`` 
 
 
 
THE EVALUATION OF STRATEGIES 
FOR PRODUCING OPTIMAL 
INHALANT THERAPY IN 
PRESCHOOL CHILDREN (2-6 YEARS) 
WITH CHRONIC ASTHMA 
 
 
 
 
André Schultz 
University of the Free State  
 
            October 2009 
 
 
 
 
 
 
 
A thesis submitted in fulfilment of the requirements for the 
degree of Doctor of Philosophy in the Faculty of Health 
Sciences, at the University of the Free State 
 
 
 
 
 
 2
 
ACKNOWLEDGEMENTS 
 
This thesis would never have been possible for me to complete without the help, support, 
and effort of the following people, to whom I would like to express my sincere gratitude.  
 
Professor Peter le Souëf gave me the opportunity work with him in Perth.  Peter spent 
considerable time and effort on teaching me scientific method.  I greatly appreciate how he 
painstakingly read and criticised my work.  I would like to thank him for all the 
exhilarating and thought provoking discussions, for sharing his passion in research, and for 
his example of dedication and hard work.   
 
Professor André Venter made it possible for me to enrol in a Ph.D.  André is a gifted 
clinician, leader, and advocate for children.  I would like to thank him for his steadfast 
encouragement of my clinical and research careers over the past ten years. 
 
Associate Professor Sunalene Devadason taught me the practical aspects of science, 
laboratory work, and the running of a clinical trial.  Sunalene made me aware of the great 
precision and rigour required in science.   
 
Professor Peter Sly gave me much needed guidance and support while I was struggling 
through the early parts of this thesis.  Throughout the thesis, Peter’s consistency and 
reliability with quality feedback, whenever needed, was superb.  
 
Members of the Aerosol Research Group, and specifically Jane Jones, who was our study 
nurse during the latter half of the clinical trial.  Jane taught me that seemingly never ending, 
repetitive tasks can be done without causing too much pain.  Jane’s kindness and altruism is 
noteworthy. 
 
Doctor Brad Zhang patiently taught me the application of most of the statistical methods 
applied in this thesis.  Donald Payne and Andrew Martin are colleagues and friends who 
are always willing to give encouragement and well considered advice.  Tim le Souëf 
contributed his time and engineering skills to help troubleshoot the challenging flow-
chamber validation.  Emeritus Professor Lou Landau kindly but meticulously read through 
the almost completed thesis to share his much respected wisdom. 
 
My parents, Archie and Reneé Schultz, have always been selfless in their tremendous effort 
to foster my learning in previous years.  
 
Special thanks to the children and parents who participated in the research. 
 
Finally, my heartfelt thanks to my fiancé, En Nee Ng, for her ongoing devotion, 
encouragement, love, support and patience. 
 
 
 
 
 
 3
 
DECLARATION 
 
The work presented in this thesis was performed by the author, unless otherwise 
acknowledged.   
   
Chapters Two and Three:  After the initial methodology was developed, and breathing 
patterns were recorded, the bench testing was performed by research assistants from the 
Aerosol Research Group, Department of Paediatrics and Child Health, University of 
Western Australia.  The recorded breathing patterns were processed with software 
purposely developed by Guicheng (Brad) Zhang.   
 
Chapter Two has been submitted as a manuscript to the Journal of Aerosol Medicine and 
Pulmonary Drug Delivery.  Estimated author contributions were as follows: 
André Schultz  50% 
Timothy J Le Souëf    5% 
Kevin Looi     5% 
Guicheng Zhang         5%   
Peter N Le Souëf        15% 
Sunalene Devadason   20% 
 
Chapter Four:  The methodology for the clinical trial was originally developed by Peter le 
Souëf, Sunalene Devadason and Peter Sly.  The author made various ammendments to the 
clinical trial design before the trial commenced, including the addition of electronic 
adherence monitoring, quality of life measurements, and breathing recording.  The author 
had the assistance of a study nurse/ research assistant (Nicole Shaeffer, Trudi Mackenzie 
and Jane Jones) during all study visits.  The research assistants also co-ordinated the day-
to-day running of the clinical trial.   
 
The author performed all data analysis except for the generalized estimating equations, 
which was performed by Guicheng Zhang.   
 
The Telethon Foundation funded my salary for one year of this study, and the Princess 
Margaret Hospital Foundation provided funding for part of this study.  
 
 4
 
Table of Contents  
 
ACKNOWLEDGEMENTS ............................................................................... 3 
DECLARATION ............................................................................................... 4 
ABSTRACT ..................................................................................................... 12 
LIST OF ABBREVIATIONS .......................................................................... 19 
1 CHAPTER ONE: Literature review ................................................ 21 
1.1 Inhalation treatment for asthma in preschool children ............................... 21 
1.2 Basic principles of aerosol behaviour ............................................................. 22 
1.3 Inhaled asthma drugs ...................................................................................... 24 
1.3.1 Bronchodilators .................................................................................................. 24 
1.3.2 Corticosteroids ................................................................................................... 25 
1.3.3 Dose-response relationship between inhaled corticosteroids and asthma control 
in preschool children .......................................................................................... 25 
1.3.4 Side effects of inhaled steroids .......................................................................... 26 
1.3.5 Delivery of inhaled asthma medication in preschool children ........................... 27 
1.4 Delivery devices ................................................................................................ 27 
1.4.1 Pressurised metered dose inhalers ..................................................................... 27 
1.4.2 Spacers and holding chambers ........................................................................... 30 
1.4.3 Breath actuated devices ...................................................................................... 32 
1.4.4 Nebulisers .......................................................................................................... 32 
1.4.5 Dry powder inhalers ........................................................................................... 33 
1.4.6 Conclusion ......................................................................................................... 33 
1.5 Testing drug delivery through spacers .......................................................... 34 
1.5.1 Overview ............................................................................................................ 34 
1.5.2 Pharmacokinetics ............................................................................................... 34 
1.5.3 Scintigraphy ....................................................................................................... 35 
1.5.4 Particle sizing ..................................................................................................... 36 
1.5.5 Filter studies ....................................................................................................... 37 
1.5.6 Breathing simulation .......................................................................................... 38 
1.6 Patient related factors influencing drug delivery ......................................... 43 
1.7 Spacer technique in preschool children with asthma ................................... 43 
1.7.1 The importance of spacer technique .................................................................. 43 
 5
1.7.2 Breathing through a spacer ................................................................................ 44 
1.7.3 Interventional strategies to improve spacer technique and the Funhaler® ........ 47 
1.7.4 Important questions about spacer technique in preschool children ................... 48 
1.8 Adherence to prescribed treatment in preschool asthmatics ....................... 49 
1.8.1 Overview ............................................................................................................ 49 
1.8.2 Specific difficulties in the preschool age group ................................................. 50 
1.8.3 Barriers to adherence ......................................................................................... 51 
1.8.4 Interventional strategies to improve adherence to inhalation therapy in 
preschool children .............................................................................................. 53 
1.8.5 Potential use of an incentive device –the Funhaler®- for improving adherence 
to prescribed aerosol treatment in preschool children. ...................................... 54 
1.8.6 Important questions regarding adherence to prescribed medication in preschool 
children .............................................................................................................. 55 
1.8.7 Assessment of adherence to prescribed treatment in asthma ............................. 56 
1.9 Assessment of asthma control in preschool children .................................... 57 
1.9.1 Asthma symptoms .............................................................................................. 57 
1.9.2 Asthma exacerbations and systemic corticosteroid use ..................................... 58 
1.9.3 Lung function measurements ............................................................................. 58 
1.9.4 Quality of life measurements ............................................................................. 63 
1.9.5 Conclusions ........................................................................................................ 64 
2 CHAPTER TWO:  Designing and validating a novel method for 
effectively recording and simulating breathing in patients using pMDI-spacers
 66 
2.1 Background ...................................................................................................... 66 
2.2 Methods ............................................................................................................. 67 
2.3 Results ............................................................................................................... 78 
2.4 Discussion .......................................................................................................... 86 
3 CHAPTER THREE:  Determining the minimum number of breaths 
and type of breathing required for effective drug delivery through pMDI-
spacers 90 
3.1 Background ...................................................................................................... 90 
3.2 Aims and hypothesis ........................................................................................ 90 
3.3 Methods ............................................................................................................. 91 
3.4 Results ............................................................................................................... 94 
3.5 Discussion .......................................................................................................... 99 
4 CHAPTER FOUR:  Clinical trial .................................................. 102 
4.1 Background .................................................................................................... 102 
4.2 Aims and Hypothesis ..................................................................................... 105 
 6
4.3 Methods ........................................................................................................... 106 
4.3.1 Study participants ............................................................................................. 106 
4.3.2 Protocol ............................................................................................................ 107 
4.3.3 Outcome measures ........................................................................................... 109 
4.4 Results ............................................................................................................. 114 
4.4.1 Demographics .................................................................................................. 114 
4.4.2 Atopy ................................................................................................................ 116 
4.4.3 Study drop-outs ................................................................................................ 117 
4.4.4 Drug dose prescribed ....................................................................................... 119 
4.4.5 Outcomes ......................................................................................................... 122 
4.4.6 Baseline visit .................................................................................................... 122 
4.4.7 All visits: Overall proficiency in spacer technique as measured by drug 
delivered to filter .............................................................................................. 124 
4.4.8 Correlation between proficiency in using delivery device and QoL ............... 125 
4.4.9 Correlation between proficiency in using delivery device, and other measures of 
clinical outcome ............................................................................................... 126 
4.4.10 Role of incentive device in influencing proficiency in spacer technique ........ 128 
4.4.11 Adherence to prescribed medication ................................................................ 131 
4.4.12 Correlation between adherence to prescribed treatment and QoL. .................. 133 
4.4.13 Correlation between adherence to prescribed treatment and other markers of 
clinical outcome. .............................................................................................. 133 
4.4.14 Role of incentive device in influencing adherence to prescribed medication .. 140 
4.4.15 Role of incentive device in influencing clinical outcome. ............................... 142 
4.4.16 Lung function ................................................................................................... 146 
4.4.17 Influence of the Funhaler on lung function ...................................................... 149 
4.5 Discussion ........................................................................................................ 152 
4.5.1 Summary of main findings ............................................................................... 152 
4.5.2 Limitations of study ......................................................................................... 155 
4.5.3 Strengths of study ............................................................................................ 159 
4.5.4 Application of results ....................................................................................... 160 
5 CHAPTER FIVE:  Conclusion and future directions ................... 161 
APPENDIX .................................................................................................... 166 
REFERENCES .............................................................................................. 167 
 
Final Word Count: 36, 488 (body of text) 
 
 7
List of Figures 
 
Figure 1.  The Funhaler® ................................................................................................... 48 
Figure 2.  Flow chamber used to record breathing. ........................................................ 71 
Figure 3.  Configuration 1. ................................................................................................. 73 
Legend.  Figures 3 to 5. ....................................................................................................... 74 
Figure 4.  Configuration 2. ................................................................................................. 74 
Figure 5.  Configuration 3. ................................................................................................. 75 
Figure 6.  Example of a breathing pattern recorded and simulated. ............................. 76 
Figure 7.  Configuration 1:  Bland-Altman plot demonstrating difference between ex 
vivo and in vitro drug delivery for 5 tidal breaths plotted against mean 
drug delivery. .................................................................................................... 79 
Figure 8.  Configuration 1.  Correlation between ex vivo filter dose and in vitro filter 
dose. ................................................................................................................... 80 
Figure 9.  Configuration 2 & 3:  Bland-Altman plot demonstrating difference between 
ex vivo and in vitro drug delivery for 5 tidal breaths plotted against mean 
drug delivery. .................................................................................................... 81 
Figure 10.  Configuration 1.  Correlation between tidal volume and peak inspiratory 
flow in breathing patterns recorded and simulated. ..................................... 82 
Figure 11.  Configuration 2 & 3.  Correlation between tidal volume and peak 
inspiratory flow in breathing patterns recorded and simulated. ................ 83 
Figure 12.  Configuration 1.  Drug delivery (ex vivo filter dose as percentage of total 
drug dose recovered) plotted against mean inhalation volume for different 
spacers. .............................................................................................................. 84 
Figure 13.  Configuration 2 & 3.  Drug delivery (ex vivo filter dose as percentage of 
total drug dose recovered) plotted against mean inhalation volume for 
different spacers. .............................................................................................. 84 
Figure 14.  Configuration 1.  Drug delivery (Ex vivo filter dose as percentage of total 
drug dose recovered) plotted against mean peak inspiratory flow of each 
corresponding set of breathing patterns. ....................................................... 85 
Figure 15.  Configuration 2 & 3.  Drug delivery (Ex vivo filter dose as percentage of 
total drug dose recovered) plotted against mean peak inspiratory flow of 
each corresponding set of breathing patterns.  Spacer = Aerochamber 
Plus®. ................................................................................................................ 85 
Figure 16.  Salbutamol doses recovered from filters are reported as percentage of total 
dose recovered from filter, spacer and pMDI sleeve. ................................... 95 
Figure 17.  Mean inhalation volumes of subjects inhaling from different spacers. ...... 96 
Figure 18.  Mean peak inspiratory flow of subjects inhaling from different spacers. .. 96 
Figure 19.  Percentage of children able to perform single maximal inhalation. ........... 97 
Figure 20.  Salbutamol doses recovered from filters. ...................................................... 98 
Figure 21.  Number of subjects attending specific study visits. .................................... 119 
 8
Figure 22.  Mean daily fluticasone dose in microgram (y-axis) prescribed at each 
study visit (x-axis). ......................................................................................... 120 
Figure 23.  Scatter plot illustrating proficiency in spacer technique, as measured by 
drug dose deposited on a filter ...................................................................... 124 
Figure 24.  Subjects younger than four years at baseline visit. .................................... 129 
Figure 25.  Histogram plotting the number of subjects (Y-axis) grouped by filter dose 
collected (X-axis) at various study visits ...................................................... 130 
Figure 26.  Scatter plot illustrating mean adherence to prescribed medication, for 
each subject, over the year long study period. ............................................ 132 
Figure 27.   Error bars comparing the mean (95CI) adherence between the Funhaler 
and the Aerochamber Plus groups. .............................................................. 141 
 9
 
 List of Tables 
 
Table 1.  Previous breathing simulation studies using paediatric breathing waveforms 
to study drug delivery through spacers ......................................................... 42 
Table 2.  Published studies where adherence to prescribed inhaled medication was 
monitored electronically on preschool children. ........................................... 50 
Table 3.  Summary from literature of factors associated with adherence to prescribed 
medication ......................................................................................................... 54 
Table 4.  Previous studies comparing forced oscillation lung function in asthmatics 
versus healthy preschoolers ............................................................................ 62 
Table 5.  Average inhalation volumes and average peak inspiratory flows for each set 
of five breathing patterns recorded and simulated in Configuration One. 69 
Table 6.  Average inhalation volumes and average peak inspiratory flows for each set 
of five breathing patterns recorded and simulated in Configuration Two 
and Three .......................................................................................................... 70 
Table 7.  Dimensions of flow chambers used to record breathing using different spacer 
devices. .............................................................................................................. 71 
Table 8.  Basic outline of protocol. .................................................................................... 92 
Table 9.  Outline of protocol for clinical trial ................................................................. 113 
Table 10.  Number of subjects randomised. ................................................................... 114 
Table 11.  Age and cigarette smoke exposure. ............................................................... 115 
Table 12.  Distribution of subjects per year group. ....................................................... 116 
Table 13. Comparison of groups in terms of atopy. ...................................................... 117 
Table 14.  Reasons for subjects not completing the study. ............................................ 118 
Table 15.  Subjects being prescribed fluticasone during the clinical trial. Numbers in 
brackets indicate the percentage of subjects still taking part in the clinical 
trial, who were still being prescribed fluticasone. ....................................... 120 
Table 16.  Fluticasone dose (μg) prescribed at each study visit. ................................... 121 
Table 17.  Number of subjects on salmeterol after study visits .................................... 121 
Table 18.  Baseline visit only.  Symptom free days as reported by diary card for the 
week before each study visit. ......................................................................... 123 
Table 19. Salbutamol dose inhaled on filter by subject at study visits.  Filter dose in 
microgram (mean of five 100μg doses)......................................................... 125 
Table 20.  Correlation between proficiency in using delivery device, as measured by 
drug dose deposited on a filter interposed between subject and spacer, and 
quality of life at the corresponding visit. ..................................................... 126 
Table 21.  Correlation between proficiency in spacer technique, as measured by drug 
dose deposited on a filter interposed between subject and spacer, and 
symptom free days in week before study visit, as determined by diary card.
 .......................................................................................................................... 127 
 10
Table 22.  Subjects younger than four years at baseline visit.  Comparison between 
Funhaler and Aerochamber Plus, in terms of filter studies performed at 
separate study visits.  Filter dose in microgram (mean of five doses). ...... 128 
Table 23.  Electronic adherence data recovery. ............................................................. 131 
Table 24.  All subjects:  Correlation between asthma symptoms (diary card for the 
week before each study visit) and electronically monitored adherence over 
the three month period in between study visits. .......................................... 134 
Table 25.  All subjects:  Correlation between asthma symptoms (day time and night 
time symptoms separated) and electronically monitored adherence over 
the three month period in between study visits. .......................................... 136 
Table 26.  Male subjects:  Correlation between asthma symptoms (diary card for the 
week before each study visit) and electronically monitored adherence over 
the three month period in between study visits. .......................................... 137 
Table 27.  Female subjects:  Correlation between asthma symptoms (diary card for 
the week before each study visit) and electronically monitored adherence 
over the three month period in between study visits. ................................. 138 
Table 28.  Funhaler group:  Correlation between asthma symptoms (diary card week 
before study visit) and electronically monitored adherence over the three 
month period in between study visits. .......................................................... 139 
Table 29.  Aerochamber Plus group:  Correlation between asthma symptoms (diary 
card week before study visit) and electronically monitored adherence over 
the three month period in between study visits. .......................................... 140 
Table 30.  Female subjects only:  Mean adherence to prescribed dose of asthma 
preventers, during the three months leading up to study visits. ................ 142 
Table 31.  Wheeze free days as reported by diary card for the week before each study 
visit. ................................................................................................................. 143 
Table 32.  Cough free days as reported by diary card for the week before each study 
visit. ................................................................................................................. 143 
Table 33.  Bronchodilator free days as reported by diary card for the week before 
each study visit. .............................................................................................. 144 
Table 34.  Quality of life scores, as determined by PedsQL version 3 (asthma module), 
completed by parents at every study visit. ................................................... 145 
Table 35.  Relative quality of life scores, as determined by PedsQL version 3 (asthma 
module),  completed by parents at every study visit.  Quality of life scores 
reported relative to scores at baseline. ......................................................... 146 
Table 36.  Number of subjects per age group, and per study- and control group, on 
whom lung function testing was successfully performed. .......................... 147 
Table 37.  Z-scores of pre-bronchodilator (baseline) lung function of all subjects..... 148 
Table 38.  Bronchodilator response in all subjects, given as percentage change relative 
to baseline lung function. ............................................................................... 148 
Table 39.  Comparison of bronchodilator response in Funhaler (FH) versus 
Aerochamber Plus (AC+) groups. ................................................................ 150 
Table 40.  Comparison of pre-bronchodilator (baseline) lung function in Funhaler 
(FH) versus Aerochamber Plus (AC+) groups.  Data presented as Z-scores.
 .......................................................................................................................... 150 
 
 11
 
 
ABSTRACT 
 
Background: 
The dose of inhaled medication reaching a patient is dependent on drug formulation, 
method of delivery, output and correct use of the delivery device and frequency of use.  
The most commonly used aerosol drug delivery device in preschool children is the 
pressurised metered-dose inhaler (pMDI) -spacer.  This study evaluated strategies for 
improving the delivery of inhalation therapy in preschool children by focusing on factors 
affecting the optimal use of pMDI-spacers and on the frequency of their use as determined 
by adherence to prescribed drug regimes. 
 
The study was divided into two parts.  Part 1 examined the number and type of breaths 
needed for efficient drug delivery through a pMDI-spacer in preschool children.  Part 2 was 
a randomised, controlled, prospective clinical trial in which a comparison was made 
between an incentive spacer device and a small volume spacer with respect to adherence, 
correct device use (spacer technique) and clinical outcome.  
 
Overall aims:   
• To determine how many tidal breaths are required to effectively inhale medication 
from different types of spacer/ valved holding chamber devices, and to determine the 
efficacy of a single maximal inhalation for drug delivery in young children. 
• To investigate the relationship between factors that determine dose delivery of 
inhaled asthma maintenance therapy and symptom control in preschool asthmatic children. 
• To determine the influence of an incentive inhalation delivery device on drug 
delivery and clinical outcome in preschool asthmatic children. 
 12
 
Part One (Chapters Two and Three):   
 
Background:  The pMDI-spacer combination is currently the most commonly used method 
of drug delivery to preschool asthmatics.  A patient’s competence in using a pMDI-spacer 
is an important part of drug delivery.  Preschool children are instructed to breathe normally 
(tidally) through spacer devices. There is little evidence on the number of breaths required 
for optimal drug delivery.  Whether the single maximal breath technique has a place in 
spacer use in preschool children also remains unclear.  Due to a lack of data, authors of 
asthma guidelines have been unable to give evidence-based instruction on how a preschool 
child should breathe through a spacer.   
 
Aims:  To determine the optimal method of breathing through a spacer for preschool 
asthmatic children to ensure effective drug delivery. 
 
Hypothesis:  Based on technical data on in vitro spacer performance and knowledge of tidal 
flow patterns in young children the hypothesis is that a limited number of breaths would be 
sufficient for efficient drug inhalation via spacer in preschool children. 
 
Methods:  A method for reliably recording and simulating breathing of patients using 
pMDI-spacer devices was designed, constructed and validated.  Breathing flow patterns 
were recorded in preschool children inhaling placebo from spacers.  The breathing patterns 
were reproduced by a breathing simulator which was connected to spacer devices.  
Breathing patterns previously recorded using each specific type of spacer, were simulated 
with the corresponding spacer type.  To estimate delivery, the mass of salbutamol was 
measured on a filter interposed between the spacer and the simulator.  Four different spacer 
devices, the Aerochamber Plus®, Funhaler®, Volumatic® and a modified 500ml plastic 
soft drink bottle were tested with a salbutamol pMDI. The effect of different numbers of 
tidal breaths and that of a single maximal breath on drug delivery were compared. 
Results:  Drug delivery via the Funhaler® mean (95CI) was 39% (34-43) and 38% (35-42) 
of total dose recovered from filter, pMDI and spacer, for two and nine tidal breaths 
respectively. Drug delivery via the Aerochamber Plus mean (95CI) was 40% (34-46) and 
41% (36-47) for two and nine tidal breaths respectively.  There was no significant 
 13
difference in drug delivery after three tidal breaths mean (95CI) 40% (36-44%) and nine 
tidal breaths nine tidal breaths; mean (95CI) 37% (33-41) for the Volumatic®.  With the 
(unvalved) modified soft drink bottle, there was no significant difference in drug delivery 
between two, five or nine tidal breaths.   
Inhalation volumes were almost double the expected tidal volumes.  The inhalation volume 
means (SD) of subjects using the Aerochamber Plus®, the Funhaler®, the Volumatic® and 
the modified soft drink bottle were respectively 393ml (247), 432ml (225), 384ml (185), 
445ml (167) during tidal breathing and 515ml (164), 550ml (239), 503ml (213), 448ml 
(259) for the single maximal breath manoeuvre.   
100% of seven year old children, 84% of six year olds, 76% of five year olds, 38% of four 
year olds and 20% of three year olds could perform a single maximal breath manoeuvre.   
Nine tidal breaths resulted in significantly greater drug delivery to filter than single 
maximal inhalation for both the Funhaler® (p=0.04) and the Volumatic® (p=0.01).  There 
was no significant difference in drug delivery to filter between single maximal inhalation 
and nine tidal breaths with both the Aerochamber Plus® and the modified soft drink bottle.  
Conclusion:  In preschool children, two tidal breaths were adequate for drug delivery 
through small volume valved spacers and a 500ml modified soft drink bottle. For a large 
volume spacer, three tidal breaths were adequate for drug delivery. 
 
 14
 
Part Two (Chapters Four and Five): 
 
Background:  Drug delivery by pMDI-spacer is determined by many different factors, 
including spacer technique and adherence to prescribed medication.  The effect of both 
spacer technique and adherence on clinical outcome has been demonstrated in older 
asthmatics.  In this part of the thesis the influence of these factors on clinical outcome in 
preschool asthmatics was firstly investigated.  Thereafter, the additional influence of an 
incentive spacer device on adherence, spacer technique and clinical outcome was also 
assessed. 
 
 Aims:   
• To investigate the effect of proficiency in spacer technique, as measured by 
deposition of drug inhaled onto a filter, on clinical outcome in preschool asthmatic 
children. 
• To investigate the effect of adherence to prescribed inhaled asthma medication on 
clinical outcome in preschool asthmatic children. 
• To investigate the influence of the use of an incentive spacer device on inhaled drug 
dose, adherence to prescribed treatment and clinical outcome in preschool asthmatic 
children. 
 
Hypothesis: 
• Proficiency in spacer technique correlates positively with improved clinical 
outcome. 
• Good adherence to prescribed medication regimens correlates positively with 
improved clinical outcome. 
• Use of an incentive spacer device, the Funhaler® , improves both competency in 
spacer technique and adherence to prescribed medication and thereby improves clinical 
outcome in preschool children with asthma. 
 
 15
Methods:  A prospective randomised, controlled clinical trial was performed.  Subjects 
were two to six year old children who had doctor-diagnosed asthma and were on daily 
maintenance therapy with inhaled corticosteroids.  Maintenance therapy was delivered by 
Funhaler® in the study group and Aerochamber Plus® in the control group.  Subjects were 
assessed for the following outcomes at three-monthly intervals for one year:   
(1) Proficiency in spacer technique was measured at each study visit by measuring the 
drug dose deposited on a filter interposed between the subject and the spacer.   
(2) Adherence was monitored using an electronic monitoring device (Smartinhaler) 
(3) Asthma symptoms were monitored using diary cards.   
(4) Quality of life (QoL) was measured using the PedsQL questionnaires.   
(5) Lung function was monitored using the forced oscillation technique.   
The Funhaler group was then compared with the Aerochamber Plus group in terms of 
determinants of drug delivery and markers of clinical outcome.  
 
Results:  One hundred and thirty two subjects were included in the study.  One hundred and 
eleven patients (84%) completed the study.  By the six month follow-up, significantly more 
subjects in the Funhaler group had dropped out of the study (p=0.04).   
Throughout the clinical trial, there was large intra-subject variation in proficiency in spacer 
technique, as measured by drug dose deposited on filter.  Individual patient drug doses 
recovered from the filters ranged from zero to 136μg (calculated as the mean of five 100μg 
pMDI actuations).  There was no significant correlation between proficiency in using the 
delivery device and any measure of asthma control (p > 0.05).  Correcting for age, gender, 
and adherence to prescribed medication did not influence the results.   
 
Inter subject variability in adherence to prescribed medication was extremely high 
throughout the study.  Adherence to prescribed medication ranged from 1% to 99%.  There 
was a significant correlation between adherence to prescribed medication and nights 
without wheeze, throughout the study period (r = 0.01; p = 0.01).  The correlation between 
adherence to prescribed medication and nights without wheeze remained after correcting 
for age, gender, proficiency in spacer technique, and the number of nights without wheeze 
at the baseline visit (r = 0.01; p = <.01).  There was also a significant correlation between 
adherence to prescribed treatment and (daytime) days without wheeze (r = 0.01; p = 0.01).  
The correlation ceased to be significant after correcting for age, gender, proficiency in 
 16
spacer technique, and (daytime) days without wheeze at the time of the baseline visit.  
There was a significant correlation between adherence to prescribed medication and 
bronchodilator free days (r = 0.01; p = 0.02) throughout the study.  After correcting for age, 
gender, proficiency in spacer technique, and bronchodilator free days at baseline, the 
correlation between adherence to prescribed medication and bronchodilator free days 
remained significant (r = 0.01; p = 0.01).  There was no significant correlation between 
adherence and other markers of clinical outcome. 
 
After correcting for age and gender, the Funhaler group demonstrated significantly higher 
proficiency in spacer technique as determined by filter dose (p = 0.05).  The improved 
proficiency in spacer technique in the Funhaler group was limited to subjects who were 
younger than 4 years of age at the baseline visit (p < 0.01).   
 
There was no significant difference in adherence to prescribed medication between the 
Funhaler group and the Aerochamber Plus group (p = 0.93).  Correcting for age and gender 
did not influence the results.   
 
At the start of the clinical trial (baseline visit), the Funhaler group reported significantly 
less days without wheeze (p = 0.03), and significantly less bronchodilator free days (p = 
0.02) than the Aerochamber Plus group in the seven days before the baseline visit.  The 
Funhaler group also scored lower than the Aerochamber group in terms of QoL scores at 
the time of randomisation (p = 0.05).  Where needed, various measures were used to correct 
for the significant differences at baseline, between the Funhaler group and the 
Aerochamber Plus group.  There was no significant difference between the Funhaler group 
and the Aerochamber Plus group in terms any of clinical outcome measures used.  
Correcting for age, gender did not influence the results. 
 
Discussion:  Use of the Funhaler® therefore appeared to specifically improve drug delivery 
in those subjects who, with a conventional spacer, would have inhaled very low doses of 
medication.  The Funhaler® was therefore partially successful as an incentive device, as its 
use positively influenced drug delivery in a specific sub-group of preschool children.   
 
Proficiency in spacer technique did not translate to improved clinical outcomes.  Various 
reasons for the lack of association between proficiency in spacer technique and clinical 
 17
outcome, including the inevitable inherent limitations in design in a clinical study, are 
discussed.   
 
Results suggest that adherence to prescribed medication regimens correlates positively with 
improved clinical outcome in preschool children with asthma.  Use of the Funhaler® did 
not improve adherence to prescribed medication, or clinical outcome, in preschool children 
with asthma.  Funhaler® therefore failed as an incentive device to improve long term 
adherence, and clinical outcome, in preschool asthmatic children.  Future design for an 
incentive device will need to consider providing feedback that is of more ongoing interest 
to the child.  
 
As the large variation, as observed in this study, in proficiency in spacer technique, and 
adherence to prescribed medication, is likely to influence results of clinical trials, an 
awareness of the variation in spacer technique and drug delivery may contribute towards 
the accurate interpretation of results in future studies.   
 
Finally, the wide variation in both proficiency in spacer technique, and adherence to 
prescribed medication, both factors that determine drug delivery to patients, highlight the 
importance of pursuing ways to improve inhalation drug delivery to preschool children in 
order to eliminate the variability in prescribed medication that eventually reaches patients.  
The delivery to the lungs of a constant, reliably repeatable inhaled drug dose should be a 
continuing aim for aerosol scientists and physicians.   
 
 
 
 
 
 
 
 
 
 
 18
 
LIST OF ABBREVIATIONS 
 
AC+…………………………………… Aerochamber Plus 
CFCs…………………………………... Chlorofluorocarbons 
cm……………………………………… Centimetre 
DPI…………………………………….. Dry powder inhaler 
eNO……………………………………. Exhaled nitric oxide 
ƒ………………………………………... Frequency 
FEV0.5 …………………………………. Forced expiratory flow at 0.5 second 
FEV0.75………………………………… Forced expiratory flow at 0.75 second 
FEV1…………………………………… Forced expiratory flow at 1 second 
FH……………………………………… Funhaler®  
FOT…………………………………….. Forced oscillation technique 
GEE……………………………………. Generalized Estimating Equations 
HFAs………………………………….....Hydrofluoroalkanes 
HR-QoL………………………….……...Health Related Quality of Life 
Hz…………………………………….....Hertz 
I : E………………………………….......Inspiratory:  expiratory ratio 
kg………………………………………..Kilogram 
kPA………………………………….…..KiloPascal 
LPM………………………………….….Litres per minute 
μg………………………………………..Microgram 
mg…………………………………....….Milligram 
ml……………………………………......Millilitre 
MMAD……………………………….…Mass median aerodynamic diameter 
NO…………………………………....…Nitric oxide 
PEF………………………………….…..Peak expiratory flow 
 19
PIF……………………………………....Peak inspiratory flow 
pMDI……………………………….…...Pressurised metered dose inhaler 
Q…………………………………….…..Flow 
QoL……………………………...….…..Quality of life 
Rint……………………………….....…..Interrupter resistance 
RR………………………………...….….Respiratory rate 
Rrs……………………………...….……Respiratory system resistance 
Rrs6……………………………......……Respiratory system resistance at six Hz 
Rrs8………………………………..……Respiratory system resistance at eight Hz 
RSS……………………………….…….Really Simple Syndication 
s……………………………………..…..Second 
Ti…………………………………….….Inspiratory time 
VHC……………………………………Valved holding chamber 
Vt………………………………………Tidal volume 
Xrs……………………………………..Respiratory system reactance 
Xrs6……………………………………Respiratory system reactance at six Hz 
Xrs8……………………………………Respiratory system reactance at eight Hz 
Zrs……………………………………..Respiratory system impedance 
 
 20
 
1 CHAPTER ONE: Literature review  
 
1.1 Inhalation treatment for asthma in preschool children 
Asthma is the most common chronic disease in preschool children in developed countries.  
It places an immense financial burden on health care systems.  Young asthmatic children 
consume three times more inpatient resources per capita than older children and adults [1], 
with rates for emergency department visits and hospitalisations more than double that of 
older children [1, 2].  Asthma fluctuates in severity, with episodic acute exacerbations 
leading to morbidity and mortality.  Inhalation drug delivery is the primary mode of asthma 
therapy in children.  Acute asthma is generally managed with inhaled beta agonists and 
systemic steroids.  Inhaled steroids are the most effective and most widely used 
maintenance therapy for asthma.  Throughout most of the developed world pressurized 
metered dose inhalers (pMDIs) used in combination with valved holding chambers (VHCs) 
or spacers are the preferred method for delivering asthma preventers in preschool children 
[3-5].  The regular use of inhaled steroids has been shown to reduce the frequency and 
severity of asthma symptoms [6].  Although asthma preventers have been shown to reduce 
asthma symptoms, asthma related morbidity still remains high.  Reasons for the continued 
high asthma related morbidity could be ascribed partly to inadequate inhalation drug 
delivery.     
 
Targeted medical treatment to the airways enables us to provide higher drug doses to the 
lungs while sparing other organs from unnecessary drug exposure. The science of 
delivering therapeutic drugs to the lungs is still being perfected: Even with the best delivery 
systems available, a significant fraction of aerosolized drug does not reach the lungs and 
either goes to waste in the atmosphere, deposits onto the delivery device [7] or deposits in 
other sites in the upper airway [8] [9].    A fraction of inhaled drug is absorbed into the 
systemic circulation via these sites [10], and even via the lungs [11].   
 
Reliable delivery of inhaled medication to children is important [12].   Accurate dosing of 
inhaled corticosteroids is especially important, as side effects can be caused by excessive 
dosing[13], and sub-optimal dosing can lead to treatment failure.  Drug delivery to a patient 
is determined by drug characteristics, the delivery system used, and patient related factors 
 21
[14].  Factors that determine aerosol drug delivery, related to the drug and delivery systems, 
include drug formulation, delivery device and prescribed medication dose.  Patient-related 
factors that influence aerosol drug delivery include an individual’s airway anatomy, 
expertise in using the delivery device and adherence to prescribed medication.  Before 
drugs and delivery systems can be discussed, it is important to understand certain basic 
principles of aerosol behaviour in relation to the airways.  
 
1.2 Basic principles of aerosol behaviour  
Whether aerosol particles are inhaled into the lungs or deposited in the upper airways is 
determined by the inertial characteristics of the particles [14-16].  Particle deposition onto 
the airway surface during inhalation, depends upon the method of inhalation, the 
characteristics of the aerosol particles and physical characteristics of the subject inhaling 
the particles [17, 18]. Therapeutic aerosol particles are designed to be deposited on the 
surface of small to medium airways.   Whether a fraction of an aerosol that reaches the 
lungs is deposited onto the airway surface or simply exhaled again is determined by 
sedimentation, due to gravitational forces [19], and impaction due to inertia.   
 
An aerosol particle’s inertial characteristics are mainly determined by its size, density and 
shape [14].  Aerosols generally consist of particles with a range of sizes, densities and 
shapes, and therefore accurately describing the particle characteristics of an aerosol can be 
challenging.  To make description and comparison possible, aerosols are often described in 
terms of mass median aerodynamic diameter and the associated geometric standard 
deviation.   Aerodynamic diameter is defined as “the diameter of a sphere of unit density 
which has the same settling velocity in air as the aerosol particle being measured” [14].  
The measurement of an aerosol’s aerodynamic diameter and geometric standard deviation 
is especially important for “particle sizing”, which is discussed below.   
 
During inhalation, therapeutic aerosol particles do not always follow airstream lines, as 
mechanical and electrostatic forces influence particle movement:  Electrostatic forces can 
play a role in aerosol delivery outside the body [20], but as the external surface of the 
airways is generally not electrostatically charged, mechanical forces are of more 
importance in determining the movement of an aerosol particle in the airways.  The forces 
that act on an aerosol particle are diffusion (Brownian movement), sedimentation 
(gravitational transport) and inertia [17, 21].  The specific type of mechanical force that 
 22
most influences the movement of a particle is determined by the size and  density of the 
particle, as well as by time, as described below:  
 
Diffusion:  Diffusion is the random motion of small particles suspended in a gas as a result 
of random thermal agitation that leads to the intermingling of molecules.  Microfine 
particles with a diameter smaller than 0.1µm are transported by diffusion [21, 22].  
Diffusional movement is not influenced by particle density, but is influenced by time and 
particle size [14].  As diffusional transportation is time dependent, it follows that during 
breathing, lung deposition by diffusion occurs in parts of the lung with the longest 
residence time i.e. the small airways and alveoli.  If the residence time is not long enough, 
i.e. when a patient’s respiratory rate is very fast, a significant fraction of inhaled microfine 
particles can be exhaled before deposition of the particles onto the surface of the airways 
occurs [22, 23]. 
 
Sedimentation: Sedimentation is also known as gravitational transport.  As particles 
increase in size, the influence of sedimentation on particle movement increases and the 
influence of diffusion on particle movement decreases [14, 19, 21].  When a unit density 
particle exceeds a diameter of one micrometer, diffusion has a negligible effect on particle 
movement [21], and the influence of sedimentation is paramount.  Movement by 
sedimentation is, like movement by diffusion, time dependent.  Lung deposition as a result 
of sedimentation therefore also mostly occurs in smaller airways, where air movement is 
slower [19, 21].   
 
Inertia:  Inertia is the property of a particle that causes it to resist changes in speed or 
direction (velocity). Aerosol particles of unit density larger than two micrometers are 
primarily deposited by inertia [14, 22].  Inertial transport is velocity dependent.  Airways 
branch, and change direction frequently. Larger particles, which are mainly transported by 
inertia, are therefore deposited onto airway surfaces of the larger airways[22, 23], where air 
flow is greater than in the smaller airways. 
 
Under laminar flow conditions, particles larger than five micrometers in diameter will 
mostly impact on larger airways [22] and will therefore not be inhaled into the lungs. Under 
turbulent flow conditions, particles larger than three micron will mostly not be inhaled past 
the nasopharyngeal bend [22].   As mentioned above, particles smaller than half a 
 23
micrometer in aerodynamic diameter do not deposit in the lungs under normal breathing 
conditions and are therefore mostly exhaled [24]. Aerosol particles are therefore most 
suitable for inhalation if they have an aerodynamic diameter between one and five 
micrometers [25]. Pharmaceutical preparations generally have MMADs (mass median 
aerodynamic diameters) of one to five micrometers [24, 26].  As described above, particles 
with a diameter larger than one micrometer are mostly submitted to inertial and to a lesser 
extent, to gravitational forces.  Drug delivery to the lung will therefore mostly be 
determined by particle size, inertial and to a lesser extent, gravitational forces, with drug 
delivery increasing due to gravitational forces during breath holding manoeuvres 
The main asthma drugs used in preschool children will be discussed below, followed by a 
discussion on delivery devices.  Emphasis will be placed on drug formulations and delivery 
devices suitable for use in preschool children, and their effect on aerosol characteristics and 
drug delivery. 
 
1.3 Inhaled asthma drugs 
Asthma pathophysiology includes bronchoconstriction, airway inflammation with mucous 
secretion and airway remodelling.  The standard drug treatment for asthma consists of 
bronchodilators and corticosteroids.  Leucotriene antagonists are also used in selected 
patients for preventive therapy.    
1.3.1 Bronchodilators 
In the preschool age group, mostly short acting β-stimulants (e.g. salbutamol) and to a 
lesser extent anticholinergics (e.g. ipratropium bromide) are used as asthma relievers or 
bronchodilators.   Beta-stimulants have a wide therapeutic index, are relatively inexpensive 
and are only used for treating acute asthma symptoms, making accuracy in dosing less 
important.  The need for repeated high doses of bronchodilators during acute asthma 
exacerbations makes fast, effective drug delivery a priority.  Long acting β-stimulants (e.g. 
salmeterol) are used in conjunction with inhaled corticosteroids as asthma controllers.  For 
delivery of β-stimulants, drug formulations with larger particles, in the upper range of one 
to five micrometers may be more desirable, as regional targeting of bronchodilators to the 
proximal airways have been shown to be more effective for bronchodilation than distal 
alveolar drug deposition [27].   
 24
1.3.2 Corticosteroids 
 Inhaled corticosteroids are used for the secondary prevention of airway inflammation and 
mucous secretion.  Where inhaled steroids are used to treat asthma, particles within the 
lower range of 1-5µm are more desirable, as inflammation in the distal lung can exceed that 
in the large airways [28].  Inhaled steroids are generally prescribed for daily or twice daily 
use as asthma preventers.  The medium to long term need for the daily- or twice daily 
administration of inhaled steroids makes a rapid, effective delivery mechanism preferable.  
A fast, effective delivery mechanism is especially preferable in preschool children who are 
known to often be resistant to being treated.  Fluticasone, budesonide, beclomethasone and 
more recently ciclesonide are commercially available inhalation steroids.   
 
Beclomethasone was the first commercially available inhaled corticosteroid.  Since the 
initial introduction of beclomethasone dipropionate to the market, the drug has been 
reformulated as an extra fine aerosol [29] with a MMAD of one micrometre.  The small 
particle size allows for improved lung deposition.  The extra fine beclomethasone 
formulation also has high systemic bio-availability, due to  absorption through the 
pulmonary vasculature [30].  Fluticasone propionate currently is one of the most widely 
used corticosteroids.  Fluticasone is a potent inhalation corticosteroid with low gastro-
intestinal bioavailability [31].  Budesonide, an older formulation, is widely used in dry 
powder inhalers and nebulisers.  Budesonide is less potent than fluticasone, which has 
higher corticosteroid receptor binding affinity [32].  Budesonide has relatively low bio-
availability due to low gastro-intestinal absorption and its tendency to bind with plasma 
proteins.  Budesonide is highly protein bound in plasma, reducing the effect of absorption 
through the airway mucosa or gastrointestinal system.  Ciclesonide is the most recent 
development in inhalation steroids.  Ciclesonide is unique as an inhalation steroid, in that it 
is inhaled as a  pro-drug, and converted to its active metabolite in the airways [33]. The use 
of ciclesonide, therefore, theoretically should reduce the chance of developing systemic 
side effects to a minimum [34].  
 
 
1.3.3 Dose-response relationship between inhaled corticosteroids and asthma control 
in preschool children 
 
 25
Although the efficacy of inhaled steroids is well known in older children and adults with 
asthma, the dose-response relationship of inhaled steroids in preschool children is currently 
still not entirely clear [35].   Interpretation of data on preschool children is made difficult 
by a large variation in age groups being studied, various definitions used for asthma and 
wheezing disorders [35] and the difficulty in obtaining objective physiological data.   
 
In a four month long double blind parallel trial [36], where the effect of budesonide 400μg 
per day was compared with that of placebo, in 41 “young wheezy children” aged 0.7-6.0 
years, budesonide had no significant effect on acute episodes of wheeze.  The results of this 
study should, however, be interpreted in the light of the relatively low subject numbers, the 
short duration of the study, and the inclusion of very young infants.    
 
In a clinical trial comparing 200μg fluticasone per day, 100μg fluticasone per day, and a 
placebo, in 237 asthmatic children aged 12 to 47 months, exacerbation rates were inversely 
related to inhaled steroid dose [37].  Thirty seven percent of the placebo group had one or 
more exacerbations during the 12 week study period.  In the treatment groups, respectively 
37%, 26% and 20% of subjects in the placebo, 100μg and 200μg groups experienced 
asthma exacerbations.   
 
Guilbert el al [38] compared the effect of long term inhaled fluticasone to that of placebo 
on 285 two- to three-year old children at high risk of developing asthma.  Over a two year 
period, the treatment group (fluticasone 88μg bi-daily) demonstrated a greater proportion of 
symptom-free days, a lower rate of asthma exacerbations, and a lower rate of 
supplementary use of controller medication.   
 
1.3.4 Side effects of inhaled steroids 
Adverse local and systemic effects caused by the use of inhaled corticosteroids have been 
well described [39-41].  Inhaled corticosteroids have been shown to have a suppressive 
effect on linear growth and may cause suppression of the hypothalamic-pituitary axis.  
Cases of adrenal crises leading to significant morbidity and mortality have been well 
documented in children using high doses of inhaled corticosteroids.   Because of the 
potential for side effects with the use of regular inhaled corticosteroids, accuracy in dosing 
should be a priority.  Unfortunately, accuracy in dosing when delivering inhaled 
 26
corticosteroids has remained an elusive goal, as many different factors influence the inhaled 
drug dose delivered.   
1.3.5 Delivery of inhaled asthma medication in preschool children 
Fast and effective delivery systems are preferred for delivery for both bronchodilators and 
inhaled steroids.  Reliability and consistency in dosing should be a priority when delivering 
inhaled steroids.  The efficiency and accuracy of drug delivery is greatly influenced by the 
choice of delivery device, which will be discussed below. 
 
1.4 Delivery devices 
1.4.1 Pressurised metered dose inhalers  
Pressurised metered dose inhalers (pMDIs) used with valved holding chambers (VHCs) or 
spacers are considered to be the method of choice for delivering aerosolized medication to 
preschool children [29, 42].  pMDIs, when used correctly, are an effective means of 
delivering medication to the airways and are relatively inexpensive and quick to use.  
Isolation and pressurization of contents protects against colonisation of the drug 
formulation by pathogens.  For very young children a major benefit of using pMDIs and 
spacers is that inspiratory effort from the patient is not essential in order for the metered 
dose to be dispensed.  Guidelines for the most effective use of pMDIs will be discussed 
later in theis thesis.  
 
pMDI design:  The pMDI is a complex configuration for delivering medication.  A pMDI 
consists of a canister that contains propellants and a drug, a metering valve, and a 
sleeve/actuator.  Each component plays a role in determining the characteristics of the 
aerosol being dispensed [43].   
 
Canister:  The drug formulation is contained within the canister.   The canister acts as a 
reservoir for the drug, propellants and excipients which make up the drug formulation.  The 
canister must be able to withstand high pressures generated by the propellant and is usually 
made of aluminium.  Chemical interaction of the drug and the material of which the 
canister is made may be prevented by coatings on the internal container surface of the 
canister [44].   
 
 27
Drug formulation:  In a pMDI the physicochemical properties of the drug formulation play 
an important role in determining the characteristics of the aerosol produced [44].  The drug 
used, propellants, and surfactants all play a part in contributing to the characteristics of a 
drug formulation.   
 
Propellants:  Propellants in pMDIs are highly volatile substances that are in liquid form 
when compressed in pMDI canisters, but change into the gaseous phase at atmospheric 
pressure [43].  When exposed to room temperature and atmospheric pressure, propellants 
immediately boil, thereby atomizing the drug, which is suspended in or dissolved with the 
propellant.  
 
Hydrofluoroalkanes (HFAs) have largely replaced chlorofluorocarbons (CFCs) as 
propellants in pMDIs.  CFCs have traditionally been used as propellants, but are in the final 
stages of being phased out by international agreement because of their  detrimental effect 
on the ozone layer [45].  HFAs do not have a damaging effect on the ozone layer [46].  
HFAs are greenhouse gases, although their potential to contribute to global warming is a 
tenth of the potential of CFCs [46].  Both HFAs and CFCs are still being used as 
propellants in pMDIs and there are still CFC propelled pMDIs available on the market [42]. 
 
Vapour pressure must be constant throughout the usage life of a pMDI to ensure consistent 
dosing.  Within a closed pMDI canister, the propellant forms a two phase system made up 
of liquid and vapour.  A dynamic equilibrium exists between the liquid and vapour phases, 
giving a constant vapour pressure.  The constant vapour pressure is maintained irrespective 
of whether the canister is full or nearly empty.  The pressure inside a pMDI canister is 
typically 300-500kPa (three to five atmospheres) [43].  
 
Drugs:  Drugs in pMDIs can be formulated to take the form of either particulate 
suspensions or solutions.  Most HFA pMDIs (with a few exceptions) and all CFC pMDIs 
are formulated as suspensions.  A difference in density between drug particles and 
propellants will cause drug particles to separate from the suspension if the pMDI is left 
standing.  The drug particles will either rise to the liquid surface or sink under the influence 
of gravity [47, 48].  Suspension formulation pMDIs therefore need to be shaken 
immediately before use to ensure uniform mixing of drug particles in the propellants to 
 28
make dosing reproducible [48].  Shaking may not be as important for HFA formulations 
[49].   
 
Aerosol droplet size for suspension formulations is reduced if the formulation has a high 
vapour pressure, a small drug particle size, or a low drug concentration [50].  For HFA 
solution formulations aerosol particle size is influenced by the initial droplet size, the 
concentration of the non-volatile components in the droplet and, to a lesser extent, the 
ambient conditions [43, 51]. 
 
Surfactants and excipients:  Surfactants (such as oleic acid or sorbitan trioleate) are used in 
suspension (mostly CFC) formulations to reduce particle aggregation and to lubricate the 
valve mechanism.  Ethanol is used as a co-solvent/ excipient in some HFA formulations 
(especially in solution formulations) to solubilise the surfactants or to solubilise the drug 
itself [42, 43].  
 
Metering valve and metering chamber:  The metering valve is the most important 
determinant of drug dose delivered by a pMDI.  The metering valve functions as a 
measuring device that delivers a reproducible amount of the liquid phase of a drug 
formulation. The volume of the metering chamber may range from 25 to 100μL [43, 51].   
Before actuation of the pMDI, there is an open channel between the body of the container 
and the metering chamber. The open channel allows for the metering chamber to be filled.  
On actuation of the pMDI this channel closes, and another opens, connecting the metering 
chamber to the atmosphere.  The drug formulation, which is under pressure, is rapidly 
expelled into the valve stem and an expansion chamber.  As soon as the propellant is 
exposed to atmospheric temperature and pressure, it begins to boil.  After actuation, a 
spring returns the valve stem to the resting position and the metering chamber refills.  In 
some devices the valves are surrounded by a retaining cup that contains the next few doses 
of the drug [43]. 
 
Actuator:  A pMDI canister is fitted into a plastic actuator.  The nozzle of an actuator is 
critical to formation of the aerosol spray [52]. The actuator’s nozzle diameter greatly 
influences aerosol particle size [44, 50].  The length of the actuator nozzle also influences 
aerosol particle size [53].  The final atomization process of the drug formulation occurs as 
follows: When the drug dose leaves the actuator nozzle, the liquid components are 
 29
separated by aerodynamic forces to form a spray of liquid droplets [43].  Evaporation of the 
propellant cools the droplets. The term “cold-freon effect” has been used to describe the 
cold pMDI plume that may impact on a patient's oropharynx, thereby momentarily altering 
a patient’s inhalation [54].  The cold-freon effect is less important in HFA powered pMDIs. 
 
Determinants of the aerosol plume:  For a CFC pMDI, the plume velocity at the start of 
pMDI actuation is around 30m/s and the plume duration is typically 100-200ms [43, 52].  
The plume may be as long as 32cm [55].  Both spray force and temperature reduction  
appear to be less pronounced with some, but not all HFA formulations [54, 56].  Actuator 
orifice diameter is the most important factor determining spray force [54].  The size and 
velocity of the aerosol plume that is expelled from a pMDI influence oropharyngeal 
deposition.  A breath actuated plume-control pMDI, which reduces the size and velocity of 
the aerosol plume significantly, has recently been designed [9].  The plume control pMDI 
increases drug delivery to the lung and decreases oropharyngeal deposition markedly.  
Oropharyngeal deposition of aerosol can be greatly reduced by the use of spacers [42].   
 
1.4.2 Spacers and holding chambers 
Spacers and VHCs have also been called add-on devices, accessory devices, extension 
devices, and holding chambers.  Both the names “spacers” and “valved holding chambers” 
are in common use today. Technically speaking, a spacer with a valve is a holding 
chamber.  The two terms are often used interchangeably.   
 
Spacers are attachments to pMDI actuators.  Spacers perform several functions:  By placing 
distance between the point of aerosol generation and the patient’s mouth, they reduce 
oropharyngeal deposition and (especially in children) increase lung deposition.  Spacers 
were initially developed to improve drug delivery with pMDIs in adult patients with 
coordination problems [57].  Valved spacers simplify pMDI use by reducing the need for 
coordination between actuation and inhalation [43].  Valved spacers prevent the actuated 
dose from being blown out of the chamber by exhalation, when actuation of the pMDI is 
not synchronised with the beginning of inhalation.    
 
Spacers are generally made out of metal or plastic.  Over time, plastic spacers build up an 
electrostatic charge which reduces drug output significantly [58, 59].  Electrostatic build-up 
 30
can be reduced for two to four weeks by rinsing spacers in detergent and leaving the 
detergent on [58, 60].  Spacers made from charge-dissipative material have been made 
commercially available and appear to be more effective for drug delivery [20, 61-63].   
 
Successful commercially available spacers range from 100 mL to 750 mL in volume [42].  
Spacers can be classified as small volume and large volume.  There is no formal agreement 
on the cut-off point between small volume and large volume spacers, but spacers with 
volumes of less than 250ml will be referred to as small volume spacers in this thesis.  Small 
volume spacers are generally used in young children, while large volume spacers are used 
in older children and adults.    
 
In young children, who may have difficulty coordinating inhalation with the actuation of 
the pMDI, it is desirable to use spacers.  If exhalation precedes inhalation, valved spacers 
prevent the drug in the holding chamber from being blown into the atmosphere before it 
can be inhaled.  In certain developing countries, plastic cold drink bottles are converted into 
unvalved spacers.  These hand made spacers have been shown to be effective in children 
older than five years of age.  A more recent publication [64] argued that a modified soft 
drink bottle spacer is as efficient as a conventional spacer for delivery of bronchodilator 
therapy in younger children.  The methodology of this particular study could be questioned; 
however, as the study population (median age (25th–75th centile) was 12 (6–25) months) 
was unlikely to have demonstrated a marked response to bronchodilator therapy per se.   
  
Different combinations of pressurized metered dose inhalers and spacers may result in 
considerable differences in dose output [65-69].  Several studies have demonstrated that the 
behaviour of an aerosolized drug with a spacer device is specific to the drug and spacer 
combination being used [10, 55, 68, 70-72].  For accuracy in drug delivery, a strong case 
can be made for using only a specified spacer with a specific drug formulation where the 
output for the specific spacer-drug combination is known [73].  However, in practice, the 
likelihood is that different drugs and spacers will be used interchangeably by both health 
care providers and patients.  Testing the influence of all different spacers on the delivery of 
all different inhaled drug formulations is impractical.  Fortunately there are certain 
generalizations that can be made with regards to drug delivery and spacer size:  In small 
volume spacers, up to the medium sized Babyhaler (350ml), when the electrostatic charge 
of spacers is reduced, the lung dose appears to be pMDI dependent and spacer independent 
[69].  At low tidal volumes, large volume spacers deliver lower inhaled doses than small 
 31
volume spacers [74].  At high tidal volumes, large volume spacers deliver higher doses than 
small volume spacers [74]. 
  
1.4.3 Breath actuated devices 
The first breath actuated inhaler was described in 1971 [75].  Breath actuated inhalers were 
designed to overcome the problem of synchronizing release of the drug with the start of 
inhalation [75].  After priming a breath actuated metered dose inhaler, the patient’s 
inhalation triggers actuation of the device.  Breath actuated devices improve drug delivery 
in adults with poor co-ordination [29, 76], but are not recommended for preschool children.  
Most preschool children are unable to perform the two- to four-second long maximal 
inhalation required for effective drug delivery through a breath actuated device [77]. 
 
1.4.4 Nebulisers 
For the delivery of asthma medication in preschool children, nebulised delivery of drugs is 
inefficient and expensive.  Some authors have stated that nebulisers should be reserved for 
children who are unable or unwilling to use pMDIs and spacers [78].  Traditional nebulisers 
are expensive, need a power source, are less efficient than pMDI-spacers in delivering 
drugs to the lungs (more drug required for similar pulmonary delivery, and higher systemic 
absorption of drug), take longer to use and are more difficult to maintain in terms of safety 
and hygiene [5, 10, 79-82].   Even in acute asthma attacks delivery of bronchodilators by 
pMDI-spacer is at least as effective as delivery by nebulizers [5, 83].    
 
Some authors suggest that if  a child is very distressed during administration of aerosols by 
pMDI-spacers, a nebulizer could possibly be a more effective acceptable alternative [84].  
However, nebulisers have not been shown to be more efficient in drug delivery in such 
circumstances and have not been proven to be more effective than pMDI-spacers when 
used to administer medication to crying children.  Hence, in many clinics, particularly in 
Australia, nebulisers are no longer prescribed for any asthmatics.  Nebulisers do play an 
important role in aerosol medication delivery where the medication is not available in 
pMDI formulation e.g. antibiotics and enzymes in the management of cystic fibrosis.  
 
Several new generation nebulisers that deliver medication rapidly have been developed 
[29], for example: Respironics I-neb, Omron MicroAir, the Nektar Aeroneb, and the Pari 
 32
eFlow [85].  These devices play a role in delivering expensive medications efficiently 
where pMDI formulations are not available.  However, high cost generally inhibits the use 
of these devices for the day to day delivery of asthma medication. 
 
1.4.5 Dry powder inhalers 
Dry powder inhalers (DPIs), like breath actuated pMDIs, reduce the need for the patient to 
co-ordinate actuation with inhalation.  DPIs are popular amongst patients because they are 
small, unobtrusive and easily portable and do not produce any greenhouse gases.  When 
using DPIs a forced inspiratory manoeuvre is required for the metered dose to be dispensed 
[29].  The inspiratory flow determines the total emitted dose and the respiratory fraction.  
The need for a forced inspiratory manoeuvre prevents the effective use of DPIs in most 
young children.  Most children below the age of six are not able to generate the inspiratory 
flow through the DPI that is needed to disperse the powder from most of DPIs [86, 87].  
The DPIs that are currently commercially available are therefore not recommended for 
children under the age of six years.   
 
1.4.6 Conclusion 
A multitude of different delivery devices are available for aerosol drug delivery. pMDIs, 
when used correctly, are an effective means of delivering medication to the airways, are 
relatively inexpensive and quick to use, the contents are protected against colonisation of 
the drug formulation by pathogens, and high inspiratory effort from the patient is not 
essential in order for the metered dose to be dispensed.  In young children, who may have 
difficulty coordinating inhalation with the actuation of the pMDI, spacers should be used in 
conjunction with pMDIs.   Nebulisers are still widely used to deliver asthma medication in 
young children.  DPIs are not suitable for use in preschool children, who are generally 
unable to perform the required forced inspiratory manoeuvre. Traditional nebulisers are less 
efficient than pMDI-spacers in drug delivery.  Because of the advantages of pMDI-spacers 
mentioned above, pMDI-spacers are considered by most authorities to be the preferred 
means of delivering asthma medication to preschool children.    
 
There are many variables that influence drug delivery through pMDI-spacers.  The next 
section will focus on drug delivery from pMDI-spacers.   
 
 33
 
 
1.5 Testing drug delivery through spacers 
1.5.1 Overview 
The dosing properties of inhalation devices can be determined by in vitro measurements of 
the quantity and quality of the emitted aerosolized drugs.  In vitro measurements of 
aerosolized drugs allow an estimation of the reproducibility of the dose and particle size 
distribution of the aerosol delivered under optimal circumstances by a given drug 
formulation-delivery device combination.  In vitro studies are useful as they isolate the 
variability of the device from the variability of patient factors in using it, and from the 
variability of aerosol and drug deposition after the aerosol is inhaled. 
 
When evaluating the in vivo performance of an inhalation device, the important parameters 
to consider are the total dose that reaches the patient and the deposition pattern of the 
inhaled dose in the airways [88].  The total dose that reaches the patient is a measure of the 
body’s exposure to the drug.  The inhaled medication’s deposition pattern, which can be 
estimated by particle sizing, is a measure of the drug distributed between the targeted and 
non-targeted areas in the body [88].  Total dose delivery and deposition pattern can be seen 
as different measures of safety and efficacy.  
 
Various in vitro and in vivo techniques are available to measure the performance of 
delivery devices.  Particle sizing is the main in vitro technique, while pharmacokinetics and 
scintigraphy are the main in vivo techniques.  Filter studies are used both in vitro and in 
vivo.  
 
1.5.2 Pharmacokinetics 
The total lung dose of an inhaled drug can be determined pharmacokinetically by 
measuring drug levels in the blood or urine [89, 90].  Pharmacokinetic studies to determine 
lung dose can only be accurate if the drug tested is not metabolized in the lung and there is 
negligible absorption of the drug through the gastro-intestinal system.  Charcoal can be 
used to limit gastro-intestinal absorption of a drug.  Pharmacokinetic estimation of lung 
deposition has been used to determine aerosol characteristics of a range of different drug 
 34
formulations [91-94].  There is strong agreement between pharmacokinetically determined 
lung deposition and scintigraphically determined lung deposition [95].   
 
1.5.3 Scintigraphy 
Gamma scintigraphy allows for the measurement of the distribution of an aerosolized drug 
throughout the delivery device, the patient’s body and the exhaled air [88].  In gamma 
scintigraphy, the drug formulation is labelled with a radio-active isotope.  Drug deposition 
is measured with an external gamma camera [11].  Two-dimensional (planar) scintigraphy 
is mostly used, but three dimensional imaging by way of single particle emission computed 
tomography is available in highly specialised laboratories [96].   
 
There are two major criticisms against using scintigraphy to determine the efficacy of 
aerosol drug delivery.  Firstly, gamma-scintigraphy exposes the patient to low doses of 
radiation.  The second major criticism against using scintigraphy for aerosol testing is that 
the labelling process may alter the formulation being tested.  The labelling process usually 
involves mixing of the drug with the label; however the drug and label are indirectly 
associated within the aerosol droplets.  More sophisticated molecular labelling has also 
been described (direct labelling) [96].  Concerns about the labelling technique are usually 
allayed by the validation process:  Validation of the labelling process is performed by 
particle sizing (see below for particle sizing) in order to ensure that the distribution of label 
within the aerosol droplets closely reflects the drug distribution.   
 
Various techniques have been used to analyze scintigraphic lung images to determine the 
distribution of the label in different anatomical areas of the lung [97-100].  These methods 
have had limited success.  Because of limited  anatomical resolution, scintigraphy generally 
focuses on whole lung deposition rather than distribution patterns within the lungs [88]. 
Some assessment of central to peripheral distribution may be made, however this is more 
feasible with 3-D (SPECT) imaging involving higher doses of radiation than 2-D planar 
imaging techniques. The radioactivity involved limits this technique to only carefully 
selected studies with optimal devices and small subject numbers, particularly in young 
children. 
 
 35
1.5.4 Particle sizing 
In vitro measurements of aerosol particle size are used in the development and quality 
control of pharmaceutical aerosols [11].  In vitro particle sizing also has a limited role to 
play in predicting lung deposition in vivo [11, 24].   
 
Several different techniques are available for measuring particle size of aerosols including 
time of flight, laser diffraction and inertial particle impaction.  Each technique has 
advantages and disadvantages: 
 
Time-of-flight techniques measure the aerodynamic diameter of individual particles 
following controlled acceleration in a well-defined flow field [24].  Time-of-flight is widely 
used for the rapid assessment of aerosols from drug delivery devices.  The main advantage 
that time-of-flight techniques offer is rapid measurement times [24, 101].  However, only a 
single particle can be measured at any given time, and while data on the single particle is 
being processed, other particles cannot be measured simultaneously.  While a single 
particle is being measured, time-of-flight methods are vulnerable to coincidence effects 
(accidental coincidence is defined as the erroneous registration of two photons).  Time-of-
flight techniques are specially vulnerable to coincidence errors when sampling concentrated 
aerosols; this vulnerability severely limits the usefulness of using time-of-flight techniques 
for measuring aerosols produced by pMDIs [24].  Another disadvantage of time-of flight 
methods is that no drug assay is performed.  Therefore, the resulting size distribution 
includes particles that do not contain any medication, e.g. excipients and surfactants that 
may be present in pMDI formulations [101], thus (generally) underestimating the particle 
size and hence deposition of drug-containing droplets. 
   
Laser diffraction, also commonly used to estimate the size range of an aerosol cloud 
produced by aerosol delivery devices, has similar advantages and disadvantages as those 
mentioned for time-of-flight techniques of particle sizing [11]. 
 
Cascade impactors and multi-stage liquid impingers are the most widely used means for the 
in vitro determination of the particle size distribution of aerosols from therapeutic inhalers 
[102].  Cascade impactors directly measure aerodynamic size using a constant suction flow 
through the device, and are used to quantify the mass medication in different particle size 
 36
ranges, independent of other non-physiologically active components of the formulation 
[102].   
 
Many aerosols change their aerodynamic characteristics after they are generated, and the 
measurement technique may have an effect on aerosol particle characteristics [88, 103].  
For instance, when one is particle-sizing wet aerosols using cascade impaction, evaporative 
losses of aerosol droplets, as they enter the impactor at ambient temperature, may give rise 
to an apparent shift in the particle size distribution, resulting in an artificially reduced mass 
median aerodynamic diameter (MMAD) [104]. Higher flow generally results in greater 
drying of particles; cooling of the impactor or humidification of the air stream and 
surroundings can ameliorate these effects. 
 
Correlations exist between particle sizing data and whole-lung deposition [9], especially for 
particles smaller than 3µm. However the use of a constant flow through these devices 
results in an overestimation of drug delivery compared with in vivo studies.  Agreement 
between in vitro and in vivo data may be improved by measuring particle size in ways that 
more closely mimic clinical use [9].  The use of impactor inlets that simulate the human 
upper airway anatomy, and the inclusion of breathing simulation in cascade impaction 
techniques are a move toward in vitro conditions that more closely mimic in vivo 
conditions.  
 
1.5.5 Filter studies 
The total drug dose delivered to a patient from pMDIs with spacers can be assessed non-
invasively by interposing a filter between the delivery device and the patient.  The amount 
of drug delivered to the filter represents the amount of drug that would have reached the 
patient’s mouth.  Filter studies can be performed either ex vivo [105, 106] or in vitro.  There 
is good agreement between ex vivo and in vitro measurements [107, 108]. 
 
Use of filters adds a resistance and dead volume to the inhaler setup.  There is often a trade-
off between resistance and dead volume (i.e. reducing the dead volume often increases the 
resistance.  These factors introduce a greater error when estimating drug delivery in 
children as it is harder for them to overcome the additional resistance, and the inspiratory 
volumes of very young children may be similar to the filter dead volume.  If the inspiratory 
 37
volume of the child is lower than the dead volume of the filter, rebreathing within the filter 
occurs, resulting in little or no drug being deposited on the filter membrane.  
 
Filter studies have been used to determine the efficacy of inhalation drug delivery devices 
and factors influencing drug delivery since the early 1990s [105, 109-112] and are widely 
used to determine drug delivery using pMDI-spacers (63-65, 67, 108-117).   
 
Filter studies cannot be used to accurately determine the dose delivered to the lungs as the 
respirable fraction of the drug dose delivered cannot be measured.  However, filter studies 
have specific advantages over other techniques for determining total drug dose delivered to 
a patient:  In vitro analysis of the drug deposited on a filter is more time- and labour 
efficient than the use of particle sizing.  Ex vivo, filter studies allow for the measurement of 
the drug dose delivered to a patient without exposing the patient to medication, 
venepuncture or urine sampling (as in pharmacokinetic studies) and without exposing the 
subjects to radiation (as in nuclear scintigraphic studies).  As mentioned, filter studies are 
an effective means of determining the total drug dose delivered to a patient.   
 
1.5.6 Breathing simulation 
1.5.6.1 Background 
In vitro drug delivery by pMDI-spacer, when tested at a constant flow, is different from 
drug delivery where breathing is incorporated [65, 72].  In vitro measurements made at 
constant high flow rates may not reveal differences in performance that may be clinically 
significant, and may lead  physicians to prescribe devices that under certain conditions may 
not deliver any drug to small children [113].  Before breathing simulation studies, much of 
the in vitro data available on drug delivery through spacers had been obtained using 
inhalation flows typical of single breath adult inhalations, and could not be extrapolated to 
children [72].   
 
Breathing simulation for in vitro testing of inhalation drug delivery devices allows for a 
more accurate assessment of drug delivery through pMDI-spacers than traditional methods.  
 
 38
1.5.6.2 Previous breathing simulation studies investigating aerosol drug delivery using 
paediatric breathing patterns  
Paediatric breathing simulation studies have increased our understanding of the effect of 
children’s breathing on drug delivery through spacers.  The contribution of pMDI-spacer 
related paediatric breathing simulation studies has up to now been greatest in demonstrating 
the following: 
• The sensitivity of pMDI-spacers to changes in breathing patterns 
• The critical importance of spacer design for drug delivery in children 
• The importance and effect of tidal volume on drug delivery 
• The dramatic effect of breathing patterns peculiar to young children on drug 
delivery 
 
The following is a summary of the contribution made by breathing simulation studies to our 
understanding of drug delivery through pMDI-spacers to children:   
Low inspiratory flow is required for optimal drug delivery through pMDI-spacers [69, 
114].  Under low flow conditions, spacer output generally correlates with tidal volume [69], 
but not for some spacers (Nebuchamber) when the tidal volume exceeds 150ml [115].  
Paediatric breathing simulation data have also demonstrated that at low tidal volumes, the 
high aerosol concentration in smaller holding chambers enhance drug delivery, while at 
high tidal volumes delivery is greatest from larger holding chambers [74].  This finding has 
been applied to clinical practice where small volume spacers are generally prescribed for 
infants and small children and large volume spacers are prescribed for older children and 
adults.  Paediatric breathing simulation studies have further demonstrated that at low tidal 
volumes, some spacers do not deliver any drug at all [113].  The poor drug delivery at low 
tidal volumes by these spacers was mostly ascribed to large areas of dead space.  In young 
children spacers with minimal dead space are therefore preferred.  Paediatric breathing 
simulator studies have also demonstrated that spacer output does not necessarily correlate 
with respiratory rate [69].  However, in line with previous in vivo work [114], breathing 
simulation has demonstrated that lung dose decreases with increased inspiratory flow [69].  
Using breathing simulation, Nikander at al (2007) demonstrated that crying reduces the 
dose that reaches the patient to 1% of the label dose [108] –certainly useful information for 
clinicians.   
 
 39
Breathing simulation studies have demonstrated that the rate of drug delivery via nebulizers 
is influenced by the configuration of the simulated breaths, e.g. peak inspiratory flow (PIF), 
tidal volume (Vt), frequency (ƒ), inspiratory time (Ti) [116].  The shape of the simulated 
wave forms is more important in pMDIs than it is in nebulizers:  With nebulizers, the use of 
sinusoidal waveforms resulted in similar drug delivery as when square wave forms were 
used [116]. Data from breathing simulation studies with nebulizers should, however, not be 
extrapolated to pMDI-spacers.  Smaldone et al (2005) demonstrated that drug delivery from 
pMDI-spacers is more sensitive to changes in breathing pattern than drug delivery through 
jet nebulisers [117].  
 
As mentioned before, there are significant differences in dose output from different 
combinations of pressurized metered dose inhalers and spacers [72, 113].  Breathing 
simulation has shown that, under certain conditions, estimated lung dose is pMDI 
dependant and spacer independent [69].  Certain spacers (Aerochamber® and 
Optichamber®) show less age and breathing pattern dependence on fine particle dose [72].   
 
Although the studies described above have advanced our understanding of drug delivery 
through spacers, there are two important points to make about the breathing patterns used in 
these studies.  Firstly, in all the above breathing simulation studies, breathing patterns were 
either ventilator produced (sinusoidal or square) wave forms, or simulations of actual 
recorded paediatric breathing patterns which were recorded on patients breathing through 
face masks.  Both methods have shortcomings in that the breathing patterns used may not 
be truly representative of children’s breathing patterns when the children are inhaling from 
the type of spacers being tested, as the ventilator produced breathing patters used were 
based on expected breathing parameters for children.  The actual breathing patterns that 
were simulated were recorded from children wearing masks. 
 
As pMDI-spacers are very sensitive to changes in breathing pattern [117, 118], it is 
essential that representative breathing patterns be used when breathing is simulated, in 
order to  effectively evaluate the delivered medication dose.  External factors like 
instrumentation can influence a patient’s breathing pattern [119].  It would therefore follow 
that breathing patterns that are used for breathing simulation are representative of breathing 
patterns that are: 
• Recorded in the patient population under investigation 
 40
• Recorded on patients while they are using the aerosol delivery device that is being 
evaluated 
• Recorded with minimum interference between the patient and the aerosol inhalation 
device. 
 
The second notable point about the studies described above is the variation in either the 
number of breaths simulated, or time of simulation, when pMDI-spacer output is tested i.e. 
five breaths, six breaths, 30 seconds.  In Table 1 all published paediatric breathing 
simulation studies and the breathing patterns used, are summarised.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 41
 
Author 
 Breathing pattern Spacers & Drugs Findings Comments 
Everard et Starling ventilator; Tidal 750ml Nebuhaler  At lowest tidal volume, high Vt smaller than Vt 
al, 1992 volumes of 25, 50, and 150 ml/ &Aerochamber aerosol concentration in measured in 
[74] 6 breaths …with masks Cromoglycate smaller chamber enhanced children breathing 
Filter study  drug delivery.  At highest through mask [120]. 
tidal volume delivery 
greatest from larger 
chamber 
Mitchell, Infant Star Aerochamber (145ml) At Vt = 50ml the significant 
1997 [113] Vt = 50ml (RR=30/min) Vent-170 (170ml) Vent-170 and differences in dose 
Vt = 100ml (RR=26/min) Space Chamber (250ml) SpaceChamber did not output from 
Vt = 200ml (RR=18/min)  deliver any drug different  
I/E = 40:60 salbutamol   combinations of 
5 inhalations beclomethasone   pMDIs and spacers 
 Face masks 
Berg, 1998 Harvard Animal Respirator metal Nebu-Chamber 250ml significant differences in constant flow higher 
[65] 20 breaths/min and AeroChamber135 mL dose output doses than 
Vt = 195 mL  with budesonide  from different combinations simulated breathing, 
sinusoidal wave form  Babyhaler 350 mL (40 mL of pMDIs and spacers less so for 
 I:E of 1:2. dead space) with fluticasone Nebuchamber 
No. of breaths used not noted Detergent coated 
Finlay, Infant:  Aerochamber Different formulations Vt used to represent 
1998 [72] Vt = 0.075L, Q= 4.8 LPM Optichamber behave differently in infant breaths 
Toddler:  Space Chamber holding chambers. possibly too small 
Vt = 0.19L, Q= 8.2 LPM E-Z spacer Aerochamber & 
Child: …with masks Optichamber 
Vt = 0.23L, Q = 11LPM Beclomethasone & Showed less age/ breathing 
Equal inh/exh flow rates  salbutamol pattern dependence to fine 
5 breaths particle dose 
Barry, Pari Sinus Breathing Simulator Aerochamber(145ml) Nebuchamber increases in Drug delivery 
1999 [115] Vt = 50,100,150,200,300ml Nebuhaler(750ml) vitro budesonide delivery increase with 
RR = 20/min metal Nebuchamber(250ml)  but delivers a greater increased Vt but not 
I:E = 40:60  percentage of the drug in with Nebuchamber 
5 simulated breathing cycles budesonide large particles when Vt>150ml 
Janssens, Sinusoidal patterns Vt = 25ml, Nebuchamber plus Lung dose decrease with Lung dose is pMDI 
2004 [69] 50ml, budesonide increased flow.  dependant and 
100ml, 150ml, Aerochamber and Spacer output correlated spacer independent 
200ml budesonide plus fluticasone with Vt but not with RR 
RR = 20-80/min Babyhaler plus fluticasone  
30 sec breathing 
Smaldone, Breathing patterns recorded on Aerochamber Leaks around the facemask pMDI-spacers more 
2005[117] children Optichamber reduce drug delivery and for sensitive to changes 
30 seconds breathing Nebulizers pMDI spacers can negate in breathing pattern 
Pattern 1: Vt = 207ml RR = the beneficial effects of than jet nebulisers 
37.01/min detergent coating. 
Duty cycle = 0.41  
Pattern 2: Vt = 75ml 
RR = 25/min 
Duty cycle = 0.40 
 
Sinusoidal patterns Aerochamber Max Improved drug delivery 
Louca Vt = 155ml Optichamber  with spacers made of charge Only 3 inhalations 
2006 [63] Inspiratory time = 0.8sec ProChamber dissipative materials per acuation of 
Total respiratory time = 2.4 sec …all with face  masks pMDI 
3 simulated breathing cycles 
 
Nikander, Human breathing patterns  Aerochamber Plus facemask with a crying  
2007 [108] recorded –representative Optichamber breathing pattern reduced 
patterns simulated  Nebulisers the inhaled mass to 1% of 
Crying 1year old breathing …all with face  masks the label dose 
recorded & simulated 
Mean Vt = 134ml 
Duty cycle = 0.26 
 
Table 1.  Previous breathing simulation studies using paediatric breathing waveforms 
to study drug delivery through spacers. Vt = tidal volume, Q = flow, RR = respiratory 
rate, I:E = inspiratory: expiratory ratio; pMDI = pressurised metered dose inhaler. 
 42
 
 
1.6 Patient related factors influencing drug delivery  
The interaction between a patient and a drug delivery device is an important determinant of 
drug delivery. Patient-device interaction can be subdivided into two categories:  Firstly, the 
patient’s proficiency in using the device and secondly, the patient’s adherence to prescribed 
medication.   As this thesis focuses on preschool asthmatics, the patient’s proficiency in 
using the delivery device will be discussed under the heading of “Spacer technique” with a 
discussion on adherence following shortly thereafter. 
 
1.7 Spacer technique in preschool children with asthma 
1.7.1 The importance of spacer technique 
Inhaled asthma drugs should be delivered as effectively as possible to improve asthma 
control, reduce side effects and offer cost-effective therapy [121].  The method for using a 
pMDI and spacer is referred to as spacer technique or device compliance.  The inability to 
use inhalers effectively has been shown to adversely affect drug delivery [114, 122, 123].  
Poor spacer technique can even render inhalation drug delivery by pMDI totally ineffective, 
resulting in morbidity [124].  Studies have shown that in many asthmatic children, inhaler 
technique is too poor to result in reliable drug delivery [125, 126].  Even after instruction in 
correct inhaler use, incorrect inhaler use is common amongst asthmatic children [127, 128]. 
To add to the problem, correct inhalation technique deteriorates over time [129].  When 
using pMDI-spacers with young children and infants, cooperation during administration is 
the most important determinant of drug delivery [84].     
   
Spacer use with a mouthpiece, as opposed to spacer use with a face mask, will be discussed 
because of its relevance to this study.  The following steps have been shown to be 
important in using a pMDI and spacer:  Firstly the pMDI should be shaken [130].  Shaking 
ensures mixing of the drug and the propellant inside the canister[131].  Shaking before each 
actuation may be less important for HFA propelled drug solutions.  The next, simple step in 
pMDI-spacer use is to take the cap off the sleeve of the pMDI.   Although taking off the 
cap seems intuitive, it is not always done.  Thirdly, the pMDI needs to be inserted correctly 
into the spacer.  The fourth step for correct pMDI-spacer use is to place the spacer into the 
 43
patient’s mouth before actuation.  Waiting between placing the spacer into a preschool 
child’s mouth and actuating can cause unnecessary delay while a portion of the aerosolised 
drug will deposit onto the spacers inside wall by sedimentation [58, 132].  A pMDI should 
only be actuated once in between breaths as multiple actuations reduce drug delivery [58, 
132].  Multiple actuations result in aggregation of aerosol particles, larger particle size and 
subsequently decreased lung delivery [133].  
 
Vodoff and associates [127] found that in children under four years of age, the most 
common errors in using a pMDI were not shaking the device before use (48% of subjects) 
and taking two consecutive puffs (28% of subjects).  The final step in using a spacer is to 
breathe through it.   Breathing through a spacer is discussed in detail below. 
 
1.7.2 Breathing through a spacer 
A patient’s breathing is an important determinant of spacer output:  Various studies have 
demonstrated that spacer output and drug delivery to the lung are strongly related to 
breathing pattern [65, 69, 72, 74, 108, 113, 115, 117, 120, 134, 135].  When a patient 
inhales aerosolised medication, slow inhalation flow (below 60 litres per minute) results in 
increased lung deposition when compared with  higher inhalation flow [136, 137].  
Inhalation rates of 120 litres per minute and higher lead to greatly reduced lung dose and 
increased deposition of aerosol in the upper airways [138].  As mentioned before, during 
crying, drug deposition to the lungs is minimal [139, 140].  
 
Two different methods are used to breathe through a spacer:  Tidal breathing, and the single 
maximal breath technique, with or without breath hold. 
 
1.7.2.1 Tidal breathing 
Preschool children are instructed to breathe tidally through spacers.  There is little evidence 
on the number of breaths required for optimal drug delivery through a spacer.  Advice on 
the number of tidal breaths required for a preschool child to effectively inhale medication 
from a spacer is at present arbitrary, based on little evidence.  Asthma guidelines 
worldwide fail to give specific instructions for preschool children on the correct method of 
breathing through a spacer [141-143].   
 
 44
Gleeson and Price (1988) demonstrated in older children with asthma, that five tidal breaths 
result in an improved bronchodilator response compared with two single maximal breaths, 
when inhaling terbutaline from a 750ml Nebuhaler [144, 145].  Pool, Greenough, Gleeson 
and Price (1988) then went on to examine the efficiency, in two to five year old asthmatic 
children, of five tidal breaths sufficient to operate the holding chamber valve [144].  
Terbutaline delivered via a Nebuhaler using five breaths resulted in a significant 
improvement in lung function in most of the preschool children studied.  The optimal 
number of breaths required for drug delivery was, however, not studied.  
 
James et al (1999) compared, in children, the bronchodilator effect between tidal breathing 
and a single maximal breath, administering 200μg of salbutamol through a large volume 
spacer [146].  They demonstrated that the bronchodilator responses resulting from the two 
breathing techniques were comparable.  However, the subjects’ mean age was 10.9 years –
significantly older than the preschool age group.  In addition, only 21 subjects participated 
in this randomised cross-over study 
 
Studies investigating spacer use in children have made use of a range of different breathing 
periods or number of tidal breaths, including 30 seconds of breathing [69, 117, 147], 60 
seconds of breathing [120],  five breaths [72, 113, 115] and six breaths [74].  
 
When delivering multiple doses or regular doses of inhaled medication to preschool 
children, the practicality of using a 30 to 60 second period for breathing is questionable.  
Preschool children do not always cooperate with parents during medication administration 
[84, 148].  For parents, administering inhalation medication to young children can therefore 
be difficult at times.  It can be postulated that if parents know that only a few breaths will 
deliver the medication they will be more motivated to adhere to treatment plans.  It could 
therefore, potentially be beneficial to patients if the minimum number of breaths required 
for effective drug delivery through a pMDI-spacer combination could be defined.   
 
1.7.2.2 The minimum number of breaths required for effective drug delivery through a 
pMDI-spacer combination 
No study has ever specifically been designed to address the issue of the number of breaths 
needed for preschool children to empty a spacer.  Everard et al (1992) used a Starling 
ventilator to investigate the influence of various design factors on the drug dose inhaled 
 45
from spacers at different tidal volumes [74].  As part of their study the authors derived a 
mathematical equation to predict the dose delivered by a spacer using different tidal 
volumes (respectively 25ml and 100ml) and different numbers of breaths.  Analysis of data 
from the manuscript suggests that five to 12 breaths would be required for maximum drug 
delivery from a 150ml valved spacer, whereas 12 breaths would be required for maximal 
drug delivery from a 750ml valved spacer.  However, Everard’s study was not specifically 
designed to determine the number needed for preschool children to empty a spacer of 
aerosolised drug.  Hence, various factors would prevent one from using the data to advise 
how preschool children should breathe through spacers.  Synthetic waveforms were used in 
the study, with breath parameters that were based on the assumption that children’s 
breathing through pMDI-spacers would not be different from normal tidal breathing.  The 
authors also pointed out that they had made various assumptions with the derivation of the 
mathematical equation, “This model assumes a zero deadspace from valve to patient, a 
valve closing and opening efficiently, and complete mixing within the chamber once the 
valve is closed.  It also assumes that taking a breath from the chamber does not affect the 
rate at which the aerosol settles out”.  
 
Berg et al (1998) simulated breathing with a Vt of 200 mL into a 350ml Babyhaler [65]: 
Although the spacer volume was less than double the Vt used, complete emptying of the 
spacers required approximately five to six breaths.  It took 15 to 20 seconds to complete the 
five to six breaths, demonstrating that drug delivery via spacer is not necessarily complete 
when the Vt multiplied by the number of tidal breaths taken exceeds the spacer volume –a 
fact that was also indirectly illustrated in a study by  Barry & O’Callaghan (1999), 
measuring drug deposited on a filter with breathing simulation studies using sinusoidal 
breathing patterns [115]. 
 
In a review article, Rubin and Fink  (2005) stated that it takes three to five breaths for an 
infant to clear a holding chamber of 145ml [149].  Their calculations were based on a Vt of 
7ml/kg for a one year old child with a weight of 10 kilograms.  They were however, 
assuming that a child would breathe at normal tidal volumes when breathing through a 
spacer, and that a spacer would empty if the Vt multiplied by the number of tidal breaths 
taken exceeded the spacer volume.  
 
 
 46
 
1.7.2.3 Breath hold technique 
Whether the single maximal breath technique can be appropriately used in preschool 
children using small volume spacers is not known.  Breath hold appears to be beneficial for 
lung deposition in adults.  A study in adults with reversible airway obstruction 
demonstrated that when a β-stimulant is inhaled through a large volume spacer, a seven 
second breath hold causes a larger bronchodilator response than a four second breath hold 
[137].  Breath holding may have little benefit for drug delivery in children. With a dry 
powder inhaler (Turbuhaler) containing terbutaline 0.25mg, breath holding for ten seconds 
has no benefit over inhalation without breath hold on bronchodilation in children aged eight 
to 14 years [150].   
 
The age at which a child can perform a single maximal breath with or without a breath hold 
has not been ascertained.  There are no data available as to whether a single maximal breath 
would be superior to tidal breathing in delivering aerosolised treatment to preschool 
children using small volume spacers.  The efficacy of tidal breathing compared with single 
maximal inhalation from spacers in preschool children is also unknown. 
 
1.7.3 Interventional strategies to improve spacer technique and the Funhaler® 
The concept of altering a child’s breathing with incentives is not new.  Various incentive 
devices have been used successfully in young children performing lung function tests 
[151].  Incentives used mostly include computer programs simulating, for example, 
blowing out candles or blowing up balloons to facilitate deep inhalation and exhalation.  
There is no literature on incentive devices being used to improve inhalation through drug 
delivery devices.  
 
The Funhaler® (Figure 1)is a small volume valved spacer with a spinning disk and whistle 
on the expiratory arm [152, 153]. The function of the spinning disk and whistle 
combination is to act as an incentive for young children to cooperate when their inhaled 
asthma preventer medication is being administered.  External factors like instrumentation 
can influence a patient’s breathing pattern [119].  Therefore, use of the Funhaler® may 
potentially influence spacer technique in young children by influencing inspiration.  To 
isolate the spinning disk and whistle from the main inspiratory circuit by a valve, the toys 
 47
on the Funhaler® are located on the device’s expiratory arm, and therefore only exhalation 
may be influenced.  However, inspiration and expiration are interrelated, and therefore it is 
likely that the characteristics of inspiration (i.e. flow and volume) would be influenced by 
any factor that may influence the preceding exhalation.   
 
If use of the Funhaler® does influence inhalation, then drug delivery will also be 
influenced.  As discussed in the sections above, an increase in inhalation volume would be 
expected to correspond with an increase in drug delivery, whereas an increase in inspiratory 
flow could potentially correspond with an increase in drug depositing in the upper airways, 
thereby reducing drug delivery to the lungs.   
 
 
Figure 1.  The Funhaler® 
 
1.7.4   Important questions about spacer technique in preschool children 
In the sections above, the importance of correct spacer technique, focusing on the correct 
breathing technique through spacers was discussed.  A patient’s breathing characteristics 
through a spacer is one of the most important determinants of drug delivery through a 
spacer, and there are important questions that need to be answered with regard to the 
correct breathing technique for preschool children using spacers:   
1. How many tidal breaths are required for a preschool child to effectively inhale 
 48
medication from a spacer? 
2. From what age should large volume spacers be used?   
3. From what age is the single maximal breath technique feasible/ useful?  
4. Can the use of an incentive spacer improve drug delivery in preschool children by 
influencing breathing technique and if so, would it improve clinical outcome? 
Questions one, two and three will be addressed in Chapters Three and Four of this thesis.   
Question four will be addressed in Chapter Five of this thesis.   
 
As mentioned above, inhaled medication dose reaching a patient is dependent on drug 
formulation, delivery mechanism, the correct use of the delivery mechanism and adherence 
to prescribed treatment.  The first three factors influencing the inhaled medication dose 
have been discussed.  The following section will address adherence to prescribed treatment. 
 
1.8 Adherence to prescribed treatment in preschool asthmatics 
1.8.1  Overview 
Preschool children are too young to assume any responsibility for adhering to a medication 
regimen.  When preschool children’s adherence is discussed in this chapter, it will refer to 
the behaviour of preschool children’s parents/carers that determines whether their children 
are administered their medication as prescribed by their health care providers.  The 
potential of the preschool child to influence its parents’ behaviour will then be discussed.  
 
Preschool children’s adherence to prescribed asthma therapy is often sub-optimal  The 
literature reports that preschool children’s adherence to prescribed medication ranges from 
zero to 100% [154-161].  In Table 2, only electronically monitored adherence data are 
reported, as electronically monitored adherence data are far more accurate than adherence 
data obtained by other means (see section on adherence monitoring, below). 
 49
 
 
Duration 
Author Year N Age of Outcome 
monitoring
Schoni el 1993 21* 2 months – al[159]. 14 years 3 – 50 days Mean adherence was 47.6% 
Gibson et 15 months Full adherence median of 50% 
al[154]. 1995 29 – 5 years 2 months of study days (range 0-94%), and 77% of prescribed doses. 
Burgess et 2007 51 18 months 1 month Median adherence was 70.5% al[160]. – 7 years (21.4 – 100%) 
Burgess et 2008 47 18 months 
Median adherence ranged from 
al[161]. – 7 years 3 months 46% - 74% for different groups over 1 month intervals 
 *children with respiratory illness (10 with diagnosis of asthma) 
Table 2.  Published studies where adherence to prescribed inhaled medication was 
monitored electronically on preschool children. 
 
Poor adherence to prescribed medication regimens leads to poor asthma control and 
increased hospital admissions for asthma [162, 163].  Poor adherence has been shown to be 
a major risk factor for near fatal asthma attacks in older children and adults [164].   
 
Improved adherence has a positive effect on asthma control in older children [165].  More 
adherent asthmatic children and adults are significantly less likely to experience 
exacerbations than their less adherent counterparts [166].  Very little research has been 
done on the effect of adherence to medication in preschool asthmatic children.   
 
1.8.2   Specific difficulties in the preschool age group 
Preschool children are a unique group as they are totally dependent on their parents for the 
administration of their asthma treatment.  Preschoolers have little insight into their disease 
or the need for asthma preventers and are notorious for refusing to take inhaled medication 
[148]. 
 50
 
Until now, attempts to improve adherence in this age group (see below) have focused on 
the parents/ caregivers [167-172].   
 
1.8.3 Barriers to adherence 
Factors that prevent patients from being adherent to their prescribed medications are 
complex.  Studies have shown [155] that barriers to adherence include prolonged and 
complex medication regimens, concerns about adverse effects and cost.  Barriers to 
adherence that relate to the doctor include treatment by one different doctor after another, 
perceived clinician disinterest, and time constraints [155].   
  
Demographic factors: 
Low-income and minority patients report the following barriers to their own adherence to 
asthma medication:  cost, difficulty in obtaining medication, daily life hassles, and a 
general distrust of the medical establishment [148].  Younger and less educated mothers are 
more likely to report a barrier to giving their children a required medication [173]. 
 
Family influences: 
Family dysfunction, dysfunctional parenting and difficulties with time management have 
been shown to be important contributors to non-adherence [174-176].  A good daily routine 
has been shown to be a marker for better adherence [177].    
 
Parent specific issues related to adherence: 
In preschool children, adherence to prescribed medication is the responsibility of the 
parent.  Parental non-adherence is not always intentional [178].  Parents may have doubts 
regarding the usefulness of medications [148], and when they misunderstand the role of 
inhaled steroids, adherence may be reduced [179].  The delayed onset of the action of 
inhaled asthma preventer medication may lead to its being perceived as ineffective.  
Asthma patients in general underestimate the severity of their condition and over-estimate 
how well their asthma is being controlled [180].  In children, both parents and doctors 
generally overestimate asthma control [181, 182].  Parents of children with asthma may 
 51
believe that their children's asthma is under good control and not severe enough to require 
daily treatment despite high asthma-related morbidity [148, 175, 181].     
 
Parents may have concerns about drug safety and cost [148, 183-185].  Children from low-
income families are less likely to adhere to prescribed treatment than children from higher-
income families [186].   
 
More specifically for the preschool child: Adherence has been shown to be inversely 
related to age [187].  Use of day care facilities is also associated with poorer adherence 
[154]. 
 
Child behaviour: 
Parent-child conflict over taking medication has been shown to reduce adherence [148].  
Asthmatic children are at high risk of behavioural problems that may indirectly contribute 
to increased asthma morbidity [176].  Behavioural problems in older asthmatic children are 
related to the severity of their asthma [188].  The earlier in life that there is an onset of 
asthma, the more risk there is that behavioural problems will increase[189].  A child’s 
behaviour may directly influence its parents’ willingness to administer asthma medications, 
and their effectiveness in doing so, as described below. 
 
Parent-child interaction: 
Parents of asthmatic children are regularly confronted with potentially difficult interactions 
with their child during medication administration [190].  The administering of medication 
may at times be fraught with child upset, crying and conflict [176]. Under such 
circumstances parents may, due to low levels of self confidence [176],  retreat and give in 
to their child’s wishes in the hope of avoiding conflict and upset [190].  By giving in to the 
child’s wishes the parents may inadvertently give their child positive feedback for 
inappropriate behaviour, thereby exacerbating negative cycles of parent-child interaction 
[191]. 
 
 52
1.8.4   Interventional strategies to improve adherence to inhalation therapy in 
preschool children 
Research suggests that team-based management strategies and cohesive family climate 
promote adherence to prescribed medication [192].  Medication routines are related to 
medical adherence [177].   
 
Complex dosing regimens have been shown to reduce patients’ adherence [193].  
Simplified dosing regimens (e.g., once-daily administration) would therefore be expected to 
improve asthma adherence [194].  However, asthma preventer dosing generally does not 
exceed twice a day in dosing frequency.  In a study investigating dosing regimens and 
adherence in preschool children with asthma [154], no relation was found between 
frequency of prescribed regimen and good adherence. This study was an observational 
study limited by low patient numbers (n = 35) and the results should therefore be 
interpreted with caution.  
 
Frequent reinforcement of the educational message to the parent/ caregiver will often 
improve adherence [169].  In the present technological age, computerized resources and 
programmes are being used in an attempt to improve adherence with promising results 
[172, 195].  These interventions are, however, expensive, resource intensive and require 
technical expertise. 
 53
 
 
Improved adherence No impact on adherence  
-Team-based management strategies  -Simplified dosing regimens 
-Cohesive family climate -Knowing the importance of inhaler 
-Medication routines (children) 
-Frequent reinforcement of the  
educational message to the parent 
-Computerized resources and 
programmes 
Table 3.  Summary from literature of factors associated with adherence to prescribed 
medication 
Table 3 summarises factors and interventions from the literature associated with adherence 
to prescribed treatment in preschool children.  As mentioned by Sherman et al (2001), 
improved outcomes are generally only seen with resource intensive intervention, and not 
with less aggressive measures [170]. 
 
1.8.5 Potential use of an incentive device –the Funhaler®- for improving adherence to 
prescribed aerosol treatment in preschool children. 
 
As discussed above, adherence to asthma preventer therapy is important for asthma control 
in adults and older children. There is some evidence suggesting a dose dependent effect of 
inhaled steroids on preschool asthma [37]. Therefore, as improvement in adherence 
increases the cumulative drug dose delivered over time, improved adherence may well lead 
to an improved clinical outcome in preschool children.  
 
Overall, adherence to asthma preventer therapy in children is poor.  The few strategies that 
have been shown to have some beneficial effect on patients’ adherence to prescribed 
treatment require considerable resources but have only modest effect.  Improved outcomes 
are only seen with the most aggressive measures [170].  However, strategies to improve 
adherence to asthma therapy in children have up to now mostly focused on the parents, 
 54
with little attention being paid to the patient.  Although medication is administered by the 
parent in this age group, the importance of parent-child interaction in influencing parental 
behaviour should not be under-estimated.   
 
As oppositional behaviour of preschool children during aerosol drug administration is 
known to adversely affect adherence to prescribed medication, strategies to improve child 
behaviour around the drug delivery process may potentially improve parental adherence to 
their child’s prescribed medication.   
 
As mentioned in the section about spacer technique, the Funhaler® is a small volume 
valved spacer with a spinning disk and whistle on the expiratory arm [152, 153]. The 
function of the spinning disk and whistle combination is to act as an incentive for young 
children to cooperate when their inhaled asthma preventer medication is being 
administered.  In a pilot study [153], parents reported subjectively improved co-operation 
from their children during drug administration when compared with co-operation using 
their previous spacer.  Parents randomised to the Funhaler-group also displayed a more 
positive attitude towards medicating their children.  The pilot study was, however, small (n 
= 30) and only spanned a two week period.  A more recent study [160] investigated 
adherence to prescribed asthma treatment, over a three month period, in  children aged 18 
months to seven years.  Subjects were randomised to using either the Funhaler®, or a 
conventional spacer, the Aerochamber Plus®, for administering their asthma medication.  
Although adherence was higher in the Funhaler-group, the difference in adherence between 
the Funhaler-group and the Aerochamber-group was not statistically significant.  Again, 
this study was small (n = 47) and had may have been underpowered.  
 
The dual concepts of focusing on the child instead of the parent, and using an incentive 
device to improve adherence to prescribed asthma treatment in preschool children, 
therefore merit further investigation.  
 
1.8.6   Important questions regarding adherence to prescribed medication in 
preschool children   
 
Following the above, questions that arise are: 
 55
• Does adherence to therapy correlate with improved asthma control in preschool 
  children, as it does in older children and adults? 
• Can adherence to prescribed treatment in preschool children with asthma be 
influenced by interventional strategies that focus on the child? 
 
….and more specifically….. 
• Would an easy to use incentive device that focuses on the patient and not the parent 
have a beneficial effect on adherence to prescribed treatment in preschool children 
with asthma?  
 
1.8.7 Assessment of adherence to prescribed treatment in asthma 
Various techniques for the measurement of patients’ adherence to prescribed treatment 
have been used.  Methods for measuring adherence described in the literature include: 
patient self report, clinical judgement by the health care provider, monitoring of remaining 
medication, pharmacy records, electronic monitoring of the medication device and 
biochemical measures [83, 157, 196].  These techniques vary substantially in accuracy.  
Direct measures of patient behaviour, such as electronic monitoring, are more accurate than 
indirect measures such as patient diaries, self-report, or clinician’s judgement [157, 163, 
196-198].     
 
The literature reports the use of different devices for the monitoring of inhalation 
medication by pMDI: The Smartmist®, the MDI Chronolog®, the MDILog® which 
evolved from the MDI Chronolog®, the Doser CT®  and the Smartinhaler® [160, 175, 
197, 199-202].  The Smartmist® is a bulky device that encases the pMDI [202].  The Doser 
CT® is a pressure activated device that connects to the top of a pMDI canister [203].  The 
Doser CT® only records the number of daily uses over a period of 45 days [203].  The 
MDI Chronolog® is a microprocessor device built into the sleeve of a pMDI; when it is 
activated by pMDI actuation, it records the date and time of the actuation [163, 199]. A 
limitation of these electronic monitoring devices in research is that the researcher is unable 
to distinguish whether the patient actually received the dose or whether the device was fired 
into the air (dumping) [83].  The MDILog®, currently the most widely used monitoring 
device for inhaled asthma medication, addresses this problem by not only monitoring 
actuation but also components of spacer technique (shaking of the canister, inhaling 
medication, inhalation timing) [175].  The Smartinhaler® is a relatively new device that 
 56
replaces the pMDI actuator/sleeve [161].  The Smartinhaler® contains a microchip that 
records the time and the date of each actuation.  
 
A limitation of using electronic adherence monitoring devices is common to measuring 
devices in general:  use of a measuring device potentially interferes with the patient’s 
medication habits. 
 
1.9 Assessment of asthma control in preschool children 
When investigating the influence of an intervention on asthma control, the perfect outcome 
variable would be an accurate representation of asthma control.  The outcome variable 
should preferably have no relation to diseases that may mimic asthma.  Furthermore, the 
outcome variable should be reproducible and reliable. 
  
1.9.1      Asthma symptoms  
Asthma symptoms can be measured by self-report or by diary card.  Researchers have used 
symptom scores in clinical trials as a measure of both frequency and intensity of respiratory 
symptoms [204, 205].  Recording the number of days without symptoms may be a more 
robust measure of asthma control, as recording the number of days without symptoms may 
lend itself to less subjectivity than the recording of symptom intensity.  Asthma symptoms 
often reported include wheeze, cough and shortness-of-breath [206-208].  To avoid using 
three different outcome variables some studies make use of the variable “symptom free 
days” to report the number of days over a period of time without any of the above 
symptoms [207, 208].  As wheezing is the most common asthma symptom, the use of “days 
without wheeze” may have advantages over using “symptom free days”, as the term 
“symptom free days” is less specific than the term “days without wheeze” and could more 
easily be misinterpreted by patients and parents.  An alternative method of quantifying 
asthma symptoms is to keep track of the frequency of a patient’s asthma reliever use 
(bronchodilator use/ rescue medication) [209]. 
   
A major disadvantage of using self report or diary cards to measure asthma control is that 
both rely on the patient’s interpretation of symptoms and on the patient’s diligence in 
keeping a record of symptoms.   
 57
 
1.9.2        Asthma exacerbations and systemic corticosteroid use 
Asthma exacerbations can be defined as a worsening of a patient’s asthma symptoms that 
requires either a change in medication (other than bronchodilator use) and/or requires visits 
to a general practitioner [37], or hospital emergency department.  The frequency of asthma 
exacerbations may be measured as a marker of asthma control.  Asthma exacerbations can 
be measured by self-report, or hospital records if the exacerbations were severe enough to 
lead to hospital admissions or Emergency Department visits.  Asthma exacerbations are 
treated with systemic steroids and therefore the number of days or the number of times that 
the patient was prescribed systemic steroids could be used as a marker of asthma control.  
 
1.9.3       Lung function measurements 
The measurement of lung function has been used for many years as an objective indicator 
of the severity of pulmonary disease.  Most lung function studies performed in adults 
require patient cooperation.  As preschool children have limited coordination skills and 
limited concentration spans, various techniques for measuring lung function have had to be 
adapted for use in preschool children.  The most common lung function tests used in adults 
for monitoring asthma control are spirometry and peak expiratory flow.   
 
1.9.3.1 Peak expiratory flow 
Peak expiratory flow (PEF) is used in adults as a marker of airway obstruction, however 
PEF is of little value in preschool children [210, 211].  Regular monitoring of PEF does not 
provide additional benefit to daily recording of asthma symptoms and bronchodilator use 
[212].  Data recorded by patients and parents on PEF diaries are unreliable [210].  In 
children, changes in PEF correlate poorly with more accurate measures of lung function 
[213].     
 
1.9.3.2 Forced expiratory flow  
The use of spirometry in preschool children is at this stage limited to specialised research 
centres.  In order to make spirometry feasible in preschool children, specially adapted 
quality control criteria are required [214, 215], and outcome variables different from the 
 58
outcome variables used in adults need to be used [216, 217]; for example, FEV0.5 and 
FEV0.75 are used instead of FEV1.  The use of spirometry in preschool children requires 
highly skilled technicians and the help of incentive devices.  In spite of the spirometry on 
preschool children being performed at highly specialised research laboratories, fewer than 
80% of three to five year olds are able to perform acceptable spirometry [218].  Spirometric 
techniques that require sedation e.g. the tidal rapid compression technique [219, 220] and 
the raised volume rapid thoraco-abdominal compression technique [221] are useful in 
infants, but not practical to perform on preschool children.  
 
1.9.3.3 Plethysmography 
Plethysmographic measurements of airway resistance are being used in preschool children 
to measure baseline lung function and bronchial responsiveness [222-224].  Specific 
resistance, a function of airway resistance and lung volumes, can be calculated by 
measuring changes in air flow relative to changes in plethysmographic volume during 
spontaneous breathing (i.e. breathing against a closed shutter not required).  Data collection 
and quality control for plethysmographic measurements of airway resistance have not yet 
been standardised for use in preschool children. 
 
1.9.3.4 The interrupter technique 
The interrupter technique is another method that can be used for measuring airway 
resistance in preschool children.  The interrupter technique is based on the assumption that 
pressures equalise rapidly throughout the airways during periods of no airflow.  When the 
airway is occluded briefly, pressure at a patient’s mouth will therefore reflect alveolar 
pressure.  Interrupter resistance (Rint) is calculated by dividing the change in mouth 
pressure after occlusion of the airway, by airflow immediately prior to the occlusion.  The 
interrupter technique requires minimal cooperation and is suitable for use in preschool 
children [225, 226].  Reversible airway obstruction in wheezy preschool children has been 
measured successfully using the interrupter technique [227, 228].  In spite of several 
problems with regard to the assumption on which the interrupter technique is based [229], 
the use of Rint shows promise as a method of measuring lung function in preschool 
children.  However, methods for performing the measurement and for reporting the 
technique need to be standardised [225, 229].   
 
 59
1.9.3.5 Exhaled nitric Oxide 
Nitric oxide (NO) is produced by the airway epithelium when L-arginine is converted to L-
citrulline by the enzyme NO synthase [230].  Activity of the calcium independent form of 
nitric oxide synthetase is inducible by certain inflammatory markers.  When detected in 
exhaled air, NO is a marker of airway inflammation [231].  Exhaled nitric oxide (eNO) can 
be measured by an in-line method, where the exhaled gas is analysed in real time, or by an 
off-line method, where the exhaled gas is collected and analysed later.  Guidelines and 
standards for measuring eNO have been published [232].  For preschool children a tidal 
breathing technique has been developed that can be used for both the in-line and the off-
line method [233, 234].      
 
Exhaled NO is raised in asthmatics and in wheezy infants but also in various other 
respiratory conditions [233-239].  Cystic fibrosis is associated with reduced eNO levels and 
primary ciliary dyskinesia is associated with an almost complete absence of eNO [240, 
241].  Exhaled NO levels drop in asthmatics and in wheezy infants when inhaled steroids 
are used [242].    
 
In spite of extensive research done on eNO over many years, evidence that eNO can be 
used as a marker for asthma control is as yet inconclusive and unconvincing [243].  Hence, 
it is unlikely that eNO has a useful role in the regular monitoring of asthma control. 
 
1.9.3.6 Forced oscillation testing 
The forced oscillation technique (FOT) for measuring lung function requires only passive 
cooperation and no coordination, and is therefore suitable to perform on preschool children 
[222, 244, 245].  The FOT that is most commonly used in the preschool age group is 
performed as follows:  Single or multiple frequency oscillations are applied at a patient’s 
mouth using a speaker.  The resulting air flow is measured at the patient’s mouth.  
Respiratory system impedance (Zrs) is calculated using pressure and the resulting flow 
variables.  Respiratory system resistance (Rrs) and reactance (Xrs) can be obtained as a 
function of frequency.  Rrs comprises the pressure-flow relationship of the portion of the 
pressure oscillation that is ‘in phase’ with airflow. Xrs is related to the portion of pressure 
oscillation that is ‘out of phase’ with air flow.  Xrs is related to the elastic forces of the 
respiratory system, and to inertial forces arising from the acceleration of tissue and gas in 
 60
the respiratory system [246].  Both baseline lung function and bronchodilator response are 
measured.    
 
Diagnostic value of FOT:   
Studies investigating the capacity of FOT to discriminate between healthy and asthmatic 
preschool aged children have had conflicting results [247-250]. Reasons for the conflicting 
results in these studies may be related to differences in the study populations, differences in 
methodology or differences in the interpretation of results (Table 4). For example, in 
studies where subjects where classified as asthmatic or healthy by questionnaires [248, 
249], or by doctors in the community [250], the FOT did not discriminate between the 
healthy and the asthmatic subjects.  In the only study where asthma was diagnosed in a 
specialist clinic [247], the baseline and change after bronchodilator in Rrs5 was 
significantly larger, and the Xrs5 significantly smaller, in the asthmatic group when 
compared with the healthy controls.  
 
FOT as a measure of asthma control: 
Nielsen et al (2000) showed that young asthmatic children’s baseline Rrs5 (Rrs at 5 Hz) 
and Xrs5 (Xrs at 5 Hz) improved with inhaled steroids [224].  The use of inhaled steroids 
also reduced the bronchodilator response at Rrs5 and Xrs5 in young children [224]. 
 61
 
 
Asthma Significant 
Difference 
Study Subjects diagnosis bronchodilator 
between Comments 
response healthy and asthmatic 
Hellinckx et al 3 - 6.5 year old  Asthma 30% decrease in No difference in 200μg 
1998 [248] Belgian diagnosed by Rrs10  baseline values 
salbutamol by 
kindergarten questionnaire 40% decrease in or BDR between 
spacer 
 
children Rrs5 healthy and asthmatic 20 min interval 
 
 
Nielsen et al 2.3 - 5.9 year Asthma patients 29% decrease in Baseline Rrs5 500μg 
2000 [224] old children  from teaching Rrs5 and Xrs salbutamol via 
hospital’s significantly metal spacer 
outpatient clinic different 20min interval 
between healthy  
and asthmatic  
children. Also significant 
response to 
BDR for Rrs5 placebo → 
but not Xrs5 ? need for 
significantly blinding 
different 
between 
asthmatic versus 
healthy children. 
Marotta et al 4 year old Asthma 15-20% No difference in 2.5mg albuterol 
2003 [249] children at risk diagnosed by decrease in baseline BUT nebulised 
of asthma questionnaire Rrs10  significant 15 min interval 
20-25% difference in 
decrease in Rrs5 BDR for Rrs5 and Rrs10  
To distinguish 
most asthmatics 
from non-
asthmatics (in 
atopic subjects) 
Thamrin et al 2 - 6 year old Diagnosed by 40% decrease in No difference in 600μg 
2007 [250] general Rrs baseline values salbutamol via 
practitioners in 
the  community 65% increase in 
or BDR between 
Xrs healthy and 
spacer  
asthmatic 15min interval 
Rrs8 and Xrs8 
most reliable 
Table 4.  Previous studies comparing forced oscillation lung function in asthmatics 
versus healthy preschoolers.  Rrs5 = resistance at five hertz; BDR = bronchodilator 
response; Xrs10 = reactance at ten hertz.  
 
A recent study demonstrated that bronchodilator response measured by FOT is strongly 
influenced by baseline lung function.  A 40% fall in Rrs or a 65% increase in Xrs appears 
to be indicative of a significant bronchodilator response (based on limits of agreement, 
taken from 95th percentiles in healthy children).  The clinical significance of bronchodilator 
response measured by FOT has yet to be established.    
 62
 
Reference values for FOT in preschool children have been well documented [251]. Current 
best evidence suggests that, in preschool children, the most reliable indicators of lung 
function measured by FOT are resistance and reactance at eight hertz (Rrs8 and Xrs8) 
[251].   
 
1.9.4        Quality of life measurements 
Clinical indices only weakly correlate with how a chronically ill child functions in 
everyday activities [252].  The World Health Organization defines health as “a state of 
complete physical, mental and social well-being and not merely the absence of disease” 
[253].  In an attempt to address social and mental wellbeing as part of the burden of 
disease, the concept of Health Related Quality of Life (HRQoL) was developed.  Quality of 
life is a distinct component of asthma health status [254].   
 
Several generic measures of QoL have been developed for use in preschool children [255-
258].  The PedsQL, developed by Dr James Varni [259, 260], has been validated as a 
reliable and responsive measure of health related quality of life in children. Advantages of 
the PedsQL include brevity, availability of age appropriate versions and parallel forms for 
child and parent [261].  A disease specific version of the PedsQL has been validated for 
asthma [259].  The PedsQL3.0 Asthma Module® was designed to measure paediatric 
asthma-specific health related quality of life.  The PedsQL has specific questionnaires for 
2-4 year old children and for 5-7 year old children.   
 
A weakness in using QoL questionnaires in children includes low reliability of responses to 
the questionnaires [262].  Most preschool children will not be able to answer a QoL 
questionnaire and a proxy is therefore needed.  Parents, who usually act as proxy for their 
preschool children, may not accurately perceive their child’s quality of life [263, 264].  
However, there is agreement between parents’ and children’s perception of QoL.  Parent 
and child perceptions of QoL agree more  for  observable functioning (e.g. physical 
HRQoL) than for non-observable functioning (e.g. emotional and social HRQoL) [265].  
Proxy and self-report correlation is higher for children with health problems than for 
healthy children [261]. 
 
 63
1.9.5   Conclusions 
All currently available measures of asthma control have unique strengths and weaknesses.   
 
Diary cards measure asthma symptoms.  Wheezing is the most common asthma symptom, 
and the use in diary cards of “days without wheeze” may have advantages over using other 
measures of asthma symptoms.  Diary cards may potentially influence a study participants’ 
behaviour or adherence to prescribed medication.  The use of self report or diary cards to 
measure asthma control could be subjective, and diary card accuracy also depends on a 
patient or caregiver’s diligence.  However, diary cards are widely used in clinical trials as 
the filling in of diary cards depends less on parental recall than history taking at study visits 
would.   
 
Asthma exacerbations are an important negative outcome measure of asthma control.  
However, when the frequency or duration of an asthma exacerbation is used as a measure 
of asthma control, the definition of an asthma exacerbation has to be accurately and well 
defined.  Systemic corticosteroid use is at best an indirect marker of asthma exacerbations.   
 
Lung function testing in preschool children could be used as an objective, albeit indirect 
marker of asthma control.  In preschool children, many different lung function tests are 
available, but the precise role of each technique has not yet been determined. The FOT for 
measuring lung function requires only passive cooperation and no coordination, and is 
therefore suitable to perform on preschool children [222, 244, 245].  Reference values for 
FOT in preschool children have been well documented [251]. Current best evidence 
suggests that, in preschool children, the most reliable indicators of lung function measured 
by FOT are resistance and reactance at eight hertz (Rrs8 and Xrs8).  A disadvantage of 
FOT is that it can only be performed in the laboratory. 
 
QoL evaluation has the potential for measuring the effect of asthma on a patient’s general 
wellbeing, but in the preschool child the accuracy of measurement may be compromised by 
the need for a proxy to fill out the questionnaires on behalf of the child.  The PedsQL has 
been validated as a reliable and responsive measure of health related quality of life in 
children. A disease specific version of the PedsQL has been validated for asthma.  A major 
advantage of the PedsQL, when used in a clinical trial, is its brevity. 
 64
 
As all current measures of asthma control have unique strengths and weaknesses, the use of 
multiple different measures (if resources allow) would improve the sensitivity and 
specificity  in a clinical trial assessing the level of asthma control as an outcome measure in 
a given study population.  Care should also be given to selecting asthma control 
assessments that match the objectives of the planned study. 
  
 65
 
2 CHAPTER TWO:  Designing and validating a novel 
method for effectively recording and simulating 
breathing in patients using pMDI-spacers 
 
2.1 Background 
This chapter describes using a flow chamber for accurately recording patients’ breathing 
while they inhale from a pMDI-spacer.   
 
There are a number of studies where breath traces recorded ex vivo are utilized for the 
simulated estimation of drug delivery [108, 117, 267].  However, recording of ex vivo 
breathing traces for simulation generally involve an alteration to the patient-device 
interface.  This chapter describes a method of assessing the influence of breathing on drug 
delivery by pMDI-spacers, which allows for the recording of breathing patterns while 
subjects are using the inhalation device tested, without addition of a measuring device, 
adaptor or filter to the patient-delivery device interface.  In previous breathing simulation 
studies where recorded human breathing patterns were simulated, breathing patterns were 
either recorded separately (i.e. while subjects were not inhaling through the device being 
tested [108, 117], or pneumotachometers and/or filters were inserted between the subjects 
and the delivery device when breathing was recorded [267].  The methodology described in 
this chapter was designed to accurately record and simulate breathing of patients when they 
inhale medication/placebo from spacers. The methodology served two purposes: (1) we 
were able to record both inspiration and expiration using a single pneumotachometer, and 
(2) we eliminated the increase in dead space and resistance that would have inevitably 
occurred if both a filter and a pneumotachograph were placed between the spacer and the 
subject. Hence, the methodology allowed for breathing recording without changing the 
physical interface between the spacer and the subject.   
 
The rationale for developing the above methodology was that subjects’ breathing could 
potentially be significantly influenced by the medication delivery process, and metered (or 
 66
bolus) drug delivery via pMDI-spacer could potentially be very sensitive to small changes 
in breathing pattern (in contrast to continuous drug delivery via nebuliser).   
The methodology validated in this chapter was used in the following chapter to determine 
the number of tidal breaths required to effectively inhale medication from different types of 
spacer devices, and to determine the efficacy of a single maximal inhalation for drug 
delivery in preschool children. 
 
2.2 Methods 
Study design 
Materials and Methods: 
 
Initially, tidal breathing traces were recorded from healthy adult subjects through a range of 
pMDI-spacers placed within a sealed flow chamber.  Ex vivo drug delivery was measured 
simultaneously by placing an inspiratory filter between the spacer mouthpiece and the 
patient’s mouth. 
 
In vitro drug delivery measurements using salbutamol (Ventolin, GlaxoSmithKline, 
Melbourne, Australia) were then carried out using a flow-volume simulator (Series 1120, 
Hans Rudolph, Kansa, USA) to replicate the ex vivo traces. A paired comparison of ex vivo/ 
in vitro drug delivery was then performed in order to compare the accuracy of the drug 
delivery measurements obtained from the flow volume simulator. 
 
Three configurations were used (described below, p.67) for the ex vivo recording and in 
vitro simulation, in order to validate different aspects of the flow chamber 
recording/simulation method for drug delivery estimation. 
 
Recording of ex vivo breathing traces 
 
Tidal breathing traces (configuration 1: n=43; configuration 2: n=14; configuration 3: 
n=12) through different spacers were recorded from two healthy, non-smoking adult male 
subjects, aged 25 and 28 years.  Subjects were “coached” in order to obtain a series of 
traces over a wide range of inspiratory flows and volumes (Tables 5 and 6). Subjects were 
 67
asked to take five slow breaths through the spacer after each actuation of the pMDI.  After 
each filter study, subjects were asked to increase or decrease their inhalation volumes, until 
a large range of filter doses (see below) were obtained.  As the aim of this study was to test 
the accuracy of the flow volume simulator in estimating ex vivo drug delivery over a wide 
range of breathing patterns, “coaching” the subjects was necessary in order to obtain a large 
range of breathing patterns.  Ethics approval was obtained from the ethics committee of 
Princess Margaret Hospital for Children, and the Telethon Institute for Child Health 
Research (1026/EP), and from the ethics committee of the University of the Free State 
(ETOVS 67/07).  
 68
 
 
Mean Mean peak  Mean Mean peak 
Spacer inhalation inspiratory Spacer inhalation inspiratory volume in flow in volume in flow in 
ml (SD) LPM (SD) ml (SD) LPM (SD) 
47 (14) 7 (2) 48 (26) 6 (3) 
65 (29) 10 (4) 56 (32) 7 (4) 
68 (11) 9 (4) 82 (24) 10 (2) 
70 (42) 8 (4) 98 (9) 9 (1) 
159 (37) 19 (4) 126 (20) 10 (2) 
159 (49) 15 (6) 217 (37) 15 (2) 
162 (62) 24 (8) 276 (44) 24 (2) 
235 (64) 22 (5) 322 (66) 20 (3) 
24 (5) 3 (1) 423 (68) 33 (5) 
61 (29) 7 (3) 438 (59) 25 (2) 
78 (30) 8 (2) 499 (38) 32 (9) 
97 (25) 9 (2) 572 (87) 30 (19) 
374 (112) 22 (4) 593 (96) 34 (5) 
410 (127) 22 (5) 673 (155) 40 (6) 
535 (118) 28 (7) 758 (83) 39 (5) 
548 (104) 33 (5) 952 (147) 43 (6) 
40 (13) 6 (2) 985 (163) 55 (3) 
48 (20)  6 (2)  
56 (30) 7 (3) 
137 (29) 11 (2) 
254 (114) 22 (8) 
404 (87) 28 (5) 
428 (47) 30 (4) 
512 (173) 31 (9) 
587 (70) 34 (3) 
762 (105) 48 (4) 
 
Table 5.  Average inhalation volumes and average peak inspiratory flows for each set 
of five breathing patterns recorded and simulated in Configuration One. 
 69
Modified soft drink bottle Funhaler Aerochamber Plus 
   
Volumatic 
 
 
Recording Mean inhalation volume Mean peak inspiratory flow 
Nr  in ml (SD) in LPM (SD) 
1 24 (16) 7 (3) 
2 38 (18) 16 (7) 
3 39 (15) 12 (5) 
4 91 (48) 18 (8) 
5 93 (35) 20 (8) 
6 121 (38) 13 (5) 
7 222 (39) 34 (5) 
8 241 (77) 39 (10) 
9 243 (96) 20 (6) 
10 337 (160) 27 (12) 
*11 751 (150) 47 (11) 
12 857 (174) 52 (8) 
13 880 (320) 34 (11) 
*14 1237 (287) 69 (18) 
 
Table 6.  Average inhalation volumes and average peak inspiratory flows for each set 
of five breathing patterns recorded and simulated in Configuration Two and Three.  
*recordings 11 and 14 only simulated in Configuration Two. 
 
 
In order to record the ex vivo breathing traces, the spacers were placed in transparent 
Perspex flow chambers, custom-built to hold each respective spacer with an attached pMDI 
(Figure 2).  Each flow chamber was constructed to completely enclose the spacer, apart 
from the mouthpiece, within a minimum volume (Table 7). 
 
 
 
 70
 
 
Figure 2.  Flow chamber used to record breathing. 
 
 
 
 Aerochamber Funhaler Volumatic Modified soft 
Plus drink bottle 
Length (cm) 19 23.5 28 25.5 
Height (cm) 15 18 17 14.5 
Width (cm) 7 8 12 8.5 
Table 7.  Dimensions of flow chambers used to record breathing using different spacer 
devices.   
 
 
Five sides of the flow chamber were constructed to form an airtight seal. The sixth side 
could be removed in order to place a clean pMDI and spacer inside but was sealed in place 
while each experiment was conducted.  A special fitting on the floor of the chamber held 
the back of the spacer and the pMDI sleeve in position.  The mouthpiece of the spacer 
protruded through an opening in the front of the flow chamber, while the exhalation 
valve(s) were contained within the chamber.  The interface between the front part of the 
spacer and the flow chamber was sealed with high viscosity putty.  A rubber washer served 
to maintain the seal when certain spacers were used. 
 
After inserting the spacer and pMDI, the ‘door’ (or back wall) of the flow chamber was 
secured with four elastic clips that were mounted on the back of the door.  The elastic clips 
were secured over four corresponding mounts on the lateral walls of the flow chamber.  
 71
The pMDI was actuated by hand via an air tight rubber actuation port at the back of the air 
tight flow chamber.  The flow chamber was air tight except for an opening in the roof 
(2.5cm in diameter) and an opening on the side (0.5cm in diameter). The opening in the 
side of the flow chamber was connected to tubing to allow a bias flow of medical air. The 
bias flow was introduced in order to prevent carbon dioxide build-up from exhaled air in 
the flow chamber.  As the bias flow of medical air was constant, all the air inhaled and 
exhaled through the spacer passed through the pneumotachometer which was positioned at 
the top of the flow chamber (Figure 2).   
 
Airflow was recorded with a 0-100 LPM pneumotachometer (Model RRS 100-HR, Hans 
Rudolph, Kansas, USA) which records flow at 50Hz.  Inhalation volumes for each breath of 
the recorded breathing patterns (RSS files) were calculated by integration of the digital 
flow signal (i.e. calculating the area under the curve of the flow-time trace). 
 
Configuration of the pneumotachometer and/ or flow chamber 
Three different configurations were used.  For each configuration, drug “inhaled” from a 
specific spacer was captured on a filter (Uni-filter Junior, GE Healthcare, Waukesha, USA) 
with a dead space of 20ml that was interposed between the spacer and either the human 
subject (ex vivo), or the flow volume simulator (in vitro).  The configurations differed in the 
positioning of the pneumotachometer and filter, or whether the flow chamber was used 
when breathing was recorded or simulated.  Filters were used for validation purposes only. 
 
Configuration One:     
This configuration was used to validate the accuracy of the breathing simulator, by 
comparing ex vivo to in vitro drug dose delivered to filter (Figure 3). Breathing was 
recorded by a pneumotachometer that was placed directly between a human subject and a 
pMDI-spacer combination.  An additional filter was placed between the human subject and 
the pneumotachometer for infection control purposes.  Breathing was simulated in an 
identical set-up, where the human subject was substituted by a breathing simulator. Filter 
studies were carried out with four different spacers: the 149ml Aerochamber Plus® 
(Trudell, London, Canada) (valved), the 225ml Funhaler® (Visiomed, Perth, Australia) 
(valved), the 750ml Volumatic® (GlaxoSmithKline, Melbourne, Australia) (valved) and a 
modified 500ml plastic soft-drink bottle (unvalved). The characteristics of the breathing 
patterns recorded and simulated in this configuration are described in table 5. Inhalation 
 72
volumes tested ranged from 26 to 1030ml.  The peak inspiratory flow of the breathing 
patterns ranged from 2.9 to 57.1 LPM.    
 
 
Figure 3.  Configuration 1. 
 73
 
 
 
Legend.  Figures 3 to 5. 
 
Configuration Two:   
This specific equipment configuration (Figure 4) was used to focus on the accuracy of the 
flow-chamber as a measuring instrument by comparing ex vivo to in vitro drug dose 
delivered to filter.  The flow-chamber was used to record breathing where the human 
subject was breathing through the spacer (Aerochamber Plus®).  An identical set-up was 
used when the breathing simulator was used to replace the human subject.  The 
characteristics of the recorded ex vivo breathing patterns are presented in Table 6. 
 
 
Figure 4.  Configuration 2. 
 
 74
 
Configuration Three:   
This configuration (Figure 5) was used in order to validate the equipment set-up for use in 
Chapter Three.  As for the previous configurations ex vivo drug dose was compared to in 
vitro drug dose delivered to filter. A flow chamber was used to record breathing in the 
human subject, but was not used during simulation. The Aerochamber Plus® was used in 
this configuration.  The characteristics of the recorded ex vivo breathing patterns are 
presented in Table 6. 
 
 
Figure 5.  Configuration 3. 
 
In vitro replication of breathing traces 
The recorded breathing patterns were stored in RSS file format.  The RSS-files were 
transferred to a flow-volume simulator by custom Hans Rudolph (Hans Rudolph, Kansas, 
USA) waveform converter software. The waveform converter software was used to 
digitally remove the bias flow that was introduced during the recording process before the 
breathing patterns were transferred to the breathing simulator in binary file format.  An 
example of a recorded breathing trace is illustrated in Figure 6.  
 
 75
 
Figure 6.  Example of a breathing pattern recorded and simulated.  Flow (LPM) on 
the Y-axis is plotted against time (s) on the X-axis. 
 
 
Ex vivo  and in vitro drug delivery measurements 
Drug delivery measurements using low resistance inspiratory filters (Uni-filter Junior, GE 
Healthcare, Waukesha, USA) with a dead space of 20ml were used to ensure that the 
equipment and technique, as described above, could be used to accurately record and 
simulate breathing.    
 
Spacers were prewashed in a mild detergent and left to drip-dry before use in order to 
eliminate electrostatic build-up. pMDIs were shaken and waste-actuated 10 times before 
each experiment.   
 
A pMDI was shaken and actuated once into the spacer.  Subjects then took five tidal 
breaths through the spacer, commencing immediately after actuation. This entire procedure 
was repeated five times per filter to ensure that a quantifiable drug dose was collected, 
while the subjects’ breathing was recorded simultaneously.  Salbutamol deposited on the 
actuator, spacer and inspiratory filter, was then measured as described below.   
 
For the in vitro drug delivery measurements, the five breathing traces recorded previously 
for each ex vivo filter study were simulated individually, with one pMDI actuation per five 
 76
tidal breath trace.  The in vitro set-up and procedure was identical to that used for the ex 
vivo filters, except that the human subject was replaced by the breathing simulator.   
 
Drug analysis 
 
Filters, spacers and pMDI-actuators were disassembled.  Salbutamol deposited on each part 
was eluted individually, using a methanol/water solution (90% HPLC-grade methanol/ 10% 
double deionised water) containing 0.01M NaOH.  The absorbance of each sample was 
measured at a wavelength of 246 nm, in duplicate, using an ultraviolet spectrophotometer 
(UV-1601; Shimadzu Scientific Corporation, Kyoto, Japan).  The absorbance of a series of 
reference standards (Salbutamol hemisulphate, Sigma-Aldrich, Sydney, Australia) over the 
concentration range 0.2-20 µg/ml were tested with each batch of samples, and found to be 
linear (r2 > 0.998). 
 
The recovery of a known amount of salbutamol from inspiratory filters using this method, 
has previously been tested and found to be 98.2% (SD 4.9; n=6)[266]. 
 
Data analysis 
 
Drug delivery to inspiratory filters is presented as a proportion of the dose recovered from 
the pMDI actuator, spacer and filter.  Comparison between drug dose on filter as “inhaled” 
by subjects compared to drug dose “inhaled” by breathing simulator was done using 
regression analysis and Bland-Altman plots.  
 
In the scatter plots, in vitro filter dose on the Y-axis was plotted against ex vivo dose on the 
X-axis.   In the Bland-Altman curves the difference between in vitro filter dose and  ex vivo 
filter dose on the Y-axis was plotted against the mean difference (ex vivo filter dose + in 
vitro filter dose)/2 on the X-axis.  Filter dose recovered was analysed as percentage of total 
dose recovered. 
 
 
 
 77
2.3 Results 
 
In each of the three different configurations and with each spacer, the matching ex vivo and 
in vitro inspiratory filter doses were comparable.   
 
Configuration One 
 
Filter dose recovered was comparable between the ex vivo and the in vitro techniques 
(Figure 7).  Ex vivo filter dose recovered ranged from 3.5 to 59.5% of total dose recovered.  
In vitro filter dose recovered ranged from 8.9 to 60.7% of total dose recovered.  The 
median difference between ex vivo and in vitro filter doses recovered (for all spacers) was 
0.4% (range -12.2% to 6.9%).  With the Aerochamber Plus, there was a tendency for in 
vitro dose delivery to overestimate drug delivery but the overestimation did not exceed 
6.9% of total dose recovered.  With the Volumatic there was a tendency for in vitro filter 
dose to be slightly lower (median difference -3.9%) than ex vivo filter dose for doses 
smaller than 30% of total dose recovered.  Conversely, with the Volumatic in vitro filter 
doses were slightly higher (median difference 2.6%) than ex vivo filter doses for doses 
larger than 40% of total dose recovered.  
 
 
 
 78
 
Figure 7.  Configuration 1:  Bland-Altman plot demonstrating difference between ex 
vivo and in vitro drug delivery for 5 tidal breaths plotted against mean drug delivery. 
Drug delivery represented as percentage of total dose recovered from filter, actuator 
and spacer.   
 
There was a strong correlation between ex vivo and in vitro filter doses, for all spacers 
tested,  R2  = 0.75, p = 0.01; R2 = 0.76, p = 0.05; R2 = 0.95, p < 0.01; and R2 = 0.87, p < 
0.01 for the Aerochamber Plus®, Funhaler®, Volumatic® and modified soft drink bottle, 
respectively (Figure 8).   
 
Mean inhalation volumes of subjects inhaling through the different spacers ranged between 
47-235ml for the Aerochamber Plus®, 24-548ml for the Funhaler®, 48-985ml for the 
Volumatic®, and 40-762ml for the modified soft drink bottle.   Mean peak inspiratory 
flows ranged between 6.6-21.7 LPM for the Aerochamber Plus®, 3.2-32.5 LPM for the 
Funhaler®, 5.6-55.3 LPM for the Volumatic®, and 5.6-47.7 LPM for the modified soft 
drink bottle.  For all spacers, for all breathing patterns tested in vitro drug delivery 
corresponded with ex vivo drug delivery (Figures 7 and 8). 
 
 79
 
Figure 8.  Configuration 1.  Correlation between ex vivo filter dose and in vitro filter 
dose.  Drug delivery represented as percentage of total dose recovered from filter, 
actuator and spacer.   
 
 
 
 
 
 
 
 80
 
Configuration Two 
 
Filter dose recovered was comparable between the ex vivo and the in vitro techniques 
(Figure 9).   Ex vivo filter dose recovered ranged from 19.2 to 49.3% of total dose 
recovered.  In vitro filter dose recovered ranged from 22.3 to 50.7% of total dose recovered.  
Ex vivo filter doses correlated well with in vitro filter doses (R2 = 0.87, p < 0.01)).  The 
median difference between ex vivo and in vitro filter doses recovered was -2.3% (range -
9.0% to 5.0%).   
 
 
Figure 9.  Configuration 2 & 3:  Bland-Altman plot demonstrating difference between 
ex vivo and in vitro drug delivery for 5 tidal breaths plotted against mean drug 
delivery.  Drug delivery represented as percentage of total dose recovered.  
Configuration 2 – closed triangles; Configuration 3 – open triangles. Spacer = 
Aerochamber Plus® 
 
 81
Configuration Three   
 
Filter dose recovered was comparable between the ex vivo and the in vitro techniques 
(Figure 9).  Ex vivo filter dose recovered ranged from 19.2 to 46.1% of total dose 
recovered.  In vitro filter dose recovered ranged from 18.5 to 49.1% of total dose recovered.  
Ex vivo filter doses correlated well with in vitro filter doses (R2 = 0.79, p < 0.01)).  The 
median difference between ex vivo and in vitro filter doses recovered was 1.7% (range -
11.5% to 3.9%).   
 
Correlation between inhalation volume and inspiratory flow 
Subjects inhaled faster as they took larger breaths, and vice versa.  For each set of breathing 
patterns, mean peak inspiratory flow increased as mean inhalation volume increased.  For 
all spacers, the increase in peak inspiratory flow was directly proportional to the increase in 
inhalation volume, with R2 = 0.82, p < 0.01; R2 = 0.98, p < 0.01; R2 = 0.94; p < 0.01 and R2 
= 0.98, p < 0.01, respectively for the Aerochamber Plus®, Funhaler®, Volumatic® and 
modified soft drink bottle in Configuration 1, and R2 = 0.80, p < 0.01 for the Aerochamber 
Plus® used in Configuration 2 and 3 (Figures 10 and 11).  
 
Aerochamber Plus Funhaler
30.0 40.0
20.0 30.0
20.0
10.0 10.0
0.0 0.0
0 100 200 300 0 200 400 600
Mean inhalation volume (ml) Mean inhalation volume (ml)
Volumatic Modified soft drink bottle
60.0 60.0
40.0 40.0
20.0 20.0
0.0 0.0
0 500 1000 0 200 400 600 800
Mean inhalation volume (ml) Mean inhalation volume (ml)
 
Figure 10.  Configuration 1.  Correlation between tidal volume and peak inspiratory 
flow in breathing patterns recorded and simulated.  Mean peak inspiratory flow 
plotted against the mean inhalation volume for each set five of breathing patterns. 
 82
Mean peak Mean peak 
inspiratory flow inspiratory flow
(LPM) (LPM)
Mean peak Mean peak 
inspiratory flow inspiratory flow
(LPM) (LPM)
 
Configuration 2 & 3: Aerochamber Plus
80.0
60.0
40.0
20.0
0.0
0 500 1000 1500
Mean inhalation volume (ml)
 
 
Figure 11.  Configuration 2 & 3.  Correlation between tidal volume and peak 
inspiratory flow in breathing patterns recorded and simulated.  Mean peak 
inspiratory flow plotted against the mean inhalation volume for each set five of 
breathing patterns.  Spacer = Aerochamber Plus®. 
 
 
Influence of tidal volume and inspiratory flow on drug delivery  
 
With all three configurations, drug delivery was related to inhalation volume and flow.  
Due to the strong correlation between mean inhalation volume and mean peak inspiratory 
flow, the precise influence of each individual parameter could not be ascertained.   
 
Drug delivery increased with an increase in inhalation volume and flow, to reach a plateau 
at inhalation volumes of approximately 250ml with the Aerochamber Plus®, between 100 
and 400ml with the Funhaler®, approximately 400ml with the Volumatic®, and between 
400ml and 500ml with the modified soft drink bottle (Figure 12 and 13).  The plateau in 
drug delivery occurred at approximately 30LPM with all spacers, with less of a plateau 
seen with the modified soft drink bottle (Figures 14 and 15).   
 83
Mean peak inspiratory 
flow (LPM)  
 
Aerochamber Plus Funhaler
70 70
60 60
50 50
40 40
30 30
20 20
10 10
0 0
0 100 200 300 0 100 200 300 400 500 600
Mean inhalation volume (ml) Mean inhalation volume (ml)
Volumatic Modified soft drink bottle
70 70
60 60
50 50
40 40
30 30
20 20
10 10
0 0
0 200 400 600 800 1000 0 100 200 300 400 500 600 700 800 900
Mean inhalation volume (ml) Mean inhalation volume (ml)
 
Figure 12.  Configuration 1.  Drug delivery (ex vivo filter dose as percentage of total 
drug dose recovered) plotted against mean inhalation volume for different spacers.   
 
Configuration 2 Configuration 3
60.0 60.0
50.0 50.0
40.0 40.0
30.0 30.0
20.0 20.0
10.0 10.0
0.0 0.0
0 500 1000 1500 0 500 1000 1500
Mean inhalation volume (ml) Mean inhalation volume (ml)
 
Figure 13.  Configuration 2 & 3.  Drug delivery (ex vivo filter dose as percentage of 
total drug dose recovered) plotted against mean inhalation volume for different 
spacers.  Spacer = Aerochamber Plus®. 
 84
Filter dose ( Ex vivo) Filter dose (ex vivo) Filter dose (ex vivo)
Filter dose ( Ex vivo) Filter dose (ex vivo) Filter dose (ex vivo)
Aerochamber Funhaler
70 70
60 60
50 50
40 40
30 30
20 20
10 10
0 0
0 10 20 30 0 10 20 30 40
Mean peak inspiratory flow (LPM) Mean peak inspiratory flow (LPM)
Volumatic Modified soft drink bottle
70 70
60 60
50 50
40 40
30 30
20 20
10 10
0 0
0 10 20 30 40 50 60 0 10 20 30 40 50 60
Mean peak inspiratory flow (LPM) Mean peak inspiratory flow (LPM)
 
Figure 14.  Configuration 1.  Drug delivery (Ex vivo filter dose as percentage of total 
drug dose recovered) plotted against mean peak inspiratory flow of each 
corresponding set of breathing patterns. 
 
Configuration 2 & 3
60.0
50.0
40.0
30.0
20.0
10.0
0.0
0 10 20 30 40 50 60 70
Peak inspiratory flow (LPM)
 
Figure 15.  Configuration 2 & 3.  Drug delivery (Ex vivo filter dose as percentage of 
total drug dose recovered) plotted against mean peak inspiratory flow of each 
corresponding set of breathing patterns.  Spacer = Aerochamber Plus®. 
 85
Filter dose (ex vivo) Filter dose ( ex vivo ) Filter dose ( ex vivo )
Filter dose ( ex vivo Filter dose ( ex vivo )
 
 
2.4 Discussion 
 
Data from Configuration One provided evidence that the simulated breathing patterns were 
satisfactorily in approximation to those of the subjects.  
 
The flow-chamber was validated as a sufficiently precise method for recording breathing in 
configuration two:  The recorded (and then simulated) breathing patterns had a similar 
effect on drug delivery as the human subjects’ breathing.   
 
Breathing simulation without using a flow chamber during breathing simulation was 
validated in configuration three:  Drug delivery with a subject inhaling from a spacer 
placed in a flow-chamber corresponded to drug delivery with a breathing simulator without 
the use of a flow chamber.  The correlation between ex vivo and in vitro filter doses in 
configuration 3 (R2 = 0.79) was comparable to the correlation between ex vivo and in vitro 
filter doses in configuration 1 (Aerochamber Plus®) and configuration 2 (R2 = 0.75 and 
0.87, respectively).   
 
Although spacers are mostly prescribed for use in children and patients with coordination 
problems, in this thesis we made use of two healthy adult male subjects for breathing 
recording and drug delivery studies.  As the aim of this study was to test the accuracy of 
our flow-chambers in recording breathing, and the accuracy of flow volume simulator in 
estimating ex vivo drug delivery over a wide range of breathing patterns, “coaching” the 
subjects was necessary in order to obtain a large range of breathing patterns.  Similar 
“coaching” would not have been possible in young children or in subjects with coordination 
problems. As output through pMDI-spacer is known to be sensitive to changes in breathing 
pattern, and slow inhalation is preferable to fast inhalation [114, 137], subjects were 
directed to inhale slowly during all recordings, and subjects were encouraged to vary their 
inhalation volume between different sets of recordings.   Although subjects were directed to 
breathe slowly at all times, and only vary their inhalation volume, both subjects appeared to 
have unconsciously increased their rate of inhalation as they increased their inhalation 
volumes (and vice versa).  The nature of the study (validation of methodology with subjects 
 86
voluntarily changing their breathing patterns), prevented a systematic and exhaustive study 
of the influence of all inhalation parameters on drug delivery.  These data should therefore 
not be used to definitively compare the efficacy of the spacers used. 
 
Our data demonstrated that drug delivery through spacer was related to inhalation volume 
and flow.  Drug delivery reached a plateau at lower inhalation volumes with the lowest 
volume spacer (Aerochamber Plus®).  Previous studies also described inhalation volume 
dependence of drug delivery through spacers [69, 74, 115].  In a study by Barry and 
O’Callaghan (1999) where sinusoidal breathing patterns were used to determine 
budesonide delivery through a 145ml Aerochamber (earlier version of Aerochamber Plus) 
at various tidal volumes [115], drug delivery continued to increase at inhalation volumes 
exceeding 200ml.  The inspiratory flows used by Barry and O’Callaghan were lower that 
the mean peak inspiratory flows where drug delivery started to plateau in this thesis.   
 
With all three valved spacers used, increased drug delivery was found with increased 
inspiratory flows up to 30LPM.  As a plateau in drug delivery was seen with peak 
inspiratory flows above 30LPM, a limiting effect of higher flows on drug delivery could 
not be excluded by the data.  In a previous study Wildhaber et al (1996) did not 
demonstrate decreased drug delivery at higher flows through two valved spacers, when 
salbutamol delivery was studied at constant flows of 10, 30, and 60LPM [58].  Similarly, 
Dalby et al (1998) demonstrated an increase in drug delivery through valved spacers as 
constant inspiratory flow was increased from 28LPM to 55LPM [268]. The constant 
inspiratory flow used by both Wildhaber et al and Dalby et al is a possible reason for the 
seemingly disconsonant findings between their findings and the findings reported in this 
chapter.  In a study using simulated breathing, Janssens et al (2004) demonstrated  an 
increase in upper airway deposition and a decrease in “lung dose” as respiratory rates 
increased, but total spacer output did not decrease as respiratory rates increased [69].  
However, the inspiratory flows in Janssens el al’s study were lower than 30LPM.  As 
mentioned above, the strong correlation between peak inspiratory flows and inhalation 
volumes described in this chapter excluded an accurate distinction between the respective 
influences on drug delivery of inhalation volumes and inspiratory flows.   
 
With the Volumatic®, drug delivery reaching a plateau when inhalation volume reached 
only approximately half of the spacer volume, may have been partly caused by a large part 
of the actuated dose being concentrated in the front part of the spacer, in the first fraction of 
 87
a second post actuation.  Time could also have influenced drug delivery, i.e. drug starts to 
settle out within the spacer if it takes too long to achieve the required volume to clear the 
spacer [113].   
 
Spacers can be used with or without facemasks.  Facemask use with spacer devices is 
usually recommended for adults with coordination problems and children under the age of 
four years [269].  The 2008 British Thoracic Society asthma guidelines [270] acknowledges 
that “in young (0-5 years) children, little or no evidence is available on which to base 
recommendations”.  At our hospital children are often trained to use spacer mouthpieces 
from the age of two.  This thesis was therefore confined to testing spacer use without 
facemasks.  If a spacer with a facemask was to be tested, a face model would have to be 
incorporated in the set-up as has been done previously in breathing simulation studies [72, 
108, 117, 271, 272]. 
 
The study described above was limited to measuring total dose delivery (to a patient’s 
mouth, before being inhaled or deposited onto the oropharyngeal surface).  If drug was to 
be inhaled in vivo, the percentage of drug that potentially would have impacted on the 
pharynx and upper airways would be expected to increase at higher inspiratory flows [114].   
 
The methodology described above could potentially be used for the following: 
• To measure and simulate breathing patterns in specific patient groups, using 
specific inhalation devices, particularly in patient groups where it would be 
difficult to perform in vivo studies i.e. preschool children.  
•  To perform multiple comparisons of different inhaler devices.  Once a database of 
breath recordings from different patient groups has been accumulated, the 
methodology described could be used to measure the influence of various external- 
or device related factors on breathing patterns, and subsequent drug delivery. 
• To screen a wide variety of different inhalers/ spacers for specific populations, to 
eliminate sub-optimal devices, in order to then proceed to in vivo testing with the 
most optimal devices. 
 
Conclusion: 
A method using breathing simulation for assessing the influence of breathing on drug 
delivery via spacer, where the simulated breathing can be recorded on subjects while they 
 88
are using spacers, with minimum increase in dead space or resistance, and no physical 
alteration in the patient-device interface, was validated. 
 
The results also demonstrate that drug delivery via spacer is a function of inhalation 
volume and flow.    
 89
 
3 CHAPTER THREE:  Determining the minimum 
number of breaths and type of breathing required for 
effective drug delivery through pMDI-spacers 
 
3.1 Background 
Wheezing disorders are more common in young children [273, 274] than in any other age.  
Medication for these children is most commonly inhaled from valved spacer devices.  Yet, 
how best to inhale from spacers is unknown for this age group and international guidelines 
lack uniformity and are mostly based on personal opinion [142, 143, 275].     
 
This chapter describes a study that was designed to determine the relationship between the 
number of tidal breaths (and single maximal breath) and drug output from various pMDI-
spacer combinations, .   Based on technical data on in vitro spacer performance [74] and 
knowledge of tidal flow patterns in young children [68] we hypothesised that a number of 
breaths limited in relation to the size of the spacer would be sufficient for efficient drug 
inhalation via spacer in preschool children. 
 
3.2 Aims and hypothesis 
Aims:  To determine the number of tidal breaths required to effectively inhale medication 
from different types of spacer/valved holding chamber devices, and to determine the 
efficacy of a single maximal inhalation for drug delivery in young children. 
Hypothesis:  Based on technical data on in vitro spacer performance [74] and knowledge of 
tidal flow patterns in young children [68], a number of breaths limited in relation to the size 
of the spacer would be sufficient for drug inhalation via the spacer in preschool children. 
 90
 
3.3 Methods 
Breathing was recorded in preschool children inhaling placebo from spacers.   The recorded 
breathing patterns were simulated to determine the minimum number of breaths and type of 
breathing required for effective drug delivery through pMDI-spacers. 
 
Study participants 
This study was performed as a sub-study from a 12 month clinical trial which compared 
two valved spacer devices, the Funhaler® and the Aerochamber Plus®, in two- to six-year 
old children.  Inclusion criteria for the clinical trial were that asthma had been diagnosed by 
a doctor in the community and that subjects were receiving inhaled steroids for treatment of 
their asthma.  Ethics approval was obtained from the ethics committee of Princess Margaret 
Hospital for Children, and the Telethon Institute for Child Health Research (933/EP, and 
1026/EP), and from the ethics committee of the University of the Free State (ETOVS 
67/07).  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 using local advertisements, flyers and from the Emergency Department and 
clinics at Princess Margaret Hospital for Children.   
 
Three separate groups where investigated.  The first group was recruited at the beginning of 
the clinical trial where tidal breathing was recorded and simulated in 34 subjects, aged 
(median (range) 55 (25-84) months; 20 male and 14 female, using either an Aerochamber 
Plus® or a Funhaler®.  In this subgroup, drug delivery with two tidal breaths was 
compared with drug delivery with nine tidal breaths.  Subjects used the spacers 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 
manoeuvre.   
The second group was investigated at the end of the year long clinical trial when 84 
children (age range 34 - 109 months) where screened for their ability to perform a single 
maximal inhalation.   
 
The third group was selected to compare tidal with single maximal breaths; it was a 
subgroup of subjects from the above two groups (seen at the end of the main clinical trial) 
 91
and included the first two subjects from each year of age who could perform a single 
maximal breath. Both tidal breathing and single maximal breathing patterns were recorded 
from these children (n= 10, aged median (range) 59 (41 - 73) months) and simulated using 
4 different spacers in a pseudo-randomised order.  As tidal breathing with small volume 
spacers had already been investigated in subgroup one, single maximal breath was 
compared with nine tidal breaths for small volume spacers in this subgroup.  Two, three, 
five and nine tidal breaths and single maximal inhalation was investigated for the large 
volume Volumatic spacer in this subgroup whereas only two, five and nine tidal breaths 
and single maximal inhalation was investigated for the smaller, unvalved, modified soft 
drink bottle.  The recorded breathing patterns in this group were digitally analysed to 
calculate, for each subject and for every different spacer used, the mean inhalation volume 
of nine tidal breaths and the volume of each single maximal inhalation.   
All subjects were weighed before breathing was recorded in order to estimate predicted 
tidal volume based on a predicted tidal volume of weight (kg) x 7ml [149]. 
 
Breathing 
Subjects recruited from clinical trial Spacers patterns 
recorded 
Beginning of 
clinical trial  
First 34 subjects (out of possible 132) Aerochamber 2 and 9 tidal 
Subjects aged 
on whom adequate breathing traces Plus® and breaths two to six 
were recorded 
years old Funhaler®  
 
One year later:  Aerochamber 
SMI and 9 tidal 
last visit of Ability Plus® and 
breaths 
clinical trial to Funhaler® 
perform First two subjects from 
 SMI SMI and 2, 3, 5, each year group on whom Volumatic® 
 evaluated and 9 tidal breaths both SMI and tidal 
and breathing was recorded (n 
breathing = 10) Modified soft drink SMI and 2, 5, and 
recorded 
bottle 9 tidal breaths 
on 84 
subjects 
Table 8.  Basic outline of protocol. 
 92
 
Technique used for recording and simulating breathing 
A custom built device was needed to accurately record breathing patterns in children 
inhaling from spacers.  The device was designed to allow breathing to be recorded without 
changing dead space, resistance, or mouthpiece if the pMDI-spacers.  The technique used 
for recording and simulating breathing is described in detail above.   
 
Breathing was recorded in children while they were inhaling placebo (GlaxoSmithKline, 
Australia) from different spacers.  The recorded tidal breathing patterns were digitally 
analysed to isolate different numbers of breaths.  All breathing patterns were then 
individually transferred to a breathing simulator (Hans Rudolph, Kansas, USA).  A filter 
was interposed between the breathing simulator and a spacer device that was connected to a 
salbutamol (Ventolin; GlaxoSmithKline, Australia) pMDI.  Immediately after actuation of 
the pMDI simulation of the recorded breathing patterns commenced.  Simulated drug 
delivery was measured using the same spacer type that was used during the ex vivo 
recording of breathing patterns.  Simulated breathing patterns matched those recorded with 
the relevant spacer.  
 
Spacers and breathing patterns 
Four different spacers were investigated; two small volume spacers (the 149ml 
Aerochamber Plus®, Trudell, Canada and the  225ml Funhaler®, Visiomed, Australia) and 
two large volume spacers (the 750ml Volumatic®; and a modified 500ml plastic soft drink 
bottle.  This range of spacer devices was selected to represent types commonly used in 
children:  The Aerochamber Plus is a commonly used small volume spacer.  The 
Volumatic® is a commonly used large volume spacer.  The Funhaler® is an example of an 
incentive spacer which may have potential to facilitate a child’s breathing and therefore 
drug delivery.  The modified soft drink bottle is an example of an unvalved spacer device 
and was tested because modified soft drink bottles are being used as spacer devices in some 
developing countries.    
 
Statistical analysis 
Comparisons were made between filter doses recovered for different breathing patterns 
using SPSS version 15.0.  Paired samples were compared using the Wilcoxon Signed 
 93
Ranks Test.  Unpaired samples were compared using the Mann-Whitney U test.  Where the 
data were normally distributed, unpaired samples were compared using the Students t-test.  
Linear regression was used to correlate data.  Bland-Altmann plots were used to compare 
different measurement techniques.  
 
3.4 Results 
The minimum number of tidal breaths required to effectively inhale salbutamol from a 
spacer depended on the type of spacer used (Figure 16).  With the small volume spacers 
(Funhaler® and Aerochamber Plus®) there was no significant difference in drug delivery 
between two tidal breaths and nine tidal breaths.  Drug delivery via the Funhaler® mean 
(95CI) was 39% (34-43) and 38% (35-42) for two and nine tidal breaths respectively. Drug 
delivery via the Aerochamber Plus® mean (95CI) was 40% (34-46) and 41% (36-47) for 
two and nine tidal breaths respectively.  With the Volumatic, drug delivery after two tidal 
breaths was significantly less than after nine tidal breaths; mean (95CI) 37% (33-41) and 
43% (40-46), respectively (p=0.02; Wilcoxon Signed Ranks).  There was no statistically 
significant difference in drug delivery after three tidal breaths mean (95CI) (40% (36-44%) 
and nine tidal breaths 43% (40-46) for the Volumatic®.  With the (unvalved) modified soft 
drink bottle, there was no significant difference in drug delivery between two, five or nine 
tidal breaths.   
 94
 
Aerochamber Plus Funhaler
75 75
50 50
25 25
0 0
2 9 2 9
Number of breaths Number of breaths
Volumatic Modified soft drink bottle
75 75
50 50
25 25
0 0
2 3 5 9 2 5 9
Number of breaths Number of breaths
 
Figure 16.  Salbutamol doses recovered from filters are reported as percentage of total 
dose recovered from filter, spacer and pMDI sleeve.  Error bars show 95% CI of 
mean. 
 
Inhalation volumes were almost double the expected tidal volumes.  The inhalation volume 
mean (SD) of subjects using the Aerochamber Plus®, the Funhaler®, the Volumatic® and 
the modified soft drink bottle was respectively 393ml (247), 432ml (225), 384ml (185), 
445ml (167) during tidal breathing and 515ml (164), 550ml (239), 503ml (213), 448ml 
(259) for the single maximal breath manoeuvre (Figure 17).  The mean (SD) weight of 
these subjects was 19.8kg (4.44).  If tidal volume was predicted using the formula wt (kg) x 
7ml, the mean tidal volume for these subjects would have been 138.6ml.  
 95
Dose inhaled Dose inhaled
Dose inhaled Dose inhaled
TIDAL BREATHING SINGLE MAXIMAL INHALATION
900 900
800 800
700 700
600 600
500 500
400 400
300 300
200 200
100 100
0 0
AC FH V C AC FH V C
Spacer type Spacer type  
Figure 17.  Mean (SD) inhalation volumes of subjects inhaling from different spacers.  
FH = Funhaler®;  AC = Aerochamber Plus®;  V = Volumatic®;  C = Modified soft 
drink bottle. 
 
With tidal breathing, mean peak inspiratory flows (SD) of subjects using the Aerochamber 
Plus®, the Funhaler®, the Volumatic® and the modified soft drink bottle was respectively 
49 (21), 50 (24), 46 (17), and 52 (19) LPM.  Inspiratory flows with the single maximal 
inhalation technique was only marginally higher at 61 (15), 66 (24), 61 (26), and 62 (25) 
LPM with the Aerochamber Plus®, the Funhaler®, the Volumatic® and the modified soft 
drink bottle respectively (Figure 18). 
 
TIDAL BREATHING SINGLE MAXIMAL INHALATION
80 100
70 90
60 80
70
50 60
40 50
30 40
20 30
20
10 10
0 0
AC FH V C AC FH V C
Spacer type Spacer type
 
Figure 18.  Mean (SD) peak inspiratory flow of subjects inhaling from different 
spacers.  FH = Funhaler®;  AC = Aerochamber Plus®;  V = Volumatic®;  C = 
Modified soft drink bottle. 
 
100% of seven year old children, 84% of six year olds, 76% of five year olds, 38% of four 
year olds and 20% of three year olds could perform a single maximal breath manoeuvre 
(Figure 19).   There was an age dependant gender difference and females were able to 
 96
Peak inspiratory flow (LPM) Inhalation volume (ml)
Peak inspiratory flow (LPM) Inhalation volume (ml)
perform a single maximal breath manoeuvre earlier than their male counterparts (100% by 
six years of age).  During this manoeuvre, two of the children screened, were noted to be 
inhaling through their noses.  This observation was made possible because their breathing 
was being recorded, and would not have come to light by clinical observation only. 
 
100%
80%
60%
40%
20%
0%
S S S S S
EA
R AR AR AR AR
Y E E E E3 4 Y 5 Y 6 Y 7 Y
 
Figure 19.  Percentage of children able to perform single maximal inhalation (Breath 
holding not tested). 
 
Nine tidal breaths resulted in significantly greater drug delivery to filter than single 
maximal inhalation for both the Funhaler® (p=0.04) and the Volumatic® (p=0.01) (Figure 
20). There was no significant difference in drug delivery to filter between single maximal 
inhalation and nine tidal breaths with both the Aerochamber Plus® and the modified soft 
drink bottle.  With the methodology not allowing for asynchrony between pMDI acuation 
and inhalation, the highest total drug delivery was seen with the (valveless) modified soft 
drink bottle. 
 
 97
Aerochamber Plus Funhaler
75 75
50 50
25 25
0 0
9 TIDAL BREATHS SINGLE MAXIMAL BREATH 9 TIDAL BREATHS SINGLE MAXIMAL BREATH
BREATHING PATTERN BREATHING PATTERN
Volumatic Modified soft drink bottle
75 75
50 50
25 25
0 0
9 TIDAL BREATHS SINGLE MAXIMAL BREATH 9 TIDAL BREATHS SINGLE MAXIMAL BREATH
BREATHING PATTERN BREATHING PATTERN
 
Figure 20.  Salbutamol doses recovered from filters, reported as percentage of total 
dose recovered from the filter, spacers and pMDI sleeve.    Error bars represent 95% 
confidence intervals. 
 98
DRUG DELIVERY DRUG DELIVERY
DRUG DELIVERY DRUG DELIVERY
 
 
3.5 Discussion 
This study has lead to two major new findings that for the first time define the information 
needed to instruct young children for optimal use of spacers.  Firstly, young children, 
breathing tidally through spacers take much larger breaths than during normal tidal 
breathing.  Secondly, we were able to define the number of tidal breaths needed for 
efficient use of different sized spacer devices:  Two for an unvalved spacer, two for the 
small volume valved spacers, and up to three for the large volume valved spacer.   
 
The finding that inhalation volume of young children breathing tidally through spacers 
differs from normal tidal breathing was not unexpected, as it has previously been 
demonstrated that instrumentation influences breathing pattern [119].  The recorded breath 
volumes were, however, higher than anticipated.  The peak inspiratory flows recorded on 
children breathing tidally through spacers were also significantly higher than flows used in 
previous spacer related paediatric breathing simulation studies [63, 65, 69, 72, 74, 108, 113, 
115, 117].   
 
Our study demonstrates that a single maximal inhalation does not result in improved drug 
delivery over tidal breathing in young children.  As the mean volume of the single maximal 
breaths was smaller than the volume of the Volumatic spacer, increased drug delivery with 
a number of tidal breaths could be expected.  The reason for increased drug delivery with 
tidal breathing over a single maximal breath with the Funhaler® is not clear from these 
data.  
 
This study was not designed to determine drug dose delivered to a patient’s lungs.  The 
filter dose captured during breathing simulation represents the total drug dose that would 
reach a patient’s mouth and not the lung dose.  However, one would not anticipate that the 
lung dose would be increased by taking further breaths through a spacer once the maximum 
total dose delivery has been reached. 
  
 99
Due to the nature of the study, breath holding was not examined.  Although breath holding 
appears to be beneficial for lung deposition in adults [137], breath holding is difficult and 
unlikely to significantly improve lung deposition in children [150].   
 
The relatively high drug doses delivered with the modified soft drink bottle highlights the 
role that valves in spacers play in filtering out drug particles that otherwise may have been 
inhaled; however, dose delivered would be expected to decrease significantly in an 
unvalved device if pMDI actuation is followed by exhalation by a patient instead on 
inhalation.  Breathing simulation was performed with the start of inhalation in synchrony 
with actuation of the pMDI, simulating a best case scenario for drug delivery.   
 
The ten patients selected for testing in the latter part of the study were not randomly 
selected, but due to their ability to perform both tidal breathing and a single maximal 
breath.  Hence, the selected group may have produced better results than those who were 
unable to perform a single maximal breath, but these would be the ones in whom this 
technique may be considered. 
 
Different bronchodilators are available for use in acute asthma and a range of different 
inhaled steroids are available for asthma preventive therapy in preschool children.  
Salbutamol was used for in vitro testing in our study as salbutamol is a commonly used 
bronchodilator and the need for knowing the minimum number of breaths needed to 
effectively inhale medication from a spacer is perhaps greatest in busy hospital emergency 
departments, where multiple doses of bronchodilators are administered to acute asthmatics 
as frequently as every 20 minutes during severe acute asthma attacks.   
 
When using pMDI-spacers in young children and infants, cooperation during 
administration is the most important determinant for efficient drug delivery [84].   
Preschool children, who are known to have short attention spans, may be more likely to 
cooperate with spacer use if they are required to take fewer, rather than more breaths 
through spacer devices.    
 
CONCLUSION 
 100
This study demonstrated that inhalation volumes and flows of young children using spacers 
are larger than expected, and therefore only a few tidal breaths are required for drug 
delivery.  These results potentially could be applied in clinical practice by all clinicians 
treating young children who require inhaled medication.  
 101
 
4 CHAPTER FOUR:  Clinical trial 
4.1 Background   
 
The efficacy of inhaled corticosteroids as asthma preventer medication in preschool 
children is recognised [276].  In many parts of the world, inhaled corticosteroids are almost 
exclusively administered to preschool children via pMDI-spacers.  Effective delivery of 
medication to a patient is a basic requirement if drug efficacy is to be expected.  For 
inhaled corticosteroids, spacer technique and adherence to prescribed medication are both 
important determinants of drug delivery.  Spacer technique is often suboptimal in preschool 
children, and inhalation is a critically important part of spacer technique.  Adherence to 
prescribed medication is also often suboptimal in preschool children. This study aims to 
examine the association between both spacer technique and adherence to prescribed inhaled 
corticosteroid therapy, and asthma control in preschool asthmatic children.  The study also 
aims to examine whether an incentive spacer device, the Funhaler®, improves drug 
delivery, by improving spacer technique and/or adherence to prescribed medication.   
 
The Funhaler’s potential capacity to influence both spacer technique and adherence to 
prescribed medication in preschool children lies in the visual and auditory feedback 
provided by the spinning disk and whistle, located on the expiratory arm of the Funhaler®.  
As the incentive component of the Funhaler® is located on the expiratory arm, an effect on 
the user’s expiration could be expected.  A change in expiration could be considered to be 
associated with a change in the subsequent inhalation, thereby influencing drug delivery.  
As the nature of an incentive is to stimulate, the likelihood that the incentive on the 
expiratory arm of the Funhaler® would increase exhalation volume, followed by an 
increase in inhalation volume, and subsequent drug delivery, was thought to be a 
worthwhile hypothesis.  
  
The audio-visual feedback provided by the Funhaler® could potentially also make the drug 
delivery process more agreeable to preschoolers.  Improved agreeability of the drug 
delivery process could lead to reduced parent-child conflict during the drug delivery 
process.  A reduction in parent-child conflict during the drug delivery process could 
 102
improve adherence to prescribed inhaled corticosteroids in preschool children.  Therefore, 
the likelihood that use of the Funhaler® would improve adherence to prescribed inhaled 
treatment in preschool children, by positively influencing parent-child interaction during 
the drug delivery process, was also investigated.  
 
The Funhaler® was chosen as an intervention because of its novel incentive properties, 
ease of implementation as an intervention, and potential to positively influence both spacer 
technique and adherence to medication.  The Funhaler® currently is the only spacer device 
purposely designed for use in preschool children. No intervention with the aim of 
improving adherence to prescribed inhalation treatment has ever been specifically aimed at 
the preschool child.  Interventions aimed at improving adherence to medication in 
preschool children are usually aimed at the children’s parents, who are responsible for their 
children’s medication administration. 
 
The methods section below will describe a clinical trial where the Funhaler® was 
compared with the Aerochamber Plus®.  The Aerochamber Plus® was chosen as a control 
because of its known acceptable drug delivery properties, widespread use; and most 
importantly, its in vitro equivalence to the Funhaler® in in vitro drug delivery.  Differences 
in outcome could therefore be expected to relate to in vivo performance.   
 
The study population used was preschool children in the community with ‘doctor 
diagnosed asthma’, who were being prescribed inhaled corticosteroids..  In the literature, 
the definition of asthma in the preschool age group has always been a contentious subject, 
with terms like wheezy bronchitis used interchangeably with asthma[277].  More recently, 
and after completion of the clinical trial described below, the  European Respiratory Task 
Force on Preschool Wheeze has suggested that wheeze-syndromes in preschool aged 
children should be classified into episodic (viral) wheeze and multiple trigger wheeze[278].  
However, the characterisation and classification of preschool wheeze syndromes and 
different asthma phenotypes in preschool children is still a contentious issue[279].  In 
Australia, preschool children with wheeze are usually labelled with "asthma" and treated 
with inhaled corticosteroids, when symptoms recur frequently and have appeared to 
respond to bronchodilators.  The decision to study preschool children with ‘doctor 
diagnosed asthma’ who were being prescribed inhaled corticosteroids in the community, 
therefore, ensured that the study population was representative of a population in which 
spacer technique, and adherence to prescribed inhaled medication, was likely to be 
 103
important.  Information was collected about atopy, as well as family history of atopy and 
asthma, and skin prick allergy testing was done, in order to better define the asthma 
“phenotypes” of the subjects studied.   
 
Other factors being equal, proficiency in spacer technique would determine eventual 
inhaled mass, from a specific pMDI-spacer combination, to a subject.  Total drug delivery 
to filter was used to quantify proficiency in spacer technique.  Filter dose is not an accurate 
measure of drug delivery to a subject’s airways, but is a more objective measure of spacer 
technique than previously-used measures of spacer technique i.e scoring by an observer the 
different steps of pMDI-spacer use by the subject [125, 126].   
 
Adherence to prescribed inhaled corticosteroids was measured by electronic monitors that 
document the time and date that the pMDI was actuated.  Subjects were not blinded to the 
fact that their adherence was being monitored.  Analysis of the electronic adherence 
monitor data could not differentiate between medication administration and the contrived 
“dumping” of medication.  However, electronic monitoring of adherence is accepted as the 
current “gold standard” for adherence monitoring.   
 
Various measures of clinical outcome were used in the clinical trial.  As discussed in 
chapter one, all clinical outcome measures have individual strengths and weaknesses, and a 
combination of different outcome measures would complement each other.  In the clinical 
trial diary cards were used to measure asthma symptoms and reliever (bronchodilator) use.  
In addition to asthma symptoms, oral corticosteroids use as prescribed by doctors in the 
community, was also documented on diary cards and used as an indirect marker of asthma 
exacerbations.  In order to include patient outcome measures that extend beyond traditional 
clinical measures, QoL measurements were made using the PedsQL version 3.0 asthma 
module.  The PedsQL was used because it has been validated specifically for use in 
preschool children with asthma, and because of its brevity (beneficial when multiple 
parameters are being assessed at a single study visit).  The PedsQL version 3.0 has been 
shown to demonstrate reliability, validity, and responsiveness in paediatric asthma [260]. 
 
Lung function testing was used as a secondary outcome measure.  FOT was used in the 
clinical trial to measure lung function.  FOT is suitable to perform on preschool children as 
only passive cooperation and no coordination is required.  The proven capacity of FOT to 
 104
detect change when inhaled corticosteroids are used in young asthmatic children [224] 
made it particularly suitable for use in a study where potential changes to the delivery of 
inhaled corticosteroids was being studied.                
 
 
4.2 Aims and Hypothesis 
Aims:   
• To investigate the effect of proficiency in spacer technique, as measured by drug 
inhaled onto a filter, on clinical outcome in preschool asthmatic children. 
  
• To investigate the effect of adherence to prescribed inhaled asthma medication on 
clinical outcome in preschool asthmatic children. 
 
• To investigate the influence of an incentive spacer device on proficiency in spacer 
technique, adherence to prescribed treatment, and clinical outcome in preschool asthmatic 
children. 
 
 
Hypothesis: 
• Proficiency in spacer technique correlates positively with improved clinical 
outcome in preschool children with asthma. 
 
• Good adherence to prescribed medication regimens correlates positively with 
improved clinical outcome in preschool children with asthma. 
 
• Use of an incentive spacer, the Funhaler®, improves proficiency in spacer 
technique and/or adherence to prescribed medication, and thereby improves clinical 
outcome in preschool children with asthma. 
 105
 
4.3 Methods 
A randomised, controlled, prospective clinical trial was performed.  The Funhaler® is a 
small volume spacer with a spinning disk and whistle on the expiratory arm [152, 153]. The 
function of the spinning disk and whistle combination is to act as an incentive for young 
children to cooperate when their inhaled asthma preventer medication is being 
administered. The Aerochamber Plus® is a standard small volume spacer.  Subjects in the 
study group were given Funhalers® for delivery of daily asthma preventer medication.  
Subjects in the control group were given Aerochamber Plus® spacers for delivery of daily 
asthma preventer medication.  The Funhaler® and the Aerochamber Plus® have similar in 
vitro drug delivery characteristics [280].  The rationale for the incentive assessment part of 
this study was therefore:  Taking in to account any confounding variables, any difference in 
terms of drug delivery and adherence to prescribed medication could be ascribed to the 
incentive component of the Funhaler®.  
 
4.3.1 Study participants 
Preschool children in the community (two to six-years old) in whom asthma had been 
diagnosed by a doctor, and who were being prescribed inhaled steroids for treatment of 
their asthma, were eligible for inclusion in the study.  Exclusion criteria were known or 
suspected immunodeficiency; other chronic lung diseases (such as bronchopulmonary 
dysplasia or cystic fibrosis); known allergy to study medication; and having been 
administered systemic steroids in the three months prior to enrolment.  Ethics approval was 
obtained from the ethics committee of Princess Margaret Hospital for Children and the 
Telethon Institute for Child Health Research (933/EP), and from the ethics committee of 
the University of the Free State (ETOVS 67/07).  Parents or guardians provided written 
informed consent.  Children were recruited between May 2005 and October 2006 using 
local advertising, flyers and direct recruitment from the Emergency Department and clinics 
at Princess Margaret Hospital for Children.   
 
Study power calculation:   
To demonstrate a 20% difference between the study group and the control group, at 80% 
power, and a significance of 0.05, 160 subjects would be required.   
 106
 
4.3.2 Protocol 
Subjects were seen at a screening visit, at a baseline visit and then followed up for a year.   
The study protocol is outlined in Table 9.   
 
Screening visit:  After subjects were checked for eligibility, eligible subjects who were on 
inhaled steroids other than fluticasone were changed over to equivalent doses of 
fluticasone.  Subjects who were on combination medication (inhaled steroid and long acting 
beta stimulant) other than fluticasone-salmeterol were changed over to equivalent doses of 
a fluticasone-salmeterol combination.  Subjects who were using spacers with face masks 
were instructed to use the mouthpiece of the spacer instead of using a facemask.  Spacer 
technique was checked, and corrected if necessary.  Background information was obtained 
by standardized questionnaire about symptoms of wheezing and coughing, personal and 
family history of atopy and asthma and smoking in the house. 
 
Instruction on using spacers:  At the screening visit, as well as every subsequent visit, each 
subject and their parents were shown an instruction video, demonstrating the correct 
procedure for using a spacer.  The video included the following steps: 
• Shake the pMDI and take off the cap. 
• Insert pMDI correctly into spacer. 
• Place mouthpiece of spacer into subject’s mouth. 
• Actuate pMDI. 
• Let subject take five tidal breaths. 
• Repeat the process if needed. 
• Wash spacer in a mild dishwashing detergent every two weeks, do not rinse and 
leave spacer to drip-dry. 
 
Run-in period:  After the screening visit there was a month long run-in period.  The run-in 
period was used to ensure that all subjects’ asthma were stable after receiving instructions 
on technique, changing face mask to mouthpiece where needed, and after changing other 
inhaled steroids to fluticasone (Flixotide®, GlaxoSmithKline) where needed.  Stable 
 107
asthma was defined as having daytime symptoms less than twice a week, having night time 
symptoms once a month or less, and a history of not requiring oral steroids for the past 
three months.  If a subject’s asthma was unstable, the run-in period was extended and the 
medication dose adjusted if considered appropriate by the study doctor.  
 
Randomisation:  After the screening period, subjects were randomized into two groups:  In 
the study group, the subjects’ parents were given an incentive spacer (Funhaler®) to 
administer their children’s asthma preventers.  In the control group, the subject’s parents 
were given an Aerochamber Plus®, to administer their children’s asthma preventers.  
Randomisation was done independently by the pharmacy.  Randomisation was done by 
block randomisation using blocks of ten.   
 
Follow-up:  After randomisation, patients were followed up at three monthly intervals for a 
year.  At each visit inhalation technique was checked and corrected if necessary.  At each 
visit, the dose of inhaled asthma preventer medication was reduced if the subject’s asthma 
was controlled and the parents agreed to it.  Asthma control was defined as having daytime 
asthma symptoms less than twice a week and night time awakenings less than once a 
month. At each visit, if the subject’s asthma was not controlled, the dose of the study 
medication was increased, if appropriate.  Doctors in the community were allowed to 
change the dose of preventer medication but study participants were instructed to notify the 
study coordinator if any change in medication dose was made.  Study medication 
(fluticasone +/- salmeterol) was prescribed by the study doctor at each visit, dispensed to 
the study nurse by the pharmacy at Princess Margaret Hospital for Children, and handed 
out to the subjects’ parents after the study visit. 
 
Allergy testing: At the final study visit, skin prick testing was performed on all willing 
participants.  Allergens tested were house dust mite, rye grass pollen, cat dander, and egg 
white.  Skin prick testing was deemed positive if the wheal caused by the allergen was 
larger than the positive control, and larger than 3mm in diameter.  A small number of 
parents refused skin prick testing on their child, on the grounds that their child had had skin 
prick allergy testing performed on them within the previous six months. These parents were 
asked whether the skin prick tests that had been performed were positive, and their answers 
were documented. 
 108
 
 
4.3.3 Outcome measures 
Asthma symptoms 
The primary outcome measure for the study was “event free days” as documented on a 
diary card, filled out by subjects’ parents during the week before each follow-up visit.  
Symptoms were divided into night time symptoms, and daytime symptoms. Specific rows 
on the diary cards provided space to document “wheeze”, “cough” and “other symptoms”.  
Bronchodilator use was also recorded each day for a week before each study visit.  Event 
free days were defined as days where no asthma symptoms were reported, and no rescue 
bronchodilator use was reported.  The header on the diary cards read “Asthma symptoms 7 
days prior to appointment”.    
 
A second diary card was used to record asthma exacerbations and days of systemic steroid 
use in the three month interval between follow-up visits.  Used diary cards were collected 
and new diary cards were handed out at each study visit.   
 
Proficiency in spacer technique 
Filter studies are explained in detail in Part One of the methodology section.  In brief, when 
using a pMDI-spacer, there are many patient-related factors that determine drug dose 
inhaled.  A filter interposed between the patient and the spacer can be used to determine the 
total drug dose delivered to a subject, and is therefore an indirect measure of proficiency in 
spacer technique. The rationale for using filter dose as a measure of proficiency in spacer 
use, was that, controlling for other factors a subject’s breathing pattern would be the major 
factor determining drug delivery from the pMDI- spacer.  It was thought that, if the 
incentive device on the Funhaler® could influence breathing pattern, it could potentially 
influence drug delivery, and eventually clinical outcome. Thus, for this study proficiency in 
spacer technique was defined as the quantity of salbutamol inhaled onto a filter when using 
a pMDI-spacer.    
 
Study subjects were asked to participate in a filter study at the baseline visit and at the 
three-, six-, and nine month follow-up visits.  With each filter study parents were asked to 
 109
administer five separate puffs of salbutamol (Ventolin®, GlaxoSmithKline, Australia) to 
their child.  Five 100μg puffs were required to ensure that sufficient drug for measurement 
would be deposited on each filter.  Filter studies were performed before reviewing pMDI-
spacer technique. 
 
Adherence monitoring 
Smartinhaler® (Nexux6, Auckland, New Zealand) [281] electronic monitoring devices 
were used to monitor adherence to prescribed medication.   Smartinhaler® devices were 
handed out to all participants at the baseline visit.  Smartinhaler® devices replace the 
original sleeve/ actuator of a pMDI.  During the study the first canister of inhaled asthma 
preventer medication (that was dispensed at each visit) was fitted in a Smartinhaler® 
device.  Study participants where instructed, when the pMDI canister needed replacement, 
to fit each new pMDI canister into the Smartinhaler® device.  Adherence data from 
Smartinhaler® devices were uploaded at each follow-up visit.  Subjects were not blinded to 
the fact that the Smartinhaler® was monitoring their adherence to prescribed medication. 
 
Smartinhalers® record the date and time of every pMDI actuation.  Specialized software, 
that accompanied the Smartinhalers® in order to upload information from Smartinhaler® 
devices, was used to input the number of medication doses prescribed.  The software 
calculated the number of doses actuated as a fraction of doses prescribed for each period of 
the day before 12pm or after 12pm.  Doses actuated before 12pm was considered to be 
morning doses.  Doses actuated after 12pm was considered to be evening doses.   
 
Subjects were only considered to be adherent for a specific dose if their pMDI was actuated 
the number of times that their fluticasone was prescribed e.g. if a subjects were prescribed 
two puffs twice a day, and only actuated their pMDI once in the morning, they were 
considered as non-adherent for their morning dose.  Manually checking all the raw 
adherence data confirmed that, subjects very rarely actuated their pMDIs for only a fraction 
of the number of doses prescribed. 
 
Subjects who actuated their pMDIs more than the prescribed number of times, in a morning 
or evening period, were considered to be adherent to the prescribed number of doses for 
that (morning or evening) dose.  When more than eight doses were actuated within a few 
seconds from each other, the subjects were thought to be “dumping” doses.  “Dumped” 
 110
doses were not considered as being administered in adherence to prescribed doses, and 
were excluded from all calculations.   
 
In summary, adherence to each individual dose was determined by analysing 
Smartinhaler® data.  Mean adherence between study visits was measured as the number of 
times that the whole prescribed dose was given expressed as a percentage of the total 
number of doses prescribed.    
 
Quality of Life measurements 
The PedsQL 3.0 Asthma Module® questionnaire for two to four year children was 
administered to subjects’ parents, who served as proxy for their children.  For five to seven 
year old children the PedsQL module had separate questionnaires for parents and children.  
While both parent and child questionnaires were administered, to remain as consistent as 
possible in obtaining QoL data between the two to four year old children and the five to 
seven year old children, only the parental questionnaires were analysed.   
 
Lung function testing 
At each study visit, lung function testing was performed on all participants who were 
willing.  Although written consent for the study was obtained at the beginning of the study, 
verbal consent for FOT was obtained at each study visit from both parents and study 
subjects.   
 
Lung function testing was performed by FOT.  Rrs and Xrs were derived from the Zrs that 
was measured at different frequencies. Commercially available equipment (I2M, Chess 
Medical, Belgium) that was built on the specifications by Landser et al [282], in accordance 
with European Respiratory Society guidelines [283], was used.   The forced oscillation 
signal was a pseudorandom signal consisting of frequency components between four and 
48 Hz.  The measurement period of the pseudorandom signal was eight seconds.    
 
Measurements were made with the patient sitting in the upright position and his/her cheeks 
supported by an investigator.  Nose clips were used during measurements.  In the few cases 
where the patients refused to wear a nose clip, one of the patient’s parents occluded the 
patient’s nose with their fingers.  Suregard® (Bird Healthcare, Australia) filters were 
 111
interposed between the patients and the measuring equipment for infection control 
purposes.  Three or more measurements were performed until the standard deviation of 
Rrs8 was less than 10%.  After the initial measurements, 600µg of salbutamol (Ventolin®, 
GlaxoSmithKline) was administered with the spacer to which each subject was randomised.  
Measurements were repeated 15 minutes after the initial measurements.  Baseline (pre-
bronchodilator) lung function was reported as Z-scores, calculated as per the formula 
derived by Hall et al [251].  Bronchodilator response was reported as percentage change, 
relative to baseline measurements.  Subjects who had been administered a short acting β-
stimulant within four hours before the measurements, and subjects who had been 
administered a long acting β-stimulant within twelve hours before the measurements, were 
excluded from this analysis.  
 112
 
Screening Baseline Three month Six month Nine month Twelve month 
visit visit*  visit visit visit visit# 
-Exclusion  
criteria Diary cards 
-Symptom Asthma symptoms week before visit 
questionnaire 
Preventer medication use since previous visit 
-Clinical 
Systemic steroid use since previous visit 
examination 
Quality of life questionnaire 
-FOT 
Electronic adherence monitor (Smartinhaler) download 
-Inhaled 
steroid Filter study on study participants (all visits except for the twelve month 
changed to visit) 
fluticasone FOT 
-All subjects Breathing patterns while using pMDI-spacers recorded by flow-chamber,  
instructed on as per Part One of thesis (all visits except for the twelve month visit) 
use 
Asthma preventer medication provided 
mouthpiece of 
spacer  
 
 *Randomise    #Skin prick 
testing 
Table 9.  Outline of protocol for clinical trial 
 
Statistical analysis 
Statistical analysis was performed using SPSS version 15.0.  Paired samples were 
compared using the Wilcoxon Signed Ranks Test.  Unpaired samples were compared using 
the Mann-Whitney U test.  Where the data were normally distributed, unpaired samples 
were compared using the Students t-test.  Linear regression was used to correlate data.   
Generalized estimating equations (GEEs) were used to analyse repeated measures, when 
basic statistics indicated that a more detailed analysis may be of benefit to clarify results. 
 113
 
4.4 Results 
4.4.1 Demographics  
Two hundred and twenty eight children were screened for eligibility.  Ninety six children 
were excluded: 47 did not meet the inclusion criteria, and 49 either actively or passively 
refused to participate.  One hundred and thirty two subjects were included in the study.  
Recruitment was discontinued at 132 subjects, when it became clear during an interim 
analysis, that there would be no significant difference in the main outcome marker, event 
free days (see Appendix for declaration by statistician).  The male: female ratio of subjects 
included in the study was 8:5 (Table 10).  
 
 
  
 Funhaler Aerochamber 
 
group     Plus group Total 
   
Male 42 40 82 
Female 23 27 50 
Total 65 67 132 
Table 10.  Number of subjects randomised.  
Subjects in the Funhaler and Aerochamber Plus groups were comparable in terms of age 
characteristics and exposure to tobacco smoke, as per parental report (Table 11).  Due to an 
oversight, one subject was randomized on his seventh birthday.  
 114
 
 
 Funhaler® Aerochamber Plus® p 
Age in months  0.94 
Median (range) 51 (24-84) 51 (25-83) 
Smokers living in 
home n (%) 11 (17) 15 (22) 0.29 
Mother smokes  N (%) 5 (8) 9 (13) 0.40 
Table 11.  Age and cigarette smoke exposure. 
 
Comparable numbers of subjects were randomised per year group in the Funhaler and in 
the Aerochamber Plus groups.  Overall, subjects were not evenly distributed by age, with 
the three- and four-year olds better represented than other year groups (Table 12).   
 
 115
 
 
Age in years Frequency (%) 
 
 
 Funhaler Aerochamber Plus Both groups 
2 
 10 10 20 (15) 
3 
 18 19 37 (28) 
4 
 16 16 32 (24) 
5 
 10 10 20 (15) 
6* 
 11 12 23 (17) 
Total 
 65 67 132 (100) 
* Single subject randomised on 7th birthday included in this group 
Table 12.  Distribution of subjects per year group. 
 
4.4.2 Atopy 
More subjects in the Funhaler group had a positive skin prick test compared with subjects 
in the Aerochamber Plus group, but the difference between the groups was not significant.  
Subjects in the Funhaler group, specifically male subjects, were more likely to have had 
eczema diagnosed by a doctor (p = 0.01, and p = 0.02 for all subjects, and for males, 
respectively) (Table 13).   
 116
 
 
Total Funhaler Aerochamb
p-value Chi 
 er Plus sq (2-sided)  
Skin prick test positive (or 
parental report of recent 31 (34%) 18 (43%) 13 (27%) 0.12 
positive skin prick test)  
Skin prick test positive in study 23 (28%) 14 (37%) 9 (20%) 0.14 
All subjects 73 (55%) 43 (66%) 30 (45%) 0.01* 
Doctor 
diagnosed Male  46 (56%) 28 (67%) 18 (45%) 0.02* 
eczema 
Female 27 (54%) 15 (65%)  12 (44%) 0.39 
1st degree relative with atopy 
 116 (88%) 60 (92%) 56 (84%) 0.06 
Table 13. Comparison of groups in terms of atopy. 
 
4.4.3 Study drop-outs 
Over the one-year follow-up period, 21 subjects (16%) dropped out of the study: Six 
subjects were lost to follow-up, four moved away from the study centre, five cited time 
constraints, four lost interest, one cited parental illness and one cited not liking the spacer 
allocated for the study.  One hundred and eleven patients (84%) completed the study.  
Table 14. 
 117
 
 Funhaler Aerochamber 
 group Plus group 
Total 
Lost to follow-up (or 
repeatedly did not attend 5 1 6 
scheduled visits) 
Moved away from study area 1 3 4 
Time constraints 5 0 5 
Parental illness 1 0 1 
Not liking holding chamber 
allocated 1 0 1 
Lost interest 4 0 4 
Table 14.  Reasons for subjects not completing the study. 
 
Subjects in the Funhaler group were more likely to drop out of the study (Figure 21).  The 
majority of subjects who discontinued taking part in the study did so between the three 
month and the nine month visits.  The difference between drop-out numbers between the 
Funhaler and the Aerochamber Plus groups became significant by the six month visit 
(p=0.04).  By the final visit seventeen (26%) subjects randomised to the Funhaler group 
versus four (six percent) in the Aerochamber Plus group had dropped out of the study (p < 
0.01).  No specific reason was recorded for the higher drop-out rate in the Funhaler group, 
except for one subject, who cited not liking the Funhaler, as the reason for dropping out.  
 
 118
80
70
67 67 64 64 63 
60 65 61
50 53
49 48 Funhaler
40  Aerochamber Plus
30
20
10
0 Baseline 3 months 6 months 9 months 12 months
 
Figure 21.  Number of subjects attending specific study visits. 
 
4.4.4 Drug dose prescribed  
A number of subjects were weaned off their inhaled steroids during the course of the study.  
There was no significant difference in fluticasone dose prescribed between the Funhaler 
group and the Aerochamber Plus group (Table 15). 
 119
 
 
 Funhaler Aerochamber 
P (Chi 
Plus square) 
   N (%) N (%)  
0-3 
months 65 (100) 67 (100) 1 
3 - 6 
months 56 (92) 59 (88) 0.57 
6 – 9 
months 44 (83) 49 (77) 0.49 
9 – 12 
months 33 (67) 45 (70) 1 
Table 15.  Subjects being prescribed fluticasone during the clinical trial. Numbers in 
brackets indicate the percentage of subjects still taking part in the clinical trial, who 
were still being prescribed fluticasone.  
The mean fluticasone dose prescribed gradually decreased during the course of the clinical 
trial (Figure 22).   
Mean fluticasone dose
250
200
150 Funhaler
100 Aerochamber Plus
50
0
Baseline 3 months 6 months 9 months
 
Figure 22.  Mean daily fluticasone dose in microgram (y-axis) prescribed at each 
study visit (x-axis).  
 120
 
At no point in the clinical trial was there a significant difference between the Funhaler and 
the Aerochamber groups in terms of fluticasone dose prescribed.  (Table 16).  
 
 Funhaler Aerochamber p 
Median (range) Median (range)  
Baseline 200 (50-500) 200 (50-500) 0.85 
3 months 100 (0-500) 200 (0-500) 0.17 
6 months 100 (0-500) 100 (0-500) 0.60 
9 months  100 (0-500) 100 (0-500) 0.84 
Table 16.  Fluticasone dose (μg) prescribed at each study visit.  
 
A large number of subjects were prescribed salmeterol during the study: Fifty (37.9%) at 
the baseline visit, decreasing to 44 (33.3%) at the final visit.  There was no significant 
difference between the Funhaler group and the Aerochamber Plus group in terms of 
salmeterol dose prescribed. (Table 17).  
 
 
Number (%) of subjects receiving salmeterol. 
Funhaler Aerochamber All subjects Chi sq  
  (n=65) Plus (n=67) (n=132) (2-sided) 
Baseline 24 (36.9) 27 (40.3) 51 (38.6) 0.69 
3 months 21 (32.3) 23 (34.3) 44 (33.3) 0.99 
6 months 23 (35.4) 25 (37.3) 48 (36.4) 0.64 
9 months 18 (27.7) 25 (37.3) 43 (32.6) 0.80 
Table 17.  Number of subjects on salmeterol after study visits. 
 121
 
4.4.5 Outcomes 
The baseline visit will be discussed first.  Thereafter results will be discussed in the order 
that the hypotheses were presented.  The relation between factors that influence aerosol 
drug delivery (i.e. proficiency in spacer technique and adherence to prescribed medication) 
and clinical outcome will be presented, followed by the influence of the Funhaler on the 
above factors.  Finally the influence of the Funhaler on clinical outcome will be discussed.  
 
4.4.6 Baseline visit  
There were significant differences between the Funhaler group and the Aerochamber Plus 
group at the baseline visit.  As the differences at baseline influenced the data analysis, the 
baseline visit will first be discussed separately.   
4.4.6.1 Baseline visit: Proficiency in spacer technique as measured by drug delivered 
to filter  
There was no significant difference between the Funhaler group and the Aerochamber 
groups in terms of proficiency in spacer technique, as determined by filter dose, at the 
baseline study visit. 
4.4.6.2 Baseline visit:  Adherence to medication 
There was no significant difference in adherence between the Funhaler group and the 
Aerochamber Plus group at the baseline study visit.   
4.4.6.3 Baseline visit:  Symptom free days 
The Funhaler group reported significantly less days without wheeze (p = 0.02), and 
significantly less bronchodilator free days (p = 0.03) than the Aerochamber Plus group in 
the seven days before the baseline visit.  When stratified for gender, males in the Funhaler 
group continued to report significantly less days without wheeze (p = 0.01) than the 
Aerochamber Plus group. (Table 18). 
 122
 
 
Baseline visit 
 
Funhaler Aerochamber Plus p 
 Mean (95%CI) Mean (95%CI)  
Event free days 6.41 (6.07-6.76) 6.66 (6.41-6.90) 0.54 
All  
subjects 5.92 (5.44-6.39) 
6.49 (6.16-6.83) 0.02* 
Wheeze free 
days Male 6.05 (5.51 – 6.59) 6.78 (6.55 – 7.00) 0.01* 
Female 5.70 (4.75 – 6.64) 6.07 (5.31 – 6.83) 0.49 
Cough free days 4.98 (4.39-5.58) 5.43 (4.89-5.97) 0.15 
Bronchodilator free days 5.63 (5.12 - 6.15) 6.28 (5.91 - 6.66) 0.03* 
Table 18.  Baseline visit only.  Symptom free days as reported by diary card for the 
week before each study visit. 
4.4.6.4 Baseline visit:  Quality of life 
Quality of life scores, as determined by PedsQL version 3 (asthma module), were 
significantly different at the baseline visit; with the Funhaler group scoring lower (lower 
score suggests lower QoL) than the Aerochamber group at the time of randomisation.   The 
respective quality of life scores (mean (95%CI)) at the baseline visit for the Funhaler group 
and the Aerochamber Plus groups were 2047 (1967-2126) and 2157 (2083-2231) (p=0.05) 
respectively.  The lower QoL scores in the Funhaler group was consistent with the fewer 
wheeze free days, and fewer bronchodilator free days reported by the Funhaler group at the 
time.  
 
4.4.6.5 Baseline visit:  Lung function 
There was no significant difference (p > 0.05, t-test) between the Funhaler group and the 
Aerochamber Plus group in terms of bronchodilator response, or baseline lung function, at 
Rrs8, or Xrs8.  
 
 123
4.4.7 All visits: Overall proficiency in spacer technique as measured by drug 
delivered to filter         
Throughout the clinical trial, there was large inter-subject variation in proficiency in spacer 
technique, as measured by drug dose deposited on filter (Figure 23).  Mean drug dose 
recovered from filters ranged from zero to 136μg (as the mean of five 100μg doses).  
Accepting ten percent variability in the nominal dose emitted from the pMDI, and a ten 
percent margin of error in measurements, could not explain the two measurements above 
120μg.  The two measurements above 120μg were therefore considered to be faulty 
measurements.  
120
80
40
0
Baseline 3 months 6 months 9 months
Visit
 
Figure 23.  Scatter plot illustrating proficiency in spacer technique, as measured by 
drug dose deposited on a filter.  Filter studies were performed on all willing subjects 
at the first four study visits.  Filter dose is given as salbutamol collected on filter, in 
micrograms (average of five 100μg doses).  
 
The mean filter dose (per five 100μg puffs, divided by five) recovered at each visit 
remained in the mid- to low 30’s (Table 19).  Overall, there was no significant change in 
mean filter dose (p > 0.05 (paired sample t-tests)) from one visit to the next, or between the 
 124
Filter dose
first study visit, and the last study visit.  Intra-subject variation in filter dose from one visit 
to the next was large.  
 
 
 
Mean (95CI) salbutamol 
Visit n 
dose recovered from filter 
 
Baseline 125 36.6 (33.2 - 40.1) 
3 months 110 35.3 (31.3 - 39.4) 
6 months 90 34.2 (30.8 - 37.5) 
9 months 85 32.4 (28.6 - 36.3) 
Table 19. Salbutamol dose inhaled on filter by subject at study visits.  Filter dose in 
microgram (mean of five 100μg doses). 
 
4.4.8 Correlation between proficiency in using delivery device and QoL  
Proficiency in using delivery device, as measured by drug dose deposited on a filter 
interposed between subject and spacer, correlated positively with quality at life at the three 
month study visit (correlation coefficient = 0.19, p = 0.05) (Table 20).  There was no 
significant correlation between filter dose and quality of life at the other study visits.  When 
stratifying by age (subjects < 4 years at randomisation), there was no significant 
correlation, at any of the study visits, between proficiency in using delivery device, and 
quality of life.  When stratifying by gender, there was no significant correlation, at any of 
the study visits, between proficiency in using delivery device, and quality of life. 
 125
 
Quality of life score (PedsQL version 3, 
asthma module) 
 Baseline 3 months 6 months  9 months 
Correlation 
0.10 0.19 0.11 0.04
Proficiency in using Coefficient
delivery device  Sig. (2-
0.25 0.05* 0.30 0.75
(filter dose) tailed) 
N 121 109 88 84
Table 20.  Correlation between proficiency in using delivery device, as measured by 
drug dose deposited on a filter interposed between subject and spacer, and quality of 
life at the corresponding visit.  
 
With GEE analysis there was no correlation between proficiency in using the delivery 
device and QoL (p > 0.05), even after correcting for age, gender, adherence to prescribed 
medication, and QoL at the baseline visit.   
 
4.4.9 Correlation between proficiency in using delivery device, and other measures of 
clinical outcome  
There was no correlation between proficiency in using the delivery device (filter dose), and 
symptom control as determined by diary card, in the week running up to each study visit.  
(Table 21).  There was no correlation between proficiency in using the delivery device 
(filter dose), and the number of days where oral steroids were used (prescribed in the 
community and documented by parents on diary cards) to control asthma symptoms.   
 
After stratifying subjects by age (year groups) there was still no correlation between 
proficiency in spacer technique and asthma symptoms.  When stratified by gender, there 
was no correlation between proficiency in using the delivery device (filter dose) and asthma 
symptoms, except at the six month visit, where, in female subjects filter dose correlated 
significantly with wheeze free days (correlation coefficient = 0.37, p = 0.02). 
 126
 
Proficiency in using the delivery device 
(filter dose) 
Baseline 3 months 6 months 9 months 
        
Correlation Coefficient 0.03 0.09 0.15 -0.06 
Number of days Sig. (2-tailed) 0.78 0.36 0.18 0.57 
no wheeze 
N 121 105 87 81 
Correlation Coefficient < 0.01 -0.10 0.07 -0.09 
Number of days Sig. (2-tailed) 0.98 0.30 0.55 0.45 
no cough 
N 121 105 86 81 
Correlation Coefficient 0.03 0.02 -0.05 -0.04 
Bronchodilator 
Sig. (2-tailed) 0.75 0.82 0.64 0.7 
free days 
N 123 108 90 84 
Correlation Coefficient 0.09 -0.01 0.06 -0.14 
Event free days Sig. (2-tailed) 0.33 0.96 0.59 0.2 
N 121 108 90 84 
Table 21.  Correlation between proficiency in spacer technique, as measured by drug 
dose deposited on a filter interposed between subject and spacer, and symptom free 
days in week before study visit, as determined by diary card.  
 
GEE analysis confirmed that there was no significant correlation (p > 0.05) between 
proficiency in using the delivery device and markers of asthma control.  Correcting for age, 
gender, and adherence to prescribed medication did not influence the results.  
 
In order to examine whether very poor spacer technique resulted in poor clinical outcome, 
poor spacer technique was arbitrarily defined at a filter dose lower than 20μg.  Only 20 
subjects had filter doses lower than 20μg (out of a possible 100μg) at the baseline visit.  As 
the low numbers prevented statistical comparison, subjects with filter doses lower than 
25μg were analysed.  There were 37 subjects who had filter doses lower than 25μg at the 
baseline visit.  When subjects with filter doses ≤ 25μg, at the baseline visit were compared 
with the rest of the subjects, there was no significant difference (p > 0.05) between the 
groups in terms of any clinical outcome measure. 
 127
 
 
4.4.10   Role of incentive device in influencing proficiency in spacer technique 
Using GEE analysis, after correcting for age and gender, the Funhaler group had 
significantly higher proficiency in spacer technique as determined by filter dose (p = 0.05).  
The improved proficiency in spacer technique in the Funhaler group was limited to subjects 
who were younger than 4 years of age at the baseline visit (p < 0.01).  Subjects in the 
Funhaler group who were four years and older at the baseline visit did not show improved 
spacer technique over the Aerochamber Plus group (p = 0.87). 
 
When analyzed visit-by-visit, drug delivery to filter in subjects who were younger than four 
years of age at randomization, was significantly higher in the Funhaler group, at the three 
month and the nine month visits (p = 0.01 and 0.01, respectively (t-test)) (Table 22 and 
Figure 24).  For older children, drug delivery was not significantly higher in the Funhaler 
group.  
 
 Funhaler Aerochamber Plus  
 n mean (95CI) n mean(95CI) P (t-test) 
Baseline 24 34 (29 - 39) 28 34 (25 - 43) 0.99 
3 months 24 36 (29 - 43) 26 24 (19 - 30) 0.01* 
6 months 17 32 (24 - 40) 19 29 (22 - 36) 0.57 
9 months 16 42 (2 - 56) 21 24 (17 - 31) 0.01* 
Table 22.  Subjects younger than four years at baseline visit.  Comparison between 
Funhaler and Aerochamber Plus, in terms of filter studies performed at separate 
study visits.  Filter dose in microgram (mean of five doses). 
 128
 
 
Spacer
Funhaler
50 Aerochamber Plus
42 Error Bars show 95.0% Cl of Mean
40
34 34 36
32
30 29
24 24
20
p = 0.01 
p = 0.01 
10
Baseline 3 months 6 months 9 months
Visit
 
Figure 24.  Subjects younger than four years at baseline visit.  Error bars comparing 
Funhaler and Aerochamber Plus, in terms of filter dose collected at separate study 
visits.  Mean filter doses indicated as values in figure.    
 
As seen in figure 25, throughout the study, there were significantly more subjects in the 
Aerochamber Plus group who demonstrated poor spacer technique (filter doses lower than 
20µg) at the baseline visit, and at the three month visit (p = 0.01; Chi-sq for both visits).  
 129
Filter dose
 
Funhaler Aerochamber Plus
12
8
4
0
25 50 75 100 125 25 50 75 100 125
Baseline Baseline
Funhaler Aerochamber Plus
15
10
5
0
25 50 75 100 125 25 50 75 100 125
3 months 3 months
Funhaler Aerochamber Plus
15
10
5
0
25 50 75 100 25 50 75 100
6 months 6 months
Funhaler Aerochamber Plus
15
10
5
0
25 50 75 100 25 50 75 100
9 months 9 months
 
Figure 25.  Histogram plotting the number of subjects (Y-axis) grouped by filter dose 
collected (X-axis) at various study visits.  Funhaler group was compared with 
Aerochamber Plus group.   
 130
Count Count Count Count
 
 
4.4.11  Adherence to prescribed medication  
Electronic adherence data were recovered on 80% of subjects during the first three months 
of the study.  Recovery of adherence data decreased to 65% for the final three months of 
the study.  As seen in Table 23, data recovery was similar for the Funhaler and the 
Aerochamber Plus groups.  Reasons cited by parents for not bringing back the electronic 
adherence monitoring devices (or bringing back damaged devices) were as follows:  Lost 
device, forgot to bring device to study visit, did not know the device was not water proof, 
device was stolen.  A small number of devices (+/- 10%) failed during the study period.  A 
number of parents admitted that they at times failed to insert new pMDI canisters into the 
Smartinhaler® monitoring device, when the old pMDI canisters needed replacement.   
 
 Funhaler Aerochamber Plus All subjects 
 N (%) N (%) N (%) 
0 – 3 months 47 (77) 56 (84) 103 (80) 
3 – 6 months 44 (83) 52 (81) 96 (82) 
6 – 9 months 34 (69) 42 (66) 76 (67) 
9 – 12 months 31 (65) 41 (65) 72 (65) 
Table 23.  Electronic adherence data recovery.  
 
Inter subject variability in adherence to prescribed medication was marked throughout the 
study.  Adherence to prescribed medication ranged from 1% to 99% (Figure 26).  The 
median adherence dropped significantly (p < 0.01; Kendalls W) over the course of the 
study.  Median (range) adherence was 68.5% (14.0 – 99.0), 60.6% (1.0 – 99.0), 60.0% (0.5 
– 99.5%) and 50.4% (0-100) for each respective three month period.    
 131
  
 
 
 
Figure 26.  Scatter plot illustrating mean adherence to prescribed medication, for 
each subject, over the year long study period.  
 132
 
 
4.4.12   Correlation between adherence to prescribed treatment and QoL. 
 
Using GEE analysis, after correcting for age and gender, adherence to prescribed 
medication throughout the study period correlated with QoL at the baseline visit (p = 0.03).  
Adherence did not correlate with QoL throughout the rest of the study (p = 0.32). 
 
4.4.13   Correlation between adherence to prescribed treatment and other markers of 
clinical outcome.   
 
GEE analysis revealed a significant correlation between adherence to prescribed 
medication and bronchodilator free days (r = 0.01; p = 0.02) throughout the study.   
After correcting for age, gender, proficiency in spacer technique, and bronchodilator free 
days at baseline, the significant correlation between adherence to prescribed medication 
and bronchodilator free days remained (r = 0.01; p = 0.01).   
 
Furthermore, there was a significant correlation between adherence to prescribed 
medication and number of symptom free days (p < 0.05), at various points, and for different 
variables in the study:  At the baseline visit, there was a significant correlation (r = 0.35; p 
< 0.01) between adherence and days without wheeze.  There was no significant correlation 
between adherence and days without wheeze at any other point during the study (Table 24).  
With GEE, however, there was no significant correlation between adherence and days 
without wheeze throughout the study.  Results were not influenced by correcting for age, 
gender, proficiency in spacer technique, or wheeze at the baseline visit. 
 
At each individual study visit, there was no significant correlation between adherence to 
prescribed medication and the number of days without cough, bronchodilator free days and 
event free days in the week before each visit.    
 133
 
  
 
  Adherence to prescribed medication 
   
  0 - 3 3 - 6 6 - 9 9 - 12 
  months months months months 
Correlation 
Number of days Coefficient 0.35 0.05 0.08 0.16 
no wheeze 
 Sig. (2-tailed) < 0.01* 0.62 0.50 0.19 
 N 101 93 74 66 
Correlation 
Number of days Coefficient 0.11 0.19 0.16 0.16 
no cough 
 Sig. (2-tailed) 0.11 0.06 0.18 0.21 
 N 101 92 74 67 
Correlation 
Number of Coefficient 0.18 0.16 0.22 0.12 
bronchodilator 
free days Sig. (2-tailed) 0.07 0.13 0.06 0.30 
 N 103 96 76 71 
Correlation 
Coefficient 0.19 0.10 0.14 0.01 
Event free days 
Sig. (2-tailed) 
 0.05 0.32 0.24 0.91 
N 103 96 76 71 
Table 24.  All subjects:  Correlation between asthma symptoms (diary card for the 
week before each study visit) and electronically monitored adherence over the three 
month period in between study visits.  
 
Day and night-time symptoms analysed separately: 
When daytime and night time symptoms were examined separately, there was a significant 
positive correlation between the number of nights without wheeze and adherence to 
prescribed treatment in the first three months of the clinical trial (Table 25).  The 
correlation between nights without wheezing and adherence remained during the three to 
six month, and nine to twelve month parts of the study, but was not significant for the six to 
nine months part of the study period.  With GEE analysis there was a significant correlation 
between adherence to prescribed medication and nights without wheeze, throughout the 
study period (r = 0.01; p = 0.01).  The correlation between adherence to prescribed 
medication and nights without wheeze remained after correcting for age, gender, 
proficiency in spacer technique, and the number of nights without wheeze at the baseline 
 134
visit (r = 0.01; p < 0.01).  GEE analysis also revealed a significant correlation between 
adherence to prescribed treatment and (daytime) days without wheeze (r = 0.01; p = 0.01).  
The correlation ceased to be significant after correcting for age, gender, proficiency in 
spacer technique, and (daytime) days without wheeze at the time of the baseline visit. 
 135
 
 
 
Adherence to prescribed medication 
 
 
0 - 3 3 - 6 6 - 9 9 - 12 
 months months months months 
Number of days Correlation 
no wheeze Coefficient 0.34 0.13 0.13 0.22 
 Sig. (2-tailed) < 0.01* 0.22 0.28 0.07 
 N 103 96 76 71 
Number of nights Correlation 
no wheeze Coefficient 0.20 0.26 0.16 0.30 
 Sig. (2-tailed) 0.04* 0.01* 0.18 0.01* 
 N 103 96 76 71 
Number of days Correlation 
no cough Coefficient 0.14 0.142 0.092 0.03 
 Sig. (2-tailed) 0.16 0.17 0.43 0.83 
 N 103 96 76 71 
Number of nights Correlation 
no cough Coefficient 0.20 0.15 0.10 0.01 
 Sig. (2-tailed) 0.05* 0.14 0.39 0.96 
 N 103 96 76 71 
Table 25.  All subjects:  Correlation between asthma symptoms (day time and night 
time symptoms separated) and electronically monitored adherence over the three 
month period in between study visits.  
 
When stratified by age (subjects younger than four years at randomisation), the only 
significant correlation between adherence and asthma symptoms were found at the three 
month visit, where adherence correlated positively with wheeze free days (correlation 
coefficient = 0.44, p = 0.01).  When stratified by gender, there was a significant correlation, 
in male subjects, between adherence and cough free nights at three months, as well as a 
significant correlation between adherence and wheeze free nights at six months (Table 26).  
 136
In females, there was a significant correlation between adherence and wheeze free days, 
wheeze free nights-, and cough free days at the three month visit (Table 27).  
 
  Adherence to prescribed medication 
   
  0 - 3 3 - 6 6 - 9 9 - 12 
  months months months months 
Correlation 
Coefficient  0.20 0.08 0.07 0.20 
Number of days 
no wheeze Sig. (2-tailed) 0.12 0.55 0.78 0.20 
  
  N 60 60 18 44 
Correlation 
Coefficient 0.06 0.27 0.07 0.20 
Number of nights 
no wheeze Sig. (2-tailed) 0.63 0.04* 0.78 0.19 
  
  N 60 60 18 44 
Correlation  
Coefficient 0.19 0.09 0.05 -0.15 
Number of days 
no cough Sig. (2-tailed) 0.14 0.50 0.83 0.33 
  
  N 60 60 18 44 
Correlation 
Coefficient 0.27 0.09 -0.12 -0.17 
Number of nights 
no cough Sig. (2-tailed) 0.04* 0.50 0.63 0.28 
  
  N 60 60 18 44 
Table 26.  Male subjects:  Correlation between asthma symptoms (diary card for the 
week before each study visit) and electronically monitored adherence over the three 
month period in between study visits.  
 137
 
  Adherence to prescribed medication 
   
  0 - 3 3 - 6 6 - 9 9 - 12 
  months months months months 
Correlation 
Coefficient  0.50 0.26 -0.08 0.25 
Number of days 
no wheeze Sig. (2-tailed) < 0.01* 0.13 0.78 0.20 
  
  N 43 36 14 27 
Correlation 
Coefficient 0.33 0.23 -0.11 0.43 
Number of nights 
no wheeze Sig. (2-tailed) 0.03* 0.18 0.70 0.03 
  
  N 43 36 14 27 
Correlation  
Coefficient 0.07* 0.25        0.19 0.33 
Number of days 
no cough Sig. (2-tailed) 0.67 0.13 0.50 0.09 
  
  N 43 36 14 27 
Correlation 
Coefficient 0.11 0.35 0.19 0.28 
Number of nights 
no cough Sig. (2-tailed) 0.50 0.04 0.52 0.16 
  
  N 43 36 14 27 
Table 27.  Female subjects:  Correlation between asthma symptoms (diary card for 
the week before each study visit) and electronically monitored adherence over the 
three month period in between study visits.  
 
When the Funhaler and Aerochamber Plus groups were analysed separately, adherence 
correlated more markedly with symptom control in the Funhaler group, with a significant 
correlation extending to days without cough (Table 28).  In the Aerochamber Plus group, 
adherence to prescribed treatment correlated only with wheeze free days in the first three 
months of the study (Table 29).   
 138
 
  Adherence to prescribed medication 
   
  0 - 3 3 - 6 6 - 9 9 - 12 
  months months months months 
Correlation 
Coefficient 0.38 0.29 0.25 0.30 
 
Number of days Sig. (2-tailed) 
no wheeze  0.01* 0.06 0.16 0.11 
  N 
   47 44 34 30 
Correlation 
Coefficient 0.30 0.36 0.14 0.40 
Number of nights 
no wheeze Sig. (2-tailed) 0.04* 0.02* 0.42 0.03* 
  
  N 47 44 34 30 
Correlation 
Coefficient 0.39 0.12 0.23 -0.02 
Number of days 
no cough Sig. (2-tailed) 0.01* 0.43 0.20 0.92 
  
  N 47 44 34 30 
Correlation 
Coefficient 0.35 0.17 0.07 0.03 
Number of nights 
no cough Sig. (2-tailed) 0.02* 0.27 0.70 0.90 
  
  N 47 44 34 30 
Table 28.  Funhaler group:  Correlation between asthma symptoms (diary card week 
before study visit) and electronically monitored adherence over the three month 
period in between study visits.  
 139
 
 
  Adherence to prescribed medication 
   
  0 - 3 3 - 6 6 - 9 9 - 12 
  months months months months 
Correlation 
Coefficient 0.33 -0.09 -0.01 0.14 
Number of days 
no wheeze Sig. (2-tailed) 0.02* 0.55 0.94 0.38 
  
  N 56 52 42 41 
Correlation 
Coefficient 0.13 0.07 0.15 0.21 
Number of nights 
no wheeze Sig. (2-tailed) 0.33 0.62 0.34 0.19 
  
  N 56 52 42 41 
Correlation 
Coefficient -0.03 0.11 -0.01 0.04 
Number of days 
no cough Sig. (2-tailed) 0.81 0.42 0.95 0.80 
  
  N 56 52 42 41 
Correlation 
Coefficient 0.10 0.06 0.11 < 0.01 
Number of nights 
no cough Sig. (2-tailed) 0.49 0.67 0.48 1.00 
  
  N 56 52 42 41 
Table 29.  Aerochamber Plus group:  Correlation between asthma symptoms (diary 
card week before study visit) and electronically monitored adherence over the three 
month period in between study visits.  
 
At no point in the study was there any significant correlation between adherence to 
medication and event free days, or days on systemic corticosteroids.  Stratification in terms 
of age, gender, or spacer group did not influence the results.  
 
4.4.14    Role of incentive device in influencing adherence to prescribed medication 
There was no significant difference in adherence between the Funhaler group and the 
Aerochamber Plus group for any three month period during the clinical trial (Figure 27).  
 140
 
 
Figure 27.   Error bars comparing the mean (95CI) adherence between the Funhaler 
and the Aerochamber Plus groups.  
 
Using GEE analysis, there was no significant difference in adherence to prescribed 
medication between the Funhaler group and the Aerochamber Plus group (p = 0.93).  
Correcting for age and gender did not influence the results. 
 
When stratified for gender, females in the Aerochamber Plus group demonstrated higher 
adherence than females in the Funhaler group (Table 30).    However, with GEE analysis 
there was no significant difference in adherence in females between the Funhaler group and 
the Aerochamber Plus group. 
 141
 
 
Visit Funhaler Aerochamber Plus p 
 median (range) median (range)  
3 months 67.3 (26.0 – 98.0) 63.8 (15 – 97) 0.77 
6 months 53.8 (11.0 – 94.0) 68.8 (11.0 – 97.0) 0.04* 
9 months 47.2 (0.5 – 94.2) 61.1 (15.4 – 94.8) 0.25 
12 months 43.8 (0.0 – 91.4) 56.0 (11.5 – 92.8) 0.25 
Table 30.  Female subjects only:  Mean adherence to prescribed dose of asthma 
preventers, during the three months leading up to study visits. 
 
4.4.15   Role of incentive device in influencing clinical outcome.  
As mentioned before, the Funhaler group and the Aerochamber Plus group were not equal 
at the time of randomisation (baseline visit) in terms of clinical outcome measures: 
 
Asthma symptoms. 
The Funhaler group reported significantly less days without wheeze (p = 0.02), and 
significantly less bronchodilator free days (p = 0.03) than the Aerochamber Plus group in 
the seven days before the baseline visit (Tables 31 and 33).   
 
After the baseline visit, the only significant difference in symptoms between the 
Aerochamber group and the Funhaler group was at the six month study visit.  At the six 
month visit, the Funhaler group reported significantly less cough free days (p = 0.03; Mann 
Whitney U) (Table 32). 
 142
 
 
Wheeze free days 
 Funhaler Aerochamber Plus p 
Mean (95%CI) Mean (95%CI)  
Baseline 5.92 (5.44-6.39) 6.49 (6.16-6.83) 0.02* 
3 month visit 6.46 (6.05-6.86) 6.55 (6.22-6.89) 0.97 
6 month visit 6.31 (5.91-6.72) 6.32 (5.89-6.75) 0.93 
9 month visit 6.19 (5.68-6.69) 6.25 (5.78-6.72) 0.73 
12 month visit 6.26 (5.76-6.76) 6.09 (5.54-6.64) 0.93 
Table 31.  Wheeze free days as reported by diary card for the week before each study 
visit. 
 
 Cough free days 
 Funhaler Aerochamber Plus p 
 Mean (95%CI) Mean (95%CI)  
Baseline 4.89 (4.39-5.58) 5.43 (4.89-5.97) 0.15 
3 month visit 5.44 (4.81-6.07) 5.85 (5.31-6.38) 0.32 
6 month visit 4.79 (3.98-5.60) 6.07 (5.57-6.56) 0.03* 
9 month visit 5.79 (5.18-6.41) 5.05 (4.37-5.73) 0.13 
12 month visit 6.07 (5.50-6.63) 5.29 (4.63-5.94) 0.11 
Table 32.  Cough free days as reported by diary card for the week before each study 
visit. 
 143
 
 Bronchodilator free days 
 Funhaler Aerochamber Plus p 
 Mean (95%CI) Mean (95%CI)  
Baseline 5.63 (5.12 - 6.15) 6.28 (5.91 - 6.66) 0.03* 
3 month visit 6.08 (5.59 - 6.57) 5.95 (5.44 - 6.47) 0.90 
6 month visit 5.83 (5.26 - 6.40) 6.20 (5.73 - 6.68) 0.17 
9 month visit 6.25 (5.79 - 6.71) 5.81 (5.24 - 6.38) 0.67 
12 month visit 6.17 (5.69 - 6.65) 6.10 (5.65 - 6.54) 0.99 
Table 33.  Bronchodilator free days as reported by diary card for the week before 
each study visit. 
 
GEE analysis did not reveal any significant difference between the Funhaler group and the 
Aerochamber Plus group in terms of wheeze, cough, or bronchodilator use (p > 0.05).  
Correcting for age, gender and symptoms at the baseline visit did not influence the results. 
 
Number of days where oral steroids were used. 
At no point in the study, was there a significant difference between the Funhaler group and 
the Aerochamber Plus group, in terms of the number of days where oral steroids were used, 
as documented by parents on a separate diary card.  Stratifying by age and gender did not 
reveal any significant difference between groups.  
 
Asthma exacerbations. 
Parents were requested to document the number of days in between study visits, where 
subjects experienced asthma exacerbations.  As the parents were never given a definition of 
asthma exacerbations, the documentation was found to be too subjective to analyse.  
 144
 
 
Quality of life. 
Quality of life scores, as determined by PedsQL version 3 (asthma module), were 
significantly different at the baseline visit; with the Funhaler group scoring lower than the 
Aerochamber group at the time of randomisation (Table 34).  Quality of life scores were 
therefore reported relative to the baseline visit scores (Table 35).  There was no significant 
difference between the Funhaler group and the Aerochamber Pus group, at any stage of the 
clinical trial, in terms of in quality of life relative to baseline.  Stratifying by age (subjects 
younger than four years, as well as year groups) and gender did not make any significant 
difference to the results.  
 
 Quality of life scores 
 Funhaler Aerochamber Plus p 
 n Mean (95%CI) n Mean (95%CI)  
Baseline 61 2047 (1967-2126) 67 2157 (2083-2231) 0.05* 
3 month visit 60 2190 (2105-2275) 67 2231 (2146-2316) 0.5 
6 month visit 50 2268 (2167-2370) 64 2395 (2329-2461) 0.03* 
9 month visit 48 2340 ((2253-2426) 62 2365 (2289-2440) 0.66 
12 month visit 38 2372 (2280-2464) 51 2388 (2280-2464) 0.81 
Table 34.  Quality of life scores, as determined by PedsQL version 3 (asthma module), 
completed by parents at every study visit.  
 145
 
 Quality of life scores relative to baseline scores 
 Funhaler Aerochamber Plus p 
 n Mean (95%CI) n Mean (95%CI)  
3 month visit 58 138 (57 – 217) 67 74 (-9 – 157) 0.31 
6 month visit 48 188 (78 – 297) 64 238 (160 – 315) 0.40 
9 month visit 46 310 (209 – 410) 62 215 (133 – 296) 0.18 
12 month visit 36 313 (187 – 439) 51 257 (166 – 348) 0.79 
Table 35.  Relative quality of life scores, as determined by PedsQL version 3 (asthma 
module),  completed by parents at every study visit.  Quality of life scores reported 
relative to scores at baseline.  
 
Using GEE analysis, and correcting for age, gender, and quality of life at the baseline visit,  
there was still no significant difference in quality of life between  the Funhaler group and 
the Aerochamber Plus group (p = 0.42). 
 
4.4.16   Lung function 
Lung function studies (forced oscillation technique) were attempted on all willing study 
subjects, at all study visits.  Acceptable lung function data (Table 36) were obtained in the 
majority of older subjects.  Success in obtaining acceptable lung function data in the 
younger subjects was limited by movement artefacts, and the subjects’ willingness to co-
operate for a sufficient period of time.  At all study visits, a number of subjects had to be 
excluded due to administration of long acting β-agonists within twelve hours before the 
study visits.  
 146
 
 
 Baseline 3 months 6 months  9 months 12 months 
Groups N (%) N (%) N (%) N (%) N (%) 
2 years 2 (10.0) 3 (15.0) 4 (20.0) 6 (30.0) 5 (25.0) 
3 years 13 (35.1) 17 (45.9) 21 (56.8) 19 (51.4) 23 (62.2) 
4 years 17 (53.1) 20 (62.5) 19 (59.4) 14 (43.8) 20 (62.5) 
5 years 14 (70.0) 15 (75.0) 16 (80.0) 15 (75.0) 13 (65.0) 
6 years 16 (72.7) 17 (77.3) 10 (45.5) 15 (68.2) 12 (54.5) 
All FH 28 (43.1) 31 (47.7) 27 (41.5) 31 (47.7) 29 (44.6) 
age AC+ 34 (50.7) 42 (62.7) 44 (65.7) 39 (58.2) 45 (67.2) 
groups 
Total 62 (47.0) 73 (55.1) 71 (53.8) 70 (53.0) 74 (56.1) 
Table 36.  Number of subjects per age group, and per study- and control group, on 
whom lung function testing was successfully performed.  Subjects who were 
administered long acting beta stimulants less than 12 hours before the study visit were 
not included.  Only subjects with pre- and post bronchodilator measurements shown. 
FH = Funhaler, AC+ = Aerochamber Plus. 
 
Subjects’ baseline (pre-bronchodilator) resistance at eight Hertz were slightly higher than 
the population mean (mean z-scores per study visit ranging from 0.47 to 0.60).  Subjects’ 
baseline reactance at eight Hertz was slightly higher than the population mean (mean z-
scores for Xrs8 ranging from 0.06 to 0.22).  Lung function results for all visits are 
presented in tables 37 and 38. 
 147
 
 
 Baseline 3 months 6 months  9 months 12 months 
 Mean Mean Mean Mean Mean (95%CI) (95%CI) (95%CI) (95%CI) (95%CI) 
Rrs8 0.57  0.53 0.47  0.56  0.60  
(0.30, 0.84)  (0.28, 0.78) (0.18, 0.76) (0.35, 0.76) (0.40, 0.80) 
Xrs8 0.14 0.22 0.22 0.06 0.09 
(-0.13, -0.40) (-0.01, 0.05) (-0.04, 0.47) (-0.18, 0.30) (-0.15, 0.34) 
Table 37.  Z-scores of pre-bronchodilator (baseline) lung function of all subjects.  
 
 
 
 Baseline 3 months 6 months  9 months 12 months 
 Mean Mean Mean Mean Mean (95%CI) (95%CI) (95%CI) (95%CI) (95%CI) 
Rrs8 -12.3 -13.5 -13.3 -12.5 -13.3 
(-8.1, -16.4) (-10.1, -16.9) (-10.4, -16.1) (-9.5, -15.6) (-10.3, -16.3)
Xrs8 19.1 20.9 24.4 28.5 27.1 
(9.6, 28.7) (13.2, 28.6) (17.7, 31.0) (22.8, 34.3) (19.5, 34.8) 
Table 38.  Bronchodilator response in all subjects, given as percentage change relative 
to baseline lung function.  
 
 
4.4.16.1 Correlation between lung function and drug delivery/ proficiency in spacer 
technique. 
 
Filter dose and bronchodilator response at the corresponding study visit. 
As bronchodilator response was used as a marker of clinical outcome, and the magnitude of 
bronchodilator response could potentially have been influenced by the subjects’ proficiency 
in inhaling the bronchodilator (and thus bronchodilator dose inhaled), the possibility of a 
 148
correlation between proficiency in inhaling salbutamol (filter dose, as used throughout the 
study) and bronchodilator response, was not investigated.   
 
Baseline lung function and filter dose. 
There was no significant correlation between filter dose (as described earlier) and baseline 
(pre-bronchodilator) lung function, at any of the study visits.  With GEE analysis there was 
no significant correlation between filter dose and baseline (pre-bronchodilator) lung 
function (p > 0.05) throughout the study.  Correcting for age, gender, adherence to 
prescribed medication, and lung function measured the beginning to the study, did not 
significantly influence the results. 
 
4.4.16.2   Correlation between adherence to prescribed medication and lung function. 
Using GEE analysis, there was no significant correlation between Rrs8, or Xrs8 and 
adherence to prescribed medication (p = 0.09 and p = 0.08, respectively). After correcting 
for age and gender, lung function at the baseline visit, and proficiency in spacer technique 
(filter dose),  there was still no significant correlation between Rrs8 or Xrs8 and adherence 
to prescribed medication (p = 0.08 and p = 0.14, respectively).   
 
4.4.17   Influence of the Funhaler on lung function 
There was no significant difference (p > 0.05, t-test) between the Funhaler group and the 
Aerochamber Plus group in terms of bronchodilator response, or baseline lung function, at  
Rrs8, or Xrs8 (Tables 39 and 40).  In subjects younger than four years of age at time of 
randomisation, there was no significant difference (p > 0.05) between the Funhaler group 
and the Aerochamber Plus group, in terms of baseline lung function or bronchodilator 
response.  There were too few data to stratify subjects per year of age.   
 149
 
 Group Baseline 3 months 6 months  9 months 12 months 
Mean Mean Mean Mean Mean 
  
(95%CI) (95%CI) (95%CI) (95%CI) (95%CI) 
Rrs8 FH -12.0 15.3 14.0 14.0 12.4 
(-5.6, -18.4) (9.7, 20.8) (9.2, 18.7) (8.7, 19.3) (7.0, 17.0) 
AC+ -12.4  -12.1 -12.8 -11.4 -13.9 
(-6.6, -18.4) (-7.7, -16.5) (-9.1, -16.6) (-7.7, -15.1) (-10.2,-17.7) 
Xrs8 FH 20.9 19.4 26.5 31.7 21.8 
(8.6, 33.2) (8.3, 30.6) (14.6, 38.3) (22.8, 40.5) (6.4, 37.3) 
AC+ 17.6 21.9 23.1 26.0 30.5 
(2.9, 32.3) (11.0, 32.8) (14.9, 31.3) (18.2, 33.8) (22.4, 38.6) 
Table 39.  Comparison of bronchodilator response in Funhaler (FH) versus 
Aerochamber Plus (AC+) groups.  Bronchodilator response presented as percentage 
change relative to baseline lung function.  No significant difference ( p > 0.05) between 
groups at any study visit.  
 
 Group Baseline 3 months 6 months  9 months 12 months 
Mean Mean Mean Mean Mean 
  
(95%CI) (95%CI) (95%CI) (95%CI) (95%CI) 
Rrs8 FH 0.85 0.65 0.53 0.79 0.80 
(0.42, 1.27) (0.24, 1.06) (-0.11, 1.18) (0.37, 1.22) (0.40, 1.21) 
AC+ 0.30 0.44 0.43 0.38 0.48 
(-0.03, 0.63) (0.12, 0.75) (0.15, 0.71) (0.20, 0.55) (0.28, 0.68) 
Xrs8 FH 0.013 0.26 0.15 -0.11 0.11 
(-0.41, 0.44) (-0.11, 0.64) (-0.32, 0.62) (-0.55, -0.32) (-0.54, 0.56) 
AC+ 0.26 (-0.08, 0.19 0.26 0.19 0.14 
0.60) (-0.12, 0.50) (-0.06, 0.57) (-0.08, 0.46) (-0.10, 0.38) 
Table 40.  Comparison of pre-bronchodilator (baseline) lung function in Funhaler 
(FH) versus Aerochamber Plus (AC+) groups.  Data presented as Z-scores. 
 
 
 150
 
Using GEE analysis, there was no significant difference in Rrs8 or Xrs8 between the 
Funhaler group and the Aerochamber Plus group (p = 0.09 and 0.46 respectively).  After 
correcting for lung function at the baseline visit, as well as for age and gender, there was 
still no significant difference in Rrs8 or Xrs8 between the Funhaler group and the 
Aerochamber Plus group (p = 0.84 for both Rrs8 and Xrs8). 
 151
 
4.5   Discussion 
4.5.1 Summary of main findings 
4.5.1.1 Proficiency in spacer technique  
Proficiency in spacer technique versus clinical outcome 
The clinical trial results suggested that proficiency in spacer technique did not translate to 
improved clinical outcomes.  Results were likely to have been influenced by various 
factors, including large variations in prescribed medication dose, carry over effect of being 
involved in a study and limitations in the study design (discussed below, under 
“Limitations of study”).  
 
Role of incentive device in influencing proficiency in spacer technique 
Subjects younger than four years of age in the Funhaler group demonstrated a higher 
proficiency in spacer technique, than subjects younger than four years of age in the 
Aerochamber Plus group.  The improved spacer technique, in children younger than four 
years of age who were using the Funhaler®, was not unexpected.  It is intuitive that very 
young children would be more likely to be influenced by the simple incentive utilized by 
the Funhaler (spinning disk and whistle).   
 
There were a greater number of subjects with poor spacer technique in the Aerochamber 
Plus group.  Use of the Funhaler® therefore appeared to specifically improve drug delivery 
in those subjects who, with a conventional spacer, would have inhaled very low doses of 
medication.  However, cross-over study would be more suited to prove the above.  
 
The hypothesis that the Funhaler may improve spacer technique in preschool children was 
therefore shown to be partially correct:  The Funhaler had a positive influence on spacer 
technique in children younger than four years of age, and on a group of children who would 
have had very poor spacer technique had they used a conventional spacer.  The Funhaler®, 
therefore, should be considered for use in children younger than four years of age, and in 
older children where poor spacer technique is suspected.   
 
 152
As mentioned above, incentive devices are widely used to influence breathing during lung 
function measurements, but to the author’s knowledge this is the first study to demonstrate 
a positive influence of an incentive device on spacer technique. 
 
Overall proficiency in spacer technique 
There was large intra-subject variation in proficiency in spacer technique, as measured by 
filter dose.  The large variation in proficiency in spacer technique which results in a large 
variation in inhalation drug delivery to preschool children highlights the importance of 
pursuing ways to improve inhalation drug delivery to preschool children, in order to reduce 
the variability in prescribed medication that eventually reaches patients.    
 
4.5.1.2 Adherence to prescribed medication  
Correlation between adherence and clinical outcome. 
Throughout the clinical trial, there were significant positive correlations between adherence 
to prescribed treatment and measures of asthma control (notably bronchodilator free days, 
and nights without wheeze) in some analyses.  The hypothesis that adherence to prescribed 
medication regimens correlates positively with improved clinical outcome in preschool 
children with asthma, was therefore proved correct.   The correlation between adherence 
and clinical outcome was not unexpected, as a similar correlation was demonstrated in 
older children [162, 163].    
 
Decreasing numbers in diary cards returned (130 at baseline decreased to 109 at the final 
visit), and decreasing adherence data (103 at three months decreased to 72 at twelve 
months) may have influenced the results towards the end of the study, causing a reduction 
in the number of outcome measures that correlated with adherence as the study progressed. 
 
An unexpected finding was that adherence to prescribed medication is influenced by QoL:  
Adherence to prescribed medication throughout the study period correlated with QoL at the 
baseline visit.  Adherence did not correlate with QoL throughout the rest of the study.  One 
could therefore conclude that adherence was influenced by baseline QoL, and not vice-
versa.  Bearing in mind that in young children, adherence to prescribed treatment is 
caregiver dependant; if QoL in young children is associated with improved adherence to 
prescribed treatment, then it follows that either the child’s behaviour influences the 
 153
caregiver’s adherence, or that overall higher QoL in the family unit is related to improved 
adherence.   
 
Barlett et al (2004) demonstrated that maternal depression is linked to poor adherence 
[284].  Our results indirectly support the concept mentioned by Barlett that identifying and 
addressing poor psychological adjustment in mothers/families may facilitate medication 
adherence in paediatric asthmatic patients.   Further research into the link between QoL and 
adherence to prescribed medication may be warranted. 
 
Role of incentive device in influencing adherence to prescribed medication 
There was no significant difference in adherence between the Funhaler group and the 
Aerochamber Plus group throughout the clinical trial.  The hypothesis, that the Funhaler 
would improve adherence to prescribed inhaled medication in preschool children, could not 
be supported.   
 
Overall adherence during clinical trial 
There was a very large range in mean adherence to prescribed medication (1% to 99%).  
The results were in keeping with previous studies where adherence was monitored in 
preschool children [154, 159-161].  This study was larger, over a longer period of time and  
with more objective measurements than previous studies investigating adherence to inhaled 
medication in preschool aged children.  Until now, the longest that adherence to inhaled 
medication was monitored electronically in preschool children was 50 days [159].  The 
year long time frame of our clinical trial, allowed for the “study effect” to wear off.  Hence, 
mean adherence therefore gradually dropped during the course of the study.   Mean 
adherence was 66% for the first three months, and decreased to 52% for the final three 
months of the study.    The decrease in adherence could be ascribed to regression to the 
mean, or to a natural decrease adherence rates as a factor of time.   
 
In spite of parents of subjects being motivated enough to attend five study visits over a 
thirteen month period, and being aware that their adherence was being monitored, the mean 
adherence of subjects was low, in keeping with previous studies of adherence to inhaled 
medication in preschool children [154, 159-161], outlined in Table 2, section 1.8.1. 
.  
 
 154
4.5.1.3   Role of incentive device in influencing clinical outcome.  
The study group and the control group were not equal at the time of randomisation 
(baseline visit) in terms of clinical outcome measures.  At the baseline visit the Funhaler 
group reported significantly fewer days without wheeze, significantly fewer bronchodilator 
free days, and scored lower on QoL than the Aerochamber Plus group.  Statistical analysis 
therefore had to correct for differences between the Funhaler group and the Aerochamber 
Plus groups in terms of baseline symptoms.  Correction of differences at the baseline visit  
in terms of the more pronounced symptoms and lower QoL in the Funaler group at the 
baseline visit could potentially have masked significant improvements in the Funhaler 
group later on in the study.  Different methods were used for QoL and for other markers of 
clinical outcome, to correct for the inequality at the beginning of the study, between the 
study group and the control group.  After correction for the difference at baseline, there was 
no significant difference between the Funhaler group and the Aerochamber group in any of 
the clinical outcome measures.  
 
The hypothesis, that use of an incentive spacer, the Funhaler, improves clinical outcome in 
preschool children with asthma, could therefore not be supported. 
 
4.5.1.4 Influence of the Funhaler on lung function 
There was no significant difference between the Funhaler group and the Aerochamber Plus 
group in terms of bronchodilator response, or baseline lung function.  Stratifying for age, 
and analysing only the atopic subjects, did not influence the results.  The FOT data could 
therefore not demonstrate a difference between groups in any aspect of the study.  
 
4.5.2 Limitations of study 
4.5.2.1 Asthma diagnosis 
Subjects were diagnosed with asthma by doctors in the community.  The diagnosis of 
asthma was therefore not standardised.  Asthma severity in the study population varied, 
ranging from subjects who required inhaled steroids throughout the study, to subjects who 
were successfully weaned off all asthma medication after three months.  The large number 
of subjects who were successfully weaned off their asthma preventer medications suggests 
 155
that a significant number of subjects may not have had asthma at all, or may have been 
overtreated at the commencement of the study.  
 
It is well recognised that asthma can be difficult to diagnose in young children.  The latest 
trend is to not diagnose asthma in preschool children, but to classify preschool wheeze into 
episodic viral wheeze and multiple trigger wheeze[278].  However, the better part of our 
study population had frequent wheezing episodes and a predisposition towards atopy, and 
therefore represent a relatively homogenous population of atopic preschool wheezers 
consistent with asthma. 
 
4.5.2.2 Differences between study group and control group. 
In spite of randomisation, the Funhaler group differed significantly from the Aerochamber 
group in terms of the following: 
• Increased asthma symptoms at the time of randomisation 
• Lower quality of life at the time of randomisation 
• Higher drop-out rate. 
• Higher atopy /doctor diagnosed eczema 
 
As clinical outcome was an important aspect of the study, the difference in 
symptomatology at the start of the study made the comparison of the two groups difficult.  
In the analysis, corrections were made for atopy, and the differences in clinical outcome 
measures at the start of the study, but it is not possible to know to what extent the 
abovementioned differences may have still influenced the results.  
 
4.5.2.3 Filter dose as a measure of proficiency in spacer technique 
Total drug delivery to filter was used as a marker of spacer technique.  Rapid inhalation, 
which is associated with increased drug deposition in the upper airway, and decreased drug 
delivery to the lower airways, could potentially have resulted in improved drug delivery to 
filter.  Total drug delivery to filter is therefore an imperfect measure of proficiency in 
spacer technique.  However, the strength of using total drug delivery to filter as a measure 
of proficiency in spacer technique lies in its ability to quantify the result of a complex set of 
patient-device interactions.  Other measures of proficiency in spacer technique, like 
 156
documenting a subject’s expertise in performing a set of steps of spacer use, relies on 
subjective observation, and the cumulative effect that various degrees of missteps would 
have on drug delivery would be virtually impossible to quantify.  
 
In the clinical trial, where filter dose was used as a measure of proficiency in spacer 
technique, the rationale was that, if a subject inhaled his/her asthma preventer effectively in 
the months before the study visit, the subject may have improved asthma control.   
 
As filter dose only represents total drug delivery to the mouth, and not respirable dose, it is 
a relatively blunt instrument in determining drug delivery to the airways.  Breathing pattern 
is an important component of spacer technique.  Differences in breathing pattern may have 
influenced the respirable fraction of drug delivery.  Differences in respirable fraction would 
not have been picked up by filter studies.  It is possible that a stronger correlation between 
spacer technique and measures of asthma control could have been demonstrated if a more 
precise measure of drug delivery to the airways was used.   
 
4.5.2.4 Variation in prescribed dose of asthma preventers 
Subjects were not prescribed a homogenous fluticasone dose at the start of the study, but 
were prescribed the fluticasone dose that they were being prescribed in the community (or 
equivalent fluticasone dose, if they were being prescribed different corticosteroid 
formulations in the community).  During the course of the clinical trial, the fluticasone dose 
prescribed was increased and decreased according to asthma symptoms.  If parents were 
not comfortable with their child’s medication being decreased, a subject’s medication 
would remain the same.  Doctors in the community also could make changes to their 
patients’ fluticasone dose, as long as the study co-ordinator was notified.  Subjects with 
poor spacer technique were not necessarily prescribed higher doses of inhaled fluticasone.   
 
The variation in dose of prescribed fluticasone from subject to subject, and from visit to 
visit, made data interpretation challenging.  The large inter-subject variation in drug 
delivery and adherence to medication may have had a mitigating effect on the difference in 
prescribed medication, thereby weakening most the outcome measures of the study.  
Control of symptoms in run-in period 
 157
A weakness in the study design was the requirement for subjects to have “stable” asthma at 
the baseline study visit.  Subjects who were experiencing regular asthma symptoms were 
not randomised, but had their run-in period extended.  As a result of the above requirement, 
subjects had little room for improvement in symptoms after being randomised.  Subjects 
who were experiencing more frequent asthma symptoms may have been more “responsive” 
to any intervention.  Reducing the fluticasone dose during the run-in period until symptoms 
occurred, before randomising subjects, could theoretically have improved the study design, 
but would have been extremely time consuming and laborious without guaranteed benefit.     
 
4.5.2.5 Subjects on long acting β-stimulants 
A significant number of subjects were prescribed salmeterol during the study.  Salmeterol 
has been shown to improve asthma control in adults and children older than 4 years of age 
[285], but published literature about salmeterol use in two to six year old asthmatic children 
is scarce.  It is possible that salmeterol use during the study may have influenced results i.e. 
suppression of asthma symptoms may have influenced the correlations between asthma 
symptoms and various parameters.  Salmeterol use was unlikely to have biased 
comparisons between the Funhaler and the Aerochamber Plus group, as salmeterol use was 
similar between groups.   
 
4.5.2.6 Inadequate measures of clinical outcome 
Asthma symptoms were reported by parents, on diary cards, for the week before every 
study visit.  The short duration of symptom recording before every visit limited the 
sensitivity of the outcome measures.  It is therefore possible that differences in clinical 
outcome, between the study group and the control group, could have been missed.  The 
only measures that parents were asked to constantly report throughout the clinical trial, 
were “days with asthma exacerbations”, and “days of oral steroid use”.  During the course 
of the study, it was realised that “days with asthma exacerbations” would have limited use, 
as the concept was never defined, and never explained to the subjects’ parents.  Although 
“days of oral steroid use” was recorded, as an indirect marker of asthma exacerbations, 
there was never any correlation between “days of oral steroid use” and other relevant 
variables during the study.  Also, there was at no point during the study any significant 
difference in “days of oral steroid use” between the study group and the control group.   
 
 158
4.5.2.7 Study effect 
The possibility that proficiency in spacer technique, and/or adherence to prescribed 
treatment, may have improved in all subjects as a direct result of participating in a clinical 
trial, cannot be excluded.  Subjects were motivated enough to attend several study visits 
over a course of a year.  Subjects were not blinded to the fact that their adherence was 
being monitored, and subjects were given regular feedback with regards to spacer use.  
Results may have been confounded by the “study effect”. 
 
4.5.3 Strengths of study 
4.5.3.1 Novel concept 
A major strength of this study was that the concept of improving inhalation technique and 
adherence to prescribed medication, by the use of a specifically designed incentive delivery 
device, is a novel concept.  Incentive devices are used to influence children’s breathing 
during lung function testing, but the influence of an incentive spacer on children’s 
breathing has never been studied before.   
 
As mentioned above, previous attempts to improve adherence in preschool children focused 
on the children’s parents.  This is the first study aimed at improving adherence to inhaled 
medication in preschool children, which targeted the intervention primarily at the children, 
and not their parents. 
   
4.5.3.2 Filter dose as a measure of proficiency in spacer technique 
This is the first clinical trial where proficiency in spacer technique was objectively 
quantified by using filter studies.  The objective quantification of spacer technique made it 
possible to investigate the influence of spacer technique on various other variables.  
 
4.5.3.3 Electronic monitoring of adherence 
Electronic monitoring is currently the gold standard for the monitoring of adherence to 
prescribed medication.  This study is the largest and longest study to date where adherence 
to inhaled treatment was monitored electronically in preschool children.  The year long 
 159
duration of the clinical trial allowed for the “study effect”, which may have falsely elevated 
adherence in the first months of the study, to wear off, thereby allowing for a more accurate 
assessment of adherence.  
 
4.5.4 Application of results 
The improved spacer technique in children under four years of age, and the decreased 
numbers of subjects with very poor spacer technique (filter doses <= 20μg) in the Funhaler 
group indicates that prescription of the Funhaler in the clinical setting may be considered in 
young patients who are suspected to have poor spacer technique.   
 
The large variation in proficiency in spacer technique, which results in a large variation in 
inhalation drug delivery to preschool children, should be acknowledged when analysing 
research studies in which inhaled medication is used as an intervention.  The variation in 
drug delivery should also be kept in mind when clinicians treat patients with inhaled 
medication.  Research that focuses on the improvement of the accuracy in aerosol drug 
delivery for preschool children should continue.  
 
The mean adherence to prescribed medication was low, and varied greatly.  Although this 
is not a novel finding, the results underscores the importance for health care providers to 
take the variation in adherence into account when managing preschool children with 
asthma.  
 
The positive correlation between adherence to prescribed treatment, and measures of 
asthma control reinforce the need to include a focus on adherence to medication, when 
treating asthmatic preschool children.  The lack of any continuing positive influence of the 
Funhaler® on adherence to prescribed medication suggest that more development of 
incentive devices aimed at preschool children would be required if incentive inhalation 
devices are to be effective in improving adherence in this age group.  Alternatively, the role 
of incentive spacers like the Funaler® may be limited to helping very young children in 
developing good inhalation technique.       
 160
 
5 CHAPTER FIVE:  Conclusion and future directions           
 
PMDI-spacers are currently the most commonly used and efficient method for delivering 
inhaled asthma medication to preschool children.  Correct spacer technique is essential for 
optimal drug delivery though pMDI-spacers.  Preschool children are instructed to breathe 
normally (tidally) through spacer devices.  Until now, there was little evidence on the 
number of breaths required for optimal drug delivery, and whether the single maximal 
breath technique should be taught to preschool children was unclear. 
 
In this thesis a method for accurately recording and simulating breathing was validated.  
The method allowed breathing to be recorded while subjects were inhaling medication or 
placebo through spacers, with minimal interference between the subject and the spacer.  
The validated methodology was then used to determine that the inhalation volumes of 
young children using spacers were larger than expected, and that only a few (e.g. two) tidal 
breaths are required for efficient drug delivery.  The results also suggested that all female 
children are able to perform a single maximal breath at six years of age, and all male 
children are able to perform a single maximal breath from seven years of age.  However, 
the results suggested that in young children, single maximal inhalation does not result in 
improved drug delivery over tidal breathing.   
 
These results potentially could be applied in clinical practice.  In busy hospital emergency 
departments, where preschool asthmatics may require multiple repeated doses of 
bronchodilators, with each dose requiring multiple pMDI actuations, requirement for fewer 
breaths after each pMDI actuation could contribute to improved patient cooperation and 
expedite the delivery of effective treatment.  In the home setting, asthma preventers are 
administered regularly over the medium to long term.  The obviation of the requirement to 
take multiple inhalations through a spacer each time that medication is administered, may 
potentially expedite the drug delivery process, making it more acceptable to the preschool 
child, and reduce parent child conflict, which is known to often be associated with the drug 
delivery process.  Also, health care providers can feel more confident about the instructions 
that they give to parents of preschool children about spacer use. 
 
 161
After the question, about how preschool children should breathe through spacers, was 
answered, two important determinants of inhaled drug delivery (proficiency in spacer 
technique and adherence to prescribed medication) both known to often be sub-optimal in 
preschool asthmatic children, were examined in a clinical trial.  In the randomised 
controlled clinical trial, the effect of an incentive device, the Funhaler®, on spacer 
technique, and adherence to prescribed inhalation corticosteroids in preschool children, was 
studied.  Results suggested that the Funhaler® had a positive influence on spacer technique 
in children between two and four years of age, but the effect did not carry through to four to 
six-year old children, and was not large enough to improve clinical outcome.  Use of the 
Funhaler® therefore appeared to specifically improve drug delivery in those subjects who, 
with a conventional spacer, would have inhaled very low doses of medication.  The 
Funhaler® was therefore partially successful as an incentive device, as its use positively 
influenced drug delivery in a specific sub-group of preschool children.   
 
The clinical trial results suggested that proficiency in spacer technique did not translate to 
improved long term clinical outcomes.  Regular use of inhaled corticosteroids has been 
shown to reduce asthma symptoms in preschool children.  The lack of association between 
proficiency in spacer technique and clinical outcome was disappointing, as improved 
spacer technique (measured by improved drug delivery) should improve asthma symptoms 
if the drug administered via the spacer is effective in decreasing asthma symptoms.  
However, as a recent meta-analysis highlighted [276], the benefit of inhaled corticosteroids 
when used in clinical trials for the treatment of preschool asthma, appears to be modest.  
Therefore, the relationship between dose and response is often difficult to observe, even in 
tightly controlled dose-response studies.  Also, there is large inter-subject variability in 
response to treatment, which can also make any true changes hard to detect.  Thus, the lack 
of association between proficiency in spacer technique and long term clinical outcome, in 
this thesis, was not especially surprising.   
 
In addition to the above, there are inevitable inherent limitations in design in a clinical 
study, such as the one described in this thesis, which may have further reduced the chances 
of detecting a correlation between proficiency in spacer technique and clinical outcome.  
Most notably would be the large variation in prescribed fluticasone dose between subjects 
and even between study visits.  Therefore, based on the results of this study only, one 
would not exclude the possibility that improved spacer technique could still have an 
important impact on clinical outcome in preschool asthmatic children.  As the Funhaler® 
 162
had a positive influence on spacer technique in children between two and four years of age, 
and specifically appeared to improve drug delivery in those subjects who would have 
inhaled very low doses of asthma preventers with conventional spacers, the potential of the 
Funhaler® to improve clinical outcome in two to four year old children who are at risk of 
inhaling sub-optimal doses of asthma preventers, could not be ruled out.  Clinicians should 
consider the option of prescribing the Funaler® for very young children to help improve 
spacer technique.   
 
Based in the Funhaler’s performance, the concept of using an incentive device to improve 
spacer technique in preschool children has shown potential.  However, if the incentive 
component of an incentive spacer remains a spinning disk and whistle only, its usefulness 
may also remain limited to a sub-group of very young children for a limited time.  As very 
young children are possibly the sub-group who are at highest risk of poor inhalation 
technique, a device more compact and robust than the Funhaler® may potentially be 
applied more effectively in this subgroup.  Also, as interest of a young child in the single 
mode of feedback offered by the Funhaler® may decay with time, a device that provides a 
range of feedback ideas directed at holding the interest of a young child for much longer 
would be worth exploring.  Furthermore, an incentive that is attached to the inspiratory arm 
of the spacer may be more effective, as the quality of feedback on the inspiratory arm could 
be linked to characteristics of the patient’s inhalation i.e. more pleasurable feedback for 
slow, deep inhalation, thereby improving drug delivery to the lungs.     
 
Results of the clinical trial suggest that adherence to prescribed medication regimens 
correlate positively with improved clinical outcome in preschool children with asthma.  Use 
of the Funhaler® did not improve adherence to prescribed medication in preschool children 
with asthma.  Funhaler® therefore failed as an incentive device to improve adherence in 
preschool asthmatic children.  Once again, this does not prove that all incentive devices 
will fail to improve adherence, but it does indicate that any future design for an incentive 
device will need to consider providing feedback that is more interesting to the child.  
 
The results of this study also suggest that future attempts to improve adherence to 
prescribed medication in preschool children would be most successful if they are aimed at 
addressing issues related to the parents of the children.  A cohesive family climate, 
medication routines, and the frequent reinforcement of the educational message to parents 
have been shown to be related to improved adherence to prescribed inhaled medication in 
 163
preschool children.  In the clinical situation, ways of facilitating the establishment of good 
medication routines should therefore be pursued, and the importance of adhering to 
prescribed regimens should be emphasised frequently.  The importance of a healthy, 
cohesive family environment can never be underestimated, and health care providers 
should continually be alert to opportunities where they can contribute to the functioning of 
their patient’s family unit, as a healthy family environment’s positive influence on a child’s 
health will not be limited to adherence to prescribed medication.  
 
The future of incentive aerosol delivery devices in preschool children is not clear.  As noted 
above, improved incentive devices that provide more pleasurable, or more varied, feedback 
may potentially be more effective.  More pleasurable and more varied feedback could 
potentially be provided by computerised electronic incentive devices (different game each 
time used).  
 
The findings of this study have further important implications for future studies and clinical 
work.  Firstly, the demonstrated wide variation in both proficiency in spacer technique, and 
adherence to prescribed medication in young children, should be taken into account during 
the development and analysis of clinical trials.  As the large variation, during clinical trials, 
in proficiency in spacer technique, and adherence to prescribed medication, is likely to 
influence results, an awareness of the variation in spacer technique and drug delivery may 
contribute towards the accurate interpretation of results.  When inhaled drugs are used in 
clinical trials, regular supervision by the research team, uniformity of delivery devices 
used, and the use of devices that are known to deliver a more consistent, and narrower dose 
range, could contribute to a reduction in variation in drug delivery.  Accurate adherence 
monitoring during clinical trials could be used to statistically correct for inter-subject 
variability in adherence. While researchers should continue to be aware of the well known 
“study effect”, implementation of the abovementioned suggestions may improve the 
accuracy and statistical power of clinical trials.   
 
Finally, the wide variation in both proficiency in spacer technique, and adherence to 
prescribed medication, both factors that determine drug delivery to patients, highlight the 
importance of pursuing ways to improve inhalation drug delivery to preschool children in 
order to eliminate the variability in prescribed medication that eventually reaches patients.  
The delivery to the lungs of a constant, reliably repeatable inhaled drug dose should be a 
continuing aim for aerosol scientists and physicians. 
 164
 
 
* 
 
This thesis has contributed to the field of aerosol medicine by introducing a novel method 
for assessing the influence of breathing on drug delivery via spacer, where the simulated 
breathing can be recorded on subjects while they are using spacers, with minimum increase 
in dead space or resistance, and no physical alteration in the patient-device interface.  
Implementation of the method demonstrated that inhalation volumes and flows of young 
children using spacers are larger than expected, and therefore only a few tidal breaths are 
required for efficient drug delivery. 
 
Furthermore, this thesis has contributed to our knowledge of inhalation therapy in 
preschool asthmatic children by illustrating the large variation drug delivery through 
pMDI-spacers due to differences in proficiency in spacer technique and adherence to 
prescribed medication, and by demonstrating that an incentive device, the Funhaler®, can 
improve spacer technique in very young children.  
 
 
*****
 165
 
APPENDIX 
 
 
 
 
 
 
 
 
 166
 
REFERENCES 
[1] Valovirta E, Kocevar VS, Kaila M, Kajosaari M, Koivikko A, Korhonen K, et al. 
Inpatient resource utilisation in younger (2-5 yrs) and older (6-14 yrs) asthmatic children in 
Finland. Eur Respir J. 2002 Aug;20(2):397-402. 
[2] Akinbami LJ, Moorman JE, Garbe PL, Sondik EJ. Status of childhood asthma in the 
United States, 1980-2007. Pediatrics. 2009 Mar;123 Suppl 3:S131-45. 
[3] Amirav I, Newhouse MT. Metered-dose inhaler accessory devices in acute asthma: 
efficacy and comparison with nebulizers: a literature review. Arch Pediatr Adolesc Med. 
1997 Sep;151(9):876-82. 
[4] Warner JO, Naspitz CK. Third International Pediatric Consensus statement on the 
management of childhood asthma. International Pediatric Asthma Consensus Group. 
Pediatr Pulmonol. 1998 Jan;25(1):1-17. 
[5] Cates CC, Bara A, Crilly JA, Rowe BH. Holding chambers versus nebulisers for 
beta-agonist treatment of acute asthma. Cochrane Database Syst Rev. 2003(3):CD000052. 
[6] Gleeson JG, Price JF. Controlled trial of budesonide given by the nebuhaler in 
preschool children with asthma. BMJ. 1988 Jul 16;297(6642):163-6. 
[7] Hess DR. Aerosol delivery devices in the treatment of asthma. Respir Care. 2008 
Jun;53(6):699-723; discussion -5. 
[8] Svartengren K, Lindestad PA, Svartengren M, Bylin G, Philipson K, Camner P. 
Deposition of inhaled particles in the mouth and throat of asthmatic subjects. Eur Respir J. 
1994 Aug;7(8):1467-73. 
[9] Shrewsbury SB, Armer TA, Newman SP, Pitcairn G. Breath-synchronized plume-
control inhaler for pulmonary delivery of fluticasone propionate. Int J Pharm. 2008 Jan 17. 
[10] Lipworth BJ, Clark DJ. Lung delivery of non-CFC salbutamol via small volume 
metal spacer and large volume plastic spacer devices compared with an open vent jet 
nebulizer. Br J Clin Pharmacol. 1998 Feb;45(2):160-3. 
[11] Snell NJ, Ganderton D. Assessing lung deposition of inhaled medications. 
Consensus statement from a workshop of the British Association for Lung Research, held 
at the Institute of Biology, London, U.K. on 17 April 1998. Respir Med. 1999 
Feb;93(2):123-33. 
[12] Bisgaard H. Future options for aerosol delivery to children. Allergy. 1999;54 Suppl 
49:97-103. 
[13] O'Callaghan C, Barry P. Delivering inhaled corticosteroids to patients. BMJ. 1999 
Feb 13;318(7181):410-1. 
[14] Heyder J, Svartengren K. Particle Behaviour in the Resiratory Tract. Lung biology 
in Health and Disease. 2002;162 - Drug Delivery to the Lung:21-45. 
[15] Stahlhofen W, Gebhart J, Heyder J. Experimental determination of the regional 
deposition of aerosol particles in the human respiratory tract. Am Ind Hyg Assoc J. 1980 
Jun;41(6):385-98a. 
[16] Sosnowski TR, Moskal A, Gradon L. Dynamics of oropharyngeal aerosol transport 
and deposition with the realistic flow pattern. Inhal Toxicol. 2006 Sep;18(10):773-80. 
[17] Newman SP, Agnew JE, Pavia D, Clarke SW. Inhaled aerosols: lung deposition and 
clinical applications. Clin Phys Physiol Meas. 1982 Feb;3(1):1-20. 
 167
[18] Bennett WD, Scheuch G, Zeman KL, Brown JS, Kim C, Heyder J, et al. Bronchial 
airway deposition and retention of particles in inhaled boluses: effect of anatomic dead 
space. J Appl Physiol. 1998 Aug;85(2):685-94. 
[19] Darquenne C, Paiva M, Prisk GK. Effect of gravity on aerosol dispersion and 
deposition in the human lung after periods of breath holding. J Appl Physiol. 2000 
Nov;89(5):1787-92. 
[20] Rau JL, Coppolo DP, Nagel MW, Avvakoumova VI, Doyle CC, Wiersema KJ, et 
al. The importance of nonelectrostatic materials in holding chambers for delivery of 
hydrofluoroalkane albuterol. Respir Care. 2006 May;51(5):503-10. 
[21] Heyder J. Deposition of inhaled particles in the human respiratory tract and 
consequences for regional targeting in respiratory drug delivery. Proc Am Thorac Soc. 
2004;1(4):315-20. 
[22] Sosnowski TR, Moskal A, Gradon L. Mechanims of aerosol particle deposition in 
the Oro-pharynx under non-steady airflow. Ann Occup Hyg. 2007 Jan;51(1):19-25. 
[23] Scheuch G, Stahlhofen W. Deposition and dispersion of aerosols in the airways of 
the human respiratory tract: the effect of particle size. Exp Lung Res. 1992 May-
Jun;18(3):343-58. 
[24] Shekunov BY, Chattopadhyay P, Tong HH, Chow AH. Particle size analysis in 
pharmaceutics: principles, methods and applications. Pharm Res. 2007 Feb;24(2):203-27. 
[25] Crowder TM, Rosati JA, Schroeter JD, Hickey AJ, Martonen TB. Fundamental 
effects of particle morphology on lung delivery: predictions of Stokes' law and the 
particular relevance to dry powder inhaler formulation and development. Pharm Res. 2002 
Mar;19(3):239-45. 
[26] Everard ML. Inhalation therapy for infants. Adv Drug Deliv Rev. 2003 Jul 
18;55(7):869-78. 
[27] Usmani OS, Biddiscombe MF, Barnes PJ. Regional lung deposition and 
bronchodilator response as a function of beta2-agonist particle size. Am J Respir Crit Care 
Med. 2005 Dec 15;172(12):1497-504. 
[28] Sutherland ER, Martin RJ. Distal lung inflammation in asthma. Ann Allergy 
Asthma Immunol. 2002 Aug;89(2):119-24; quiz 24-5, 211. 
[29] Devadason SG. Recent advances in aerosol therapy for children with asthma. J 
Aerosol Med. 2006 Spring;19(1):61-6. 
[30] Freiwald M, Valotis A, Kirschbaum A, McClellan M, Murdter T, Fritz P, et al. 
Monitoring the initial pulmonary absorption of two different beclomethasone dipropionate 
aerosols employing a human lung reperfusion model. Respiratory research. 2005;6:21. 
[31] Kelly HW. Establishing a therapeutic index for the inhaled corticosteroids: part I. 
Pharmacokinetic/pharmacodynamic comparison of the inhaled corticosteroids. J Allergy 
Clin Immunol. 1998 Oct;102(4 Pt 2):S36-51. 
[32] Hubner M, Hochhaus G, Derendorf H. Comparative pharmacology, bioavailability, 
pharmacokinetics, and pharmacodynamics of inhaled glucocorticosteroids. Immunology 
and allergy clinics of North America. 2005 Aug;25(3):469-88. 
[33] Manning P, Gibson PG, Lasserson TJ. Ciclesonide versus other inhaled steroids for 
chronic asthma in children and adults. Cochrane Database Syst Rev. 2008(2):CD007031. 
[34] Skoner DP, Maspero J, Banerji D. Assessment of the long-term safety of inhaled 
ciclesonide on growth in children with asthma. Pediatrics. 2008 Jan;121(1):e1-14. 
 168
[35] Brand PL, Baraldi E, Bisgaard H, Boner AL, Castro-Rodriguez JA, Custovic A, et 
al. Definition, assessment and treatment of wheezing disorders in preschool children: an 
evidence-based approach. Eur Respir J. 2008 Oct;32(4):1096-110. 
[36] Wilson N, Sloper K, Silverman M. Effect of continuous treatment with topical 
corticosteroid on episodic viral wheeze in preschool children. Arch Dis Child. 1995 
Apr;72(4):317-20. 
[37] Bisgaard H, Gillies J, Groenewald M, Maden C. The effect of inhaled fluticasone 
propionate in the treatment of young asthmatic children: a dose comparison study. Am J 
Respir Crit Care Med. 1999 Jul;160(1):126-31. 
[38] Guilbert TW, Morgan WJ, Zeiger RS, Mauger DT, Boehmer SJ, Szefler SJ, et al. 
Long-term inhaled corticosteroids in preschool children at high risk for asthma. N Engl J 
Med. 2006 May 11;354(19):1985-97. 
[39] Allen DB. Effects of inhaled steroids on growth, bone metabolism, and adrenal 
function. Adv Pediatr. 2006;53:101-10. 
[40] Adams N, Lasserson TJ, Cates CJ, Jones PW. Fluticasone versus beclomethasone or 
budesonide for chronic asthma in adults and children. Cochrane Database Syst Rev. 
2007(4):CD002310. 
[41] Pedersen S. Clinical safety of inhaled corticosteroids for asthma in children: an 
update of long-term trials. Drug Saf. 2006;29(7):599-612. 
[42] Bell J, Newman S. The rejuvenated pressurised metered dose inhaler. Expert Opin 
Drug Deliv. 2007 May;4(3):215-34. 
[43] Newman SP. Principles of metered-dose inhaler design. Respir Care. 2005 
Sep;50(9):1177-90. 
[44] Smyth HD. The influence of formulation variables on the performance of 
alternative propellant-driven metered dose inhalers. Adv Drug Deliv Rev. 2003 Jul 
18;55(7):807-28. 
[45] Molina M. Stratospheric sink for chlorofluoromethanes: chlorine atomcatalyzed 
destruction of ozone. Nature. 1974;249:1810-2. 
[46] Dolovich M. New delivery systems and propellants. Can Respir J. 1999 May-
Jun;6(3):290-5. 
[47] Hallworth G. The formulation and evaluation of pressurised metered dose inhalers. . 
In: Ganderton D, Jones T, editors. 1987;Drug delivery to the respiratory tract.(Chichester, 
United Kingdom: Ellis Horwood):87-118. 
[48] Berg E. In vitro properties of pressurized metered dose inhalers with and without 
spacer devices. J Aerosol Med. 1995 Sep;8 Suppl 3:S3-10; discussion S1. 
[49] Rubin BK, Durotoye L. How do patients determine that their metered-dose inhaler 
is empty? Chest. 2004 Oct;126(4):1134-7. 
[50] Polli GP, Grim WM, Bacher FA, Yunker MH. Influence of formulation on aerosol 
particle size. J Pharm Sci. 1969 Apr;58(4):484-6. 
[51] O'Callaghan C, Wright P. The metered dose inhaler. In: Bisgaard H, O'Callaghan C, 
Smaldone GC, (Eds), Drug delivery to the lung. 2002;New York: Marcel Dekker:337-70. 
[52] Clark AR. MDIs: physics of aerosol formation. J Aerosol Med. 1996 Mar;9 Suppl 
1:S19-26. 
[53] Vervaet C, Byron PR. Drug-surfactant-propellant interactions in HFA-formulations. 
Int J Pharm. 1999 Sep 10;186(1):13-30. 
 169
[54] Gabrio BJ, Stein SW, Velasquez DJ. A new method to evaluate plume 
characteristics of hydrofluoroalkane and chlorofluorocarbon metered dose inhalers. Int J 
Pharm. 1999 Sep 10;186(1):3-12. 
[55] Barry PW, O'Callaghan C. In vitro comparison of the amount of salbutamol 
available for inhalation from different formulations used with different spacer devices. Eur 
Respir J. 1997 Jun;10(6):1345-8. 
[56] Brown B. Dispelling the myths of MDIs. Drug Delivery Technology. 
2002;2(7):115-23. 
[57] Dolovich M, Ruffin R, Corr D, Newhouse MT. Clinical evaluation of a simple 
demand inhalation MDI aerosol delivery device. Chest. 1983 Jul;84(1):36-41. 
[58] Wildhaber JH, Devadason SG, Eber E, Hayden MJ, Everard ML, Summers QA, et 
al. Effect of electrostatic charge, flow, delay and multiple actuations on the in vitro delivery 
of salbutamol from different small volume spacers for infants. Thorax. 1996;51(10):985-8. 
[59] Kenyon CJ, Thorsson L, Borgstrom L, Newman SP. The effects of static charge in 
spacer devices on glucocorticosteroid aerosol deposition in asthmatic patients. Eur Respir J. 
1998 Mar;11(3):606-10. 
[60] Pierart F, Wildhaber JH, Vrancken I, Devadason SG, Le Souef PN. Washing plastic 
spacers in household detergent reduces electrostatic charge and greatly improves delivery. 
Eur Respir J. 1999;13(3):673-8. 
[61] Coppolo DP, Mitchell JP, Nagel MW. Levalbuterol aerosol delivery with a 
nonelectrostatic versus a nonconducting valved holding chamber. Respir Care. 2006 
May;51(5):511-4. 
[62] Khan Y, Tang Y, Hochhaus G, Shuster JJ, Spencer T, Chesrown S, et al. Lung 
bioavailability of hydrofluoroalkane fluticasone in young children when delivered by an 
antistatic chamber/mask. J Pediatr. 2006 Dec;149(6):793-7. 
[63] Louca E, Leung K, Coates AL, Mitchell JP, Nagel MW. Comparison of three 
valved holding chambers for the delivery of fluticasone propionate-HFA to an infant face 
model. J Aerosol Med. 2006 Summer;19(2):160-7. 
[64] Zar HJ, Streun S, Levin M, Weinberg EG, Swingler GH. Randomised controlled 
trial of the efficacy of a metered dose inhaler with bottle spacer for bronchodilator 
treatment in acute lower airway obstruction. Arch Dis Child. 2007 Feb;92(2):142-6. 
[65] Berg E, Madsen J, Bisgaard H. In vitro performance of three combinations of 
spacers and pressurized metered dose inhalers for treatment in children. Eur Respir J. 
1998;12(2):472-6. 
[66] Janssens HM, Heijnen EM, de Jong VM, Hop WC, Holland WP, de Jongste JC, et 
al. Aerosol delivery from spacers in wheezy infants: a daily life study. Eur Respir J. 
2000;16(5):850-6. 
[67] Dubus JC, Anhoj J. Inhaled steroid delivery from small-volume holding chambers 
depends on age, holding chamber, and interface in children. J Aerosol Med. 2004 
Fall;17(3):225-30. 
[68] Barry PW, O'Callaghan C. Inhalational drug delivery from seven different spacer 
devices. Thorax. 1996;51(8):835-40. 
[69] Janssens HM, Krijgsman A, Verbraak TF, Hop WC, de Jongste JC, Tiddens HA. 
Determining factors of aerosol deposition for four pMDI-spacer combinations in an infant 
upper airway model. J Aerosol Med. 2004 Spring;17(1):51-61. 
 170
[70] Ahrens R, Lux C, Bahl T, Han SH. Choosing the metered-dose inhaler spacer or 
holding chamber that matches the patient's need: evidence that the specific drug being 
delivered is an important consideration. J Allergy Clin Immunol. 1995 Aug;96(2):288-94. 
[71] Lipworth BJ, Clark DJ. Early lung absorption profile of non-CFC salbutamol via 
small and large volume plastic spacer devices. Br J Clin Pharmacol. 1998 Jul;46(1):45-8. 
[72] Finlay WH, Zuberbuhler P. In vitro comparison of beclomethasone and salbutamol 
metered-dose inhaler aerosols inhaled during pediatric tidal breathing from four valved 
holding chambers. Chest. 1998 Dec;114(6):1676-80. 
[73] Becker A, Berube D, Chad Z, Dolovich M, Ducharme F, D'Urzo T, et al. Canadian 
Pediatric Asthma Consensus guidelines, 2003 (updated to December 2004): introduction. 
Cmaj. 2005 Sep 13;173(6 Suppl):S12-4. 
[74] Everard ML, Clark AR, Milner AD. Drug delivery from holding chambers with 
attached facemask. Arch Dis Child. 1992 May;67(5):580-5. 
[75] Crompton GK. Breath-activated aerosol. Br Med J. 1971 Jun 12;2(5762):652-3. 
[76] Newman SP, Weisz AW, Talaee N, Clarke SW. Improvement of drug delivery with 
a breath actuated pressurised aerosol for patients with poor inhaler technique. Thorax. 1991 
Oct;46(10):712-6. 
[77] Devadason SG, Huang T, Walker S, Troedson R, Le Souef PN. Distribution of 
technetium-99m-labelled QVAR delivered using an Autohaler device in children. Eur 
Respir J. 2003 Jun;21(6):1007-11. 
[78] O'Callaghan C, Barry PW. How to choose delivery devices for asthma. Arch Dis 
Child. 2000 Mar;82(3):185-7. 
[79] Brocklebank D, Ram F, Wright J, Barry P, Cates C, Davies L, et al. Comparison of 
the effectiveness of inhaler devices in asthma and chronic obstructive airways disease: a 
systematic review of the literature. Health Technol Assess. 2001;5(26):1-149. 
[80] Lin YZ, Hsieh KH. Metered dose inhaler and nebuliser in acute asthma. Arch Dis 
Child. 1995 Mar;72(3):214-8. 
[81] Silkstone VL, Corlett SA, Chrystyn H. Relative lung and total systemic 
bioavailability following inhalation from a metered dose inhaler compared with a metered 
dose inhaler attached to a large volume plastic spacer and a jet nebuliser. Eur J Clin 
Pharmacol. 2002 Jan;57(11):781-6. 
[82] Zar HJ, Weinberg EG. Treatment of acute asthma--a metered dose inhaler with 
spacer is an optimal delivery system. S Afr Med J. 2001 Aug;91(8):653-5. 
[83] Dolovich MB, Ahrens RC, Hess DR, Anderson P, Dhand R, Rau JL, et al. Device 
selection and outcomes of aerosol therapy: Evidence-based guidelines: American College 
of Chest Physicians/American College of Asthma, Allergy, and Immunology. Chest. 2005 
Jan;127(1):335-71. 
[84] Janssens HM, Tiddens HA. Aerosol therapy: the special needs of young children. 
Paediatr Respir Rev. 2006;7 Suppl 1:S83-5. 
[85] Waldrep JC, Dhand R. Advanced nebulizer designs employing vibrating 
mesh/aperture plate technologies for aerosol generation. Curr Drug Deliv. 2008 
Apr;5(2):114-9. 
[86] Amirav I, Newhouse MT, Mansour Y. Measurement of peak inspiratory flow with 
in-check dial device to simulate low-resistance (Diskus) and high-resistance (Turbohaler) 
dry powder inhalers in children with asthma. Pediatr Pulmonol. 2005 May;39(5):447-51. 
[87] Nielsen KG, Skov M, Klug B, Ifversen M, Bisgaard H. Flow-dependent effect of 
formoterol dry-powder inhaled from the Aerolizer. Eur Respir J. 1997 Sep;10(9):2105-9. 
 171
[88] Clark AR, O'Callaghan C. In Vitro Testing of Pharmaceutical Aerosols and 
Predicting Lung Deposition from In Vitro Measurements. In: Bisgaard H, O'Callaghan C, 
Smaldone GC, (Eds), Drug delivery to the lung. 2002:105-42. 
[89] Borgstrom L, Nilsson M. A method for determination of the absolute pulmonary 
bioavailability of inhaled drugs: terbutaline. Pharm Res. 1990 Oct;7(10):1068-70. 
[90] Richards R, Dickson CR, Renwick AG, Lewis RA, Holgate ST. Absorption and 
disposition kinetics of cromolyn sodium and the influence of inhalation technique. J 
Pharmacol Exp Ther. 1987 Jun;241(3):1028-32. 
[91] Bondesson E, Bengtsson T, Borgstrom L, Nilsson LE, Norrgren K, Trofast E, et al. 
Planar gamma scintigraphy--points to consider when quantifying pulmonary dry powder 
aerosol deposition. Int J Pharm. 2003 Jun 4;258(1-2):227-40. 
[92] Borgstrom L. Deposition patterns with Turbuhaler. J Aerosol Med. 1994;7(Suppl 
1):S49-53. 
[93] Borgstrom L, Newman S, Weisz A, Moren F. Pulmonary deposition of inhaled 
terbutaline: comparison of scanning gamma camera and urinary excretion methods. J 
Pharm Sci. 1992 Aug;81(8):753-5. 
[94] Wildhaber JH, Devadason SG, Wilson JM, Roller C, Lagana T, Borgstrom L, et al. 
Lung deposition of budesonide from turbuhaler in asthmatic children. Eur J Pediatr. 1998 
Dec;157(12):1017-22. 
[95] Newman S, Steed K, Hooper G, Kallen A, Borgstrom L. Comparison of gamma 
scintigraphy and a pharmacokinetic technique for assessing pulmonary deposition of 
terbutaline sulphate delivered by pressurized metered dose inhaler. Pharm Res. 1995 
Feb;12(2):231-6. 
[96] Newman SP, Pitcairn GR, Hirst PH, Rankin L. Radionuclide imaging technologies 
and their use in evaluating asthma drug deposition in the lungs. Adv Drug Deliv Rev. 2003 
Jul 18;55(7):851-67. 
[97] Newman SP, Moren F, Trofast E, Talaee N, Clarke SW. Deposition and clinical 
efficacy of terbutaline sulphate from Turbuhaler, a new multi-dose powder inhaler. Eur 
Respir J. 1989 Mar;2(3):247-52. 
[98] Smaldone G, Perry R, Bennet W, Meddina M, Zwang J, Ilowite J. Iterpretation of 
"24 hour lung retention" in studies of mucociliary clearance. J Aerosol Med. 1988;1:11-20. 
[99] Agnew JE, Lopez-Vidriero MT, Pavia D, Clarke SW. Functional small airways 
defence in symptomless cigarette smokers. Thorax. 1986 Jul;41(7):524-30. 
[100] Newman SP, Hirst PII, Pitcairn GR, Clark AR. Understanding regional lung 
deposition in gamma scintigraphy. In: Respiratory Drug Delivery VI. 1998;Hilton Head, 
SC:19-26. 
[101] Mitchell JP, Nagel MW. Time-of-flight aerodynamic particle size analyzers: their 
use and limitations for the evaluation of medical aerosols. J Aerosol Med. 1999 
Winter;12(4):217-40. 
[102] Mitchell JP, Nagel MW, Wiersema KJ, Doyle CC, Migounov VA. The delivery of 
chlorofluorocarbon-propelled versus hydrofluoroalkane-propelled beclomethasone 
dipropionate aerosol to the mechanically ventilated patient: a laboratory study. Respir Care. 
2003 Nov;48(11):1025-32. 
[103] Dolovich M, Smaldone GC. Estimating the particle size characteristics of 
therapeutic aerosols. J Aerosol Med. 1999 Winter;12(4):215-6. 
 172
[104] Kwong WT, Ho SL, Coates AL. Comparison of nebulized particle size distribution 
with Malvern laser diffraction analyzer versus Andersen cascade impactor and low-flow 
Marple personal cascade impactor. J Aerosol Med. 2000 Winter;13(4):303-14. 
[105] Lodrup Carlsen KC, Nikander K, Carlsen KH. How much nebulised budesonide 
reaches infants and toddlers? Arch Dis Child. 1992 Sep;67(9):1077-9. 
[106] Nikander K, Bisgaard H. Impact of constant and breath-synchronized nebulization 
on inhaled mass of nebulized budesonide in infants and children. Pediatr Pulmonol. 1999 
Sep;28(3):187-93. 
[107] Dahlstrom K, Thorsson L, Larsson P, Nikander K. Systemic availability and lung 
deposition of budesonide via three different nebulizers in adults. Ann Allergy Asthma 
Immunol. 2003 Feb;90(2):226-32. 
[108] Nikander K, Berg E, Smaldone GC. Jet nebulizers versus pressurized metered dose 
inhalers with valved holding chambers: effects of the facemask on aerosol delivery. J 
Aerosol Med. 2007;20 Suppl 1:S46-55; discussion S-8. 
[109] Miller MR, Bright P. Differences in output from corticosteroid inhalers used with a 
volumatic spacer. Eur Respir J. 1995 Oct;8(10):1637-8. 
[110] Grigg J, Arnon S, Jones T, Clarke A, Silverman M. Delivery of therapeutic aerosols 
to intubated babies. Arch Dis Child. 1992 Jan;67(1 Spec No):25-30. 
[111] Fink JB, Dhand R, Duarte AG, Jenne JW, Tobin MJ. Aerosol delivery from a 
metered-dose inhaler during mechanical ventilation. An in vitro model. Am J Respir Crit 
Care Med. 1996 Aug;154(2 Pt 1):382-7. 
[112] Garner SS, Wiest DB, Bradley JW, Lesher BA, Habib DM. Albuterol delivery by 
metered-dose inhaler in a mechanically ventilated pediatric lung model. Crit Care Med. 
1996 May;24(5):870-4. 
[113] Mitchell JP, Nagel MW. In vitro performance testing of three small volume-holding 
chambers under conditions that correspond with use by infants and small children. J 
Aerosol Med. 1997 Winter;10(4):341-9. 
[114] Dolovich M, Ruffin RE, Roberts R, Newhouse MT. Optimal delivery of aerosols 
from metered dose inhalers. Chest. 1981 
 Dec;80(6 Suppl):911-5. 
[115] Barry PW, O'Callaghan C. The output of budesonide from spacer devices assessed 
under simulated breathing conditions. J Allergy Clin Immunol. 1999 Dec;104(6):1205-10. 
[116] Nikander K, Denyer J, Smith N, Wollmer P. Breathing patterns and aerosol 
delivery: impact of regular human patterns, and sine and square waveforms on rate of 
delivery. J Aerosol Med. 2001 Fall;14(3):327-33. 
[117] Smaldone GC, Berg E, Nikander K. Variation in pediatric aerosol delivery: 
importance of facemask. J Aerosol Med. 2005 Fall;18(3):354-63. 
[118] Nikander K, Denyer J. Breathing Patterns. Eur Respir Rev. 2000;10(76):576-9. 
[119] Perez W, Tobin MJ. Separation of factors responsible for change in breathing 
pattern induced by instrumentation. J Appl Physiol. 1985 Nov;59(5):1515-20. 
[120] Bisgaard H. A metal aerosol holding chamber devised for young children with 
asthma. Eur Respir J. 1995 May;8(5):856-60. 
[121] Vella C, Grech V. Assessment of use of spacer devices for inhaled drug delivery to 
asthmatic children. Pediatr Allergy Immunol. 2005 May;16(3):258-61. 
[122] Newman SP, Pavia D, Clarke SW. How should a pressurized beta-adrenergic 
bronchodilator be inhaled? Eur J Respir Dis. 1981 Feb;62(1):3-21. 
 173
[123] Brennan VK, Osman LM, Graham H, Critchlow A, Everard ML. True device 
compliance: the need to consider both competence and contrivance. Respir Med. 2005 
Jan;99(1):97-102. 
[124] Giraud V, Roche N. Misuse of corticosteroid metered-dose inhaler is associated 
with decreased asthma stability. Eur Respir J. 2002 Feb;19(2):246-51. 
[125] Kamps AW, van Ewijk B, Roorda RJ, Brand PL. Poor inhalation technique, even 
after inhalation instructions, in children with asthma. Pediatr Pulmonol. 2000;29(1):39-42. 
[126] Boccuti L, Celano M, Geller RJ, Phillips KM. Development of a scale to measure 
children's metered-dose inhaler and spacer technique. Ann Allergy Asthma Immunol. 1996 
Sep;77(3):217-21. 
[127] Vodoff MV, Gilbert B, de Lumley L, Dutau G. [Method for using inhalation 
chambers with facial masks in asthma. Evaluation in 60 children below four years of age]. 
Arch Pediatr. 2001 Jun;8(6):598-603. 
[128] Marguet C, Couderc L, Le Roux P, Jeannot E, Lefay V, Mallet E. Inhalation 
treatment: errors in application and difficulties in acceptance of the devices are frequent in 
wheezy infants and young children. Pediatr Allergy Immunol. 2001 Aug;12(4):224-30. 
[129] Brand PL. Key issues in inhalation therapy in children. Curr Med Res Opin. 
2005;21 Suppl 4:S27-32. 
[130] Thorsson L, Edsbacker S. Lung deposition of budesonide from a pressurized 
metered-dose inhaler attached to a spacer. Eur Respir J. 1998 Dec;12(6):1340-5. 
[131] Fink JB, Rubin BK. Problems with inhaler use: a call for improved clinician and 
patient education. Respir Care. 2005 Oct;50(10):1360-74; discussion 74-5. 
[132] Barry PW, O'Callaghan C. The effect of delay, multiple actuations and spacer static 
charge on the in vitro delivery of budesonide from the Nebuhaler. Br J Clin Pharmacol. 
1995 Jul;40(1):76-8. 
[133] Barry PW, O'Callaghan C. Multiple actuations of salbutamol MDI into a spacer 
device reduce the amount of drug recovered in the respirable range. Eur Respir J. 1994 
Sep;7(9):1707-9. 
[134] Lindgren S, Bake B, Larsson S. Clinical consequences of inadequate inhalation 
technique in asthma therapy. Eur J Respir Dis. 1987 Feb;70(2):93-8. 
[135] David V, Mely L, Siret D, Dubus JC. Inhalers and nebulizers in the children. Arch 
Pediatr. 2002 Aug;9 Suppl 3:415s-21s. 
[136] Dolovich M, Ruffin RE, Roberts R, Newhouse MT. Optimal delivery of aerosols 
from metered dose inhalers. Chest. 1981 Dec;80(6 Suppl):911-5. 
[137] Newman SP, Pavia D, Clarke SW. Simple instructions for using pressurized aerosol 
bronchodilators. J R Soc Med. 1980 Nov;73(11):776-9. 
[138] Ryan G, Dolovich MB, Obminski G, Cockcroft DW, Juniper E, Hargreave FE, et al. 
Standardization of inhalation provocation tests: influence of nebulizer output, particle size, 
and method of inhalation. J Allergy Clin Immunol. 1981 Feb;67(2):156-61. 
[139] Iles R, Lister P, Edmunds AT. Crying significantly reduces absorption of 
aerosolised drug in infants. Arch Dis Child. 1999;81(2):163-5. 
[140] Tal A, Golan H, Grauer N, Aviram M, Albin D, Quastel MR. Deposition pattern of 
radiolabeled salbutamol inhaled from a metered-dose inhaler by means of a spacer with 
mask in young children with airway obstruction. J Pediatr. 1996;128(4):479-84. 
[141] Partridge MR. Introduction to the Global Initiative for Asthma and the new 
guidelines. West Indian Med J. 2003;52(Suppl 7):6-9. 
 174
[142] Global strategy for asthma management and prevention. Bethesda M. National 
Institutes of Health,.  2002. 
[143] British Guideline on the Management of Asthma. Thorax. 2003;58:i1-i94. 
[144] Gleeson JG, Price JF. Nebuhaler technique. Br J Dis Chest. 1988 Apr;82(2):172-4. 
[145] Pool JB, Greenough A, Gleeson JG, Price JF. Inhaled bronchodilator treatment via 
the nebuhaler in young asthmatic patients. Arch Dis Child. 1988 Mar;63(3):288-91. 
[146] James RW, Masters IB. Single breath versus panting technique in salbutamol 
delivery through a 750 mL spacing device. Pediatr Pulmonol. 1990;8(4):263-7. 
[147] Agertoft L, Pedersen S. Influence of spacer device on drug delivery to young 
children with asthma. Arch Dis Child. 1994 September 1, 1994;71(3):217-9. 
[148] Bender BG, Bender SE. Patient-identified barriers to asthma treatment adherence: 
responses to interviews, focus groups, and questionnaires. Immunology and allergy clinics 
of North America. 2005 Feb;25(1):107-30. 
[149] Rubin BK, Fink JB. Optimizing aerosol delivery by pressurized metered-dose 
inhalers. Respir Care. 2005 Sep;50(9):1191-200. 
[150] Hansen OR, Pedersen S. Optimal inhalation technique with terbutaline Turbuhaler. 
Eur Respir J. 1989 Jul;2(7):637-9. 
[151] Neve V, Edme JL, Devos P, Deschildre A, Thumerelle C, Santos C, et al. 
Spirometry in 3-5-year-old children with asthma. Pediatr Pulmonol. 2006 Aug;41(8):735-
43. 
[152] Watt PM, Clements B, Devadason SG, Chaney GM. Funhaler spacer: improving 
adherence without compromising delivery. Arch Dis Child. 2003;88(7):579-81. 
[153] Chaney G, Clements B, Landau L, Bulsara M, Watt P. A new asthma spacer device 
to improve compliance in children: a pilot study. Respirology. 2004 Nov;9(4):499-506. 
[154] Gibson NA, Ferguson AE, Aitchison TC, Paton JY. Compliance with inhaled 
asthma medication in preschool children. Thorax. 1995;50(12):1274-9. 
[155] Bender BG. Overcoming barriers to nonadherence in asthma treatment. J Allergy 
Clin Immunol. 2002 Jun;109(6 Suppl):S554-9. 
[156] Celano M, Geller RJ, Phillips KM, Ziman R. Treatment adherence among low-
income children with asthma. J Pediatr Psychol. 1998;23(6):345-9. 
[157] Rand CS, Wise RA. Measuring adherence to asthma medication regimens. Am J 
Respir Crit Care Med. 1994;149(2 Pt 2):S69-76; discussion S7-8. 
[158] Sawyer SM, Aroni RA. Sticky issue of adherence. J Paediatr Child Health. 2003 
Jan-Feb;39(1):2-5. 
[159] Schoni MH. [Compliance with inhalation therapy in children with respiratory 
diseases]. Schweiz Rundsch Med Prax. 1993 Nov 2;82(44):1218-21. 
[160] Burgess SW, Sly PD, Cooper DM, Devadason SG. Novel spacer device does not 
improve adherence in childhood asthma. Pediatr Pulmonol. 2007 Aug;42(8):736-9. 
[161] Burgess SW, Sly PD, Morawska A, Devadason SG. Assessing adherence and 
factors associated with adherence in young children with asthma. Respirology. 2008 
Jun;13(4):559-63. 
[162] Ordonez GA, Phelan PD, Olinsky A, Robertson CF. Preventable factors in hospital 
admissions for asthma. Arch Dis Child. 1998 Feb;78(2):143-7. 
 175
[163] Milgrom H, Bender B, Ackerson L, Bowry P, Smith B, Rand C. Noncompliance 
and treatment failure in children with asthma. J Allergy Clin Immunol. 1996 Dec;98(6 Pt 
1):1051-7. 
[164] Fregonese L, Silvestri M, Sabatini F, Defilippi AC, Rossi GA. Severe and near-fatal 
asthma in children and adolescents. Monaldi Arch Chest Dis. 2001 Oct;56(5):423-8. 
[165] Smith NA, Seale JP, Ley P, Mellis CM, Shaw J. Better medication compliance is 
associated with improved control of childhood asthma. Monaldi Arch Chest Dis. 1994 
Dec;49(6):470-4. 
[166] Stern L, Berman J, Lumry W, Katz L, Wang L, Rosenblatt L, et al. Medication 
compliance and disease exacerbation in patients with asthma: a retrospective study of 
managed care data. Ann Allergy Asthma Immunol. 2006 Sep;97(3):402-8. 
[167] Mellins RB, Evans D, Clark N, Zimmerman B, Wiesemann S. Developing and 
communicating a long-term treatment plan for asthma. Am Fam Physician. 2000 Apr 
15;61(8):2419-28, 33-4. 
[168] Rietveld S, Creer TL. Psychiatric factors in asthma: implications for diagnosis and 
therapy. Am J Respir Med. 2003;2(1):1-10. 
[169] Rubin BK, Fink JB. The delivery of inhaled medication to the young child. 
Pediatric Clinics of North America. 2003;50(3):717-31. 
[170] Sherman JM, Baumstein S, Hendeles L. Intervention strategies for children poorly 
adherent with asthma medications; one center's experience. Clin Pediatr (Phila). 2001 
May;40(5):253-8. 
[171] Teach SJ, Crain EF, Quint DM, Hylan ML, Joseph JG. Improved asthma outcomes 
in a high-morbidity pediatric population: results of an emergency department-based 
randomized clinical trial. Arch Pediatr Adolesc Med. 2006 May;160(5):535-41. 
[172] Wise M, Gustafson DH, Sorkness CA, Molfenter T, Staresinic A, Meis T, et al. 
Internet Telehealth for Pediatric Asthma Case Management: Integrating Computerized and 
Case Manager Features for Tailoring a Web-Based Asthma Education Program. Health 
Promot Pract. 2006 Aug 23. 
[173] Sleath BL, Jackson E, Thomas KC, Galloway J, Dumain L, Thorpe J, et al. Literacy 
and perceived barriers to medication taking among homeless mothers and their children. 
Am J Health Syst Pharm. 2006 Feb 15;63(4):346-51. 
[174] Bender B, Milgrom H, Rand C, Ackerson L. Psychological factors associated with 
medication nonadherence in asthmatic children. J Asthma. 1998;35(4):347-53. 
[175] Rand CS. Adherence to asthma therapy in the preschool child. Allergy. 2002;57 
Suppl 74:48-57. 
[176] Morawska A, Stelzer J, Burgess S. Parenting asthmatic children: identification of 
parenting challenges. J Asthma. 2008 Aug;45(6):465-72. 
[177] Fiese BH, Wamboldt FS, Anbar RD. Family asthma management routines: 
connections to medical adherence and quality of life. J Pediatr. 2005 Feb;146(2):171-6. 
[178] Adams CD, Dreyer ML, Dinakar C, Portnoy JM. Pediatric asthma: a look at 
adherence from the patient and family perspective. Curr Allergy Asthma Rep. 2004 
Nov;4(6):425-32. 
[179] Farber HJ, Capra AM, Finkelstein JA, Lozano P, Quesenberry CP, Jensvold NG, et 
al. Misunderstanding of asthma controller medications: association with nonadherence. J 
Asthma. 2003 Feb;40(1):17-25. 
[180] Worstell M. Asthma: individual patient perspective and current unmet needs. Clin 
Exp Allergy. 2000 Jun;30 Suppl 1:11-5. 
 176
[181] Dozier A, Aligne CA, Schlabach MB. What is asthma control? Discrepancies 
between parents' perceptions and official definitions. J Sch Health. 2006 Aug;76(6):215-8. 
[182] Gustafsson PM, Watson L, Davis KJ, Rabe KF. Poor asthma control in children: 
evidence from epidemiological surveys and implications for clinical practice. Int J Clin 
Pract. 2006 Mar;60(3):321-34. 
[183] Chan PW, DeBruyne JA. Parental concern towards the use of inhaled therapy in 
children with chronic asthma. Pediatrics International. 2000;42(5):547-51. 
[184] Yoos HL KH, Mc Mullen A. Barriers to anti-inflammatory medication use in 
childhood asthma. Ambul Pediatr. 2003 Jul-Aug;3(4):181-90. 
[185] Zhao X, Furber S, Bauman A. Asthma knowledge and medication compliance 
among parents of asthmatic children in Nanjing, China. J Asthma. 2002 Dec;39(8):743-7. 
[186] Blais L, Beauchesne MF, Levesque S. Socioeconomic status and medication 
prescription patterns in pediatric asthma in Canada. J Adolesc Health. 2006 May;38(5):607 
e9-16. 
[187] McQuaid EL, Kopel SJ, Klein RB, Fritz GK. Medication adherence in pediatric 
asthma: reasoning, responsibility, and behavior. J Pediatr Psychol. 2003 Jul-
Aug;28(5):323-33. 
[188] Eksi A, Molzan J, Savasir I, Guler N. Psychological adjustment of children with 
mild and moderately severe asthma. Eur Child Adolesc Psychiatry. 1995 Apr;4(2):77-84. 
[189] Kaugars AS, Klinnert MD, Bender BG. Family influences on pediatric asthma. J 
Pediatr Psychol. 2004 Oct;29(7):475-91. 
[190] Calam R, Gregg L, Simpson B, Morris J, Woodcock A, Custovic A. Childhood 
asthma, behavior problems, and family functioning. J Allergy Clin Immunol. 2003 
Sep;112(3):499-504. 
[191] Horner SD, Surratt D, Smith SB. The impact of asthma risk factors on home 
management of childhood asthma. J Pediatr Nurs. 2002 Jun;17(3):211-21. 
[192] Fiese BH, Everhart RS. Medical adherence and childhood chronic illness: family 
daily management skills and emotional climate as emerging contributors. Curr Opin 
Pediatr. 2006 Oct;18(5):551-7. 
[193] Bauman LJ, Wright E, Leickly FE, Crain E, Kruszon-Moran D, Wade SL, et al. 
Relationship of adherence to pediatric asthma morbidity among inner-city children. 
Pediatrics. 2002;110(1 Pt 1):e6. 
[194] O'Connell EJ. Optimizing inhaled corticosteroid therapy in children with chronic 
asthma. Pediatr Pulmonol. 2005 Jan;39(1):74-83. 
[195] Wise M, Gustafson DH, Sorkness CA, Molfenter T, Staresinic A, Meis T, et al. 
Internet telehealth for pediatric asthma case management: integrating computerized and 
case manager features for tailoring a Web-based asthma education program. Health Promot 
Pract. 2007 Jul;8(3):282-91. 
[196] Cochrane GM, Horne R, Chanez P. Compliance in asthma. Respir Med. 1999 
Nov;93(11):763-9. 
[197] Coutts JA, Gibson NA, Paton JY. Measuring compliance with inhaled medication in 
asthma. Arch Dis Child. 1992 Mar;67(3):332-3. 
[198] Mushlin AI, Appel FA. Diagnosing potential noncompliance. Physicians' ability in 
a behavioral dimension of medical care. Arch Intern Med. 1977 Mar;137(3):318-21. 
 177
[199] Rand CS, Wise RA, Nides M, Simmons MS, Bleecker ER, Kusek JW, et al. 
Metered-dose inhaler adherence in a clinical trial. Am Rev Respir Dis. 1992 
Dec;146(6):1559-64. 
[200] O'Connor SL, Bender BG, Gavin-Devitt LA, Wamboldt MZ, Milgrom H, Szefler S, 
et al. Measuring adherence with the Doser CT in children with asthma. J Asthma. 2004 
Sep;41(6):663-70. 
[201] Apter AJ, Tor M, Feldman HI. Testing the reliability of old and new features of a 
new electronic monitor for metered dose inhalers. Ann Allergy Asthma Immunol. 2001 
Apr;86(4):421-4. 
[202] Julius SM, Sherman JM, Hendeles L. Accuracy of three electronic monitors for 
metered-dose inhalers. Chest. 2002 Mar;121(3):871-6. 
[203] Bender B, Wamboldt FS, O'Connor SL, Rand C, Szefler S, Milgrom H, et al. 
Measurement of children's asthma medication adherence by self report, mother report, 
canister weight, and Doser CT. Ann Allergy Asthma Immunol. 2000 Nov;85(5):416-21. 
[204] Chavasse RJ, Bastian-Lee Y, Richter H, Hilliard T, Seddon P. Inhaled salbutamol 
for wheezy infants: a randomised controlled trial. Arch Dis Child. 2000 May;82(5):370-5. 
[205] Birken CS, Parkin PC, Macarthur C. Asthma severity scores for preschoolers 
displayed weaknesses in reliability, validity, and responsiveness. J Clin Epidemiol. 2004 
Nov;57(11):1177-81. 
[206] Kooi EM, Schokker S, Marike Boezen H, de Vries TW, Vaessen-Verberne AA, van 
der Molen T, et al. Fluticasone or montelukast for preschool children with asthma-like 
symptoms: Randomized controlled trial. Pulm Pharmacol Ther. 2008 Oct;21(5):798-804. 
[207] Bacharier LB, Guilbert TW, Zeiger RS, Strunk RC, Morgan WJ, Lemanske RF, Jr., 
et al. Patient characteristics associated with improved outcomes with use of an inhaled 
corticosteroid in preschool children at risk for asthma. J Allergy Clin Immunol. 2009 
May;123(5):1077-82, 82 e1-5. 
[208] Schokker S, Kooi EM, de Vries TW, Brand PL, Mulder PG, Duiverman EJ, et al. 
Inhaled corticosteroids for recurrent respiratory symptoms in preschool children in general 
practice: randomized controlled trial. Pulm Pharmacol Ther. 2008;21(1):88-97. 
[209] Baker JW, Kemp J, Uryniak T, Silkoff PE. Asthma control in pediatric patients 
treated with once-daily or twice-daily nebulized budesonide inhalation suspension 
(Pulmicort Respules). Allergy Asthma Proc. 2008 May-Jun;29(3):280-5. 
[210] Kamps AW, Roorda RJ, Brand PL. Peak flow diaries in childhood asthma are 
unreliable. Thorax. 2001 Mar;56(3):180-2. 
[211] Sly PD, Flack F. Is home monitoring of lung function worthwhile for children with 
asthma? West J Med. 2001 Nov;175(5):344-5. 
[212] Uwyyed K, Springer C, Avital A, Bar-Yishay E, Godfrey S. Home recording of 
PEF in young asthmatics: does it contribute to management? Eur Respir J. 1996 
May;9(5):872-9. 
[213] Sly PD, Cahill P, Willet K, Burton P. Accuracy of mini peak flow meters in 
indicating changes in lung function in children with asthma. Bmj. 1994 Feb 
26;308(6928):572-4. 
[214] Aurora P, Stocks J, Oliver C, Saunders C, Castle R, Chaziparasidis G, et al. Quality 
control for spirometry in preschool children with and without lung disease. Am J Respir 
Crit Care Med. 2004 May 15;169(10):1152-9. 
[215] Arets HG, Brackel HJ, van der Ent CK. Forced expiratory manoeuvres in children: 
do they meet ATS and ERS criteria for spirometry? Eur Respir J. 2001 Oct;18(4):655-60. 
 178
[216] Cogswell JJ, Hull D, Milner AD, Norman AP, Taylor B. Lung function in 
childhood. I. The forced expiratory volumes in healthy children using a spirometer and 
reverse plethysmograph. Br J Dis Chest. 1975 Jan;69(1):40-50. 
[217] Piccioni P, Borraccino A, Forneris MP, Migliore E, Carena C, Bignamini E, et al. 
Reference values of Forced Expiratory Volumes and pulmonary flows in 3-6 year children: 
a cross-sectional study. Respiratory research. 2007;8:14. 
[218] Pesant C, Santschi M, Praud JP, Geoffroy M, Niyonsenga T, Vlachos-Mayer H. 
Spirometric pulmonary function in 3- to 5-year-old children. Pediatr Pulmonol. 2007 
Mar;42(3):263-71. 
[219] Taussig LM, Landau LI, Godfrey S, Arad I. Determinants of forced expiratory 
flows in newborn infants. J Appl Physiol. 1982 Nov;53(5):1220-7. 
[220] Le Souef PN, Hughes DM, Landau LI. Effect of compression pressure on forced 
expiratory flow in infants. J Appl Physiol. 1986 Nov;61(5):1639-46. 
[221] ATS/ERS statement: raised volume forced expirations in infants: guidelines for 
current practice. Am J Respir Crit Care Med. 2005 Dec 1;172(11):1463-71. 
[222] Klug B, Bisgaard H. Specific airway resistance, interrupter resistance, and 
respiratory impedance in healthy children aged 2-7 years. Pediatr Pulmonol. 1998 
May;25(5):322-31. 
[223] Bisgaard H, Nielsen KG. Bronchoprotection with a leukotriene receptor antagonist 
in asthmatic preschool children. Am J Respir Crit Care Med. 2000 Jul;162(1):187-90. 
[224] Nielsen KG, Bisgaard H. The effect of inhaled budesonide on symptoms, lung 
function, and cold air and methacholine responsiveness in 2- to 5-year-old asthmatic 
children. Am J Respir Crit Care Med. 2000 Oct;162(4 Pt 1):1500-6. 
[225] Beydon N, Davis SD, Lombardi E, Allen JL, Arets HG, Aurora P, et al. An official 
American Thoracic Society/European Respiratory Society statement: pulmonary function 
testing in preschool children. Am J Respir Crit Care Med. 2007 Jun 15;175(12):1304-45. 
[226] Lombardi E, Sly PD, Concutelli G, Novembre E, Veneruso G, Frongia G, et al. 
Reference values of interrupter respiratory resistance in healthy preschool white children. 
Thorax. 2001 Sep;56(9):691-5. 
[227] Phagoo SB, Wilson NM, Silverman M. Evaluation of a new interrupter device for 
measuring bronchial responsiveness and the response to bronchodilator in 3 year old 
children. Eur Respir J. 1996 Jul;9(7):1374-80. 
[228] Bridge PD, Ranganathan S, McKenzie SA. Measurement of airway resistance using 
the interrupter technique in preschool children in the ambulatory setting. Eur Respir J. 1999 
Apr;13(4):792-6. 
[229] Sly PD, Lombardi E. Measurement of lung function in preschool children using the 
interrupter technique. Thorax. 2003 Sep;58(9):742-4. 
[230] Gustafsson LE, Leone AM, Persson MG, Wiklund NP, Moncada S. Endogenous 
nitric oxide is present in the exhaled air of rabbits, guinea pigs and humans. Biochem 
Biophys Res Commun. 1991 Dec 16;181(2):852-7. 
[231] Davis SD. Neonatal and pediatric respiratory diagnostics. Respir Care. 2003 
Apr;48(4):367-84; discussion 84-5. 
[232] AmericanThoracicSociety. Recommendations for standardized procedures for the 
on-line and off-line measurement of exhaled lower respiratory nitric oxide and nasal nitric 
oxide in adults and children-1999. This official statement of the American Thoracic Society 
was adopted by the ATS Board of Directors, July 1999. Am J Respir Crit Care Med. 1999 
Dec;160(6):2104-17. 
 179
[233] Visser MJ, de Wit MC, van Aalderen WM, Postma DS, Brand PL. Exhaled nitric 
oxide in children measured by tidal breathing method: differences between asthmatics and 
nonasthmatic controls. Pediatr Pulmonol. 2000 Jun;29(6):434-7. 
[234] Avital A, Uwyyed K, Berkman N, Godfrey S, Bar-Yishay E, Springer C. Exhaled 
nitric oxide and asthma in young children. Pediatr Pulmonol. 2001 Oct;32(4):308-13. 
[235] Kharitonov SA, Barnes PJ. Clinical aspects of exhaled nitric oxide. Eur Respir J. 
2000 Oct;16(4):781-92. 
[236] Baraldi E, Dario C, Ongaro R, Scollo M, Azzolin NM, Panza N, et al. Exhaled 
nitric oxide concentrations during treatment of wheezing exacerbation in infants and young 
children. Am J Respir Crit Care Med. 1999 Apr;159(4 Pt 1):1284-8. 
[237] Wildhaber JH, Hall GL, Stick SM. Measurements of exhaled nitric oxide with the 
single-breath technique and positive expiratory pressure in infants. Am J Respir Crit Care 
Med. 1999 Jan;159(1):74-8. 
[238] Katarzyna K, Dariusz Z. Exhaled nitric oxide in various respiratory diseases. 
Pneumonol Alergol Pol. 2002;70(9-10):509-17. 
[239] Wang CH, Liu CY, Lin HC, Yu CT, Chung KF, Kuo HP. Increased exhaled nitric 
oxide in active pulmonary tuberculosis due to inducible NO synthase upregulation in 
alveolar macrophages. Eur Respir J. 1998 Apr;11(4):809-15. 
[240] Lundberg JO, Nordvall SL, Weitzberg E, Kollberg H, Alving K. Exhaled nitric 
oxide in paediatric asthma and cystic fibrosis. Arch Dis Child. 1996 Oct;75(4):323-6. 
[241] Lundberg JO, Weitzberg E, Nordvall SL, Kuylenstierna R, Lundberg JM, Alving K. 
Primarily nasal origin of exhaled nitric oxide and absence in Kartagener's syndrome. Eur 
Respir J. 1994 Aug;7(8):1501-4. 
[242] Moeller A, Franklin P, Hall GL, Turner S, Straub D, Wildhaber JH, et al. Inhaled 
fluticasone dipropionate decreases levels of nitric oxide in recurrenty wheezy infants. 
Pediatr Pulmonol. 2004 Sep;38(3):250-5. 
[243] Franklin PJ, Stick SM. The value of FeNO measurement in asthma management: 
the motion against FeNO to help manage childhood asthma--reality bites. Paediatr Respir 
Rev. 2008 Jun;9(2):122-6. 
[244] Ducharme FM, Davis GM. Measurement of respiratory resistance in the emergency 
department: feasibility in young children with acute asthma. Chest. 1997 Jun;111(6):1519-
25. 
[245] Malmberg LP, Pelkonen A, Poussa T, Pohianpalo A, Haahtela T, Turpeinen M. 
Determinants of respiratory system input impedance and bronchodilator response in healthy 
Finnish preschool children. Clin Physiol Funct Imaging. 2002 Jan;22(1):64-71. 
[246] Goldman MD. Clinical application of forced oscillation. Pulm Pharmacol Ther. 
2001;14(5):341-50. 
[247] Nielsen KG, Bisgaard H. Discriminative capacity of bronchodilator response 
measured with three different lung function techniques in asthmatic and healthy children 
aged 2 to 5 years. Am J Respir Crit Care Med. 2001 Aug 15;164(4):554-9. 
[248] Hellinckx J, De Boeck K, Bande-Knops J, van der Poel M, Demedts M. 
Bronchodilator response in 3-6.5 years old healthy and stable asthmatic children. Eur 
Respir J. 1998 Aug;12(2):438-43. 
[249] Marotta A, Klinnert MD, Price MR, Larsen GL, Liu AH. Impulse oscillometry 
provides an effective measure of lung dysfunction in 4-year-old children at risk for 
persistent asthma. J Allergy Clin Immunol. 2003 Aug;112(2):317-22. 
 180
[250] Thamrin C, Gangell CL, Udomittipong K, Kusel MM, Patterson H, Fukushima T, et 
al. Assessment of bronchodilator responsiveness in preschool children using forced 
oscillations. Thorax. 2007 Sep;62(9):814-9. 
[251] Hall GL, Sly PD, Fukushima T, Kusel MM, Franklin PJ, Horak F, Jr., et al. 
Respiratory function in healthy young children using forced oscillations. Thorax. 2007 
Jun;62(6):521-6. 
[252] Juniper EF, Guyatt GH, Feeny DH, Ferrie PJ, Griffith LE, Townsend M. Measuring 
quality of life in children with asthma. Qual Life Res. 1996 Feb;5(1):35-46. 
[253] WorldHealthOrganization. Constitution of the World Health Organization. . WHO 
Basic Documents. 1948;Geneva. 
[254] Juniper EF, Wisniewski ME, Cox FM, Emmett AH, Nielsen KE, O'Byrne PM. 
Relationship between quality of life and clinical status in asthma: a factor analysis. Eur 
Respir J. 2004 Feb;23(2):287-91. 
[255] Oostenbrink R, Jansingh-Piepers EM, Raat H, Nuijsink M, Landgraf JM, Essink-
Bot ML, et al. Health-related quality of life of pre-school children with wheezing illness. 
Pediatr Pulmonol. 2006 Oct;41(10):993-1000. 
[256] Klassen AF, Lee SK, Raina P, Chan HW, Matthew D, Brabyn D. Health status and 
health-related quality of life in a population-based sample of neonatal intensive care unit 
graduates. Pediatrics. 2004 Mar;113(3 Pt 1):594-600. 
[257] Fekkes M, Theunissen NC, Brugman E, Veen S, Verrips EG, Koopman HM, et al. 
Development and psychometric evaluation of the TAPQOL: a health-related quality of life 
instrument for 1-5-year-old children. Qual Life Res. 2000;9(8):961-72. 
[258] Varni JW, Seid M, Rode CA. The PedsQL: measurement model for the pediatric 
quality of life inventory. Med Care. 1999 Feb;37(2):126-39. 
[259] Chan KS, Mangione-Smith R, Burwinkle TM, Rosen M, Varni JW. The PedsQL: 
reliability and validity of the short-form generic core scales and Asthma Module. Med 
Care. 2005 Mar;43(3):256-65. 
[260] Varni JW, Burwinkle TM, Rapoff MA, Kamps JL, Olson N. The PedsQL in 
pediatric asthma: reliability and validity of the Pediatric Quality of Life Inventory generic 
core scales and asthma module. J Behav Med. 2004 Jun;27(3):297-318. 
[261] Upton P, Eiser C, Cheung I, Hutchings HA, Jenney M, Maddocks A, et al. 
Measurement properties of the UK-English version of the Pediatric Quality of Life 
Inventory 4.0 (PedsQL) generic core scales. Health Qual Life Outcomes. 2005;3:22. 
[262] Matsuda T, Noguchi M, Umeno Y, Kato N. [QOL research in child health. Present 
state and issues]. Nippon Koshu Eisei Zasshi. 2006 Nov;53(11):805-17. 
[263] Guyatt GH, Juniper EF, Griffith LE, Feeny DH, Ferrie PJ. Children and adult 
perceptions of childhood asthma. Pediatrics. 1997 Feb;99(2):165-8. 
[264] Juniper EF. How important is quality of life in pediatric asthma? Pediatr Pulmonol 
Suppl. 1997 Sep;15:17-21. 
[265] Eiser C, Morse R. Can parents rate their child's health-related quality of life? 
Results of a systematic review. Qual Life Res. 2001;10(4):347-57. 
[266] Devadason SG, Everard ML, Linto JM, Le Souef PN. Comparison of drug delivery 
from conventional versus "Venturi" nebulizers. Eur Respir J. 1997 Nov;10(11):2479-83. 
[267] Bosco AP, Rhem RG, Dolovich MB. In vitro estimations of in vivo jet nebulizer 
efficiency using actual and simulated tidal breathing patterns. J Aerosol Med. 2005 
Winter;18(4):427-38. 
 181
[268] Dalby RN, Somaraju S, Chavan VS, Jarvis D. Evaluation of aerosol drug output 
from the OptiChamber and AeroChamber spacers in a model system. J Asthma. 
1998;35(2):173-7. 
[269] Global Initiative for Asthma. Global strategy for asthma management and 
prevention. . (wwwginasthmaorg). Revised 2006. 
[270] British Guideline on the Management of Asthma. Thorax. 2008 May;63 Suppl 
4:iv1-121. 
[271] Esposito-Festen JE, Ates B, van Vliet FJ, Verbraak AF, de Jongste JC, Tiddens HA. 
Effect of a facemask leak on aerosol delivery from a pMDI-spacer system. J Aerosol Med. 
2004 Spring;17(1):1-6. 
[272] Sangwan S, Gurses BK, Smaldone GC. Facemasks and facial deposition of 
aerosols. Pediatr Pulmonol. 2004 May;37(5):447-52. 
[273] Kuehni CE, Davis A, Brooke AM, Silverman M. Are all wheezing disorders in very 
young (preschool) children increasing in prevalence? Lancet. 2001 Jun 9;357(9271):1821-
5. 
[274] Pearce N, Ait-Khaled N, Beasley R, Mallol J, Keil U, Mitchell E, et al. Worldwide 
trends in the prevalence of asthma symptoms: phase III of the International Study of 
Asthma and Allergies in Childhood (ISAAC). Thorax. 2007 Sep;62(9):758-66. 
[275] Anonymous. Global Initiative for Asthma. Global atrategy for asthma management 
and prevention. . (wwwginasthmaorg). Revised 2006. 
[276] Castro-Rodriguez JA, Rodrigo GJ. Efficacy of inhaled corticosteroids in infants and 
preschoolers with recurrent wheezing and asthma: a systematic review with meta-analysis. 
Pediatrics. 2009 Mar;123(3):e519-25. 
[277] Davis JB. Asthma and wheezy bronchitis in children. Skin test reactivity in cases, 
their parents and siblings. A controlled population study of sex differences. Clin Allergy. 
1976 Jul;6(4):329-38. 
[278] Brand P. New guidelines on recurrent wheeze in preschool children: implications 
for primary care. Prim Care Respir J. 2008 Dec;17(4):243-5. 
[279] Schultz A, Payne D. Danger of using an unreliable classification system for 
preschool wheeze. Eur Respir J. 2009 Apr;33(4):944-5; authors reply 5. 
[280] Owen J, Roller C, Walker S, Le Souef PN, Devadason SG. Comparison of an 
Innovative Spacer Device (Funhaler) with Two Small Volume Spacers. Am J Respir Crit 
Care Med. 2003;167(7):A269. 
[281] Burgess SW, Wilson SS, Cooper DM, Sly PD, Devadason SG. In vitro evaluation 
of an asthma dosing device: the smart-inhaler. Respir Med. 2006 May;100(5):841-5. 
[282] Landser FJ, Nagles J, Demedts M, Billiet L, van de Woestijne KP. A new method to 
determine frequency characteristics of the respiratory system. J Appl Physiol. 1976 
Jul;41(1):101-6. 
[283] Oostveen E, MacLeod D, Lorino H, Farre R, Hantos Z, Desager K, et al. The forced 
oscillation technique in clinical practice: methodology, recommendations and future 
developments. Eur Respir J. 2003 Dec;22(6):1026-41. 
[284] Bartlett SJ, Krishnan JA, Riekert KA, Butz AM, Malveaux FJ, Rand CS. Maternal 
depressive symptoms and adherence to therapy in inner-city children with asthma. 
Pediatrics. 2004 Feb;113(2):229-37. 
[285] Markham A, Jarvis B. Inhaled salmeterol/fluticasone propionate combination: a 
review of its use in persistent asthma. Drugs. 2000 Nov;60(5):1207-33. 
 182
 
********************************************************************* 
 183