
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