Home-made spacer as an auxiliary device in administration of beclomethasone via pressurized metered dose inhaler for asthma control. A randomized controlled pragmatic trial

Respiratory Medicine 126 (2017) 52e58

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Home-made spacer as an auxiliary device in administration of beclomethasone via pressurized metered dose inhaler for asthma control. A randomized controlled pragmatic trial ^
Angelo Deborah Schor a, Jose Rizzo a, b, *, Decio Medeiros a, Ana Carolina Dela Bianca a, a
rio Morais-Almeida d, Emanuel Sarinho a Almerinda Rego Silva , Carlos Nunes c, Ma a

Center for Research in Allergy and Clinical Immunology, Health Sciences Post-Graduation Program, Clinical Hospital, Federal University of Pernambuco, Recife, Brazil Pneumology Department, Clinical Hospital, Federal University of Pernambuco, Recife, Brazil c ~o, Portugal Algarve Immuno-Allergology Center, Portima d CUF Descobertas Hospital, Immuno-Allergy Department, Lisbon and CINTESIS (Center for Research in Health Technologies and Information Systems), Faculdade de Medicina Do Porto, Portugal b

a r t i c l e i n f o

a b s t r a c t

Article history: Received 19 December 2016 Received in revised form 16 February 2017 Accepted 21 March 2017 Available online 22 March 2017

Background: Holding chambers or spacers can enhance the efficacy of pressurized metered dose inhalers (pMDI) in delivering inhaled medications, as they reduce the need for hand-breath coordination and improve lower airways deposition. Nevertheless, their cost can be high for patients in low-income countries. Objective: To compare asthma control achieved with beclomethasone-dipropionate administered through a hydrofluoroalkane-driven pMDI (BDp-pMDI) coupled to a home-made spacer (HmS) or to a valved commercial spacer (VCS) as auxiliary devices. Methods: Sixty-three patients with poorly controlled asthma that had a BDp-pMDI prescription were randomized to use the inhaler coupled to a HmS made of 500 ml plastic bottles (Group HmS, n ¼ 32) or to a VCS (Group VCS, n ¼ 31) for 60 days. All were given training sessions. Asthma control was assessed through the Asthma Control Test (ACT) and forced expiratory volume in the first second (FEV1), both measured before, and 30 and 60 days after treatment began. Results: Both groups showed significant improvement in ACT scores after 30 and 60 days compared to baseline values (an increase of 7 and 7.8 points for the HmS group and 5.9 and 7.0 points for the VCS group, respectively, p < 0.001). There was no statistically significant difference in ACT scores between groups at any observation time (P ¼ 0.261). FEV1 showed the same behavior. Conclusions: A similar level of asthma control was achieved with beclomethasone-dipropionate administered through a pMDI whether the inhaler was coupled to the HmS or VCS. These results are significant for asthma control planning strategies in low-income communities. (Trial Register Number: RBR-5x4dc9). © 2017 Published by Elsevier Ltd.

Keywords: Asthma Inhalers Spacers Beclomethasone-dipropionate Asthma control

1. Introduction

* Corresponding author. Rua de Apipucos, 235/1901, CEP 52071-000 Recife, PE, Brazil. E-mail addresses: [email protected] (D. Schor), [email protected] ^ Rizzo), [email protected] (D. Medeiros), [email protected] (J.A. (A.C. Dela Bianca), [email protected] (A.R. Silva), [email protected] (C. Nunes), [email protected] (M. Morais-Almeida), emanuel.sarinho@ gmail.com (E. Sarinho). http://dx.doi.org/10.1016/j.rmed.2017.03.017 0954-6111/© 2017 Published by Elsevier Ltd.

Asthma is a global problem that affects more than 300 million people worldwide, many of them in low-income countries [1]. The treatment goal is to achieve the best disease control and the main drug administration route is inhalation [2,3]. Pressurized metereddose inhalers (pMDIs) are widely used to deliver inhaled betaagonist bronchodilators or steroids directly to the lower airways, owing to their effectiveness, safety, portability and low cost [4,5]. Many patients make incorrect use of these devices and this is one of

D. Schor et al. / Respiratory Medicine 126 (2017) 52e58

the main causes of failure to achieve asthma control. Lack of coordination between aerosol discharge from pMDIs and patient inhalation (hand-breath coordination) is one of the most common errors committed by the patients [6e8]. Valved spacers (VCS) are pMDI accessory devices designed to improve aerosolized medication penetration into the airway. They are manufactured in different volumes and shapes and have a oneway valve, usually near the mouth opening, which allows some delay between pMDI actuation and aerosol inhalation, minimizing patient's need for hand-breath co-ordination. This delay also facilitates particle evaporation and size reduction, minimizing oropharyngeal drug deposition and local side effects, and improving medication penetration into peripheral airways [9e11]. Nevertheless, the cost of the VCS, although not high, can be prohibitive for low-income populations. Some studies have evaluated the efficacy of treatment of acute asthma using bronchodilator drugs delivered through a pMDI coupled to non-valved home-made spacers manufactured from various recycled materials, such as 500 ml plastic soft drinks bottles, cardboard tubes, plastic cups or empty plastic saline solution bottles [12e15]. However, only the first showed results comparable to those obtained with the same drugs administered by nebulizers or pMDIs coupled to valved commercial spacers [13,15]. The objective of this study was to compare asthma control achieved by the inhaled steroid beclomethasone-dipropionate administered through an HFA-driven pMDI coupled either to a 500 ml non-valved home-made spacer or to an industrially produced valved one in cases of poorly controlled asthma. 2. Material and methods This was an open parallel controlled pragmatic randomized clinical trial [16] conducted in the city of Recife, in the Brazilian State of Pernambuco. Patient inclusion and follow-up occurred between July 2010 and May 2012 and recruitment was carried out during the patient's first visit to the outpatient clinics from the Allergy and the Pulmonology Departments of the Hospital das Clinicas at the Federal University of Pernambuco - Brazil. ES, DM, ACDB and ARS, who were also the attending physicians, recruited the patients. The Institutional Ethics Committee approved the study under the number 0297.0.172.000e1 and all parents/guardians and/or patients signed an informed consent or assent form. The patient shown in Fig. 2 gave her consent for publication. Trial Register Number: RBR-5x4dc9. Patients were invited to participate if they lived within the metropolitan area of the city, were aged between 14 and 65 years, and their asthma was considered non-controlled as defined by the Global Initiative for Asthma [3]. After the initial evaluation, all participants had been prescribed inhaled Beclomethasone for daily use as maintenance treatment by the attending specialist. Hydrofluoroalkane-driven Beclomethasone is the inhaled steroid distributed free-of-charge by the Brazilian health system. Participants were reimbursed only for transport expenses and were offered a lunch. At beginning of the trial (Visit 1) all patients underwent forced expiratory volume in the first second (FEV1) measurements before and after administration of an inhaled bronchodilator using a calibrated spirometer (MicroQuark, Cosmed, Rome-Italy) in accordance with ATS/ERS guidelines [17]. The patients also completed the Asthma Control Test (ACT) questionnaire [18,19] translated into Portuguese (Brazil) and validated [20]. Only those patients who showed a 10% increase in FEV1 after bronchodilator administration and had a score 18 points on the ACT were included in the trial. Patients were excluded if they had smoked in the past decade, had other lung diseases or failed to

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perform the maneuvers for FEV1 measurements properly. Patients were allocated in equal proportion to use the beclomethasone-HFA pMDI coupled to home-made spacer or to valved commercial spacer following a simple block randomization (blocks of four) carried out by a person not involved in the research. The same person generated the randomization sequence on the Excel 2010 program (Microsoft Corp.) and kept it in a sealed envelope. The study was not blinded as it was not possible to mask the spacers. A person not involved in the inclusion process notified field researchers of the allocations. The beclomethasone (Clenil HFA - Chiesi e Brazil) dose was chosen according to patient's asthma severity classification: 250 mcg/day for those with mild persistent asthma, 500 mcg/day for those with moderate persistent and 1000 mcg/day for patients with severe persistent asthma in accordance with Brazilian asthma guidelines recommendations for treatment at the time of the research project elaboration [21]. Fifty and 250 mg/puff canisters were dispensed according to dosage allocations. Patients on 250 mcg/day were instructed to use two puffs in the morning and three at night from the 50 mcg/puff canister; those on 500 mcg/day or 1000 mcg/day were instructed to take one or two puffs in the morning and at night, respectively, from the 250 mcg/puff canister. All patients were also provided with an Albuterol pMDI 100mcg/puff (Aerolin, GSK e Brazil) for recovery as needed (2 puffs each time, maximum six times a day). Patients were told to return to the clinic in case of exacerbations that did not respond to the recovery medication. After allocation, patients were instructed to use the pMDI coupled to the home-made spacer (HmS group) or valved spacer (VCS group) using a movie specifically produced for this purpose following steps adapted from GINA [3] and Melani et al. [22] in order to minimize bias. At the end of the session, patients were asked to repeat the learned technique. If errors were made the patient could watch the movie up to two more times. Patients only remained in the study if they did not commit critical errors in the use of pMDI coupled to the spacer. Critical errors were those that prevented medication inhalation. As the HmS has no valve, an inhalation delay of more than 3 s after pMDI actuation was considered a critical error. Other critical errors were more than one pMDI actuation in the same inhalation, inhalation through the nose, stopping inhalation immediately after pMDI actuation and not positioning the inhaler upright before actuation [22]. Thirty days after treatment began (Visit 2 - V2), patients underwent a second evaluation with FEV1 measurements and completed the ACT questionnaire. Those who made mistakes in the use of pMDI/spacer underwent further training as described above. The same procedures were carried out 60 days after the first visit (Visit 3 - V3). (Fig. 1). Patients were given a telephone call (when available) between visits, reminding them of the time of the next appointment. The ACT [18e20] is a 5-item survey for asthma control assessment with questions about asthma disruption of work, home or school activities, shortness of breath, sleep disturbance, use of recovery medication and the patient's own classification of disease control in the last four weeks. The ratings vary on a Likert-like scale ranging from 1(worse) to 5 (best) e maximum 25 points. Patients with a score 18 points are considered to have non-controlled asthma [19]. The ACT was read to all patients by DS on all occasions to circumvent the problem of illiteracy. No clarifications were provided regarding the ACT questions after the enrolment visit. To make the home-made spacers, identical 500 ml mineral water bottles (Indai
a, Recife, Brazil) were purchased at a local supermarket. A heated iron cast was used to produce a hole in the bottom of the transparent polyethylene plastic bottles for coupling

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D. Schor et al. / Respiratory Medicine 126 (2017) 52e58

Fig. 1. Home-made spacer in use.

the pMDI as tightly as possible. The patient positioned the open bottle mouth between the lips and pressed the pMDI to inhale the medication after a full exhalation (Fig. 1). The commercial valved holding chamber used was a spindle shaped, one valve, 700 ml ~o Paulo, Brazil), made of semi-transparent polyFlumax® (Sa carbonate plastic with no audible feedback mechanism and no antistatic properties [23]. The inhalation technique instructions were identical to those for the home-made spacers. All HmS and VCS were previously dipped into detergent diluted in water and allowed to dry in ambient air in order to reduce electrostatic charge [11,24]. This procedure was not repeated. Patients were instructed not to wash the devices and to keep them in a dry place inside a transparent plastic bag. 2.1. Statistical analysis The study was designed considering a bilateral hypothesis for the comparison of groups regarding ACT score. The sample size calculation assumed a standard deviation of 4.4 points on the ACT in poorly controlled patients [19] and a minimum clinically important difference for patients with persistent asthma of 3 points in this test [25]. The number of subjects required to detect this difference between groups in the final score was 32 patients per group, considering a probability of a and b errors of 0.05 and 0.80 respectively. For comparison of data between baseline and at the two subsequent visits in both groups the general linear model for longitudinal repeated measurements was adopted considering two factors: group and time. The Sidak test was performed to correct the significant differences among multiple comparisons between the 3 visits. All analyses were conducted by a professional statistician using SPSS for Windows version 18.0 and a P-value of <0.05 was considered statistically significant. A per-protocol analysis was carried out using the data of patients that completed visits 2 and 3. An intention-to-treat analysis was conducted using the data from available patients returning for a clinical consultation up to 60 days after the last scheduled visit date. 3. Results One hundred and eighteen invited patients agreed to participate. Fifty-five did not meet the inclusion criteria. No patients that fulfilled the inclusion/exclusion criteria refused to participate in the research. Sixty-three patients were randomized, completed the first 30-day observation period and attended visit 2. Forty-nine

patients completed the second observation period and returned for the third study visit. Fig. 2 shows the flowchart of inclusion/ exclusion and dropout of patients. The planned number was not achieved in the VCS group owing to the deadline for inclusion. The general data of the randomized study population that completed V2 are shown in Table 1. There were no imbalances between groups in parameters that could affect the comparison, such as level of education, severity of asthma, previous pMDI use and baseline ACT and FEV1. All patients reported that they had previous experience with pMDI inhalers prescribed by primary care physicians but all said they used them very scarcely for reason of non-availability or noncompliance. Medications previously used were beclomethasone or albuterol by pMDI or budesonide by dry-powder inhaler but these were mostly used only to recover from asthma attacks. All denied having any experience with spacers or holding chambers. On Visit 1, before the training session, 27 patients allocated to the HmS group and 25 to the VCS group committed critical errors. On visit 2 this occurred with five patients from the HmS and three from the VCS group and, on visit 3, with four patients from the HmS and with six from the VCS group. Most of these errors were inhalation delay of more than 3 s after pMDI actuation with the HmS or two canister actuations, more than one pMDI actuation in the same inhalation and stopping inhalation immediately after pMDI actuation for both spacers. No critical errors were committed after the training sessions given during each visit. No patient was excluded from initial recruitment or from final analysis for this reason. In order to ensure no critical errors were committed after the initial training session, twenty patients in the HmS group were required to watch the training film once only, 10 twice and 2 three times. In the VCS group, the numbers were nineteen, ten and two, respectively. There were no differences between groups (chi-squared test, p ¼ 0.77). Seven patients in each group did not show up for visit 3 and were considered lost to follow-up. Efforts were made to re-contact all these patients and ten of them (five in each group) that latter attended the medical visit (30e60 days after the final schedule for visit 3) declared that failure to attend to visit 3 was mainly caused by transportation difficulties, despite transport fare reimbursement. None reported asthma exacerbation.

3.1. Asthma Control Test (ACT) In the analysis model adopted, no differences were found between groups at any time (F (1, 47) ¼ 1.297, P ¼ 0.261). However, there was a significant effect of time, as the multiple comparisons showed statistically significant differences between V1 and both V2 and V3 (F (2, 47) ¼ 181.748, P < 0.001) (Table 2 and Fig. 3 A). In terms of absolute change in the ACT score, all but one patient in the HmS group had a variation of more than three points on V2 (minimally significant clinical variation). In this group, one had an increase of five points on V2, but then returned to baseline (15 points) on V3. This patient complained of cold symptoms in the period between V2 and V3. In the VCS group, only one patient had no increase in ACT on V2 and this situation persisted until V3. No asthma exacerbations that needed systemic steroids or hospitalization were observed or reported during the study. In the HmS group 21/32 patients (66%) scored 20 or more points on the ACT (well controlled asthma) on visit 2 and 19/25 (76%) on visit 3. In the VCS group, this cut-off point was achieved by 16/31 (52%) on V2 and 13/24 (56%) on V3, although there were no significant differences between groups (c2 [2] ¼ 0.763, P ¼ 0.380 and c2 [2] ¼ 1.703, P ¼ 0.140, respectively).

D. Schor et al. / Respiratory Medicine 126 (2017) 52e58

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Fig. 2. Flow diagram of the study. Caption: pMDI/HmS ¼ pressurized metered-dose inhaler coupled to home-made spacer. pMDI/VCS ¼ pressurized metered-dose inhaler coupled to valved commercial spacer.

Table 2 ACT Score and FEV1(l/sec) for each group.

Table 1 Baseline demographic and clinical characteristics of each group.

VISITS

Group HmS

Age Gender School years Minimum Wage

Persistent Asthma Previous pMDI use ACT Score FEV1(%pred)

D %Post BD

14 < 40 years 40 years M/F <4 years 4 years <1 1e2 >2 Mild Moderate Severe <3months 3months Mean 95% CI Mean 95% CI Mean 95% CI

VCS

n ¼ 32

n ¼ 31

11 21 10/22 11 21 4 24 4 16 12 4 4 28 13.3 12.0e14.7 59.7 53.4e66.0 18.8 15.1e22.5

17 14 11/20 6 25 4 22 5 13 16 2 6 25 12.9 11.7e14.1 60.7 54.0e67.3 24.0 17.5e30.5

V1 (baseline)

V2 (30 days)

V3 (60 days)

ACT score HmS (n) Mean* 95%CI VCS (n) Mean* 95%CI

32 13.3 12.0e14.7 31 12.9 11.7e14.1

32 20.3 19.3e21.3 31 18.8 17.3e20.3

25 21.1 19.6e22.6 24 19.9 18.0e21.7

FEV1 (liters/sec) HmS (n) Mean** 95%CI VCS (n) Mean** 95%CI

32 1.75 1.52e1.98 31 1.86 1.59e2.14

32 2.12 1.88e2.35 31 2.19 1.89e2.50

25 2.15 1.86e2.44 24 2.21 1.87e2.56

P-value

0.13* 0.79* 0.26*

0.63*

0.75* 0.69* 0.56** 0.37** 0.12**

Key: HmS: Home-made spacer; VCS: Valved commercial spacer (holding chamber); F: female; M: male; minimum wage at the time of the data collection (510 Brazilian Reais ¼ 290 US Dollars); pMDI: pressurized metered-dose inhaler; CI: confidence interval; D% Post BD: FEV1 variation after inhaled bronchodilator expressed as percentage of baseline. * Chi-squared. ** t-test.

3.2. FEV1 There were no differences between mean values for the groups at any time (F (1, 47) ¼ 0.029, P ¼ 0.866) (P ¼ 0.812) but there was a significant effect of time when comparing visits 1 to the mean values for visits 2 and 3 (F (2, 47) ¼ 28.817. P < 0.001), (Table 2 and

Key: V: Visit; HmS: Home-made spacer; VCS: Valved commercial spacer; (n): number of individuals in each group; CI: Confidence interval. *Multiple comparisons: V1 versus V2 and V3, p < 0.001. V2 versus V3, p ¼ 0.031. **Multiple comparisons: V1 versus V2 and V3, p < 0.001. V2 versus V3, p > 0.999.

Fig. 3 B). 4. Discussion The present study found similar clinical and functional improvement of asthma control comparing the treatment with beclomethasone pMDI-HFA coupled to home-made spacers or to commercial valved ones as auxiliary devices in poorly controlled patients. In both groups the changes from baseline in the Asthma Control Test (ACT) were statistically significant and clinically relevant at 30 and 60 days of treatment. The improvement in FEV1 was

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D. Schor et al. / Respiratory Medicine 126 (2017) 52e58

Fig. 3. Mean ACT Score (A) and pre-bronchodilator FEV1 (B) on each visit. Caption: Bars: Standard Error. HmS: Home-made spacers; VCS: valved commercial spacers (holding chambers).

also significant in both groups over the same periods compared to baseline. Studies aiming to improve lung deposition and reduce local inhaled corticosteroid side effects with different spacers attached to pMDIs have been being carried out for several decades. One of the earliest studies of the administration of budesonide by pMDI coupled to a spacer in adult patients with asthma showed significant improvement in lung function compared to pMDI without a spacer as well as a significant reduction in oropharyngeal drug deposition [26]. Several other studies followed, in both adults [27] and children [28], showing the same results, and led to the recommendation for the use of pMDIs coupled to spacers to optimize treatment effects [29]. Commercial spacers and valved holding chambers of different shapes and sizes have been produced and marketed, but cost and lack of availability limits their use in developing countries. In an attempt to circumvent this problem, studies have been conducted in patients with asthma exacerbations to evaluate the effectiveness of home-made spacers made from plastic soft drink bottles [11e15,30,31]. In children with acute asthma, Zar et al. demonstrated that the use of beta-2 agonist pMDI coupled to spacers manufactured from 500 ml plastic bottles resulted in significant symptomatic and functional improvement, similar to the group that used commercial spacers [12]. Another study compared the use of salbutamol administered via jet nebulizer or pMDI coupled to home-made 500 ml plastic bottles spacers and showed no significant differences in peak expiratory flow, respiratory rate and clinical score in children and adolescents with acute asthma [13]. Comparing the pulmonary deposition of aerosols using two models of commercial small-volume spacers and a spacer made of a 500 ml plastic bottle, Zar et al. found that the home-made spacer produced greater lung aerosol deposition than the small-volume commercial spacers [30], suggesting that, in these patients, spacer volume is more important than the valve. Static electrical charge inside the spacer may have some influence on medication dose delivery. Studies of this have been conducted, although the clinical significance has still not been effectively determined [32]. For those VCS not produced with antistatic materials, dipping in detergent solution and allowing to

air dry may reduce the field charge [11]. All spacers (home-made or not) given to our patients were treated in this manner. In clinical practice, assessment of asthma control takes into account frequency and severity of symptoms, need for bronchodilator use for recovery, nighttime awakenings, impairment of daily activities and also objective parameters for assessing the degree of obstruction, such as FEV1 [3,33]. Questionnaires have been developed to standardize information collection and to allow comparisons between research centers. The Asthma Control Test (ACT) has been a useful tool in monitoring patients, evaluating asthma control and guiding treatment adjustments, both at individual and population levels [18]. Furthermore, a variation of 3 points has been found to be the minimum clinically significant difference for this questionnaire [25]. However, as it is a multidimensional construct which does not include any objective measure of airway caliber, it is important to include an airway functional objective measurement such as the FEV1, as has been done in the present study. Clinical and functional responses of non-controlled asthma patients to treatment have already been observed in the first two weeks of treatment with inhaled steroids, as shown by Pauwels et al. [34]. Our choice of evaluation moments at 30 and 60 days after start of treatment was based on this response time. All but one patient in each group showed improvement in ACT score equal to or greater than the minimal clinically significant difference of three points [25] on visit 2. In all but one case this improvement was sustained on visit 3. The mean maximal improvement in FEV1 was achieved in the first 4 weeks of treatment (Table 2 and Fig. 3). Although it was not possible in the present study to check compliance objectively, which may be a limitation, the improvement in both the ACT and FEV1 of patients suggests satisfactory adherence among those who completed the study. It should be noted that, regardless of treatment response, many patients committed some critical errors on visits 2 and 3, despite being able to correctly use the pMDI with the spacers after the training sessions. This is very common in everyday practice and inhalers use must be checked at each visit to assure their correct use and proper medication delivery to lower airways, regardless of whether spacers or holding chambers are used as auxiliary devices [7].

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The patients recruited were poorly controlled when referred to the specialized clinic before enrolment and this was an inclusion criterion. This population is representative of what happens among many asthma patients all over the world due to limited drug access, poor adherence or poor inhaler use technique [35]. All the patients living in the metropolitan area of the hospital to whom a prescription of inhaled steroid for non-controlled persistent asthma was given by the attending physician at the tertiary center were invited to participate in the trial. As our hospital receives patients from all over Pernambuco and neighboring states but only those living in the metropolitan area of the city of Recife were invited, this limited the study population and delayed recruitment. One hundred and eighteen patients agreed to participate and 63 met the inclusion/exclusion criteria. Another possible source of bias was the follow-up loss between visits 2 and 3, mainly due missing appointment dates - a real-life problem for an underprivileged population serviced by poor public transportation. Although it represents 22% of the study sample, the missing data was balanced between the two groups (seven in each). Efforts to explain the need for adherence to protocol visits and telephone calls (when available) were made one week before the scheduled visit. Nine of the fourteen patients that missed scheduled visits did not have telephone access. A delay of more than fifteen days excluded patients from the per-protocol analysis. An attempt to re-contact all patients was made and five in each group returned 30e60 days after the final scheduled visit. Although 2 patients in the HmS group and three in the VHC group patients declared they had used the medication irregularly on some days, none said their condition had deteriorated. An intention-to-treat analysis including data from these patients did not change the conclusions. A further criticism of the design of the present study could be the absence of a third group using the beclomethasone pMDI without a spacer. However, this was not the primary aim of the study and Levy et al. [8] have shown that patients who used pMDIs with a spacer had better asthma control than those who used pMDIs alone. Protocol deviations were not considered a caveat to our conclusions. Our findings show that, in patients with non-controlled asthma, non-valved 500 ml home-made spacers or commercial valved spacers are equally effective as auxiliary devices to beclomethasone pMDI in achieving disease control. Further studies including more patients, especially children and severe asthma patients, are required to expand our results but, until then, home-made spacer use should be encouraged worldwide, especially in developing countries, where the cost of treating disease can represent up to 25% of the income of these families [36]. Public health policy makers should implement educational programs for health professionals and patients to enable them to take full advantage of inhaled medications for asthma control. Funding Hospital das Clínicas. Universidade Federal de Pernambuco. Conflict of interest Authors disclose no conflict of interests regarding this research. Acknowledgements We are thankful to Prof. Camila Sarteschi for statistical advice and Peter Ratcliffe for language revision.

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Appendix A. Supplementary data Supplementary data related to this article can be found at http:// dx.doi.org/10.1016/j.rmed.2017.03.017. References [1] T. To, S. Stanojevic, G. Moores, G. Moores, A.S. Gershon, E.D. Bateman, A.A. Cruz, L.P. Boulet, Global asthma prevalence in adults: findings from the cross-sectional world health survey, BMC Public Health 12 (2012) 204. [2] British Thoracic Society, Scottish Intercollegiate Guidelines network. British Guideline on the Management of Asthma, A National Clinical Guideline, May 2008. Revised June 2009. 121p, Available at: https://www.brit-thoracic.org. uk/document-library/clinical-information/asthma/btssign-asthma-guideline2008/. [3] Global Initiative for Asthma e GINA, Global Strategy for Asthma Management and Prevention, 2009. Available from: www.ginasthma.org. [4] G.K. Crompton, J.C. Virchow, R.D. Negro, R. Pedersen, A. Magnan, J. Seidenberg, J. Barnes, Importance of inhaler devices in the management of airway disease, Respir. Med. 102 (2008) 19e29. [5] F. Lavorini, C.J. Corrigan, P.J. Barnes, P.R. Dekhuijzen, M.L. Levy, S. Pedersen, N. Roche, W. Vincken, G.K. Crompton, Retail sales of inhalation devices in European countries: so much for a global policy, Respir. Med. 105 (7) (2011) 1099e1103. [6] G.K. Crompton, Problems patients have using pressurized aerosol inhalers, Eur. J. Respir. Dis. 63 (Suppl 119) (1982) 101e104. [7] A.S. Melani, M. Bonavia, V. Cilenti, C. Cinti, M. Lodi, P. Martucci, M. Serra, N. Scichilone, P. Sestini, M. Aliani, M. Neri, Inhaler mishandling remains common in real life and is associated with reduced disease control, Respir. Med. 105 (6) (2011) 930e938. [8] M.L. Levy, A. Hardwell, E. McKnight, J. Holmes, Asthma patients' inability to use a pressurised metered-dose inhaler (pMDI) correctly correlates with poor asthma control as defined by the Global Initiative for Asthma (GINA) strategy: a retrospective analysis, Prim. Care Respir. J. 22 (4) (2013) 406e411. [9] S.P. Newman, M.T. Newhouse, Effect of add-on devices for aerosol drug delivery: deposition studies and clinical aspects, J. Aerosol Med. 9 (1) (1996) 55e70. [10] F. Lavorini, G.A. Fontana, Targeting drugs to the airways: the role of spacer devices, Expert Opin. Drug Deliv. 6 (2009) 91e102. [11] K. Nikander, C. Nicholls, J. Denyer, J. Pritchard, The evolution of spacers and valved holding chambers, J. Aerosol Med. Pulm. Drug Deliv. 27 (Suppl 1) (2014 Aug) S4eS23. [12] H.J. Zar, M. Liebenberg, E.G. Weinberg, H.J. Binns, M.D. Mann, The efficacy of alternative spacer devices for delivery of aerosol therapy to children with asthma, Ann. Trop. Paediatr. 18 (1998) 75e79. [13] M. Duarte, P. Camargos, Efficacy and safety of a home-made non-valved spacer for bronchodilator therapy in acute asthma, Acta Paediatr. 91 (2002) 909e913. [14] H.J. Zar, M.J. Asmus, E.G. Weinberg, A 500-ml plastic bottle: an effective spacer for children with asthma, Pediatr. Allergy Immunol. 13 (2002) 217e222. [15] H.J. Zar, S. Streu, M. Levin, E.G. Weinberg, G.H. Swingler, Randomised controlled trial of the efficacy of a metered-dose inhaler with bottle spacer for bronchodilator treatment in acute lower airway obstruction, Arch. Dis. Child. 92 (2007) 142e146. [16] M. Zwarenstein, S. Treweek, J.J. Gagnier, D.G. Altman, S. Tunis, B. Haynes, A.D. Oxman, D. Moher, Improving the reporting of pragmatic trials: an extension of the CONSORT statement, BMJ 337 (2008) a2390. [17] M.R. Miller, J. Hankinson, V. Brusasco, F. Burgos, R. Casaburi, A. Coates, R. Crapo, P. Enright, C.P. van der Grinten, P. Gustafsson, R. Jensen, D.C. Johnson, N. MacIntyre, R. McKay, D. Navajas, O.F. Pedersen, R. Pellegrino, G. Viegi, J. Wanger, Standardisation of spirometry, Eur. Respir. J. 26 (2005) 319e338. [18] R.A. Nathan, C.A. Sorkness, M. Kosinski, M. Schatz, J.T. Li, P. Marcus, J.J. Murray, T.B. Pendergraft, Development of the asthma control test: a survey for assessing asthma control, J. Allergy Clin. Immunol. 113 (2004) 59e65. [19] M. Schatz, C.A. Sorkness, J.T. Li, P. Marcus, J.J. Murray, R.A. Nathan, M. Kosinski, T.B. Pendergraft, P. Jhingran, Asthma Control Test: reliability, validity and responsiveness in patients not previously followed by asthma specialists, J. Allergy Clin. Immunol. 117 (2006) 549e556. [20] J.P.F. Roxo, E.V. Ponte, D.C.B. Ramos, L. Pimentel, A. D'Oliveira Junior, A.A. Cruz, Portuguese-language version of the Asthma control Test: validation for use in Brazil, J. Bras. Pneumol. 36 (2010) 159e166.
, IV Diretrizes Brasileiras para o Manejo da [21] R. Stirbulov, L.A.G. Bernd, D. Sole Asma, J. Bras. Pneumol. 32 (supl 7) (2006) S447eS474. [22] A.S. Melani, D. Zanchetta, N. Barbato, P. Sestini, C. Cinti, P.A. Canessa, S. Aiolfi, M. Neri, Inhalation technique and variables associated with misuse of conventional metered-dose inhalers and newer dry powder inhalers in experienced adults, Ann. Allergy Asthma Immunol. 93 (2004) 439e446. [23] J.A. Rubim, C.J.R. Simal, L.M.L.B.F. Lasmar, P.A.M. Camargos, Assessment of a spacer device manufactured in Brazil: aerosol deposition and clinical performance, J. Pediatr. (Rio) 76 (2000) 434e442. €f, Washing [24] F. Pierart, J.H. Widhaber, I. Vrancken, S.G. Devadason, P.N. Le Soue plastic spacers in household detergent reduces electrostatic charge and greatly improves delivery, Eur. Respir. J. 13 (1999) 673e678.

58

D. Schor et al. / Respiratory Medicine 126 (2017) 52e58

[25] M. Schatz, M. Kosinski, A.S. Yarias, J. Hanlon, M.E. Watson, P. Jhingran, The minimally important difference of the Asthma Control Test, J. Allergy Clin. Immunol. 124 (2009) 719e723. [26] J.H. Toogood, J. Baskerville, B. Jennings, N.M. Lefcoe, S.A. Johansson, Use of spacers to facilitate inhaled corticosteroid treatment of asthma, Am. Rev. Resp. Dis. 129 (1984) 723e729. [27] A. Nair, D. Menzies, P. Hopkinson, L. McFarlane, B.J. Lipworth, In vivo comparison of the relative systemic bioavailability of fluticasone propionate from three anti-static spacers and a metered dose inhaler, Br. J. Clin. Pharmacol. (2009) 67191e67198. [28] K.G. Nielsen, H. Bisgaard, The effect of inhaled budesonide on symptoms, lung function and cold air methacoline responsiveness in 2-to-5-year-old asthmatic children, Am. J. Respir. Crit. Care Med. 162 (2000) 1500e1506. [29] B.K. Rubin, J.B. Fink, Optimizing aerosol delivery by pressurised metered edose inhalers, Respir. Care 50 (2005) 1191e1200. [30] H.J. Zar, E.G. Weinberg, H.J. Binns, F. Gallie, M.D. Mann, Lung deposition of aerosol e a comparison of different spacers, Arch. Dis. Child. 82 (2000) 495e498. [31] C. Rodriguez, M. Sossa, J.M. Lozano, Commercial versus home-made spacers in delivering bronchodilator therapy for acute therapy in children, Cochrane

[32]

[33]

[34]

[35]

[36]

Database Syst. Rev. (2) (2008 Apr 16) CD005536, http://dx.doi.org/10.1002/ 14651858.CD005536.pub2. M.L. Levy, P. Dekhuijzen, P.J. Barnes, M. Broeders, C.J. Corrigan, B.L. Chawes, L. Corbetta, J.C. Dubus, T. Hausen, F. Lavorini, N. Roche, J. Sanchis, O.S. Usmani, J. Viejo, W. Vincken, T. Voshaar, G.K. Crompton, S. Pedersen, Inhaler technique: facts and fantasies. a view from the aerosol drug management improvement team (ADMIT), NPJ Prim. Care Respir. Med. 26 (2016) 16017. Joint Task Force on Practice Parameters, American academy of allergy, asthma and immunology; American college of Allergy, asthma and immunology and joint council of Allergy, asthma and immunology. attaining optimal asthma control: a practice parameter, J. Allergy Clin. Immunol. 116 (2005) S3eS11. R.A. Pauwels, C.G. Lofdahl, D.S. Postma, A.E. Tattersfield, P. O'Byrne, P.J. Barnes, A. Ullman, Effect of inhaled budesonide on exacerbations of asthma, New Engl. J. Med. 337 (1997) 1405e1411. A.I. Papaioannou, K. Kostikas, E. Zervas, L. Kolilekas, S. Papiris, M. Gaga, Control of asthma in real life: still a valuable goal? Eur. Respir. Rev. 24 (2015) 361e369. R. Franco, H.F. Nascimento, A.A. Cruz, A.C. Santos, C. Souza-Machado, E.V. Ponte, A. Souza-Machado, L.C. Rodrigues, M.L. Barreto, The economic impact of severe asthma to low-income families, Allergy 64 (2009) 478e483.