Respiratory Medicine 201 (2022) 106940

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Respiratory Medicine
journal homepage: www.elsevier.com/locate/rmed

Short communication

Digital spacer data driven COPD inhaler adherence education: The

OUTERSPACE proof-of-concept study
Boudewijn J.H. Dierick a, b, Sandra Been-Buck c, Titia Klemmeier c, Paul Hagedoorn d, i,
Susanne J. van de Hei e, g, Huib A.M. Kerstjens f, i, Janwillem W.H. Kocks g, h, i, Tanja R. Zijp a,
A. Mireille A. Wessels a, Daan J. Touw a, i, Job F.M. van Boven a, i, *
a
University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD (GRIAC), Department of Clinical Pharmacy &
Pharmacology, Groningen, the Netherlands
b
University of Groningen, University Medical Center Groningen, Department of General Practice & Elderly Care Medicine, Groningen, the Netherlands
c
Department of Pulmonary Diseases, Martini Hospital, Groningen, the Netherlands
d
Department of Pharmaceutical Technology and Biopharmacy, Groningen Research Institute of Pharmacy, University of Groningen, Groningen, the Netherlands
e
University of Groningen, University Medical Center Groningen, Department of Health Sciences, Groningen, the Netherlands
f
University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD (GRIAC), Department of Pulmonology and
Tuberculosis, Groningen, the Netherlands
g
General Practitioners Research Institute, Groningen, the Netherlands
h
Observational and Pragmatic Research Institute, Singapore
i
Medication Adherence Expertise Center of the Northern Netherlands (MAECON), Groningen, the Netherlands

A B S T R A C T

Pressurized metered dose inhalers are recommended to be used in combination with spacers, yet inhaler technique and adherence are poor. A novel digital "smart"
spacer can record spacer use and technique errors and could facilitate personalized education. In this proof-of-concept study, we assessed the usability of the digital
spacer and explored its effects on inhaler technique, adherence, long-term systemic drug exposure and clinical outcomes in COPD. Usability was deemed high. One
month after personalized digital spacer inhaler education, the mean number of errors per patient per day decreased with 36%, from 6.40 errors/day to 4.07 errors/
day (p = 0.038). Drug exposure was confirmed by bioanalytical scalp hair analysis of formoterol. No significant change in clinical outcomes was observed. This study
demonstrates the digital spacer’s potential value in inhaler education, but larger, longer-term studies are required.

1. Introduction errors including: multiple actuations, no inhalation, delayed inhalation,

To overcome challenges in actuation-breathe coordination, pressur­
ized metered dose inhalers (pMDIs) are recommended to be combined
with a spacer device [1–3]. However, inhalers and spacer devices only
work when properly used and this turns out to be an ongoing challenge
for patients and clinicians [4]. Correct use of spacers can help maxi­
mizing airway deposition and includes a slow, deep inhalation which
immediately follows a single actuation [5–7]. Clinicians usually high­
light these aspects during a once-off clinical visit but are blinded to
patients’ spacer use at home, hampering personalized educational in­
terventions. Recently, a digital “smart” spacer based on one of the
world’s most widely used spacers, i.e. the Aerochamber, was developed
(Fig. 1) [8]. In short, it is a rechargeable device that measures exact
moment of intake of both reliever and controller, as well as inhaler
excessively high flow and low inhaled volume. The internal resistance of
the digital Aerochamber is not different from the original Aerochamber
[8]. Data are stored on an SD-card that can be read out and visualized.
The aim of this study was to assess the usability of the digital spacer and
explore its potential effects on inhaler technique, adherence, long-term
systemic drug exposure and clinical outcomes. This study is the first of
the OUtcomes following Tailored Education and Retraining: Studying
Performance and AdherenCE in asthma and COPD (OUTERSPACE) trial
program.
2. Methods
In this 2-month single-center study performed at the Martini Hospital
Groningen, 12 patients >40 years with spirometry-confirmed COPD

* Corresponding author. Department of Clinical Pharmacy & Pharmacology, University Medical Center Groningen, Hanzeplein 1 (internal postcode AP50), 9700
RB, Groningen, the Netherlands.
E-mail address: j.f.m.van.boven@rug.nl (J.F.M. van Boven).

https://doi.org/10.1016/j.rmed.2022.106940
Received 10 June 2022; Received in revised form 12 July 2022; Accepted 21 July 2022
Available online 31 July 2022
0954-6111/© 2022 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
B.J.H. Dierick et al. Respiratory Medicine 201 (2022) 106940

(TAI-10) score of 49.4 (SD: 1.5). Seven patients used beclomethasone/

formoterol/glycopyrronium (Trimbow® pMDI) and five used beclome­
thasone/formoterol (Foster® pMDI), all as twice-daily controller medi­
cation. Six patients (50%) additionally used Ventolin®/salbutamol
pMDI as pro re nata reliever. The study was approved by the ethics
committee and registered at the Netherlands Trial Registry (NL9037).
Once written informed consent was obtained (visit 1), all patients
used the smart spacer for one month. This was done to establish baseline
use of the smart spacer and make patients familiar with the device. After
one month, the intervention visit took place (visit 2), during which the
smart spacer data were extracted by the pulmonary nurse, inhaler usage
patterns were discussed with the patient, and tailored inhaler education
was provided, with adherence interventions standardized using the TAI
Toolkit [9]. Thereafter, patients were provided with a new fully charged
smart spacer and used it for another month. At visit 3, inhaler technique,
adherence and clinical (lung function, CCQ) outcomes were re-assessed.
To assess long-term systemic drug exposure, a scalp hair sample was
taken where feasible. Notably, hair functions as a cumulative reservoir
of long-term substance exposure, contrasting to blood that only provides
a “snapshot” of exposure in the last 1–2 days. Given hair grows about 1
cm per month, the first centimeter from the scalp represents mean
monthly systemic exposure post-intervention while the second centi­
meter represents pre-intervention exposure. As formoterol was used by
all patients and is technically detectable in hair, concentrations in these
two hair segments were analyzed with modifications on a previously
published assay [10]. Finally, patient reported usability of the smart
spacer was assessed with the System Usability Scale (SUS).

3. Results

The total number of errors (pre-intervention: N = 2227; post-

intervention: N = 1413) as well as the mean number of errors per pa­
tient per day decreased with 36%, from 6.40 errors/day to 4.07 errors/
day (paired samples t-test, p = 0.038). This reduction was mostly driven
by a decrease in patients demonstrating an excessively high flow
(Fig. 1). Accordingly, the mean monthly inhaler technique score
significantly increased from 65% to 78% (p = 0.017). Notwithstanding
potentially relevant individual patient variation, mean monthly adher­
ence was similar (p > 0.05) pre-intervention (74.3%) versus post-
intervention (73.8%). Mean reliever use was approximately equal
(monthly mean/patient: 23.8 puffs pre versus 22.3 puffs post-
intervention, p > 0.05).
Between pre- and post-intervention periods, no significant differ­
ences in mean FEV1% predicted (48.2 vs 44.6), TAI (49.1 vs 50.0) or
CCQ scores (2.43 vs 2.67) were observed (all, p > 0.05). In all six pa­
tients that provided hair samples, formoterol was detected (pre-inter­
vention average: 1.5 pg/mg [range: 1.1–1.9]; post-intervention: 1.2 pg/
mg [range: 1.0–1.4]) (Fig. 1). One of the 24 devices was replaced due to
technical complications. Patients valued the smart spacer with a mean
SUS score of 79.8 (SD: 12.6) out of 100.

4. Discussion

This is the first study demonstrating the potential value of using a

Fig. 1. (A): the digital spacer; (B): adherence, inhaler technique score and
digital spacer to tailor inhaler education for patients with COPD. The
formoterol concentrations in scalp hair before and after smart spacer driven
digital spacer is based on one of the most widely used traditional spacers
inhaler education and (C): inhaler errors before and after smart spacer driven
inhaler education.
and is compatible with a wide range of pMDIs, offering high generaliz­
ability. Also, this is the first study where digitally registered inhalations
were compared with long-term systemic drug exposure, with ranges in
(FEV1/FVC<0.7), already using pMDIs with an Aerochamber and no
line with previous validation studies [10]. The relationship between
exacerbations in the last 3 months, were included. Because this was a
digitally-assessed inhaler technique and long-term systemic drug expo­
proof-of-concept study, no formal statistical sample size calculation was
sure in hair needs however further validation in larger samples. Limi­
performed. The population consisted of 75% males with a mean age of
tations of this study include the single-arm pre-post design, short
68.0 years (SD: 8.4), mean number of packyears of 40.3 (SD: 19.8), mean
follow-up period, single-center setting and small sample size. A limita­
body mass index of 26.2 (SD: 6.5), mean Clinical COPD Questionnaire
tion of the hair analysis is that it does not differentiate between inhaled
(CCQ) score of 2.6 (SD: 1.2) and mean Test of Adherence to Inhalers
and absorbed formoterol and ingested formoterol. However,

2
B.J.H. Dierick et al.
bioavailability after inhalation is 60% of the inhaled dose of which only
11–22% is through the oral route and the remainder through the inha­
lation route [11]. Most of the formoterol found in the hair is thus from
the inhalation route. Although we used a baseline period of one month,
this baseline period may be prone to the Hawthorne effect, resulting in
higher than real-world adherence. Future studies should apply a ran­
domized controlled design while reflecting real-world practice as much
as possible. While the current mode of digital spacer application mainly
supported inhaler technique improvement, additional features such as
audiovisual reminders may further help to enhance more regular drug
intake. On the long-term, this may result in less symptoms and better
clinical (e.g. exacerbations) and economic outcomes, but this requires
further (cost)effectiveness studies.
In conclusion, personalized, digital spacer-based education was well
accepted and significantly reduced inhaler errors with around one third.
Associations between inhaler errors, systemic drug exposure, clinical
and economic outcomes need to be further assessed in larger longer-
term studies.
Funding information
This investigator initiated study was funded by an unrestricted
educational grant from Trudell Medical.
Notation of prior abstract publication/presentation
An abstract of this work has been presented at the European Respi­
ratory Society Research Seminar entitled “Digital technologies to
enhance respiratory medication adherence and outcomes” (Lisbon,
Portugal, May 27–28, 2022).
CRediT authorship contribution statement
Boudewijn J.H. Dierick: Conceptualization, Methodology, Formal
analysis, Software, Data curation, Writing – original draft. Sandra Been-
Buck: Investigation, Writing – review & editing. Titia Klemmeier:
Investigation, Writing – review & editing. Paul Hagedoorn: Method­
ology, Validation, Writing – review & editing. Susanne J. van de Hei:
Writing – review & editing. Huib A.M. Kerstjens: Writing – review &
editing. Janwillem W.H. Kocks: Writing – review & editing. Tanja R.
Zijp: Writing – review & editing. A. Mireille A. Wessels: Investigation,
Formal analysis, Writing – review & editing. Daan J. Touw: Concep­
tualization, Methodology. Job F.M. van Boven: Funding acquisition,
Conceptualization, Methodology, Software, Writing – review & editing,
Supervision.
Declaration of competing interest
HAMK reports a fee for a one time consultancy from Trudell outside
Respiratory Medicine 201 (2022) 106940
the realm of this study, and grants and fees for consultancy or advisory
board participation from AstraZeneca, Boehringer Ingelheim, Chiesi,
GlaxoSmithKline and Novartis all outside of the submitted work. All
were paid to his institution. JWK reports grants, personal fees and non-
financial support from AstraZeneca, grants, personal fees and non-
financial support from Boehringer Ingelheim, grants and personal fees
from Chiesi Pharmaceuticals, grants, personal fees and non-financial
support from GSK, grants from Mundi Pharma, grants and personal
fees from TEVA, personal fees from MSD, personal fees from COVIS
Pharma, outside the submitted work; he holds 72.5% of shares in the
General Practitioners Research Institute. DJT received grants from
Chiesi and ZonMW outside the submitted work and all paid to his
institution. JVB received a grant from Trudell Medical related tot his
study, paid to his institution and grants and/or consultancy fees from
AstraZeneca, Chiesi, European Commission COST (COST Action 19132
“ENABLE”), GSK, Novartis, Teva, and Trudell Medical, outside the
submitted work and all paid to his institution. Other authors declare no
relevant conflicts of interest.
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