FormalPara Key Points

Evaluation of use errors with inhalers is challenging because of differences in the definitions of critical and non-critical errors, plus performance characteristics of an inhaler can influence clinical effectiveness.

Breezhaler® is a single unit-dose dry powder inhaler that has relatively low rates of critical errors.

Breezhaler® has low airflow resistance, making it easier for patients across a wide age range and disease severities to achieve the inhalation flow rate required for effective drug deposition in the lungs.

1 Introduction

While inhalation is the delivery route of choice for many drug formulations used in the treatment of lung diseases such as chronic obstructive pulmonary disease (COPD), asthma and cystic fibrosis, incorrect use of the inhalation devices can lead to poor symptom control and even disease worsening [1]. Correct use of the various inhaler devices results in high bronchial concentrations of treatments while keeping systemic bioavailability to a minimum [2]. However, in 2005, Fink and Ruben reported that 28–68% of patients did not use their pressurised metered-dose inhaler (pMDI) or dry powder inhaler (DPI) well enough to provide clinical benefit from their prescribed medication; they also reported that 39–67% of healthcare workers failed to describe the critical steps for inhaler use to their patients [3].

In asthma, despite available therapies, many patients remain uncontrolled with poor inhaler technique identified as a key contributing factor [4]. A recent study has reported that incorrect inhaler handling was present in nearly 70% of patients with asthma [5]. For the majority of inhaler devices, with the exception of the recent development of digital ‘smart inhaler’ devices, patients are unable to ascertain whether they have inhaled the drug dose correctly [6]. In reality, it is likely that patients believe that they are using the devices correctly but are, in fact, using them incorrectly; this can result in reduced drug delivery and effectiveness, leading to reduced adherence and lung function, increased symptoms and risk of hospitalisation, and reduced quality of life.

There are a number of different types of errors that can occur with inhaler use, and the type of error can be specific to the inhaler device or type of device. Identification of critical errors, specific to the inhaler device, may help improve patient outcomes [4]. Furthermore, a recent study of inhaler use in patients with COPD found that ease of use (self-explaining) should be considered when prescribing inhalers for the first time [7], and that this should be accompanied by training and repeated counselling to increase correct inhaler use [8,9,10]. Counselling has also been shown to improve pMDI inhaler technique in adolescents with asthma [11]. In addition, performance characteristics of the device, such as airflow resistance, can also influence effective use in the real-world setting. This review evaluates the types of errors that can occur with inhaler device use, how the Breezhaler® compares with other devices in terms of inhalation errors and the impact that device airflow resistance can have on effective use.

2 Types and Clinical Impact of Errors

Although there are a number of definitions of errors and critical errors with respect to inhaler use, in this review, we largely restrict our appraisal to those studies using the most common definition of the term, namely incorrect inhaler technique(s) that leads to low or no deposition of medication in the airways and lungs [12,13,14,15,16,17,18,19,20,21,22,23,24]. Whilst important, the possibilities of overdosing when using an inhaler will not be considered in this review, it will focus on the errors and critical errors that result in the active drug not reaching the airways to the extent required to have a clinical effect.

It should be mentioned that in a recent review [12] an error was defined as critical if it had an impact on the effectiveness of the drug. A systematic review conducted to define ‘critical’ errors and their impact on health outcomes in asthma and COPD reported that out of 36 studies giving specific examples of ‘critical’ errors, 32 included a definition of ‘critical’ inhaler errors but the definition varied between studies [25]. In most cases, studies did not provide information on the origin of their definition of a critical error; however, where this information was provided, definitions were commonly taken from previous studies, rather than being formulated by the study researchers [25]. The most common definition was an action affecting the lung deposition of an inhaled drug, resulting in little or no medicine being inhaled or reaching the lungs (n = 27; 14 definitions stated a critical error “would” affect inhalation and drug delivery; 13 others said a critical error “could” affect these). Four articles defined a critical error in terms of effectiveness (i.e. an error that would make aerosol therapy useless), and one publication used a combined definition of deposition and effectiveness (i.e. an error that compromised the potential benefit of the treatment, such as impeding drug deposition or the delivery of an insufficient dose) [25]. This non-consensus between the authors of published studies in the categorisation of critical vs non-critical errors has affected attempts to compare studies and collectively understand the impact of inhaler errors in daily clinical practice [25], which indicates a need for a consensus in defining critical and non-critical errors. It is possible that different definitions between groups/studies in what constitutes a critical error could contribute to different conclusions, even with the same inhaler device type [25]. Overall, the difference between the definitions used can be explained by the fact that the demonstration of inhaler use is only a ‘snapshot’ of reality (i.e. it occurs at a single time point); observation and checking of correct device usage has to be repeated regularly (and any errors corrected) to have a clinical impact for the patient.

The role that errors and critical errors play in asthma treatment outcomes was reported recently in the CritiKal study, which investigated the association between specific inhaler errors and asthma outcomes [4]. The CritiKal study found associations between specific inhaler errors and poorer asthma outcomes, including an increased likelihood of having uncontrolled symptoms and increased exacerbation rates. The study aimed to identify critical inhaler errors, with ‘critical’ meaning those errors related to poor disease outcomes. The analysis utilised data from the iHarp Asthma Review Service and was undertaken between 2011 and 2014 using data from Australia and seven European countries; details from over 5000 patients including data on demographic characteristics were included. The devices tested were Turbuhaler®, Diskus® and pMDI, and errors associated with uncontrolled asthma and an increased risk of exacerbations were: insufficient inspiratory effort; did not breathe out to empty lungs before inhalation; dose compromised after preparation because of shaking or tipping (DPIs only); not sealing lips around the mouthpiece; not removing cap/sliding cover open; head in incorrect position; no breath-hold (or hold breath for less than 3 seconds); actuation did not correspond with inhalation (pMDI only); exhaled into device before inhalation; did not actuate (pMDI only) or did not inhale through mouth [4].

3 Breezhaler® Inhaler

Breezhaler® is a single unit-dose dry powder inhaler (Fig. 1a); in COPD, the device is used to deliver the long-acting β2-agonist indacaterol, the long-acting muscarinic antagonist glycopyrronium, and the combination of indacaterol and glycopyrronium. The combination of indacaterol and the inhaled corticosteroid mometasone furoate (QMF149) and the combination of indacaterol/glycopyrronium/mometasone furoate, both delivered via Breezhaler®, have recently been approved for once-daily treatment of asthma in Europe, Japan and Canada [26,27,28]. In asthma, Breezhaler® is also used to deliver the inhaled corticosteroid budesonide.

Fig. 1
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Image of (a) Breezhaler® and (b) Aerolizer®

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In addition to correct handling and inhalation, different inhaler designs and formulation differences can lead to remarkable differences in dispersion efficiency and lung delivery [29]. Breezhaler® has low airflow resistance (compared with Handihaler®), making it easier for patients of varying disease severity to achieve the inhalation flow rate required for lung deposition of treatment [30]. High-resistance devices require greater effort by the patient to achieve inspiratory flows adequate to ensure fine particle dose delivery [31], and some patients with significant pulmonary disease struggle to generate these flows [32, 33].

Altman et al. [34] acknowledge that different types of DPI have their own intrinsic resistance, which affects the required inspiratory effort for effective inhalation of the drug from the device. The pressure differential within the DPI created by the patient’s inspiratory manoeuvre drives the speed of airflow, which is dependent on the inhaler’s intrinsic airflow resistance. Those inhalers with low airflow resistance allow patients to inhale with reduced effort [34]. In the study comparing peak inspiratory flow (PIF) achieved by patients with moderate-to-severe COPD who inhaled through Breezhaler®, Handihaler® or Ellipta® inhalers, patients achieved inhalation with the lowest inspiratory effort and produced the highest average PIF reading through the Breezhaler® compared with the other two inhalers; this was irrespective of the severity of COPD, patient age or sex [34]. As can be seen in Fig. 2, the internal resistance of the Breezhaler® device is lower than those of the Diskus®, Turbuhaler® and Handihaler®, allowing a greater flow rate to be achieved with less inspiratory effort [32, 35,36,37,38], which may be beneficial in elderly patients and patients with moderate-to-severe respiratory disease who have difficulty generating the necessary inspiratory flow to achieve an efficient drug delivery from DPIs [32, 33].

Fig. 2
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Flow rate at various inspiratory efforts through different dry powder inhaler devices [32, 36,37,38]

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Van der Palen et al. [39] noted that patients find low-resistance DPIs more acceptable than high-resistance devices. In elderly patients, irrespective of whether they have COPD, there is a reduced or compromised ability to produce inspiratory flow through DPIs [32]. Bearing this in mind, Molimard and D’Andrea [35] noted that low-resistance DPIs are relatively insensitive to variations in PIF, meaning that the low airflow resistance associated with Breezhaler® would benefit this group of patients and overall can be expected to elicit consistent drug delivery to the lungs.

Similar to Breezhaler®, the Aerolizer® device is a DPI used for single-dose delivery of powder formulations contained in a capsule for inhalation (Fig. 1b). The Aerolizer® is used in the management of asthma and COPD, it has a low airflow resistance and Haidl et al. [1] set values for a requisite minimum flow rate at 40 L/min and an optimum PIF rate at 65 L/min. Two studies by Boshra et al. [40, 41] demonstrated the effectiveness of salbutamol delivered via the Aerolizer® device at a flow rate of >40 L/min and suggested that patients achieving flow rates of >30 L/min should inhale twice through the device to ensure full dose delivery. For both devices, the geometry of the capsule rotation housing and the air inlets are similar to allow similar powder disaggregation even at low flow rates. It is notable that the incidence of critical errors when using Aerolizer® were similar both in patients with asthma and patients with COPD [42, 43] (Table 1).

Table 1 Errors in inhaler technique with Aerolizer® in patients with asthma and patients with COPD [42]
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The similar intrinsic resistance values and inspiratory flow rates associated with the Aerolizer® and Breezhaler® devices [37], together with similarities in geometry and their operational designs, enables potential extrapolation of critical errors with Breezhaler® in COPD to Breezhaler® in asthma and of critical errors reported with Aerolizer® in asthma to Breezhaler® in asthma, although caution is needed when doing this because of intra- and inter-inhaler variability in the emitted dose. It should be noted that the use/handling of the two devices is different, thus each device requires separate instructions on use.

4 Device Handling Errors

In a review intended as a policy document, the Inhaler Error Steering Committee [17] concluded that outcomes for COPD and asthma control are less than optimal and are inferior to those noted in clinical trials, with a major factor contributing to this being inadequate inhaler technique. In reality, multiple errors are made during inhaler use by patients in the community, reducing benefits seen in clinical trials [13]. The findings of this study and other studies on device handling errors imply that there is a requirement for continuing education of both prescribers and patients in the correct use of these devices to promote improvement in the efficacy of treatment [2, 13]. A large observational study involving 3811 primary care patients receiving inhaled medication either via a pMDI or via one of four DPIs (Aerolizer®, Autohaler®, Diskus® or Turbuhaler®) found that the most common errors made by patients are independent of the device being used and fall into categories that include failure to breathe out prior to actuating the device (28.9%) and not holding the breath for a few seconds after inhaling (28.3%) [2]. That said, 76% of patients made at least one error with a pMDI compared with 49–55% with DPIs (Table 2). Critical errors (defined as those that could significantly affect drug disposition to the lungs) were made only by 11–12% of patients treated with Aerolizer®, Autohaler® or Diskus® compared with 28% and 32% of patients treated with pMDI and Turbuhaler®, respectively (Table 2).

Table 2 Error summary by inhaler device in primary care patients [2]
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In the same study, critical errors for DPIs included blowing into the device before inhaling, lack of capsule insertion, lack of two-button press and release (Aerolizer®); not raising the lever to vertical position (Autohaler®); not sliding the lever as far as possible (Diskus®); and not holding inhaler upright for grip rotation and missing rotating grip clockwise then counter-clockwise until ‘click’ (Turbuhaler®) [2].

In a study of patient-related factors of asthma control, Molimard and Le Gros [14] noted that over 20% of patients were not using inhaler devices correctly, leading to a 0.84-point increase in the asthma control score. It was concluded that, among other factors, the incorrect usage of delivery devices exerts a significant negative effect on the control of asthma.

In a French study conducted by Girodet et al. [44], the use of DPIs in the management of COPD using four devices including Aerolizer® was assessed in terms of the frequency of critical errors. This is of interest because in this instance Aerolizer®, which shares technical characteristics with Breezhaler®, was being used to deliver medication suitable for COPD management rather than asthma management. This study bridges the gap between Aerolizer® and Breezhaler®, enabling possible extrapolation of findings in asthma studies to be viewed as similar to findings in COPD studies. The findings of the study indicated that the frequency of critical errors associated with Aerolizer® (11.5–14.9%) was lower than for those using Autohaler® (37.4%) or Diskus® (38.1%).

Chronic obstructive pulmonary disease studies have shown relatively low rates of critical errors with Breezhaler® [45] (Table 3), and the low frequency of critical errors reported for Aerolizer® in the COPD setting in the study by Girodet et al. [44] (Table 4) further supports the possibility of functional similarity between the two devices in both the COPD and the asthma treatment arena. Using Aerolizer® in patients with suboptimal asthma control, it was reported that 98% of patients treated with formoterol via Aerolizer® correctly performed all essential inhalation manoeuvres compared with 86% of patients treated with formoterol via Turbuhaler® [46]. While clinical efficacy was similar for formoterol delivered via the two devices, handling of Aerolizer® was easier than Turbuhaler® [46].

Table 3 Device handling errors for patients with chronic obstructive pulmonary disease [45]
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Table 4 Handling errors reported by patients with chronic obstructive pulmonary disease using various devices [44]
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The results of a study evaluating the device handling errors with Breezhaler® in patients with asthma or COPD found similar errors reported in both patient populations [43] (Table 5), and these were similar to those reported with Aerolizer® in the two populations [42]. This is perhaps not unexpected as the two devices share many technical characteristics (e.g. both are single-dose capsule DPIs with low internal airflow resistance) and many of the learnings with Aerolizer® in asthma are expected to be applicable to Breezhaler®.

Table 5 Errors with Breezhaler® when used by patients with asthma or COPD [43]
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It is noteworthy that similarly to Aerolizer® [47], Breezhaler® has some patient feedback features: a ‘Hear–Feel–See’ mechanism aims to reassure patients that they have successfully inhaled the medication [35]. During inhalation, the capsule containing the dry powder formulation spins in the device chamber and produces a ‘whirring noise’, providing positive auditory feedback; a fraction of the lactose component of the drug formulation will deposit in the user’s mouth during inhalation, which the patient tastes, confirming that the drug has left the device; and after inhalation, the patient can visually check that the transparent capsule is empty. The instructions for use ask patients to repeat the inhalation step in case of remaining powder in the capsule, and the device type allows patients to make sure the full dose has been inhaled in a second inhalation if the first inhalation was not sufficient to allow delivery of the entire dose (although it should be noted that the two devices open in slightly difference ways: the Breezhaler® tilts on a hinge whereas the Aerolizer® rotates). Furthermore, these feedback features would apply irrespective of whether a patient had asthma or COPD. However, caution needs to be exercised when results from COPD are extrapolated to asthma as there are differences in the patient populations such as age and comorbidities, which might affect device usability. Yet, this is potentially valid for all devices not just Breezhaler®; therefore, the comparability between devices will probably remain similar.

5 Dose Delivery Considerations

In contrast to pMDIs, DPIs are breath actuated, with most devices relying on a rapid and powerful inhalation manoeuvre for drug delivery [25]. Such inhalation manoeuvres, involving a fast initial acceleration rate, are required to generate a turbulent force inside the inhaler, thus enabling a break-up of the drug formulation into particles [33]. All DPIs demonstrate flow-dependent dose emission [33]. Peak inspiratory flow is related to acceleration rate and variations in PIF values achieved when using different DPIs are linked to the severity of the obstruction and the airflow resistance of the device [33]. For the plethora of DPIs currently available, inspiratory flows between 30 and 90 L/minute are usually required for effective drug delivery to the lungs; however, if the minimum inspiratory flow specific to each of the devices is not achieved, the inhaled dose can be reduced considerably [3].

Although historically PIF has been viewed as the parameter exerting the greatest influence on the performance of dose delivery, a recent study has indicated that flow acceleration, or airflow ramp-up, also contributes to variations in dose delivery to the lungs using DPIs. Ung and Chan [48] examined the effect of airflow ramp-up, or flow acceleration, on dose delivery performance and in doing so compared seven different DPIs: Simoon™ (engineered particles), Podhaler® (engineered particles), Breezhaler® (lactose carrier blend), Diskus® (lactose carrier blend), Handihaler® (lactose carrier blend), Flexhaler® (soft agglomerates) and Twisthaler® (soft agglomerates). Measurement of drug dose delivered and aerosol emission kinetics was undertaken using photometry to ascertain the degree of fluidisation of bulk powder and clearance of the aerosol from each of the seven inhalers under investigation. These were in vitro studies utilising the Alberta idealised mouth–throat model to determine aerosol dispersion quality, deagglomeration, and associated performance with respect to the aerosol reaching the lungs assessed by measurement of the total lung dose. The effect of flow ramp on the total lung dose was found to be relatively small for all investigated DPIs including Breezhaler®, except for Asmanex® and Twisthaler®. Thus, Breezhaler® appears to have the potential for a high level of consistency of lung delivery [48] across a wide range of flow rates [49]. High consistency of lung delivery from Breezhaler® was observed in a pharmacokinetic study by Vaidya et al. [50], which demonstrated lower variability in blood exposure to mometasone furoate following inhalation via Breezhaler® compared with exposure to mometasone furoate via Twisthaler®.

The Breezhaler® inhaler is a low-resistance device that achieves effective dose delivery in the form of a fine particulate fraction (the fraction of particles < 5 µm in diameter—the optimum size for bronchial and alveoli deposition, for a review, see [35]) at low flow rates; this is because with the Breezhaler®, powder ejected from the spinning capsule can undergo multiple collisions with the inhaler walls of the round-shaped rotation chamber, which provides an effective source of dispersion energy through inertial impaction. Colthorpe et al. [51] showed that delivery of a fine particulate fraction of glycopyrronium via Breezhaler® was higher and achieved more consistent intrathoracic deposition, regardless of age or severity of disease in COPD, than tiotropium delivery via Handihaler®. This implies that the Breezhaler® device is ideal for use by patients with a broad range of disease severities [35, 51].

A biophysical model has demonstrated a high level of consistency in lung delivery of the combination of indacaterol/glycopyrronium delivered via Breezhaler® at inspiratory flows between 30 and 90 L/min [49]. Again, this finding provides support for use of the Breezhaler® device by patients across various ages and lung disease severities.

6 Conclusions

Overall, the evaluation of errors in use with the different inhaler devices is challenging to quantify as a result of differences in the definitions of critical and non-critical errors and limitations in our understanding of their use in the real world. Repeated training and counselling on correct inhaler use are essential to optimise clinical effectiveness of inhaled therapy in patients. The relatively low rates of critical errors with Breezhaler® and Aerolizer®, with similarities in the critical errors reported, together with similarities in the usability support the functional similarity between the two devices in both asthma and COPD. The low resistance of the dose-confirming Breezhaler® results in an inspiratory effort that patients over a wide range of ages, disease severities and indications can easily achieve.