Objective Assessment of Adherence to Dry Powder Inhalers Attached with Flow Velocity Detection Devices in Asthmatic Children: a cohort study

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Objective Assessment of Adherence to Dry Powder Inhalers Attached with Flow Velocity Detection Devices in Asthmatic Children: a cohort study

https://doi.org/10.21203/rs.3.rs-4666018/v1

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Background

Suboptimal adherence to asthma medication is one of the major causes of asthma exacerbation. Currently, there is no report on the objective and scientific evaluation of medication adherence among asthmatic children. We aimed to identify and quantify adherence and techniques of using dry powder inhalers (DPIs) among pediatric asthmatic patients with a newly developed electronic device that can monitor the use pattern of DPIs during inhalation.

Methods

A prospective, single-center, observational cohort study was conducted. On discharge from the hospital, pediatric asthmatic patients were given Diskus DPIs with attached electronic devices. The frequency, flow velocity, volume, duration and angle were analyzed to determine the adherence and technical proficiency of DPI use.

Results

Pediatric asthmatic patients (n = 128) with a mean age of 7.8 years, a mean forced expiratory volume in 1 second (FEV₁) of 1.5 L, and a mean FEV₁% of 93.5% were recruited. Total 4096 results were recorded. The most common error types were short duration (98.8%), low volume (94.5%), wrong angle (33.3%), missed use (27.9%), low peak inspiratory flow rate (PIFR) (24.4%), exhalation (15.8%) and multiple use (0.8%). The mean actual adherence was 0.1% (standard deviation (SD), 0.9%). The errors in Diskus DPI use were correlated with asthmatic children's age, basic lung function, and desensitization treatment status.

Conclusion

Our study is the first to objectively characterize the primary types and proportions of technique errors among asthmatic children using modified Diskus DPIs and revealed that asthmatic children’s real-world actual adherence to DPIs was unsatisfactory.

Health sciences/Diseases/Respiratory tract diseases/Asthma

Health sciences/Health care/Paediatrics/Paediatric research

pediatric asthma

Diskus dry powder inhaler

adherence

electronic device

Asthma, the most common chronic inflammatory airway disease in children, causes wheezing, coughing, shortness of breath, and variable expiratory airflow limitation.¹ Around 334 million people, mostly children, visit the ER for asthma, the third leading cause.² Poor asthma management lowers children's quality of life, lengthens hospital stays, and wastes medical resources. Long-term asthma control requires keeping children "asymptomatic" by preventing chronic symptoms, maintaining lung function, and allowing normal daily activities.³ Metered dose inhalers (MDIs) or dry powder inhalers (DPIs) are asthma essentials.⁴ Due to medication adherence, inhaler efficacy may not match real-world or clinical effectiveness. Regular and proficient inhaled medication use is indicated by temporal and technique adherence. Previous adult studies found 12.0% – 83.7% suboptimal inhaler technique^4–6 and 17.4% – 87.2% inhaler adherence.^7–9 In asthmatic children, it was found inhaler technique errors was 43% − 100% and only 34.6% of asthmatic children used DPI devices correctly.^10,11 Parental supervision, device training, and physical incompetence can cause child nonadherence. Poor inhaler technique and adherence can cause uncontrolled asthma in children despite effective medications.^12,13

Despite adult studies showing challenges, children's DPI handling errors and treatment adherence have not been adequately studied.^4,14,15 Children's DPI inhaler technique and adherence are difficult to measure. Self-reporting and pharmacy refill checks are subjective and inaccurate.¹⁶ Electronic monitors objectively track inhaler use.^17–20 Electronic monitors objectively track inhaler use. Previous studies using INCA found poor technique and low DPI adherence in COPD or asthma adults.²¹ Electronic inhaler reminders with biofeedback improved DPI therapy adherence.¹⁸ However, INCA can be disturbed by ambient noise and lacks inspiratory angle recording, which may affect dry powder deposits in the lungs but has been overlooked.

No study has objectively assessed asthmatic children's electronic inhaler adherence and technique. We developed an electronic monitoring device for the salmeterol/fluticasone Diskus DPI inhaler (GSK, Uxbridge, UK) to address this issue. This flow velocity detector objectively measured DPI angle, interval, and duration. This was the first study to test a modified Diskus DPI with a pediatric asthmatic inhalation detector. This study objectively identified and quantified Diskus DPI error types and adherence in asthmatic children using inhalers. To inform individualized intervention, asthmatic children's adherence, technique errors, and DPI usage were studied.

2.1 Study design and participants

This was a prospective, single-blinded, self-controlled observational study. The study was conducted in a single center at the Children’s Hospital, Zhejiang University School of Medicine from November 2020 to February 2022 and was approved by the Ethical Committee of the hospital (2020 - TRB − 143). This study was conducted following the Declaration of Helsinki. All procedures were performed in accordance with relevant guidelines and regulations.

Children and adolescents aged 4 to 16 years old with mild asthma were screened for eligibility and informed consent was obtained from all subjects and their legal guardians.Inclusion criteria and exclusion criteria were listed in the supplementary materials. Patients were treated with salmeterol/fluticasone Diskus DPIs (GSK, Uxbridge, UK) for asthma after discharge. Once informed consent was obtained from patients, a novel flow velocity detection device (Laikelide, Suzhou) was attached to the Diskus DPIs for monitoring patients’ adherence. The study procedures were also detailed in the supplementary materials.

2.2 Instructions for the modified Diskus DPIs

The recording device of the modified Diskus DPIs consists of a dust cover, a battery, solid-state memory storage, a central processing unit, a gyroscope, a pressure sensor and a Bluetooth (Fig. 1A - G). The device can be easily attached to the Diskus DPI and the time of use, inspiratory flow velocity, duration of use, the total volume of inhalation and holding angle during inhalation were recorded through the application connected with the device by Bluetooth, as illustrated in Fig. 1. All of this information was compiled and uploaded to a cloud platform for further analysis (Fig. 1H,I). The specific components of the inhaler are described in the supplementary material.

2.3 Outcome measures

The primary outcomes were the overall rates of different error types, including simple and compound error types, in asthmatic children using the modified Diskus DPIs. The angle (0–30 degrees) was applied according to the FDA guideline to a previous study.²²

We evaluated seven distinct simple error types: low peak inspiratory flow rate (PIFR), low volume, wrong angle, short duration, exhalation, multiple use, and missed use. Compound error types refer to original technique error, attempted error and modified technique error (Table 1). Secondary outcomes were the individual attempted adherence, use adherence and actual adherence to the modified Diskus DPIs (Table 1).

Table 1

Definition of inhaler error types and individual adherence to Diskus DPIs in asthmatic children.
Error types*/ Individual adherence	Definitions	Referenced criteria
Simple error types in the whole population
Multiple use	The time interval between two uses of the device meets 1 h ≤ Δ t ≤ 5 h.	FDA guideline ²⁵
Missed use	The time interval between two uses of the device meets Δ t > 15 h.	FDA guideline ²⁵
Low PIFR	The value of PIFR accords with 0 L/min < PIFR < 30 L/min.	FDA guideline ²⁵
Exhalation	PIFR < 0 L/min occurred during the use of the device.	FDA guideline ²⁵
Short duration	The duration of a single-use device is less than 5 s. (t < 5 s).	FDA guideline ²⁵
Low volume	No exhalation error occurs, and the total volume of inhaled gas is less than 2 L.	FDA guideline ²⁵
Wrong angle	The angle of using the device is less than 0° or more than 30°.	A thesis ²²
Compound error types for individual
Original technique error	The above seven simple error types except multiple use and missed use.
Attempted error	Multiple use and missed use.
Modified technique error	Technique error except short duration and low volume.
Individual adherence (The expected number of uses were 64 doses per patient)
Attempted adherence	The percentage of the number of attempts to the expected number of uses.
Use adherence	The percentage of number of correct attempts (excluding multiple use and missed use) to the expected number of uses.
Actual adherence	The percentage of number of completely correct use to the expected number of uses.
*Use for many times in a short time only counts as one use record, because it may be caused by poor contact of the device.

2.4 Statistical analysis

Descriptive statistics were used to present basic details for the included patients. Means ± SDs or Medians (IQRs) are presented for continuous variables, and frequencies and percentages for categorical variables. The Shapiro-Wilk test was used to test the normality. For individual error rates and adherence, Mann-Whitney test was performed between subgroups. The Spearman correlation analysis were applied to identify possible correlations between various technical errors in inhaler use and patients’ basic clinical features. Agglomerative hierarchical method and wards-linkage function with squared Euclidian distance were conducted to cluster patients. All the analyses except cluster analysis were performed using SPSS for Windows version 26.0 (IBM, USA). The level of statistical significance was set at p < 0.05. Cluster analysis was carried out by MATLAB R2022b (MathWorks, USA).

3.1 Participant characteristics

Between November 2020 and February 2022, 168 asthmatic children were recruited and treated with the modified Diskus DPIs after discharge for a 32-day period. Forty patients (23.8%) were lost to follow-up, 128 patients (76.2%) completed the study, and a total of 4096 results were recorded. The majority of participants were boys (69%) with a mean age of 7.8 (standard deviation (SD), 2.0) years, mean BMI of 16.1 (SD, 2.4) and FEV₁ of 1.5 L (SD, 0.5) and 93.5% (SD, 16.0%) as predicted. In addition, 41 patients received desensitization treatment, while the other 68 patients did not.

3.2 Overall error rates of Diskus DPI use among asthmatic children

The most often made simple error in DPI use included 4048 short duration events with an overall rate of 98.8%, followed by 3870 low volume events in 94.5% of asthmatic children, wrong angle (n = 1363, 33.3%), low PIFR (n = 998, 24.4%), exhalation (n = 649, 15.8%), missed use (n = 1143, 27.9%), and multiple use (n = 33, 0.8%) (Fig. 2A-H).

3.3 Individual adherence of inhaler use among asthmatic children.

Most patients used their modified Diskus DPIs irregularly: 26 children used the modified Diskus DPIs with excessive dosing, accounting for 33 multiple uses with a mean attempted multiple use error rate of 1.1% (SD, 2.7%); 127 children missed Diskus DPI doses, accounting for 1143 missed uses with a mean attempted missed use error rate of 35.0% (SD, 26.0%). In addition, the mean original technique error rate was 99.4% (SD, 3.3%), and the mean modified technique error rate was 73.0% (SD, 19.8%).

The mean attempted adherence rate was 50.0% (SD, 25.1%). In addition, using a cut-off value of ≥ 80% for good adherence²³, 14.8% of patients exhibited good attempted adherence, while 85.2% of patients did not (Fig. 2I). In addition, the mean use adherence rate was 35.6% (SD, 25.8%), and the mean actual adherence rate was 0.1% (SD, 0.9%). We discovered that the mean attempted adherence, use adherence, and actual adherence were significantly different (p < 0.001, Fig. 2J).

3.4 Factors related to the adherence of asthmatic children

The mean attempted error rates, mean original and modified technique error rates, and mean adherence rates between different subgroups were compared. The results showed that there was no significant difference in the attempted error rates or modified technique error rates or mean adherence rates among all subgroups. The mean original technique error rate was significantly different between desensitization treatment subgroups (p = 0.034), while the difference between the two age and sex subgroups was not (Supplementary table 1).

Spearman correlation analysis showed that a low PIFR error rate had a strong negative correlation with the age and FEV₁ of asthmatic children (r = -0.240 and − 0.261, p = 0.006 and 0.003, respectively) (Fig. 3A,B). In addition, the exhalation and missed use error rates both had a significant positive correlation with FEV₁ (r = 0.199 and 0.214, p = 0.025 and 0.016, respectively) (Fig. 3C,D). The low volume error rate showed a significant positive correlation with FEV₁% (r = 0.208, p = 0.019) (Fig. 3E). In addition, we found that asthmatic children who did not receive desensitization treatment had fewer short duration errors but more low PIFR errors (r = -0.129 and 0.238, p = 0.013 and 0.007, respectively) (Fig. 3F,G).

3.5 Clustering of the patterns of inhaler use

We also characterized patterns of Diskus DPI adherence by cluster patients based on the attempted adherence rate, normal technique error rate and modified technique error rate (Fig. 4A). Almost all children did not adhere to the FDA's recommendation (Fig. 4B). Thus, after excluding duration and volume index, we reclustered participants (Fig. 4C). Hierarchical clustering indicated 4 well-separated clusters of approximately equal size corresponding to distinct patterns of behavior. Cluster 1 (n = 11; 8.6%) was defined by a high percentage of attempted adherence (mean, 81.2%), intentional adherence and a low rate of technique error (mean, 38.0%), unintentional nonadherence. Cluster 2 (n = 54; 42.2%) was characterized by a high rate of attempted adherence (mean, 68.5%) and a high rate of technique error (mean, 73.7%). Cluster 3 (n = 21; 16.4%) was characterized by a low percentage of attempted adherence (mean, 22.8%) and technique error (mean, 58.5%). Cluster 4 (n = 29; 22.7%) was characterized by a low rate of attempted adherence (mean, 27.9%) and intentional adherence and a high error rate (mean, 94.0%) and unintentional nonadherence, leading to poor actual adherence.

This study examined 128 asthmatic children's use of modified Diskus DPIs with flow velocity detection devices. Fewer asthmatic children (14.8%) had adherence rates ≥ 80% to DPI usage. When technique errors and dose intervals were considered, the mean actual adherence rate was 0.1%. An observational study of 103 adult asthma and COPD patients in Ireland found that only 50% had an attempted adherence rate ≥ 80%, with a mean actual adherence rate of 47%.²⁴ In adults, 19% of 48 asthma and COPD patients had an attempted adherence rate ≥ 80%, with a mean actual adherence rate of 42.7%.¹⁶ Our study demonstrated that children's adherence was significantly lower than the adults'. We also found a significant difference between attempted and actual adherence, suggesting that technique errors could lower actual adherence even in those with good intentional adherence. Asthmatic children's DPI duration and volume often mismatch FDA guidelines due to physiological differences. Thus, we excluded these two factors from cluster analysis. Most patients (42.2%) were in cluster 2, which had good attempted adherence but poor technique. This shows that DPI technique issues persist despite good adherence.

The adherence was much lower than expected, especially for DPI techniques. No criteria exist for DPI use in children. In 179 COPD and 103 asthma/COPD patients, low PIFR and multiple use errors were the most common technique errors.^21,24 Another observational study found that multiple use and short duration technique errors were most common.¹⁶ Short duration, low volume, and wrong angle were the most common DPI use concerns among children, while multiple use and exhalation, which are traditionally the most common errors, were underrepresented. Due to physiological and anatomical differences in respiratory system and lung function between children and adults and children's imperfect neuropsychological cognitive development, inhaler use did not meet FDA standards. Children had a lower probability of multiple use errors than adults, possibly due to their lower medicine use proclivity and self-motivation. Our study found no effects of inhalation angle on asthmatic children's DPI adherence. It's a crucial but overlooked factor. A simulation study found that poor angles cause medication particles to deposit in improper locations and degrade efficiency, suggesting angles should be further characterized.²²

DPI use guidelines for adherence and technique are difficult to choose, and there are no recommendations for children. We found that most children did not follow FDA inhaler usage guidelines. Our findings suggest that this FDA guideline may only apply to adults, while the DPI guideline for children requires specific instructions. Normal 4- to 12-year-old children's lung capacity is 1/4 to 1/6 of adults', and their airways are smaller. Aerodynamic modelling experiments and clinical studies may help establish DPI guidelines for children of different ages.

We found that the probability of having a low PIFR error was inversely related to age and FEV₁, suggesting that children's undeveloped cognitive and physical abilities may be addressed as they grow up. Exhalation, missed use, and low volume error rates increased with FEV₁ and FEV₁%. Lower PIFR errors were less common in asthmatic children who received desensitisation. Patients and their carers pay more attention to illness depending on their fundamental lung function and whether they receive desensitisation therapy, which can explain the above phenomena. Thus, inhaler devices that adapt to children's anatomical, physiological, and psychological cognition characteristics and patient and carer education to control these factors are urgently needed. Understanding patients' DPI use patterns can also help develop personalised adherence interventions or interventions.

This was a single-center observational study. A large-scale multicenter study among children with moderate and severe asthma using the device to examine how electronic monitoring devices affect inhaler use and asthma control to establish a theoretical and experimental foundation for inhaler use standards and child-friendly equipment. For ethical reasons, we recruited children with mild asthmatic symptoms. Therefore, the results may underestimate adherence in children with severe asthmatic symptoms, who intentionally need better disease control. Fortunately, the patients and parents gave no negative feedback, allowing us to safely perform multicenter studies using the device in children with severe asthma. Moreover, only the use of one of the most popular inhalers was examined, more work should be done on other popular dry powder inhalers like Symbicort turbuhalers.

Our research objectively showed the main types and proportions of technique errors asthmatic children made when using modified Diskus DPIs for the first time and demonstrated that their real-world DPI use was poor. Meanwhile, age, basic lung function, and desensitisation treatment status were linked to DPI use in asthmatic children. This emphasises the need for standardized training and close supervision of DPI use in asthmatic children and the need for special inhalers for physically and intellectually unable to adhere.

Contributors

YX, LW and YW conceived and designed the study. YX, JS, CZ, SL, XY and LW conducted the experiment, collected the data and participated the analysis of results. JS, CZ and QQ analyzed the results and made the figures. HR developed and provided the electronic device. JS and YX wrote and revised the manuscript. QQ participated in the data analysis and interpretation. LW, YW and YW provided funding support.

Declaration of interests

The authors have no financial conflicts of interest.

Data sharing

The datasets used and/or analysed during the current study available from the corresponding author on reasonable request.

Funding

This work was supported by Grants from the National Natural Science Foundation of China (No. 82173819 to YX, No. 62076218 to YW); the National Key R&D program of China (No. 2019YFE0126200 to YW); the Zhejiang Province Public Welfare Technology Application Research Project (No. LGF22H010002 to LW).

Author Contribution

Acknowledgement

The language is edited by the American Journal Experts (AJE) with the verification code D9EB-76D8-24A1-33C7-1CFP.

Data Availability

The datasets used and/or analysed during the current study available from the corresponding author on reasonable request.

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No competing interests reported.

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You are reading this latest preprint version

Objective Assessment of Adherence to Dry Powder Inhalers Attached with Flow Velocity Detection Devices in Asthmatic Children: a cohort study

Status:

Version 1

Abstract

Background

Methods

Results

Conclusion

Figures

1. Introduction

2. Methods

2.1 Study design and participants

2.2 Instructions for the modified Diskus DPIs

2.3 Outcome measures

2.4 Statistical analysis

3. Results

3.1 Participant characteristics

3.2 Overall error rates of Diskus DPI use among asthmatic children

3.3 Individual adherence of inhaler use among asthmatic children.

3.4 Factors related to the adherence of asthmatic children

3.5 Clustering of the patterns of inhaler use

4. Discussion

Declarations

Declaration of interests

Data sharing

Funding

Author Contribution

Acknowledgement

Data Availability

References

Additional Declarations

Supplementary Files

Status:

Version 1