Introduction
============

Inhaled corticosteroids (ICSs) are the standard treatment for asthmatic children. Non-adherence with prescribed ICS treatment clearly causes uncontrolled asthma ^[@ref-1]^. Feedback from parents is the traditional approach to assess the adherence to the treatment regimen; however, there is an overestimation by the patients of the remaining amount of medication ^[@ref-2]^. Even though integration of a dose counter into the inhaler device improves the tracking adherence to prescribed medication ^[@ref-3]^, the metered-dose inhalers (MDIs) currently available for ICS delivery do not offer integrated dose counters.

Weighing of the MDI canisters may be an alternative method to assess a patient\'s medication adherence. The present authors previously developed a linear regression equation using canister weight to calculate the number of doses actuated from the MDIs ^[@ref-4]^. Weighing of the canisters was implemented into our asthma care system in March 2013. This study was designed to assess a patient\'s medication adherence after the integration of regular weighing of the canisters into the routine service.

Methods
=======

Study design and subjects
-------------------------

A cohort study was carried out between May 2013 and April 2014. The inclusion criteria were children aged less than 8 years with a diagnosis of asthma who attended the Pediatric Allergy Clinic at Songklanagarind Hospital (Hat Yai, Songkhla, Thailand) and had exacerbation of asthma requiring hospitalization or an emergency department visit within the previous year. Patients who had a previous history of intubation or other chronic conditions were excluded.

The research protocol (REC 55-021-01-1-2) was approved by the Human Research Ethics Committee, Faculty of Medicine, Prince of Songkla University. Informed consent was obtained from the parents/guardians.

Asthma management
-----------------

Fluticasone propionate was selected as the ICS therapy for the study. A FLIXOTIDE® 125 Inhaler (GlaxoSmithKline) is a pressurized metered-dose inhaler, which delivers 125 microgram of fluticasone propionate per actuation. Each canister supplies 120 actuations. FLIXOTIDE® 125 Inhaler and BabyHALER® (GlaxoSmithKline), a device to help patients taking inhaled medicine, were prescribed to all participants. The dosage of fluticasone propionate was one actuation twice a day. The add-on asthma therapies were provided according to the GINA guideline ^[@ref-5]^. Participants needed to participate in a regular schedule every 8 weeks to obtain a new FLIXOTIDE® 125 inhaler. For patients who did not achieve adequate control or maintain the adherence rate, the inhalation technique and medication doses were revised at the time they visited the clinic. Exacerbation was defined as asthma deterioration that required treatment with systemic corticosteroids or emergency department utilization or hospitalization.

Adherence assessment
--------------------

The duration of adherence assessment was 24 weeks. Each participant received three canisters of FLIXOTIDE® 125 Inhaler. Parents were asked to collect the discarded inhalers at the 8-week (visit 1), 16-week (visit 2), and 24-week (visit 3) after recruitment. The discarded MDI canisters were weighed by a laboratory scale (Sartorius Basic®). The weight of each canister was replaced in the regression equation to calculate the number of doses actuated from the MDIs. A regression equation for a fluticasone propionate MDI canister gives the number (n) of doses actuated from the MDIs:

              n = 276.16 -- (14.62 × canister weight). ^[@ref-4]^

Statistical analysis
--------------------

All of the statistical analyses were conducted with R software (version 3.3.2) by the R Foundation for Statistical Computing. Adherence in each 8-week interval was calculated as the amount of medication actuated divided by the amount prescribed. Percentage of adherence was reported as median and range.

Results
=======

A total of 52 asthmatic children participated in the study. The characteristics of the participants are shown in [Table 1](#T1){ref-type="table"}. Half of the participants were male. The median age was 52.7 months (range, 18.3--91.7) and the age at the onset of asthma was 12 months (range, 1.0--48.0). Parents were the major caregivers. In total, 32% of the participants had other allergic co-morbidities. Most of participants had received ICS therapy for longer than 3 months. At the end of 24 weeks, 44, 33, and 23 (total 100) discarded MDI canisters were collected from visits 1, 2, and 3, respectively. The remaining median weights of the discarded canisters from visits 1, 2, and 3 were 11.172g, 11.229g, and 11.113 g, respectively, and the median percentages of adherence were 96.8%, 96.3%, and 96.3%, respectively. In 11 discarded canisters (11%), the remaining medication was more than 30% of the labeled doses. Approximately 90% of the participants had no asthma exacerbation during 24-week study period ( [Table 2](#T2){ref-type="table"}).

###### Demographic data of asthmatic children.

  -----------------------------------------------------------------
  Variable                                    Results (N=52)
  ------------------------------------------- ---------------------
  Male, n (%)                                 29 (55.8)

  Weight, kg, median (range)                  18.2 (10.9--30.0)

  Height, cm, median (range)                  107.4 (84.6--127.5)

  Age, months, median (range)                 52.7 (18.3--91.7)

  Age onset, months, median (range)           12 (1.0--48.0)

  Allergic disease, n (%)\                    17 (32.7)\
        •    Atopic dermatitis\               3 (5.8)\
        •    Allergic rhinitis\               12 (23.1)\
        •    Food allergy                     5 (9.6)

  Caregiver, n (%)\                           \
        •    Parents\                         44 (84.6)\
        •    Grandparents                     7 (13.5)

  Number of hospitalizations, times/\         1 (1--5)
  person, median (range)                      

  Number of exacerbations within previous\    3 (1--9)
  year, times/person, median (range)          

  Duration from last exacerbation, months,\   4 (3--11)
  median (range)                              

  Duration of ICS therapy, n (%)\             \
        •    0--3 months\                     15 (28.9)\
        •    More than 3 months               37 (71.1)

  Number of studied canisters, n (%)\         \
        •    Visit 1\                         44 (84.6)\
        •    Visit 2\                         33 (63.4)\
        •    Visit 3                          23 (44.2)
  -----------------------------------------------------------------

###### Canister weight and percentage of adherence.

  ------------------------------------------------------------------------------------------
  Variables                         Visit 1            Visit 2            Visit 3
  --------------------------------- ------------------ ------------------ ------------------
  Number of canisters               44                 33                 23

  New canister weight, g,\          18.838\            18.819\            18.812\
  median (range)                    (18.663--18.929)   (18.607--18.907)   (18.470--18.913)

  Discard canister weight, g,\      11.172\            11.229\            11.113\
  median (range)                    (7.889--16.042)    (7.825--17.146)    (9.400--16.020)

  Actuated doses calculated from\   112.8\             112.0\             113.7\
  canister weight, median (range)   (41.6--160.8)      (25.5--161.8)      (42.0--138.7)

  Percentage of adherence,\         96.8%\             96.3%\             96.3%\
  median (range)                    (33.0--143.6)      (20.2--126.4)      (36.8--118.7)

  Number of participants with\      1                  2                  1
  exacerbation                                                            
  ------------------------------------------------------------------------------------------

###### 

Raw data of canister weight (original and discarded weight), results of the actuated dose equation and percent of adherence.

###### 

Click here for additional data file.

Copyright: © 2017 Chuenjit W et al.

2017

Data associated with the article are available under the terms of the Creative Commons Zero \"No rights reserved\" data waiver (CC0 1.0 Public domain dedication).

Discussion
==========

The present study demonstrated high adherence rates with low variations between the three visits. The percentage of discarded canisters, which had more than 30% of the labeled dosage of medication remaining, reduced from 22% in our previous cross-sectional study ^[@ref-6]^ to 11% in this study. Achieving good adherence in this cohort could be explained by the Hawthorn effect: the parents and participants knew that their adherence would be measured by weighing the canisters; therefore, the individuals modified or improved their adherence in response to the awareness of being observed.

Approximately 90% of the participants had no asthma exacerbation throughout the study period. In our previous study, only 59% of the patients had adequate control ^[@ref-6]^. Patients had access to the same educational and medication intervention, but the adherence rates were significantly different. Previous studies verified that the adherence rates had an association between lower adherence rates and poor asthma control ^[@ref-7],\ [@ref-8]^.

Although weighing of canisters was less accurate than a dose counter for measuring adherence ^[@ref-9]^, the present study demonstrated that a weight-remaining dose correlation could be used to determine the inhaler medication adherence in real life, and intensive monitoring of adherence was successful in achieving control.

In conclusion, our results demonstrated that high adherence rates were achieved after integration of canister weighing into the asthma care service. The present study highlighted the need to incorporate a method to monitor medical adherence in clinical practice, which may contribute to adequate asthma control.

Data availability
=================

The data referenced by this article are under copyright with the following copyright statement: Copyright: © 2017 Chuenjit W et al.

Data associated with the article are available under the terms of the Creative Commons Zero \"No rights reserved\" data waiver (CC0 1.0 Public domain dedication). <http://creativecommons.org/publicdomain/zero/1.0/>

**Dataset 1: Canister weight and percent of adherence.** Raw data of canister weight (original and discarded weight), results of the actuated dose equation and percent of adherence. doi, [10.5256/f1000research.10710.d150970](http://dx.doi.org/10.5256/f1000research.10710.d150970) ^[@ref-10]^

10.5256/f1000research.11547.r24513

Referee response for version 1

Piboonpocanun

Orathai

1

Referee

Division of Allergy and Immunology, Department of Pediatrics, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand

**Competing interests:**No competing interests were disclosed.

9

8

2017

Version 1

The authors tried to use canister weight to calculate the number of doses actuated from the MDIs and to assess medical adherence to MDIs.

There are some issues which need clarification Please clarify why the numbers of collected MDI canisters were not the same in each visit.Please mentioned about patients who had exacerbation. Were they the same patients? Were these patients nonadherence to medication or did they have any specific problem?

I have read this submission. I believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.

10.5256/f1000research.11547.r22150

Referee response for version 1

Lee

Bee Wah

1

Referee

Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore

**Competing interests:**No competing interests were disclosed.

24

4

2017

Version 1

This study evaluated adherence to ICS prophylaxis in asthmatic children by using weight of canister as a means to determine inhaler compliance, by calculating doses used by using a regression equation based on canister weight. The authors conclude that in the absence of an inbuilt dose counter, weighing the canister was a useful means of improving adherence to daily treatment with ICS.

Detailed comments: There were 52 children participating in the study. However, with each follow up visit (n=3)the number of canisters measure reduced progressively (44, 33, 23). Was there loss to follow up or did these patients fail to return their canisters? Could these patients be used as their comparative group in terms of asthma control over the period of follow up?For the subjects with the 11 canisters that had remaining medication, was their asthma control affected by non compliance?It may be more appropriate to use the term 'used' rather than 'discarded' canisters.Under the paragraph: adherence assessment. Some editing of sentences may improve readability: Parents were asked to 'return' the 'used inhalers at the 8 week.....

'The weight of the canister was replaced in the regression equation' to "The number of remaining doses

of remaining doses was extrapolated by using the weight of the used MDI canisters into the regression equation as shown:........

I have read this submission. I believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above.

10.5256/f1000research.11547.r21967

Referee response for version 1

Manuyakorn

Wiparat

1

Referee

https://orcid.org/0000-0003-4278-1186

Division of Allergy, Immunology, and Rheumatology, Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand

**Competing interests:**No competing interests were disclosed.

21

4

2017

Version 1

The article is well written. However, there is some minor comment.

1\. The authors mentioned that \"The metered-dose inhalers (MDIs) currently available for inhaled

corticosteroid delivery do not offer an integrated dose counter\". This statement was true at the time when this study was performed. But currently, there are some MDIs that have dose counter. So this statement needs some amendment.

2\. Method: the authors mentioned that \"Participants needed to participate in a regular schedule every 8 weeks to obtain a new FLIXOTIDE® 125 inhaler.\" And the duration of treatment was 24 weeks. So it means that each participant would receive 3 inhalers. A total of 52 children was participated. So I wonder why only 100 MDI canister was evaluated. It should be 52\*3=156?. This may need the clarification.

I have read this submission. I believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.

[^1]: All authors contributed to study design, interpretation of study findings, manuscript preparation, and approved the final manuscript. WC, VE and AY contributed to data acquisition and validation. PS was responsible for project management, data analysis and funding.

[^2]: **Competing interests:**No competing interests were disclosed.
