i TITLE: In vivo gamma scintigraphy comparison of inhaled corticosteroid monotherapy delivered by pressurised metered dose inhaler with and without a spacer in adolescents with asthma CANDIDATE: Natalie Johnson BSc MEDICAL SCHOOL DIVISION OF PAEDIATRICS University of Western Australia This Thesis is presented in partial fulfilment of the requirements for the degree of Master of Child Health Research of the University of Western Australia. 2017
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i
TITLE: In vivo gamma scintigraphy comparison of inhaled corticosteroid monotherapy delivered by pressurised metered dose inhaler with and without a spacer in adolescents with asthma
CANDIDATE:
Natalie Johnson BSc
MEDICAL SCHOOL DIVISION OF PAEDIATRICS
University of Western Australia
This Thesis is presented in partial fulfilment of the requirements for the degree
of Master of Child Health Research of the University of Western Australia.
2017
ii
THESIS DECLARATION
I, Natalie Johnson, certify that:
This thesis has been substantially accomplished during enrolment in the
degree.
This thesis does not contain material which has been accepted for the award of
any other degree or diploma in my name, in any university or other tertiary
institution.
No part of this work will, in the future, be used in a submission in my name, for
any other degree or diploma in any university or other tertiary institution without
the prior approval of The University of Western Australia and where applicable,
any partner institution responsible for the joint-award of this degree.
This thesis does not contain any material previously published or written by
another person, except where due reference has been made in the text.
The work(s) are not in any way a violation or infringement of any copyright,
trademark, patent, or other rights whatsoever of any person.
Written patient consent has been received and archived for the research
involving patient data reported in this thesis.
The following approvals were obtained prior to commencing the relevant work
described in this thesis: Ethics ID 2013105EP
The work described in this thesis was funded by [PMH (now PCH)
Foundation].
Technical assistance was kindly provided by Joyce Wilson and Karen Hindley
to perform the Nuclear Medicine scans described in 2.2.6.3.
This thesis does not contain work that I have published, nor work under
review for publication.
Signature: Date: 1-12-17
iii
ABSTRACT
Spacer use is considered essential for children using inhaled corticosteroids
(ICS) delivered via pressurised metered dose inhaler (pMDI) and recommended
for all ages by the Asthma Foundation of Australia. Spacer recommendation is
primarily to reduce oropharyngeal deposition and associated corticosteroid-
induced side effects. Additionally, spacers minimise the effects of incorrect
inhaler use, which commonly occurs and is associated with reduced medication
compliance. However, anecdotal evidence indicates that spacers are seldom
used as recommended, particularly by adolescents.
The recommendation for spacer use with a pMDI may not be necessary, with
some asthma medications available in Australia generating fine and extrafine
aerosols (fine= <2.5 μm mass median aerodynamic diameter (MMAD),
extrafine= <2.0 μm). These aerosols result in less oropharyngeal deposition
compared to coarse aerosols (>2.5–10 μm MMAD). Thus, the aims of this study
were 1) to establish if spacers are required for use with a pMDI in adolescents
and 2) investigate the effect of pMDI aerosol MMAD on lung distribution, both
with and without a spacer.
To investigate these aims, this thesis evaluates in vivo lung deposition of two
ICS pMDI produced aerosols, one coarse, one fine, each delivered either with
or without a spacer, utilising a radiolabelling technique validated in vitro.
Retrospective analysis to confirm the integrity of previously used radiolabelling
methodology for the drugs (fluticasone propionate formulated as Flixotide®
(coarse, 2.8 μm MMAD) and beclomethasone dipropionate (BDP) formulated as
QVAR® (extrafine, 1.2 μm MMAD)), as used in this study, was also reported on.
We recruited fourteen adolescents aged 13–17 years (6 male, 8 female) with
mild stable asthma for a randomised crossover study on the use of one of the
two pMDIs mentioned above, with or without a spacer. On the study day, after
validation of the radiolabelled drug was confirmed successful, radiolabelled drug
was inhaled by the participant using a single maximal inhalation and breath-hold
technique. Dose of drug deposited was quantified immediately with 2D gamma
scintigraphy. Drug deposition was compared in adolescents inhaling the same
iv
drug with and without a spacer, then further analysed with multivariate statistical
modelling.
Univariate analysis showed no significant difference in total lung deposition with
the coarse aerosol when a spacer was used, compared to pMDI use alone
(p=0.31), or in the group inhaling the extrafine aerosol (p=0.52). There was a
mean decrease of 32% in oropharyngeal deposition when using a coarse
aerosol with a spacer, compared to a decrease of only 10% when using an
extrafine aerosol. The mean ratio of peripheral to central lung deposition
achieved with the extrafine aerosol was not significantly different with and
without spacer use (p=0.82), and similar results were seen in users of the
coarse aerosol (p=0.15), although a more peripheral deposition was seen
visually with the extrafine aerosol. After multivariate analysis, deposition in the
actuator (p=<0.0001), sex, age and BMI were significantly associated with lung
deposition with the extrafine aerosol only.
Dependent on further investigation in a larger cohort we recommend that BDP
as QVAR™ (MMAD 1.2 μm) may be used without a spacer in adolescents,
assuming regular inhaler technique training (every 30 days) with an
appropriately trained clinical professional. Spacer use should still be
Those who reported using either Seretide Accuhaler
or Symibcort Turbuhaler were classified as dry
powder users. Those who reported using Flutiform,
Flixotide, Alvesco, Seretide, or Spiriva were classified
as pMDI users. The individuals who reported using
Singular used this in combination with their inhaled
drug and so singular was not included in survey
results. One participant was only prescribed Ventolin,
indicated in survey as “not prescribed”
Many people forget to
take their medications
occasionally. How
often do you forget to
take it?
Two possible outcomes
from this question;
Adherence to
prescription Y/N, Daily
adherence Y/N
Often (1), Rarely (2), Occasionally (1), Frequently
(2), Never (3), Not really (1), 2-3times/week (1), 1-
2times/week (3).
Those who answered “never” (3), were allocated
YES in daily adherence. All other answers were NO.
Those who answered either frequently or often were
allocated NO to adherence to prescription. All others
were YES.
Do you take your
medication with or
without a spacer?
Consistency of spacer
use Y/N
With and without (2), no-DPI (4), with (5),
without/occasionally with (2), without.
Those who answered ONLY “with” were allocated
YES, all others were allocated NO. Answers were
ranked most to least consistent; “with”, “with and
without” and “without/occ. with”
40
2.2.6.2 Inhalation technique
On study day, immediately prior to inhalation of the study drug, all participants
(n=14) were trained by the clinical nurse asthma specialist to use their pMDI or
pMDI/spacer combination. PMDI training was in accordance with National
Asthma Council guidelines for inhalation technique using a single maximal
inhalation and breath-hold, either with or without a spacer (National Asthma
Council Australia, 2016b). Training involved the nurse specialist first
demonstrating the technique required, then asking the adolescent to
demonstrate this, and training was repeated until correct demonstration was
observed. All participants were assessed as competent and included in the
study.
2.2.6.3 Gamma scintigraphy to assess drug deposition in vivo
Four gamma scintigraphy scans were successively taken using the 2D gamma
camera (Ecam, Siemens), at PMH Nuclear Medicine department, all with a
120 second acquisition time. Firstly, prior to inhalation of the study drug, a scan
was taken of a planar flood source containing ~37 MBq Tc99m. Secondly, a
transmission scan was taken of the participant using the same planar flood
source to allow for assessment of attenuation of body tissues by gamma
radiation (Macey & Marshall, 1982). Thirdly, immediately after the participant
had inhaled the study drug, simultaneous anterior and posterior planar
scintigraphy scans were taken of the chest and abdomen with lateral positioning
of the head and neck. Lastly, Device components (pMDI actuator, spacer,
exhalation filters) were scanned immediately after the participant. Times
between all abovementioned scans were recorded in order to calculate decay
correction in analysis stages. There was not more than a 15 minute duration
between the initial scan and the final scan.
2.2.6.4 Gamma scintigraphy image acquisition and analysis
Images were acquired using Syngo VE31F software. Each participant had
regions of interest (ROI) subjectively delineated for their transmission, anterior
and posterior scan, by a single trained user. ROI were each whole lung, central
and peripheral lung regions, oropharyngeal, oesophagus, and stomach. The
central lung region was defined as a rectangle one third of the length and half
41
the width of a rectangular ROI drawn to just contain the entire lung, centred on
the proximal boundary of the rectangle. The lung ROI, (Figure 2-4) except for
the central box, was defined as peripheral lung (Figure 2-5). Total counts and
the area in pixels were obtained for each ROI, the flood source, and a
background count for transmission, device component, anterior and posterior
scans.
Figure 2-4 Subjective delineation of the lungs depicting method for quantifying central and
peripheral regions as described in 2.2.6.4. The total region of the lung (orange/red) is drawn around the
whole lung (green) in order to measure a third of the length and half the width (blue box).
Figure 2-5 Depiction of peripheral to central ratios. Central region of lung depicted inside blue box.
Anything not inside this region, but within the lung region (red/orange delineation) was considered
peripheral deposition.
42
2.2.6.5 Using gamma scintigraphy data to calculate an attenuation
corrected interpretation of emitted radiation in each region of
interest (ROI)
Calculations were completed using the three steps below. Attenuation
correction was done in accordance with (Macey & Marshall, 1982). All means
below are geometric for the purpose of log-linear decay.
1) Obtaining and calculating the geometric means of each ROI
Corrected counts (one count is one disintegration of one radioactive nucleus)
were determined (Equation 2-1) for all ROI; the lungs, oropharyngeal,
oesophagus, stomach, and central and peripheral lung regions.
Equation 2-1 Where: A = the background count in the 2D scan from an area
equal to the ROI, subtracted from the total counts in each ROI, and divided by
the area of the ROI in pixels. A was then divided by the acquisition time
(120 seconds) to get the corrected counts per second (cps);
𝐴
120= 𝑐𝑜𝑟𝑟𝑒𝑐𝑡𝑒𝑑 (𝑐𝑝𝑠)
Equation 2-2 The mean of the corresponding anterior and posterior (cps) was
calculated;
√𝑎𝑛𝑡𝑒𝑟𝑖𝑜𝑟 (𝑐𝑝𝑠) × 𝑃𝑜𝑠𝑡𝑒𝑟𝑖𝑜𝑟 (𝑐𝑝𝑠) = 𝑚𝑒𝑎𝑛 (𝑐𝑝𝑠)
2) Obtaining and calculating an attenuation correction factor
specific to each ROI.
Equation 2-3 Counts per pixel were obtained for the flood source by dividing
area in pixels by the counts;
𝑓𝑙𝑜𝑜𝑑 𝑠𝑜𝑢𝑟𝑐𝑒 𝑐𝑜𝑢𝑛𝑡𝑠
𝑎𝑟𝑒𝑎 𝑖𝑛 𝑝𝑖𝑥𝑒𝑙𝑠= 𝑓𝑙𝑜𝑜𝑑 𝑠𝑜𝑢𝑟𝑐𝑒 𝑐𝑜𝑢𝑛𝑡𝑠 𝑝𝑒𝑟 𝑝𝑖𝑥𝑒𝑙
43
Equation 2-4 Using the decay correction formula the flood source counts per
pixel were adjusted to the time of the patient scan. Where A=the negative time
from the patient scan to the flood source scan divide by the half-life of
technetium in minutes;
𝑓𝑙𝑜𝑜𝑑 𝑠𝑜𝑢𝑟𝑐𝑒 𝑐𝑜𝑢𝑛𝑡𝑠 𝑝𝑒𝑟 𝑝𝑖𝑥𝑒𝑙 × 2(𝐴)
= 𝑑𝑒𝑐𝑎𝑦 𝑐𝑜𝑟𝑟𝑒𝑐𝑡𝑒𝑑 𝑓𝑙𝑜𝑜𝑑 𝑠𝑜𝑢𝑟𝑐𝑒 𝑐𝑜𝑢𝑛𝑡𝑠 𝑝𝑒𝑟 𝑝𝑖𝑥𝑒𝑙
Equation 2-5 Transmission counts per pixel were also corrected to the time of
the patient scan using the decay correction formula. Where A=the negative time
from the patient scan to the transmission scan divide by the half-life of
technetium;
𝑡𝑟𝑎𝑛𝑠𝑚𝑖𝑠𝑠𝑖𝑜𝑛 𝑐𝑜𝑢𝑛𝑡𝑠 𝑝𝑒𝑟 𝑝𝑖𝑥𝑒𝑙 × 2(𝐴)
= 𝑑𝑒𝑐𝑎𝑦 𝑐𝑜𝑟𝑟𝑒𝑐𝑡𝑒𝑑 𝑡𝑟𝑎𝑛𝑠𝑚𝑖𝑠𝑠𝑖𝑜𝑛 𝑐𝑜𝑢𝑛𝑡𝑠 𝑝𝑒𝑟 𝑝𝑖𝑥𝑒𝑙
Equation 2-6 Transmission counts per pixel were then calculated by;
𝑑𝑒𝑐𝑎𝑦 𝑐𝑜𝑟𝑟𝑒𝑐𝑡𝑒𝑑 𝑡𝑟𝑎𝑛𝑠𝑚𝑖𝑠𝑠𝑖𝑜𝑛 𝑐𝑜𝑢𝑛𝑡𝑠
𝑎𝑟𝑒𝑎 𝑖𝑛 𝑝𝑖𝑥𝑒𝑙𝑠= 𝑡𝑟𝑎𝑛𝑠𝑚𝑖𝑠𝑠𝑖𝑜𝑛 𝑐𝑜𝑢𝑛𝑡𝑠 𝑝𝑒𝑟 𝑝𝑖𝑥𝑒𝑙
Equation 2-7 The attenuation of activity of the flood source counts per pixel by
body tissues are then calculated for each ROI;
√𝑑𝑒𝑐𝑎𝑦 𝑐𝑜𝑟𝑟𝑒𝑐𝑡𝑒𝑑 𝑓𝑙𝑜𝑜𝑑 𝑠𝑜𝑢𝑟𝑐𝑒 𝑐𝑜𝑢𝑛𝑡𝑠
𝑡𝑟𝑎𝑛𝑠𝑚𝑖𝑠𝑠𝑖𝑜𝑛 𝑐𝑜𝑢𝑛𝑡𝑠 𝑝𝑒𝑟 𝑝𝑖𝑥𝑒𝑙= 𝑎𝑡𝑡𝑒𝑛𝑢𝑎𝑡𝑖𝑜𝑛 𝑓𝑎𝑐𝑡𝑜𝑟
Equation 2-8 The mean (cps) is then multiplied by the attenuation correction factor to obtain attenuation corrected (cps) in a region of interest;
𝑚𝑒𝑎𝑛 (𝑐𝑝𝑠) 𝑖𝑛 𝑟𝑒𝑔𝑖𝑜𝑛 𝑜𝑓 𝑖𝑛𝑡𝑒𝑟𝑒𝑠𝑡
× 𝑎𝑡𝑡𝑒𝑛𝑢𝑎𝑡𝑖𝑜𝑛 𝑐𝑜𝑟𝑟𝑒𝑐𝑡𝑖𝑜𝑛 𝑓𝑎𝑐𝑡𝑜𝑟
= 𝑎𝑡𝑡𝑒𝑛𝑢𝑎𝑡𝑖𝑜𝑛 𝑐𝑜𝑟𝑟𝑒𝑐𝑡𝑒𝑑 𝑚𝑒𝑎𝑛 𝑐𝑝𝑠
44
3) Using the attenuation corrected means to interpret radiation
per ROI.
Equation 2-9 Attenuation corrected (cps) of the means were converted to a
reading of MBq in each ROI;
𝑚𝑒𝑎𝑛 (𝑐𝑝𝑠) × 𝑎𝑡𝑡𝑒𝑛𝑢𝑎𝑡𝑖𝑜𝑛 𝑓𝑎𝑐𝑡𝑜𝑟
𝑐𝑎𝑚𝑒𝑟𝑎 𝑒𝑓𝑓𝑖𝑐𝑖𝑒𝑛𝑐𝑦= 𝑀𝑏𝑞 𝑖𝑛 𝑅𝑂𝐼
This MBq reading in each ROI is defined as the percent of total detected dose.
2.2.6.6 Camera efficiency
Camera efficiency was measured as cps per MBq, and this measurement was
taken on the study day by using a uniform flood source of known concentration
with a lookup table (Radpharm®). The lookup table was based on known
constant decay rates for a Cobalt-57 flood source (see appendices 5.8). The
average of measurements taken (n=6) was used to interpret all participant data
(105 cps/MBq). The efficiency was confirmed by camera servicing history to
have little inter-day variation.
2.2.7 STATISTICAL ANALYSIS
Gamma scintigraphy deposition data was preliminarily assessed via t-test in
paired analysis with and without a spacer for each drug group using GraphPad
Prism. Group demographics for FP and BDP were assessed with a Chi-Square
test (SAS) for categorical variables; sex, age, height, weight and BMI.
To complete multivariate analysis, drug and actuator deposition variables were
transformed using the arcsine square root transformation for analysis with SAS
ver. 9.4. The BMI variable was used to simplify variables of weight and height.
Univariate assessment first looked at the relationship on total lung deposition
with each variable separately, in each drug group; age, sex, body mass index
(BMI), visit order, sequence, actuator deposition, and spacer. Multivariate
assessment was then employed to look at total lung deposition in each drug
group (proc mixed, SAS) in a full model including variables: age, sex, body
mass index (BMI), visit order, sequence, actuator deposition, spacer and
random effect (a compulsory variable for mixed models). Multivariate analysis
with backward selection (significance level of 0.05) further assessed the
relationship.
45
All statistical analyses using SAS version 9.4 for Windows (SAS Institute Inc.,
USA) were performed with assistance from the Centre for Applied Statistics, at
the University of Western Australia. Analysis done with GraphPad Prism v. 7.02
(GraphPad Software, Inc.) were performed unassisted.
2.2.7.1 Power calculations
A pre-study calculation based on previous data within our group (C. M. Roller,
Zhang, Troedson, Leach, Le Souef, et al., 2007) showed that with a sample size
of (n=28), 14 in each of the experimental groups, the study had 80% power to
detect a 10% difference in lung dose at alpha=0.5.
46
3 CHAPTER III: RESULTS
3.1 IN VITRO VALIDATION OF RADIOLABELLED DRUG
PREPARATION TO DETERMINE IN VIVO REPORTING
To confirm successful validation, particle size distributions (with stages divided
into four groups), are shown for fluticasone propionate (FP) and
beclomethasone diproprionate (BDP) in Figure 3-1 and 3-2 respectively, with
the corresponding ratio comparison displayed in table 3-1 and 3-2 respectively.
Additional confirmation that radiolabelling the commercial drug has not
significantly altered the aerodynamic diameter of the labelled drug is shown via
total recoveries of mass (Figure 3-1, A, C FP, and Figure 3-2, A, C, BDP) for
pre-study and study day reference and labelled drugs.
47
A BP re -S tu d y (n = 6 )
S tu d y d a y (n = 1 2 )
Refe
ren
ce
Lab
elled
0
5 0
1 0 0
M e a n + /-S D flu tic a s o n e p ro p io n a te
1 2 5 u g a c tu a tio n p re -s tu d y v a lid a tio n (n = 6 )
% o
f T
ota
l re
co
ve
ry
Actu
ato
r -T
hro
at
Jet-
Zero
On
e-T
wo
Th
ree-F
ilte
r
0
2 0
4 0
6 0
8 0
M e a n (9 5 % C I) p re -s tu d y v a lid a tio n
o f ra d io la b e llin g m e th o d (n = 6 ) 2 0 1 6
% o
f T
ota
l re
co
ve
ry
R e fe re n c e
L a b e lled
R a d io tra c e r
Refe
ren
ce
Lab
elled
0
5 0
1 0 0
M e a n + /-S D flu tic a s o n e p ro p io n a te
1 2 5 u g a c tu a tio n s tu d y v a lid a tio n (n = 1 2 )
% o
f T
ota
l re
co
ve
ry
Ac
tua
tor -
Th
roa
t
Je
t-Z
ero
On
e-T
wo
Th
ree
-Fil
ter
0
2 0
4 0
6 0
8 0
M e a n (9 5 % C I) s tu d y v a lid a tio n
o f ra d io la b e llin g m e th o d (n = 1 2 ) 2 0 1 6
% o
f T
ota
l re
co
ve
ry
L a b e lled
R a d io tra c e r
R e fe re n c e
C D
Figure 3-1 (A, C) Recovery of FP 125 μg per actuation, comparison of reference to labelled drug,
The corresponding ratios of reference to labelled drug (A, C) were 0.89 and 0.97 respectively. Particle size
distribution was divided into four groups, to determine if the labelled drug and radiotracer counterpart fall
within the 95% CI of the reference drug (B, D).
Table 3-1 Fluticasone propionate particle size distribution assessment comparisons. Ratios
confirmed that validation was successful when within the range of 0.85–1.18 or ±2% for the groups that
had under 10% of the total drug.
Stage of
ACI:
Actuator to
throat
Jet to 0
(difference
from
reference)
One to two
(difference from
reference)
Three to filter
Ratio
obtained
from
Pre-
study
Study
day
Pre-
study
Study
day
Pre-
study
Study
day
Pre-
study
Study
day
Reference
/labelled
canister
1.12 1.06 ±2% ±2% ±2% ±2% 0.83 0.85
Reference/
radiotracer
0.95 1.07 ±2% ±2% ±2% ±2.746% 0.86 0.81
48
A BP re -S tu d y (n = 6 )
S tu d y d a y (n = 8 )C D
Refe
ren
ce
Lab
elled
0
5 0
1 0 0
M e a n + /- S D p re -s tu d y v a lid a t io n (n = 6 ) 2 0 1 6
% o
f T
ota
l re
co
ve
ry
Actu
ato
r -T
hro
at
Jet-
Zero
On
e-T
wo
Th
ree-F
ilte
r
0
2 0
4 0
6 0
8 0
M e a n (9 5 % C I) p re -s tu d y v a lid a tio n
o f ra d io la b e llin g m e th o d (n = 6 ) 2 0 1 6
% o
f T
ota
l re
co
ve
ry
R e fe re n c e
L a be lled
R a d io tra c e r
Refe
ren
ce
Lab
elled
0
5 0
1 0 0
M e a n + /- S D s tu d y v a lid a t io n (n = 8 ) 2 0 1 6
% o
f T
ota
l re
co
ve
ry
Actu
ato
r -T
hro
at
Jet-
Zero
On
e-T
wo
Th
ree-F
ilte
r
0
2 0
4 0
6 0
8 0
M e a n (9 5 % C I) s tu d y v a lid a tio n
o f ra d io la b e llin g m e th o d (n = 8 ) 2 0 1 6%
of
To
tal
re
co
ve
ry
L a be lled
R e fe re n c e
R a d io tra c e r
Figure 3-2 (A, C) Recovery of BDP 100 μg per actuation, comparison of reference to labelled, The
corresponding ratios of reference to labelled drug (A,C) were 1.03, and 0.97 respectively. Particle size
distribution was divided into four groups, to determine if the labelled drug and radiotracer counterpart fall
within the 95% CI of the reference drug (B, D).
Table 3-2 Beclomethasone di-propionate particle size distribution assessment comparison. Ratios
confirmed that validation was successful when within the range of 0.85–1.18 or ±2% for the groups that
had under 10% of the total drug.
Stage of ACI Actuator to
throat
Jet to 0
(difference
from
reference)
One to two
(difference from
reference)
Three to filter
Ratio
obtained
from
Pre-
study
Study
day
Pre-
study
Study
day
Pre-
study
Study
day
Pre-
study
Study
day
Reference
/labelled
canister
1.08 1.11 ±2% ±2% ±2% ±2% 0.87 0.88
Reference/
radiotracer
1.07 1.04 ±2% ±2% ±2% ±2% 0.90 0.92
49
3.2 RETROSPECTIVE ANALYSIS OF RADIOLABELLED FP AND
BDP
Confirmation of successful validation of previous data, as described in C. Roller
(2012) for FP and C. M. Roller, Zhang, Troedson, Leach, Le Souef, et al. (2007)
for BDP, particle size distributions (with stages divided into four groups), is
shown, reanalysed, for fluticasone propionate (FP) and beclomethasone
diproprionate (BDP) in Figure 3-4 and 3-6 respectively. Corresponding ratio
comparisons are displayed in table 3-3 and 3-4 respectively. Additional
confirmation that radiolabelling the commercial drug has not significantly altered
the aerodynamic diameter is shown via total recoveries of mass (Figure 3-4, A,
C, FP, and Figure 3-6, A, C, BDP) for pre-study and study day reference and
labelled drugs. Radiolabelling validation results for FP from this study (3.1,
Figure 3-1) were compared to retrospectively analysed results (3.2, Figure 3-4)
confirming that the radiolabelling method is robust over time. FP particle size
distribution varied with each study due to the difference in mass delivered per
actuation (125 and 250 μg), Figure 3-3, which was not the case for BDP (Figure
3-5) as both studies used 100 μg per actuation. The lower dose used for FP in
this study resulted in a higher respirable fraction (Three to Filter), and lower
Actuator to Throat fraction. Radiolabelling validation results for BDP from this
study (3.1, Figure 3-2) were compared to retrospectively analysed results (3.2,
Figure 3-6) confirming that the radiolabelling method is robust over time.
50
Actu
ato
r -T
hro
at
Jet-
Zero
On
e-T
wo
Th
ree-F
ilte
r
0
2 0
4 0
6 0
8 0
1 0 0
G ro u p e d fra c t io n s o f p a r t ic le s iz e d is tr ib u t io n
fro m a n d e rs o n c a s c a d e im p a c to r s ta g e s fo r F P
A n d e rs o n c a s c a d e im p a c to r s ta g e g ro u p in g s
Pe
rc
en
t o
f to
tal
re
co
ve
ry
Figure 3-3 Grouped comparison of two different radiolabelled validation results for FP, 125 μg
(hatched) and 250 μg per actuation. Grouped comparison of mean radiotracer and labelled to mean
reference (95% CI) for FP radiolabelling method shows little variation over time or between users. Labelled
drug (Dark Grey) and Radiotracer (Black) were marginally outside the 95% CI of the Reference (Light
Grey) drug, similar over time from 2006 (filled columns) to 2016 (hatched columns).
51
A BP re -S tu d y (n = 5 )
S tu d y d a y (n = 1 0 )C D
Refe
ren
ce
Lab
elled
0
1 0 0
2 0 0
M e a n + /- S D
p re -s tu d y v a lid a t io n (n = 5 ) 2 0 0 4
% o
f T
ota
l re
co
ve
ry
Actu
ato
r -T
hro
at
Jet-
Zero
On
e-T
wo
Th
ree-F
ilte
r
0
2 0
4 0
6 0
8 0
M e a n (9 5 % C I) p re -s tu d y v a lid a tio n o f
ra d io la b e llin g m e th o d (n = 5 ) 2 0 0 4
% o
f T
ota
l re
co
ve
ry
R e fe re n c e
L a be lled
R a d io tra c e r
Refe
ren
ce
Lab
elled
0
1 0 0
2 0 0
M e a n + /- S D s tu d y v a lid a t io n
(n = 1 0 ) 2 0 0 4
% o
f T
ota
l re
co
ve
ry
Ac
tua
tor -
Th
roa
t
Je
t-Z
ero
On
e-T
wo
Th
ree
-Fil
ter
0
2 0
4 0
6 0
8 0
M e a n (9 5 % C I) S tu d y V a lid a tio n (n = 1 0 ) 2 0 0 4
% o
f T
ota
l re
co
ve
ry
R e fe re n c e
L a be lled
R a d io tra c e r
Figure 3-4 (A, C) Recovery of FP 250 μg per actuation, comparison of reference to labelled, (B, D)
Corresponding ratio between the reference to labelled drug (A,C) was 1.13, and 1.09 respectively. Particle
size distribution was divided into four groups, to determine if the labelled drug and radiotracer counterpart
fall within the 95% CI of the reference drug (B, D).
Table 3-3 Fluticasone propionate particle size distribution assessment comparisons. Ratios
confirmed that validation was successful when within the range of 0.85–1.18 or ±2% for the groups that
had under 10% of the total drug.
Stage of ACI Actuator to
throat
Jet to 0
(difference
from
reference)
One to two
(difference from
reference)
Three to filter
Ratio
obtained
from
Pre-
study
Study
day
Pre-
study
Study
day
Pre-
study
Study
day
Pre-
study
Study
day
Reference
/labelled
canister
0.91 1.02 ±2% ±2% >±2% >±2% 1.25 1.06
Reference/
radiotracer
0.93 0.99 ±2% ±2% >±2% >±2% 1.01 0.94
52
Actu
ato
r -T
hro
at
Jet-
Zero
On
e-T
wo
Th
ree-F
ilte
r
0
2 0
4 0
6 0
8 0
1 0 0
G ro u p e d fra c t io n s o f p a r t ic le s iz e d is tr ib u t io n f ro m a n d e rs o n
c a s c a d e im p a c to r s ta g e s fo r B D P
Pe
rc
en
t o
f to
tal
re
co
ve
ry
A n d e rs o n c a s c a d e im p a c to r s ta g e g ro u p in g s
Figure 3-5 Grouped fraction comparison of two different radiolabelled validation results for BDP,
both used 100 μg per actuation. Grouped comparison of mean radiotracer and labelled to mean
reference (95% CI) for BDP radiolabelling method shows no variation over time or between users.
Labelled drug (Dark Grey) and Radiotracer (Black) were comparable to the 95% CI of the Reference (Light
Grey) drug, the integrity of the radiolabelling method unchanging over time from 2006 (filled columns) to
2016 (hatched columns).
53
A BP re -S tu d y (n = 1 0 )
S tu d y d a y (n = 1 5 )C D
Re
fere
nc
e
La
be
lle
d
0
5 0
1 0 0
M e a n + /- S D p re -s tu d y v a lid a t io n
(n = 1 0 ) 2 0 0 4
% o
f T
ota
l re
co
ve
ry
Ac
tua
tor -
Th
roa
t
Je
t-Z
ero
On
e-T
wo
Th
ree
-Fil
ter
0
2 0
4 0
6 0
8 0
M e a n (9 5 % C I) p re -s tu d y v a lid a tio n o f
ra d io la b e llin g m e th o d (n = 1 0 ) 2 0 0 4
% o
f T
ota
l re
co
ve
ry
R e fe re n c e
L a be lled
R a d io tra c e r
Re
fere
nc
e
La
be
lle
d
0
5 0
1 0 0
M e a n + /- S D s tu d y v a lid a t io n
(n = 1 5 ) 2 0 0 4
% o
f T
ota
l re
co
ve
ry
Ac
tua
tor -
Th
roa
t
Je
t-Z
ero
On
e-T
wo
Th
ree
-Fil
ter
0
2 0
4 0
6 0
8 0
M e a n (9 5 % C I) s tu d y v a lid a tio n
o f ra d io la b e llin g m e th o d (n = 1 5 ) 2 0 0 4
% o
f T
ota
l re
co
ve
ry
R e fe re n c e
L a be lled
R a d io tra c e r
Figure 3-6 (A, C) Recovery of BDP 100 μg per actuation, comparison of reference to labelled.
Corresponding ratio between the reference to labelled drug (A,C) was 0.93, 0.94 respectively. Particle size
distribution was divided into four groups, to determine if the labelled drug and radiotracer counterpart fall
within the 95% CI of the reference drug (B, D).
Table 3-3 Beclomethasone di-propionate particle size distribution assessment comparison. Ratios
confirmed that validation was successful when within the range of 0.85–1.18 or ±2% for the groups which
had under 10% of the total drug.
Stage of ACI Actuator to
throat
Jet to zero
(difference
from
reference)
One to two
(difference from
reference)
Three to filter
Ratio
obtained
from
Pre-
study
Study
day
Pre-
study
Study
day
Pre-
study
Study
day
Pre-
study
Study
day
Reference
/labelled
canister
0.98 0.97 ±2% ±2% ±2% ±2% 1.05 0.97
Reference/
radiotracer
0.90 0.93 ±2% ±2% ±2% ±2% 1.09 0.98
54
3.3 IN VIVO DRUG DEPOSITION STUDY RESULTS
3.3.1 STUDY POPULATION
The demographic information for the cohort is displayed in Table 3-5 for the full
cohort. The mean demographics assessed were similar within drug groups
(Table 3-6) and to the full cohort demographic means (Table 3-5). There was no
significant difference between groups in any variable (Table 3-6).
Table 3-4 Full cohort (n=14) demographics
Variable Mean, Range
Sex (n) 6 Male, 8 Female
Age (yrs) 15 y, 13–17 years
Height (cm) 169, 158–179
Weight (kg) 67, 46–110
BMI (kg/m2) 23.4, 16–40
55
Table 3-5 Group demographics separated for BDP and FP
Drug BDP FP
Variable Mean Range Mean Range P-value
Sex 1 Male, 6
Female
5 Male, 2 Female 0.10
Age 15 years 14–16
years
15 years 13–17 years 1.00
Height 166 cm 158–175
cm
172 cm 157–179 cm 0.19
Weight 64 kg 46–89
kg
71 kg 47–110 kg 0.49
BMI 23 18–29 24 17–40 0.76
56
3.3.1.1 Screening questionnaire data
All participants (n=14) completed a screening questionnaire (Figure 3-7),
involving adherence to medication and related issues. Approximately 50% of
participants who required a spacer used it regularly. Over 75% of participants
who were prescribed inhaled corticosteroids for their asthma reported regularly
taking them, but only 25% of those participants said they take them every day
(Figure 3-7).
Figure 3-7 Survey of adherence to pMDI delivered corticosteroid asthma drugs and related questions in mildly asthmatic adolescents. Nearly 70 % of participants did not adhere to their
prescribed daily puffer medication, and of those who did approximately half used their spacers.
0.00%
10.00%
20.00%
30.00%
40.00%
50.00%
60.00%
70.00%
80.00%
90.00%
100.00%
Dry powder use Consistency tospacer use
Adherance toprescription
Daily adherence
Survey of adherence to use of asthma drugs by study participants (n=14)
Not prescribed
Yes
No
57
3.3.2 SHOT WEIGHT DELIVERED BY PMDI
The dose of drug delivered to each participant, measured via mass, is shown in
Figure 3-8. Two significant outliers were observed with BDP, and two with FP,
both confirmed to be due to inhaler variability per shot (Figure 3-8).
n=2
n=5
n=10
0 .0 5
0 .0 6
0 .0 7
0 .0 8
0 .0 9
S h o t w e ig h t (m e a n S D , F P la b e lle d )
M e a n o f a c u ta t io n s p e r d a ta p o in t
ma
ss
pe
r a
ctu
ati
on
dis
pe
ns
ed
(g
m)
n=2
n=5
n=10
0 .0 5
0 .0 6
0 .0 7
0 .0 8
0 .0 9
S h o t w e ig h t (m e a n S D , B D P la b e lle d )
M e a n o f a c u ta t io n s p e r d a ta p o in t
ma
ss
pe
r a
ctu
ati
on
dis
pe
ns
ed
(g
m)
Figure 3-8 Mass of drug delivered to each participant on study day reduced in variability with
multiple shots per mean. Variability of the same labelled canister reduced when obtaining the mean of 5
and 10 actuations, showing natural variability, and not an effect of a flawed radiolabelled drug. Additionally,
inter user variability was present at n=2.Timepoints were obtained successively for n=5,10 and 2.
3.3.3 GAMMA SCINTIGRAPHY IN VIVO DEPOSITION AFTER INHALATION
OF RADIOLABELLED DRUG
Gamma scintigraphy images were taken, obtained, and analysed, according to
methods sections 2.2.6.3, 2.2.6.4, and 2.3.6.5, respectively. Results of gamma
scintigraphy deposition data for FP and BDP are displayed regionally in Figure
3-9 and Table 3-7. Deposition data was defined as percentage of total ex-valve
dose as detected via gamma camera (MBq). Data show a fivefold decrease in
oropharyngeal deposition with a spacer with FP, (p= 0.001), although only
twofold decrease was seen with BDP (p=0.03) (Figure 3-9, A). Lung deposition
was higher with a spacer, although not significantly higher with FP (p=0.31), or
BDP (p=0.52) (Figure 3-9, B). Mean peripheral to central ratio with was higher
with a spacer (FP p=0.16, BDP p=0.81).
58
F P B D P
A
B
C
Sp
acer
+ p
MD
I
pM
DI o
nly
0
2 0
4 0
6 0
8 0
O ro p h a ry n g e a l d e p o s it io n (% e x -v a lv e )
* *
Sp
acer
+ p
MD
I
pM
DI o
nly
0
2 0
4 0
6 0
8 0
O ro p h a ry n g e a l d e p o s it io n (% e x -v a lv e )
*
Sp
acer
+ p
MD
I
pM
DI o
nly
0
2 0
4 0
6 0
8 0
L u n g d e p o s it io n (% e x -v a lv e )
p = 0 .3 1
Sp
acer
+ p
MD
I
pM
DI o
nly
0
2 0
4 0
6 0
8 0
L u n g d e p o s it io n (% e x -v a lv e )
p = 0 .5 2
Sp
acer
+ p
MD
I
pM
DI o
nly
0
1
2
3
R e g io n a l lu n g d e p o s it io n
Pe
rip
he
ra
l to
ce
ntr
al
ra
tio
(P
:C)
p = 0 .1 6
Sp
acer
+ p
MD
I
pM
DI o
nly
0
1
2
3
R e g io n a l lu n g d e p o s it io n
Pe
rip
he
ra
l to
ce
ntr
al
ra
tio
(P
:C)
p = 0 .8 1
Figure 3-9 Univariate analysis after transformation of gamma scintigraphy deposition data, as
percentage of ex-valve, for FP (n=7) and BDP (n=7): A) mean±SD paired oropharyngeal deposition,
after inhalation with radiolabelled drug, B) mean±SD paired lung deposition after inhalation of radiolabelled
drug C) mean±SD regional lung deposition after inhalation of radiolabelled drug as a peripheral to central
ratio.
59
Table 3-6 Comparison of mean (SD) deposition data for purpose of cross study comparison. Deposition values are displayed for each region of interest as percent of ex-valve
or ex-actuator
FP BDP
Spacer
pMDI only Spacer
pMDI only
Ex-valve
(%)
Ex-actuator (%) Ex-valve
(%)
Ex-actuator
(%)
Ex-valve
(%)
Ex-actuator
(%)
Ex-valve
(%)
Ex-actuator
(%)
Actuator 20±9 - 18±8 - 40±27 - 52±31 -
Lung 37±6 46±5 33±9 40±13 34±19 56±14 29±22 54±14
OP 9±7 11±8 49±12 59±13 4±5 9±5 14±8 32±9
Spacer 33±9 41±11 - - 13±9 21±9 - -
Exhaled 1±2 2±2 <0.5±1 <1±1 7±6 13±10 5±4 11±9
60
Visual review of the gamma scintigraphy images, shown for FP in Figure 3-10,
revealed higher oropharyngeal deposition (OP) and deposition around the major
bifurcations, with hot spots in the lungs, particularly when drug was
administered via a pMDI without a spacer. BDP deposition visually showed an
even spread in the lungs with either device, and a slight decrease in OP
deposition when a spacer was used (Figure 3-11). Images were not altered
after obtaining from software.
Figure 3-10 Qualitative analysis of gamma scintigraphy lung deposition images (FP). Image data
show paired data; (A) Deposition with pMDI alone, (B) Deposition with pMDI/spacer combination.
Figure 3-11 Qualitative analysis of gamma scintigraphy lung deposition images (BDP). Image data
show paired data; (A) Deposition with pMDI alone, (B) Deposition with pMDI/spacer combination.
A B
A B
61
3.3.4 STATISTICAL ANALYSIS OF GAMMA SCINTIGRAPHY DEPOSITION
DATA AFTER TRANSFORMATION
When each variable was analysed separately with drug with BDP, percent
deposition in the actuator significantly reduced lung deposition (Table 3-8). After
adjustment in a full model, age, sex and BMI additionally affected lung
deposition with BDP only, and remained significant after backward elimination
at significance level alpha 0.05 (Table 3-8).
Table 3-7 Analysis of regional deposition data after transformation. Lung deposition from each drug
was analysed: with a single variable (Spacer etc.), in a full model to adjust for confounders, then variables
were eliminated via backward selection at 0.05 level of significance, until the final model was left (exit point
p-values displayed).
Univariate Full Model
(adjusted)
Final Model
(backward
selection)
Drug FP BDP FP BDP FP BDP
Variable
Spacer 0.27 0.45 0.51 0.76 0.50 0.76
Age 0.92 0.57 0.44 0.02 0.09 0.002
Sex 0.28 0.36 0.61 0.004 0.61 0.0004
Randomisation
order
0.90 0.70 0.25 0.74 0.41 0.71
Visit order 0.16 0.74 0.33 0.68 0.12 0.60
BMI 0.12 0.20 0.09 0.004 0.12 0.0003
Actuator 0.54 <0.0001 0.58 <0.0002 0.59 <0.0001
62
4 CHAPTER IV: DISCUSSION
Lung deposition with use of the pMDI producing the extrafine aerosol (BDP), or
the coarse aerosol (FP) by adolescents in this study was not significantly
different with or without use of a spacer, and peripheral airway deposition was
equivalent regardless of spacer use. Whilst the MMAD for FP was assessed
here to be 2.8 μm and is therefore marginally a coarse aerosol, it appears to
have some of the characteristics demonstrated by a fine aerosol (≤2.5 μm
MMAD) in this study, perhaps as it is very marginally coarse. Our findings for
BDP, QVAR™, are consistent with a previous study of this drug formulation that
reported equivalent lung deposition with or without a spacer in an adult cohort
(C. L. Leach & Colice, 2010). Furthermore, levels of lung deposition found here
with pMDI producing an extrafine aerosol are consistent in both adult
populations without a spacer (CL Leach et al., 1998; C. L. Leach, Davidson,
Hasselquist, & Boudreau, 2002; C. L. Leach et al., 2005), and child populations
with a spacer, assuming correct and reproducible inhalation technique (C. M.
Roller, Zhang, Troedson, Leach, Le Souef, et al., 2007). The recommendation
for a spacer as an additional device would thus be unnecessary with a extrafine
preventer aerosol (≤~2 μm MMAD), assuming reproducible results in a larger
adolescent cohort or other supportive evidence such as that obtained by
Guilbert et al. (2017), who saw no clinical improvement with use of a spacer
compared to pMDI alone in a retrospective study of patient clinical data. A
combination of epidemiological and/or survey methods combined with evidence
based studies such as ours, would provide the best approach to supporting
change in practice.
Implementing this change in practice would make progress toward addressing
the long overdue issue of incorrect pMDI usage, shown to be unchanged over
the 40 years prior to 2014 in a systematic review by Sanchis et al. (2016). The
Global Initiative for Asthma identifies incorrect pMDI use as a contributor to
decreased asthma control levels (Reddel et al., 2015) which are shown to be
low - 24% of adolescents with asthma in the Asia Pacific region have
uncontrolled asthma, a further 63% only partly controlled, and only 13% well
(2016) also found that, despite spacer use, pMDI technique remained poor.
63
Interestingly, the recommendation for use of a spacer currently attempts to
address incorrect inhaler use. Furthermore, spacer use has proved difficult to
implement in practice, particularly in populations that require special clinical
management to encourage medication compliance, such as adolescents
(Michaud, 2007), and so it seems that change to this practice is also long
overdue and would particularly benefit the adolescent population.
Adolescents are a special population whose adherence to medication is directly
influenced by healthy family psychosocial functioning, where family support can
improve autonomy in the journey toward adulthood and help foster a positive
attitude toward medication self-management (Rhee et al., 2010). Positive
attitude toward self-management can include increased likelihood of visiting a
health professional when required – and a good relationship with the health
care provider is key to improving asthma control levels (Haskard Zolnierek &
DiMatteo, 2009). Conversely, when this support is not available, issues with
self-management become apparent and negatively impact asthma control,
increasing morbidity and the risk of hospitalisation (Chen et al., 2003; Rhee et
al., 2010). These issues can be further compounded by a multitude of generally
accepted issues with asthma treatment: inadequacies with the medication
delivery itself, inadequate health education contributing to false beliefs about
the safety of asthma medication or the chronic nature of the disease, and false
perceptions about the ease of effective drug delivery contributing to non-
compliance with treatment recommendations (spacer use). Whilst improving
family psychosocial functioning is an infinitely more challenging task, those
compounding issues can more easily be addressed, such as, by improving drug
delivery, and investigating the requirement (or not) for spacer use, (particularly
as adolescents display an aversion to using them). Real-life outcomes of spacer
use have been studied by Guilbert et al. (2017), however, to our knowledge
ours is the first study to assess the clinical recommendation, via lung deposition
study, for spacer use with ICS formulations produced by pMDI, both with and
without a spacer, in a solely adolescent population. Our study widens already
established findings that show increased delivery efficacy in adults, of an
extrafine aerosol, by extending that finding to the adolescent age group.
Our study showed a high lung to oropharyngeal deposition ratio per dose with
the extrafine aerosol only (i.e. 60:40 lung to oropharyngeal). The findings in our
64
study are supported extensively with previous studies for the extrafine aerosol,
showing consistent lung deposition of ~55% (ex-actuator dose) and
oropharyngeal deposition of ~40% (ex-actuator dose) with a pMDI alone (CL
Leach et al., 1998; C. L. Leach et al., 2002, 2005). Limited lung deposition
studies were available to compare our coarse aerosol data with, none with and
without a spacer in any population. With the coarse aerosol pMDI alone, we
recorded lung deposition of ~40% (ex-actuator), which contrasted a previous
adult study reporting ~25% (ex-actuator). With a pMDI+spacer, however, we
reported lung deposition of ~45% (ex-actuator), comparable to a previous study
(C. Roller, 2012) reporting ~25% (SD 10), range 15–45%, (ex-actuator) in a
child cohort. It is reasonable to conceive a higher lung deposition would be
observed in an older cohort and lung deposition may have been additionally
increased by the lower dose per actuation used in our study. As seen in our
validation retrospective analysis, the higher dose per actuation (250 μg) used by
C. Roller (2012) resulted in a decreased respirable fraction, compared to our
lower dose (125 μg). At higher doses, particles may coagulate after
aerosolisation, resulting in larger particles, and thus a decreased dose delivered
to the lungs (Tolpekin, Duits, van den Ende, & Mellema, 2004; Tsuda et al.,
2011). Use of a lower dose may reduce the potential of this occurring.
Considering a 44 μg dose was used by C. L. Leach et al. (2015) this may also
confirm that the dose used in our study was optimal for a pMDI producing a
coarse aerosol. Alternatively, a lower dose estimate consistent with that
obtained by C. L. Leach et al. (2015) may be more reasonable, which could
highlight the importance of recognising even minor inconsistencies from
radiolabelling validation guidelines, as seen with fluticasone propionate in our
study. Radiolabelling validation of fluticasone propionate as previously reported
by C. L. Leach et al. (2015) and C. Roller (2012) however, demonstrably similar
inconsistencies to our study, such as the “tailing effect”, where <5% of total un-
incorporated radiation is observed. Thus, it is unlikely to affect study
comparability, although exact ratios and confidence intervals were not provided
by C. L. Leach et al. (2015) and so a more accurate reflection cannot be made.
To recommend the required change against spacer use in clinical practice,
evidence of high lung to oropharyngeal deposition ratio per dose is necessary.
The concern where this is absent is an increased systemic ICS bioavailability
and resultant side effects. Our results confirm that when using a pMDI
65
producing extrafine aerosol, you receive a higher respirable fraction of the total
dose, which corresponds to an increased therapeutic dose.
Our study in adolescents demonstrated equivalent lung deposition regardless of
spacer use, or drug formulation, as has been found previously with a extrafine
aerosol only (C. L. Leach & Colice, 2010). This indicates a spacer may not be
needed to improve lung deposition with a coarse aerosol or with an extrafine
aerosol, building on a previous epidemiological study where spacer use did not
improve asthma outcomes for a fine or extrafine aerosol (Guilbert et al., 2017).
The observed equivalence in lung deposition regardless of spacer use or drug
in our study, may be due to the relatively small difference in MMAD of the
chosen drugs (2.8 µm versus 1.2 µm), with the coarse aerosol consideration for
a fine aerosol (fine aerosol= >0.1–2.5 μm) (Australian Government, 2004).
Alternatively, it could be an effect of repeated inhaler technique training,
(Kamps et al., 2000) although statistical analysis in this study did not find an
association, i.e. there was no evidence of greater lung deposition on the second
visit compared with the first. It is commonly accepted that inhaler technique
remains poor in practice (Price et al., 2013; Sanchis et al., 2016) regardless of
technique assessment by clinical observation (Biswas et al., 2016), yet this may
be substantially due to insufficient or incomplete initial training programs
(Haahtela et al., 2006; Papi et al., 2011). In this study adolescents were
considered able to coordinate an adequate inhalation technique, during training
with a clinical nurse asthma specialist, which suggests a spacer may not
necessarily be required to decrease the effects caused by lack of coordination
under these circumstances. Whilst our small sample size limits generalisable
conclusions, our data emphasises the potential of an appropriately and
repeatedly trained, clinically observed, adolescent to use a pMDI producing an
inhaled corticosteroid aerosol <2.8 μm MMAD to achieve approximately
equivalent lung deposition to that seen with use of the same drug with a spacer.
A short acting beta 2 agonist, even if formulated with a <2.8 μm MMAD may not
produce a similar result, as a symptomatic patient may give a different pattern
of inhalation; usually an increase in rate of inhalation and a resulting more
central and oropharyngeal deposition (Laube, Norman, & Adams, 1992).
Additionally, coordination may not be optimal when patients are symptomatic
and so the user may still benefit from use of a spacer.
66
With the pMDI producing an extrafine aerosol we reported an increased
proportion of the total dose depositing in the peripheral airways regardless of
spacer use. This finding is comparable to other studies and demonstrates no
effect of spacer on regional deposition (C. L. Leach et al., 2006; C. L. Leach et
al., 2015). Whilst the 2D imaging method used in this study may be limited in its
ability to estimate regional lung deposition compared to 3D methods, C. L.
Leach et al. (2006) confirmed this systematic under- and over-estimation was
marginal. Additionally, a recently validated diagnostic method for 2D
assessment of lung deposition showed increased sensitivity in detecting
regional deposition, and could reduce this bias in future studies (Bennett, Xie,
Zeman, Hurd, & Donaldson, 2014). Based on our study, it is reasonable to
assume a spacer is not required for use, additional to a pMDI producing an
extrafine aerosol, to increase peripheral deposition in this age group. This may
mean that a future focus on pMDIs producing a fine aerosol, particularly those
considered extrafine (≤~2 μm MMAD) as used in our study, would be a useful
approach to target peripheral lung disease.
If clinical practice was to change, based on this and larger future studies, it
would highlight the need for improved clinician and patient pMDI technique
training programs, particularly from the point of initial treatment (Fink & Rubin,
2005; Haahtela et al., 2006). PMDIs are cheap and portable devices for orally
inhaled delivery of corticosteroids, and the most recommended device
worldwide for the treatment of asthma, (Brocklebank et al., 2001) however,
clearly, the problem of inhaler technique compliance still exists outside of a
clinical setting, and is associated with an increased risk of exacerbation and
hospitalisation (Levy et al., 2013; Sanchis et al., 2016). An improvement in
education and training for the delivery of ICS, if combined with easy to
implement therapies is advantageous to the wider population, and particularly
valuable to special populations with reduced medication adherence, such as
adolescents (Dima et al., 2015). The extrafine aerosol formulation produced by
pMDI used in this study shows a repeatable increase in lung deposition when
compared to coarse aerosols, and is already available in Australia and
worldwide, emphasising the possibility for imminent changes to clinical
recommendation (CL Leach et al., 1998; C. L. Leach et al., 2006; C. L. Leach et
al., 2002, 2005; C. L. Leach et al., 2012; C. L. Leach et al., 2015).
67
Based on results of this study, significant effectors of lung deposition with an
extrafine aerosol, such as deposition of drug in the actuator, BMI, sex, and age,
may be useful inclusions of future study designs. The effect of repeated training
(inclusion of a visit order variable) is a particularly recommended inclusion.
The introduction of the international guidelines for inhaled radiolabelled
preparations in 2012 (Devadason et al., 2012), should lead to improved
consistency of reporting and so it is increasingly possible that studies completed
under the new guidelines, such as ours, are easily comparable. Evidence from
this and previous studies suggests that the MMAD of an aerosol has a
significant effect on lung deposition with ICS asthma drug formulations. PMDIs
producing a fine aerosol (MMAD<2.5 µm), specifically those considered extra-
fine (MMAD ~2 µm), result in almost double the lung deposition and half the
oropharyngeal deposition, achieved in previous studies using coarse (>2.5–10
µm MMAD) formulations. This emphasises the necessity of changes to clinical
recommendations, such as spacer use, particularly for the adolescent
population, where ease of implementation is especially important.
4.1 CONCLUSION
Results presented here investigate the MMAD of two inhaled corticosteroids,
and pragmatically addresses the recommendation for spacer use in a
population whom are less likely to manage their disease optimally, more likely
to have poor asthma control, and express an aversion to use the spacer device.
It builds on prior work done in adults showing that an extrafine aerosol can
achieve equivalent lung deposition with or without a spacer, when inhaled with
good technique, by expanding these same findings to an adolescent age group.
It supports prior epidemiological work showing no improvements in asthma
outcomes are evident with spacer use with a fine ICS aerosol. This thesis
shows that, whether or not a spacer is used, an extrafine preventer aerosol
achieves equivalent regional and total lung deposition and comparable
oropharyngeal dose. Considering our findings in the extrafine aerosol are
supported by previous work, discontinuing spacer recommendation for this
formulation could potentially simplify asthma treatment in non-compliant
patients.
68
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