OBJECTIVE: The goal was to determine the number of breaths required to inhale salbutamol from different spacers/valved holding chambers (VHCs).
METHODS: Breathing patterns were recorded for 2- to 7-year-old children inhaling placebo from 4 different spacers/VHCs and were simulated by a flow generator. Drug delivery with different numbers of tidal breaths and with a single maximal breath was compared.
RESULTS: With tidal breathing, mean inhalation volumes were large, ranging from 384 mL to 445 mL. Mean values for drug delivery with an Aerochamber Plus (Trudell, London, Canada) were 40% (95% confidence interval [CI]: 34%–46%) and 41% (95% CI: 36%–47%) of the total dose with 2 and 9 tidal breaths, respectively. Mean drug delivery values with these breath numbers with a Funhaler (Visiomed, Perth, Australia) were 39% (95% CI: 34%–43%) and 38% (95% CI: 35%–42%), respectively. With a Volumatic (GlaxoSmithKline, Melbourne, Australia), mean drug delivery values with 2 and 9 tidal breaths were 37% (95% CI: 33%–41%) and 43% (95% CI: 40%–46%), respectively (P = .02); there was no significant difference in drug delivery with 3 versus 9 tidal breaths. With the modified soft drink bottle, drug delivery. Drug delivery was not improved with a single maximal breath with any device.
CONCLUSION: For young children, tidal breaths through a spacer/VHC were much larger than expected. Two tidal breaths were adequate for small-volume VHCs and a 500-mL modified soft drink bottle, and 3 tidal breaths were adequate for the larger Volumatic VHC.
WHAT'S KNOWN ON THIS SUBJECT:
For young children, aerosolized medication often is delivered through pressurized metered dose inhalers with spacers/valved holding chambers. Because of a lack of data, asthma guidelines fail to give specific instructions regarding the correct method for breathing through spacers/valved holding chambers.
WHAT THIS STUDY ADDS:
The breathing patterns of young children differ markedly from usual patterns when they use spacers/valved holding chambers. When using these devices, 2 or 3 tidal breaths are adequate for drug delivery in young children .
Wheezing disorders are more common among young children1,2 than in any other age group. Medication for these children is most commonly inhaled through spacer/valved holding chamber (VHC) devices. How best to inhale through spacers/VHCs is not known for this age group, however, and international guidelines lack uniformity and are based primarily on expert opinion.3,4
Inhaled asthma drugs should be delivered as simply and efficiently as possible, to improve medication adherence and symptom control and to minimize side effects.5 Spacer/VHC output and drug delivery to the lung are strongly related to breathing patterns6,–,15 but for preschool-aged children, who generally are instructed to breathe tidally through spacers/VHCs, there are no data on the number of breaths required for optimal delivery. Therefore, advice on the number of tidal breaths required for a preschool-aged child to inhale medication effectively through a spacer/VHC currently is arbitrary. Whether the single maximal inhalation technique is preferable for optimal drug delivery for certain children in this age group also is unclear.
This study was designed to determine the number of tidal breaths required to inhale medication effectively through different types of spacer/VHC devices and to determine the efficacy of a single maximal inhalation for drug delivery for preschool-aged children. On the basis of technical data on in vitro VHC performance8 and knowledge of tidal flow patterns in young children,16 we hypothesized that a limited number of breaths would be sufficient for efficient drug inhalation through spacer/VHC devices for preschool-aged children.
This study was performed as a substudy from a 12-month clinical trial that compared 2 VHCs, the Funhaler (Visiomed, Perth, Australia) and the Aerochamber Plus (Trudell, London, Canada), for 2- to 6-year-old children. Inclusion criteria for the clinical trial were that asthma had been diagnosed by a doctor in the community and subjects were receiving inhaled steroids for treatment of their asthma. Ethics approval was granted by the Princess Margaret Hospital for Children ethics committees. Parents or guardians provided written informed consent. Children gave verbal assent to have their breathing recorded. Children were recruited between May 2005 and October 2006 through local advertisements and flyers and from the emergency department and clinics at Princess Margaret Hospital for Children.
Three separate groups were investigated. The first group was recruited at the beginning of the clinical trial, when tidal breathing was recorded and simulated for 34 subjects (median age: 55 months [age range: 25–84 months]; 20 boys and 14 girls) by using either an Aerochamber Plus or a Funhaler. In this subgroup, drug delivery with 2 tidal breaths was compared with drug delivery with 9 tidal breaths. Subjects used the VHCs allocated to them in the clinical trial in which they were participating. All 34 children were able to provide records of tidal breathing but not all could perform the single maximal breath maneuver. The second group was investigated at the end of the year-long clinical trial, when 84 children (age range: 34–109 months) were screened for their ability to perform a single maximal inhalation.
The third group was selected to compare tidal breaths with single maximal breaths; this was a subgroup of subjects from the aforementioned 2 groups (seen at the end of the main clinical trial) and included the first 2 subjects for each year of age who could perform a single maximal inhalation. Both tidal breathing and single maximal breathing patterns were recorded for these children (n = 10; median age: 59 months [age range: 41–73 months]) and were simulated by using 4 different spacers/VHCs in a pseudo-randomized order. Because tidal breathing with small-volume VHCs had already been investigated in subgroup 1, a single maximal inhalation was compared with 9 tidal breaths for small-volume VHCs in this subgroup. Two, 3, 5, and 9 tidal breaths and a single maximal inhalation were investigated for the large-volume Volumatic VHC (GlaxoSmithKline, Melbourne, Australia) in this subgroup, whereas only 2, 5, and 9 tidal breaths and a single maximal inhalation were investigated for the smaller, valveless, modified soft drink bottle. The recorded breathing patterns in this group were analyzed digitally to calculate, for each subject and for every different spacer/VHC used, the mean inhalation volume of 9 tidal breaths and the volume of each single maximal inhalation. All subjects were weighed before breathing was recorded, to estimate predicted tidal volume on the basis of a predicted tidal volume of weight (in kilograms) × 7 mL.17
Techniques Used to Record and to Simulate Breathing
A custom-built device was needed to record accurately the breathing patterns of children inhaling from spacers/VHCs. The device was designed to allow breathing to be recorded without changes in the dead space, resistance, or mouthpiece of the pressurized metered dose inhaler (pMDI)-spacer/VHC. The techniques used to record and to simulate breathing were described in detail elsewhere.18 Subjects used spacers/VHCs without masks (subjects interfaced directly with the spacer/VHC mouthpiece).
Breathing was recorded for children while they were inhaling placebo (GlaxoSmithKline, Melbourne, Australia) from different spacers/VHCs. The recorded tidal breathing patterns were analyzed digitally to isolate different numbers of breaths. All breathing patterns were then transferred individually to a breathing simulator (series 1120 [Hans Rudolph, Kansas City, KS]). A filter was interposed between the breathing simulator and a spacer/VHC device that was connected to a pMDI containing salbutamol (Ventolin [GlaxoSmithKline]). Immediately after actuation of the pMDI, simulation of the recorded breathing patterns commenced. Simulated drug delivery was measured by using the same spacer/VHC type that was used during the in vivo recording of breathing patterns. Simulated breathing patterns matched the spacer/VHC on which the breathing patterns were recorded. Drug delivery to inspiratory filters was measured as a percentage of the total dose recovered from the pMDI actuator, spacer, and filter.
Spacers/VHCs and Breathing Patterns
Four different spacers/VHCs were investigated, including 2 small-volume VHCs (the 149-mL Aerochamber Plus and the 225-mL Funhaler) and 2 large-volume spacers/VHCs (the 750-mL Volumatic and a modified, 500-mL, plastic soft drink bottle). This range of spacer/VHC devices was selected to represent different types of spacers/VHCs commonly used by children. The Aerochamber Plus is a commonly used small-volume VHC, and the Volumatic is a commonly used large-volume VHC. The Funhaler is an example of an incentive VHC, which may have the potential to alter a child's breathing patterns and therefore drug delivery. The modified soft drink bottle is an example of a valveless spacer device and was tested because modified soft drink bottles are being used as spacer devices in some developing countries. To limit the influence of electrostatic charge, which can be expected to accumulate on plastic spacers/VHCs over a 4-week period,19 spacers/VHCs were washed in a mild detergent solution and left to drip-dry shortly before each experiment.20
Comparisons between filter doses recovered for different breathing patterns were made by using SPSS 15.0 (SPSS, Chicago, IL). Paired samples were compared by using the Wilcoxon signed rank test. Unpaired samples were compared by using the Mann-Whitney U test. When the data were distributed normally, unpaired samples were compared by using the Student t test.
The minimal number of tidal breaths required to inhale salbutamol effectively from a spacer/VHC depended on the type of spacer/VHC used (Fig 1). With the small-volume VHCs (Funhaler and Aerochamber Plus), there was no significant difference in drug delivery between 2 tidal breaths and 9 tidal breaths. Mean drug delivery values with the Funhaler were 39% (95% confidence interval [CI]: 34%–43%) and 38% (95% CI: 35%–42%) of the total with 2 and 9 tidal breaths, respectively. Mean drug delivery values with the Aerochamber Plus were 40% (95% CI: 34%–46%) and 41% (95% CI: 36%–47%) of the total with 2 and 9 tidal breaths, respectively. With the Volumatic VHC, drug delivery was significantly less with 2 tidal breaths than with 9 tidal breaths, with means of 37% (95% CI: 33%–41%) and 43% (95% CI: 40%–46%) of the total, respectively (P = .022). There was no significant difference in drug delivery between 3 tidal breaths (mean: 40% [95% CI: 36%–44%] of the total) and 9 tidal breaths with the Volumatic VHC. With the valveless, modified soft drink bottle, there was no significant difference in drug delivery between 2, 5, and 9 tidal breaths.
Inhalation volumes were almost double the expected tidal volumes. The inhalation volume values (mean ± SD) for subjects using the Aerochamber Plus, the Funhaler, the Volumatic, and the modified soft drink bottle were 393 ± 247 mL, 432 ± 225 mL, 384 ± 185 mL, and 445 ± 167 mL, respectively, during tidal breathing and 515 ± 164 mL, 550 ± 239 mL, 503 ± 213 mL, and 448 ± 259 mL, respectively, with the single maximal breath maneuver (Fig 2). The weight (mean ± SD) of these subjects was 19.8 ± 4.44 kg.
One hundred percent of 7-year-old children, 84% of 6-year-old children, 76% of 5-year-old children, 38% of 4-year-old children, and 20% of 3-year-old children could perform a single maximal breath maneuver (Fig 3). There was an age-dependent gender difference, and girls were able to perform a single maximal breath maneuver earlier than their male counterparts (100% by 6 years of age). Two of the children screened were noted to be inhaling through their noses during this maneuver. This observation could be made because their breathing was being recorded and would not have come to light through clinical observation only.
Nine tidal breaths resulted in significantly greater drug delivery, compared with single maximal inhalation, for both the Funhaler (P = .037) and the Volumatic (P = .007) (Fig 4). There was no significant difference in drug delivery between single maximal inhalation and 9 tidal breaths for the Aerochamber Plus or the modified soft drink bottle.
This study has made 3 major new findings that, for the first time, define the information needed to instruct young children regarding the optimal use of spacers/VHCs. Firstly, young children breathing tidally through the mouthpiece of a spacer/VHC take much-larger breaths than normal tidal breathing. Secondly, we were able to define the number of tidal breaths needed for efficient use of different-sized spacers/VHCs, that is, 2 breaths for the valveless spacer and the small-volume VHCs and 3 breaths for the large-volume VHC. The finding that the inhalation volumes for young children breathing tidally through a spacer/VHC differed from those of normal tidal breathing was not unexpected, because it was demonstrated previously that instrumentation influences breathing patterns.21 The recorded breath volumes were higher than anticipated, however.
Our study demonstrates that single maximal inhalation does not result in improved drug delivery, compared with tidal breathing, for young children. Because the mean volume of the single maximal breaths was smaller than the volume of the Volumatic VHC, increased drug delivery with a number of tidal breaths could be expected. The reason for increased drug delivery with tidal breathing over single maximal breaths with the Funhaler is unclear.
A study limitation was that this study was not designed to determine drug doses delivered to patients' lungs. The filter dose captured during breathing simulation represents the total drug dose that would reach a patient and not the lung dose. It would not be anticipated that the lung dose would be increased by taking additional breaths through a spacer/VHC once the maximal total drug delivery had been reached. When the single maximal inhalation volume exceeds the tidal breath volume, however, more drug would be expected to cross the dead space in the larger airways and to reach the smaller airways. In our study, the single maximal inhalation volume did not greatly exceed the “tidal” breath volume. Although we cannot exclude the possibility that a small increase in inhalation volume might result in greater airway deposition for children with small airways, the clinical significance is likely to be modest.
Because of the nature of the study, breath-holding was not examined. Although breath-holding seems to be beneficial for lung deposition in adults,22 breath-holding is unlikely to improve lung deposition in children significantly.23
Subjects used spacers/VHCs without masks. Use of masks would have resulted in a different patient-device interface and possibly different breathing patterns.21 Therefore, the results cannot be applied to cases of children using spacers/VHCs with masks. The use of masks greatly reduces drug delivery to the lower airways,13 especially when the mask does not fit tightly.24,25 In our experience, almost all children >2 years of age can be trained, with little effort, to use a spacer/pMDI without a mask.
The relatively high drug doses delivered with the modified soft drink bottle highlight the role that valves in VHCs play in filtering out drug particles that otherwise might be inhaled; however, the dose delivered would be expected to decrease significantly with a valveless device if pMDI actuation was followed by exhalation by the patient instead of inhalation. Breathing simulation was performed with the start of inhalation in synchrony with actuation of the pMDI, which simulates a best-case scenario for drug delivery.
The 10 patients selected for testing in the latter part of the study were selected not randomly but because of their ability to perform both tidal breathing and a single maximal inhalation. Therefore, the selected group might have produced better results, compared with patients who were unable to perform a single maximal inhalation.
Different bronchodilators are available for use in acute asthma, and a range of different inhaled steroids are available for asthma preventive therapy for preschool-aged children. Salbutamol was used for in vitro testing in our study because salbutamol is a commonly used bronchodilator and the need for knowledge regarding the minimal number of breaths needed to inhale medication effectively through a spacer/VHC is perhaps greatest in busy hospital emergency departments, where multiple doses of bronchodilators are administered to patients with asthma as frequently as every 20 minutes during acute asthma attacks.
When pMDIs-spacers/VHCs are used for young children and infants, cooperation during administration is the most important determinant for efficient drug delivery.26 Preschool-aged children, who are known to have short attention spans, may be more likely to cooperate with spacer/VHC use if they are required to take fewer breaths through spacers/VHCs.
This study has provided clear evidence for practical use for all clinicians who treat young children with wheezing disorders. We have established that inhalation volumes for young children using spacers/VHCs are larger than expected; therefore, only a few tidal breaths are required for efficient drug delivery.
This study was made possible by a research grant from the Princess Margaret Hospital for Children Foundation and a fellowship from the Telethon Foundation (Perth, Australia).
- Accepted August 31, 2010.
- Address correspondence to André Schultz, PhD, Princess Margaret Hospital for Children, GPO Box D184, Perth, WA, 6840, Australia. E-mail:
FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.
- pMDI =
- pressurized metered dose inhaler •
- VHC =
- valved holding chamber •
- CI =
- confidence interval
- Pearce N,
- Ait-Khaled N,
- Beasley R,
- et al
- 3.↵British Thoracic Society; Scottish Intercollegiate Guidelines Network. 2008 British Guideline on the Management of Asthama - updated June 2009. Available at: www.brit-thoracic.org.uk/clinical-information/asthma/asthma-guidelines.aspx. Accessed October 18, 2010
- 4.↵Global Initiative for Asthma. Global strategy for asthma management and prevention Updated 2009. Available at: www.ginasthma.com/Guidelineitem.asp??l1=2&l2=1&intId=1561. Accessed October 18, 2010
- Berg E,
- Madsen J,
- Bisgaard H
- Everard ML,
- Clark AR,
- Milner AD
- Barry PW,
- O'Callaghan C
- Schultz A,
- Le Souëf TJ,
- Looi K,
- Zhang G,
- Le Souëf PN,
- Devadason SG
- Piérart F,
- Wildhaber JH,
- Vrancken I,
- Devadason SG,
- Le Souëf PN
- Wildhaber JH,
- Devadason SG,
- Eber E,
- et al
- Perez W,
- Tobin MJ
- Newman SP,
- Pavia D,
- Clarke SW
- Hansen OR,
- Pedersen S
- Copyright © 2010 by the American Academy of Pediatrics