Delivery of Therapeutic Aerosols to Newborns and Small Infants
Keyword : Aerosols; Newborns
Therapeutic aerosols are widely used in the treatment of a variety of lung diseases, notably asthma, in both children and adults. Their use in newborns and small infants are however limited. Compared to systemic medications, aerosols have a faster action as they are directly delivered to their site of action (the bronchial tree). Furthermore, because of the high topical concentration, smaller doses of the medications are used with the consequent reduction in unwanted side effects. The most commonly used therapeutic aerosols include bronchodilators, cromolyn sodium, and corticosteroids, but other medications such as antimicrobials and frusemide can also be given via the pulmonary route.
Inhaled bronchodilators and corticosteroids may be particularly useful in treating infants with bronchopulmonary dysplasia (BPD)1-9 which is characterised by the presence of obliterative bronchiolitis resulting from mucosal inflammation, edema, constriction, and fibrosis of the airways, as well as hypertrophy of the bronchial smooth muscle.10-12 For these infants, systemic bronchodilators can bring about temporary relief of the bronchiolar constriction,13,14 and systemic corticosteroids can shorten the length of mechanical ventilation.15-24 It is possible that when given directly to the lungs in aerosol form, both medications can produce faster and more significant improvement, and with fewer systemic side effects such as tachycardia, hypertension, hyperglycaemia, impairment of bone growth, and suppression of the hypothalamic-pituitary-adrenal axis.
The therapeutic effects of aerosolised bronchodilators on BPD infants have been well reported in medical literature. Several observational4,7,8,25 and controlled2,3,5,6,9,26 studies have shown that both beta-agonists (salbutamol, terbutaline, isoproterenol, and isoetharine) and anticholinergic (ipratropium bromide) given in the aerosol form are effective in improving the clinical state or lung mechanics of the infants. The usefulness of inhaled corticosteroids have not been confirmed but there is recently a great deal of interest in this issue among paediatricians.
Despite their potential advantages, however, paediatricians remain sceptical about the values of aerosolised medications in treating small infants due mainly to the uncertainty of the amount of medication that can be delivered to the infant's lungs. As the beneficial effects of the medications are often not readily assessable, paediatricians are reluctant to use the inhaled route unless they are convinced that a therapeutically sufficient quantity of the drugs can reach the infants' airway. They are also confused by the methods of delivery since no formal comparison has been made on the efficiency of the various types of aerosol delivery devices on newborns or small infants.
Clinical aerosols can be generated by the metered dose inhaler (MDI) which is usually used together with a aerosol holding spacer device, the nebulisers (jet and ultrasonic), or dry powder inhalers. Dry powder inhalers are not suitable for small infants since they are breath-actuated and their operation requires a relatively high inspiratory flow rate. The characteristics of the other devices are briefly described as follows:
This is at present the most commonly used device for aerosol delivery to infants and small asthmatic children. Its operation requires an external source of compressed gas. When the gas stream passes through the nebuliser nozzle at a high speed, it entrains liquid placed in the nebuliser reservoir through a capillary tube by the Venturi effect, and the entrained liquid is atomised by the blast of gas into aerosol droplets. Larger particles impact on the baffle and the walls of the nebuliser, and reflux back to the reservoir for re-nebulisation, while the smaller particles leave the nebuliser and become available to the patient. The amount of aerosol that can penetrate the upper and conducting airways into the small bronchioles is determined by two major factors: the amount of aerosol output, and the particle size of the aerosol. More aerosol will be available to the infants with larger output, and only particles of mass median aerodynamic diameter 1-5 μm are considered "respirable" - the larger ones will impact on the upper and conducting airway, and the smaller ones may be exhaled as they behave like a gas and do not deposit in the lungs. Both factors are related to the gas flow rate - increasing the flow rate increases aerosol output and reduces the particle size. For most commercially available jet nebulisers, the optimal operating flow rate appears to be 6 to 8 L/min.
Unlike jet nebulisers, the operation of an ultrasonic nebuliser does not require any external gas source. Its atomising energy is generated by a piezoelectric crystal that transmits high-frequency electric oscillations into mechanical vibrations. The vibrations are transmitted through the coupling fluid and a thin-walled cup to the nebuliser solution, and produce a fountain of liquid droplets. The latter are carried to the patients either by the airstream flowing through the ventilator circuit (ventilated infants), or by the patients' own inspiratory effort (spontaneously breathing infants). The rate of aerosol production and droplet size are both related directly to the intensity of the ultrasonic vibrations which is fixed according to the design by the manufacturer.
Both the jet and ultrasonic nebulisers have their advantages and disadvantages. The operating flow rate of the jet nebuliser can be easily adjusted to produce a wide range of respirable particles while the oscillation frequency of the ultrasonic nebuliser is not amenable to changes. However, the jet nebuliser is a noisy device and its use causes cooling of the inspired gas. It requires an external gas flow, and, when used on patients on mechanical ventilation, requires adjustment of the ventilator flow rate to ensure a constant pressure. In contrast, the ultrasonic nebuliser is silent and warm, and, as it is not driven by an external gas source, no adjustment of ventilator flow rate is necessary.
Metered dose inhaler (MDI):
The MDI is currently the most popular aerosol device for both adults and children. The drug is either dissolved or suspended as fine particles in a volatile liquid propellant mixture of chlorofluorocarbon (CFC) in a sealed canister.
The high vapour pressure of the propellant keeps the mixture in liquid phase within the canister. Actuation of the MDI opens the metering valve which supplies a fixed volume of solution to a small metering chamber. The propellant evaporates rapidly on meeting atmospheric pressure, and the contents are released with rapid vaporisation of the propellant. This breaks up the liquid into droplets, providing the aerosol.
On leaving the MDI, the aerosol particles are of large size and travel at high speed. Both factors tend to increase aerosol impaction at the oropharynx. In adults, the majority of the drug dose (80% or more) delivered by a MDI impacts in the oropharynx, and only 10% is delivered to the lungs.27-29 As particle size and velocity both decreases with increasing distance from the actuator orifice, lung deposition can be improved by firing the MDI 3 to 5 cm away from the mouth during a slow, steady inhalation, followed by a period of 10 seconds' breath holding. For small infants who cannot master this skill, aerosol delivery can be optimised by using the MDI together with a spacer device placed between the MDI and the patient's lips, or, in the case of ventilated infants, between the MDI and the endotracheal tube. The spacer allows the particles to decrease in size through evaporation of their water content, and to reduce their velocity before they enter the patient's airway. Using the spacer device minimises the need for patient cooperation, and reduces the amount of aerosol impaction at the oropharynx. When the MDI is used to deliver corticosteroid, the latter has resulted in a decrease in the occurrence of oropharyngeal candidiasis and dysphonia.
Aerosol Delivery to Newborns and Small Infants
Both nebulisers and MDI have been shown to deliver 5 to 10% of their aerosol output to the lower respiratory tract of spontaneously breathing adults and older children, and about 2% in the ventilated ones. Little is known, however, about the pulmonary deposition of aerosol in newborns and small infants. Aerosol deposition in the lower respiratory tract is related directly to the tidal volume of the patient,30,31 and also the time allowed for the particles to sediment in the lung.30-33 On the other hand, impaction at the upper and conducting airway results in aerosol loss, and the amount of impaction is related inversely to the radius of these airways. Because of the small size of their airways, their small tidal volume and relatively short inspiratory time, it is expected that aerosol deposition at the lower respiratory tract of small infants would be much less than that in older subjects. In ventilated infants, pulmonary deposition would be even smaller due to aerosol loss resulting from impaction on the ventilator tubings and the endotracheal tube. Furthermore, most of the aerosol delivered into the ventilator circuit is not available to the infants, being washed down the expiratory tubing by the continuous gas flow. Humidification of the ventilator circuit also significantly reduces pulmonary deposition due to a substantial increase in particle size resulting from absorption of moisture by the particles. It has been shown that at 95% humidity, the diameter of NaCI particles tripled and at 100% humidity, the size of the particles can increase without bound.34,35
Quantifying Aerosol Deposition in the Lower Respiratory Tract of Small Infants
Studies in ventilated small lung models using filters or small animals have shown a deposition of 0.5 to 2% of the aerosol generated by any of the above devices.36-40 Only very few studies have investigated the deposition in spontaneously breathing small lung models and the findings were comparable to those in the ventilated ones.41,42 There are however limitations with these studies as filter lung models lack the branching airway and mucous epithelium, and tend to retain even very tiny particles which are normally exhaled by the lungs. In animals, the branching pattern of the airway is different from that in humans, and aerosol deposition in healthy animal lungs may be very different from that in the diseased lungs of human subjects. Pulmonary aerosol deposition has been estimated indirectly in infants by estimating the urinary excretion of sodium cromoglycate following a dose of the medication delivered by the inhaled route.38,43 The method is commonly used in adults in whom a fixed proportion of a lung dose is excreted in the urine within 24 hours.44-46 In infants, however, the metabolism and urinary clearance of sodium cromoglycate is unknown, and one previous study has shown that after the intrabronchial instillation of sodium cromoglycate, the amount excreted in 24 hours varied between 22.3% to 59.7%.43 Currently the only method for the direct estimation of pulmonary deposition in human subjects is provided by gamma scintigraphy. Following the administration of a radio-labelled aerosol, deposition in the lungs can be measured using a gamma camera. The method is used commonly in adults, but its use in paediatrics is restricted by the concerns around the exposure of small children and infants to radioactivity.
In a study attempting to directly estimate aerosol deposition in the lungs of small infants, we delivered Technetium-99m labelled salbutamol to 10 ventilated infants and 13 non-ventilated infants with BPD, and measured the amount of radioactivity in the infant's lungs using a gamma camera.47 The infants had gestations of 24-36 weeks, birth weight 460 - 3520g, and body weight of 910-4200g at the time of study. Each infant was given two doses of the radiolabelled medication 24 hours apart at random sequence using the MDI or a jet nebuliser (MedicAid, UK). The aerosol from either device was delivered to the non-ventilated infants through a face mask. When the MDI was used, the face mask was connected to a spacer device (Neonatal Aerochamber, Trudell Inc., Canada). For the ventilated infants, the nebuliser was connected to the inspiratory limb of the circuit 20 cm away from the endotracheal tube, and, for the delivery of the MDI-aerosol, a spacer (MV 15 Aerochamber, Trudell Inc., Canada) was connected between the Y-connector of the ventilator circuit and the endotracheal tube. Our results showed that with both devices, aerosol deposition in the lungs was small and variable in both groups of infants. In the non-ventilated infants, deposition ranged from 0.12% to 2.26% (mean ± sem 0.67 ± 0.17%) of the actuated dose for the MDI, and 0.12% to 0.66% (mean ± sem 0.28 ± 0.04%) of the initial nebuliser dose for the jet nebuliser. In the ventilated infants, deposition from the MDI was 0.35% to 2.12% (mean ± sem 0.98 ± 0.19%) of the actuated dose, and, for the jet nebuliser, 0.09% to 0.90% (0.22 ± 0.08%) of the initial nominal dose. Thus our findings confirmed the observations of previous workers that only a minimal amount of aerosol could be deposited in small lungs. The inter-subject variability in aerosol deposition was also consistent with that observed by Salmon et al on larger intants,44 suggesting that a uniform dosing regime might not be applicable to all infants.
The above observations do not however necessarily rule out the use of therapeutic aerosol on newborns and small infants. After all, as long as the desired therapeutic effect can be achieved, the small lung dose could be an advantage as it is expectedly associated with less systemic side effects. Several studies have demonstrated improvement in the clinical state and lung function of infants with BPD following the use of aerosolised bronchodilators. Corticosteroid aerosol has also be shown to improve the lung mechanics of ventilated preterm infants with respiratory distress syndrome. In a group of infants with BPD, we have demonstrated a reduction by 50% of respiratory system resistance 30 minutes after two puffs of salbutamol delivered by the MDI. One study compared the effect of intravenous and aerosolised salbutamol on the lung mechanics of BPD infants, and reported similar improvement in the infants' airway resistance.3
Methods to Improve Lung Deposition
Notwithstanding the above observations, however, there is still a need to look for means to maximise lung deposition since the therapeutic effects of aerosols are dose dependent.7,48 A more efficient method of delivery will allow the use of a smaller nominal dose and hence reduce cost. For the jet nebuliser, lung deposition might be increased by increasing the volume fill inside the reservoir,49 and by using a device that can produce submicronic particles.40,50 For the MDI, actuating the canister at the beginning of inspiration, and using a spacer made of anti-static material have both been shown to improve aerosol delivery.
In the quest for the most efficient method of delivery, we have compared a jet nebuliser, the MDI plus a spacer, and an ultrasonic nebuliser on ventilated rabbits, and also infants with BPD. The ultrasonic nebuliser achieved significantly greater aerosol deposition in the animal lungs especially when it was used together with a small medication cup. In both ventilated and non-ventilated BPD infants, the device also produced the greatest improvement in the respiratory system resistance and functional residual capacity. We have also compared the delivery of MDI-aerosol to paralysed, fully ventilated rabbits and rabbits who were able to breathe spontaneously on slow intermittent mandatory ventilation. Pulmonary deposition in the non-paralysed animals was more than twice that in the paralysed one, suggesting that the spontaneous breaths of the animals augmented aerosol delivery.51
There is no universally accepted protocol in using the abovementioned delivery devices on newborns and small infants. There is also no uniformity in the choice of the devices among individual centres or paediatricians. In general, both nebulisers and MDI can be used to deliver medications available in solution form. However, in the delivery of corticosteroids which are formulated as suspended particles, both jet and ultrasonic nebulisers may result in aerosolisation of the suspending fluid without the particles,52 and MDI should be the method of choice.
When the devices are used on ventilated infants, both jet and ultrasonic nebulisers may be inserted into the inspiratory tubing of the ventilator circuit at a short distance (10-20cm) from the endotracheal tube. The medication should be diluted in the nebuliser reservoir with isotonic saline to a volume fill of at least 3 to 4 ml. Using water as diluent may induce bronchoconstriction, and too small a volume fill will significantly reduce the efficiency of nebulisation.31 The jet nebuliser should be driven with a gas mixture at a flow rate of 6-8L/min., and the oxygen concentration of the driving gas should be identical to that in the ventilator circuit. The ventilator flow rate should be reduced accordingly so that the peak inspiratory pressure and total flow rate inside the ventilator circuit remain unchanged. The ultrasonic nebuliser does not require any external gas source and therefore no adjustment of the ventilator flow rate is required. Nebulisation can be continued until the reservoir becomes "dry" - i.e. when no more aerosol is visibly generated by the nebuliser. In general, the nebulisers will become "dry" within 10 to 15 minutes. When the MDI is used, the medication may be actuated directly into the endotracheal tube after the latter is temporarily disconnected from the ventilator tubing, or more preferably, into a spacer device (e.g. MV15 Aerochamber, Trudell Inc., Canada) which is inserted into the inspiratory tubing or between the Y-connector of the tubing and the endotracheal tube. The MDI should be actuated at end-expiration, and the canister should be shaken vigorously for at least 10 sec. before each actuation. When more than one puff is required, there should be an interval of at least 30 sec. between each actuation to allow re-accumulation of vapour pressure inside the canister. The spacer device can be removed one to two minutes after the last puff. Actuation of MDI has been shown to reduce the oxygen concentration inside the ventilator circuit, which may be a concern when the device is used on infants with high oxygen requirements.
When used on non-ventilated infants, both nebuliser and MDI aerosols should be delivered through a face mask rather than just being blown on the infant's face. The jet nebuliser can be connected to the face mask through a Y-connector so that excessive gas can escape through the efferent limb of the connector. As the face mask has to be hand held tightly over the infant's face, the nursing staff often prefer to use the MDI as the relatively long nebulisation time of the nebulisers poses considerable inconvenience. The MDI should be used with a spacer device. Commercially available devices that are suitable for use on infants include the Neonatal Aerochamber (Trudell Inc., Canada)42,53 and Babyhaler (Glaxo, UK).8,54,55 Both devices are fitted with a face mask which however are too large for small babies. To ensure better fit with the infant's face, the face mask can be replaced with a smaller size neonatal face mask such as the Laerdal Resuscitation Mask (Laerdal, Stavanger, Norway). This however will increase the cost significantly. Alternatively, a coffee cup can be used as both the spacer and face mask by inserting the MDI through a hole made on the bottom of the cup. This homemade device has been shown to be effective in delivering aerosol to small babies.42
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