Achieving good adherence to inhaled corticosteroids after weighing canisters of asthmatic children

Background: The metered-dose inhalers (MDIs) currently available for inhaled corticosteroid delivery do not offer an integrated dose counter; therefore, it is difficult to evaluate adherence of patients. The present authors developed a linear regression equation using canister weight to calculate the number of doses actuated from the MDIs. This study aimed to assess medical adherence after the integration of regular weighing of the canisters into the routine service. Methods: A cohort study was carried out between May 2013 and April 2014. Children aged less than 8 years with a diagnosis of asthma were recruited. The duration of adherence assessment was 24 weeks. Participants had a regular schedule every 8 weeks to obtain a new FLIXOTIDE® 125 inhaler. Parents were asked to collect the discarded MDI canisters, which were then weighed by a laboratory scale. The weight of each canister was replaced in the regression equation to calculate the number of doses actuated from the MDIs. Results: A total of 52 asthmatic children participated in the study. The median age was 52.7 months. At the end of 24 weeks, 44, 33, and 23 discarded MDI canisters were collected from visits 1, 2, and 3, respectively. 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. Conclusion: High adherence rates were achieved after integration of canister weighing into the asthma care service.


Grant information:
The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Introduction
Inhaled corticosteroids (ICSs) are the standard treatment for asthmatic children. Non-adherence with prescribed ICS treatment clearly causes uncontrolled asthma 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 2 . Even though integration of a dose counter into the inhaler device improves the tracking adherence to prescribed medication 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 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.

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® (Glax-oSmithKline), 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 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). 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. 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).

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 crosssectional study 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 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 7,8 .
Although weighing of canisters was less accurate than a dose counter for measuring adherence 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. Author contributions 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.

Competing interests
No competing interests were disclosed.
The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. 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?

If applicable, is the statistical analysis and its interpretation appropriate? Yes
Are all the source data underlying the results available to ensure full reproducibility? Partly

Are the conclusions drawn adequately supported by the results? Partly
No competing interests were disclosed. 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.

If applicable, is the statistical analysis and its interpretation appropriate? Yes
Are all the source data underlying the results available to ensure full reproducibility? Yes

Are the conclusions drawn adequately supported by the results? Yes
No competing interests were disclosed.

Competing Interests:
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.