Climate change in healthcare: Exploring the potential role of inhaler prescribing.

Climate change has been described as the biggest global health threat of the 21st century. As a result, governments around the world are committing to legislative change in order to reduce greenhouse gas emissions (GHGEs). The healthcare sector makes a significant contribution to GHGEs and in line with national legislation in the UK, the NHS has recently committed to achieving net zero emissions by 2050. The management of asthma and COPD largely depends on the prescribing of medications that are delivered through inhalers. In the UK, the use of pressurized metered dose inhalers (pMDIs), which rely on hydrofluorocarbon (HFC) propellants accounts for 3.5% of the NHS's total carbon footprint. In contrast, dry powder inhalers (DPIs) have a much lower carbon footprint due to the absence of a HFC propellant. Here we review evidence of the impact of inhaler choices across four domains: environmental impact, clinical effectiveness, cost effectiveness and patient preferences. We find that as well as a lower global-warming potential, DPIs have additional benefits over pMDIs in other domains and should be considered first line where clinically appropriate.

Pathways for Improving Inpatient Pediatric Asthma Care (PIPA): A Multicenter, National Study.

BACKGROUND AND OBJECTIVES: Pathways guide clinicians through evidence-based care of specific conditions. Pathways have been demonstrated to improve inpatient asthma care but mainly in studies at large, tertiary children's hospitals. It remains unclear if these effects are generalizable across diverse hospital settings. Our objective was to improve inpatient asthma care by implementing pathways in a diverse, national sample of hospitals. METHODS: We used a learning collaborative model. Pathway implementation strategies included local champions, external facilitators and/or mentors, educational seminars, quality improvement methods, and audit and feedback. Outcomes included length of stay (LOS) (primary), early administration of metered-dose inhalers, screening for secondhand tobacco exposure and referral to cessation resources, and 7-day hospital readmissions or emergency revisits (balancing). Hospitals reviewed a sample of up to 20 charts per month of children ages 2 to 17 years who were admitted with a primary diagnosis of asthma (12 months before and 15 months after implementation). Analyses were done by using multilevel regression models with an interrupted time series approach, adjusting for patient characteristics. RESULTS: Eighty-five hospitals enrolled (40 children's and 45 community); 68 (80%) completed the study (n = 12 013 admissions). Pathways were associated with increases in early administration of metered-dose inhalers (odds ratio: 1.18; 95% confidence interval [CI]: 1.14-1.22) and referral to smoking cessation resources (odds ratio: 1.93; 95% CI: 1.27-2.91) but no statistically significant changes in other outcomes, including LOS (rate ratio: 1.00; 95% CI: 0.96-1.06). Most hospitals (65%) improved in at least 1 outcome. CONCLUSIONS: Pathways did not significantly impact LOS but did improve quality of asthma care for children in a diverse, national group of hospitals.

Benefits of glycopyrrolate/formoterol fumarate metered dose inhaler (GFF MDI) in improving lung function and reducing exacerbations in patients with moderate-to-very severe COPD: a pooled analysis of the PINNACLE studies.

BACKGROUND: The Phase III PINNACLE studies assessed the efficacy and safety of glycopyrrolate/formoterol fumarate metered dose inhaler (GFF MDI), a dual long-acting bronchodilator for chronic obstructive pulmonary disease (COPD). Here we present a pre-specified pooled analysis of PINNACLE-1, PINNACLE-2, and PINNACLE-4. METHODS: PINNACLE-1, -2, and -4 were multicenter, double-blind, randomized controlled trials that enrolled patients with moderate-to-very severe COPD, with no requirement for exacerbation history or a high symptom burden. Patients received GFF MDI 18/9.6 µg, glycopyrrolate (GP) MDI 18 µg, formoterol fumarate (FF) MDI 9.6 µg, or placebo MDI, twice-daily for 24 weeks. The primary endpoint of the pooled analysis was the change from baseline in morning pre-dose trough forced expiratory volume in 1 s (FEV1) at week 24. Secondary endpoints included COPD exacerbations and clinically important deterioration (CID). Adverse events were also assessed. RESULTS: The pooled intent-to-treat population included 4983 patients; of these, 61.9% had a COPD assessment test (CAT) score ≥15, and 25.0% had experienced ≥1 moderate/severe exacerbation in the past year. At week 24, GFF MDI improved morning pre-dose trough FEV1 versus GP MDI (least squares mean [LSM] difference [95% confidence interval (CI)]: 59 mL [43, 75]), FF MDI (65 mL [48, 81]), and placebo MDI (146 mL [125, 166]); all p < 0.0001. GFF MDI reduced the risk of a moderate/severe exacerbation by 18% (p = 0.0168), 15% (p = 0.0628), and 28% (p = 0.0012) compared with GP MDI, FF MDI, and placebo MDI, respectively. In general, exacerbation risk reduction with GFF MDI versus comparators was greater in subgroups of symptomatic patients (CAT ≥15) and those who had an exacerbation history, than in the pooled intent-to-treat population. The risk of CID was also lower with GFF MDI versus GP MDI (23% decrease), FF MDI (17%), and placebo MDI (49%); all p < 0.0001. All treatments were well tolerated, with no unexpected safety signals. CONCLUSIONS: This pooled analysis of the PINNACLE studies demonstrated that GFF MDI improved lung function and reduced the risk of exacerbations compared with monocomponents and placebo in patients with COPD. Exacerbation reductions with GFF MDI versus comparators were generally greater in patients with higher symptom burden and those with exacerbation history. TRIAL REGISTRATION: ClinicalTrials.gov NCT01854645, NCT01854658, and NCT02343458. Registered 13 May 2013 (NCT01854645, NCT01854658) and 6 January 2015 (NCT02343458).

Bone and ocular safety of budesonide/glycopyrrolate/formoterol fumarate metered dose inhaler in COPD: a 52-week randomized study.

BACKGROUND: Long-term use of inhaled corticosteroids (ICSs) has been associated with increased risk of bone and ocular comorbidities. We evaluated the effects of the triple fixed-dose combination budesonide/glycopyrrolate/formoterol fumarate metered dose inhaler (BGF MDI), formulated using co-suspension delivery technology, on bone mineral density (BMD) and ocular safety in patients with moderate-to-very severe chronic obstructive pulmonary disease (COPD). METHODS: In this extension study, a subset of patients from the 24-week, phase III, randomized, double-blind KRONOS study (NCT02497001) continued treatment (BGF MDI 320/18/9.6 µg, budesonide/formoterol fumarate [BFF] MDI 320/9.6 µg or glycopyrrolate/formoterol fumarate [GFF] MDI 18/9.6 µg, as a non-steroidal comparator) for an additional 28 weeks. Primary endpoints were percentage change from baseline in lumbar spine BMD and change from baseline in lens opacities classification system III posterior subcapsular cataract (P) score, both at Week 52. Adverse events were also assessed. RESULTS: In total, 456 patients were included in the safety population (53.1% male, mean age 62.8 years). Changes from baseline in lumbar spine BMD (least squares mean [LSM] range - 0.12 to 0.38%) and P score (LSM range 0.02-0.15) were small for all treatments. Both BGF MDI and BFF MDI were non-inferior to GFF MDI using margins of -2% (BMD) and 0.5 units (P score). The incidence of treatment-emergent adverse events (TEAEs)  was generally similar among groups. Rates of confirmed pneumonia were low overall (2.4%) and highest in the GFF MDI group (3.4%), followed by BGF MDI (2.1%) and BFF MDI (1.1%). There were no cumulative adverse effects of treatment over time as the incidence and types of TEAEs, were generally similar in the first 24 weeks of the study and after Week 24. CONCLUSIONS: In patients with COPD, both ICS-containing therapies were non-inferior to GFF MDI for the primary BMD and ophthalmological endpoints. Changes from baseline in all three treatment groups over 52 weeks were small and not clinically meaningful. All treatments were well tolerated with no new or unexpected safety findings. TRIAL REGISTRATION: ClinicalTrials.gov NCT02536508. Registered 27 August 2015.

Imperative Instruction for Pressurized Metered-Dose Inhalers: Provider Perspectives.

BACKGROUND: Reports show that many patients do not use their pressurized metered-dose inhalers (pMDIs) effectively. The National Heart, Lung, and Blood Institute recommends that health-care providers educate and assess patients' pMDI technique at each opportunity. However, limited data exist regarding how often pediatric primary care providers perform assessments and which methods they use. We sought to (1) identify instructional methods used to teach pMDI use, (2) describe how pMDI use is reassessed at follow-up visits, and (3) describe primary care provider attitudes and barriers to in-office pMDI instruction. METHODS: A 34-item electronic survey was distributed from August to December 2016 via E-mail to local pediatric primary care providers. Descriptive statistics were used for analysis. RESULTS: Sixty two of 223 potential primary care providers (28%) responded. Physicians and nurse practitioners were identified most often as the providers of pMDI education (53%). When first prescribing a pMDI, only 10% reported having the patient practice inhaler use in the office and receive feedback. Only 19% "always" reassessed the technique, even for patients with poorly controlled asthma. Among those who reassessed the technique, most (76%) did so verbally, and only 42% asked the patients to demonstrate pMDI use. Only 32% reported that typical patient education in their setting was adequate to ensure proper pMDI use. Commonly cited barriers included time (84%) and access to demo pMDIs (67%). Provider solutions included video tutorials and access to demo inhalers. CONCLUSIONS: Many pediatric primary care providers did not demonstrate or have patients practice pMDI use when teaching or assessing pMDI technique, and the reassessment rate was low even for patients with poorly controlled asthma. Identifying and training a consistent pMDI educator and obtaining demo pMDIs may abate some barriers. Respiratory therapists could appropriately fulfill this educator role. Brief, repeated pMDI practice for motor learning could promote more stable pMDI mastery.

Nuevos inhaladores o mejora en el manejo de los actuales. La parábola de los ciegos (Brueghel) / Inhaler Devices: Better Management or New Devices? The Blind Leading the Blind

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In vitro and clinical characterization of the valved holding chamber AeroChamber Plus® Flow-Vu® for administrating tiotropium Respimat® in 1-5-year-old children with persistent asthmatic symptoms.

BACKGROUND: When characterizing inhalation products, a comprehensive assessment including in vitro, pharmacokinetic (PK), and clinical data is required. We conducted a characterization of tiotropium Respimat® when administered with AeroChamber Plus® Flow-Vu® anti-static valved holding chamber (test VHC) with face mask in 1-5-year-olds with persistent asthmatic symptoms. METHODS: In vitro tiotropium dose and particle size distribution delivered into a cascade impactor were evaluated under fixed paediatric and adult flow rates between actuation and samplings. The tiotropium mass likely to reach children's lungs was assessed by tidal breathing simulations and an ADAM-III Child Model. PK exposure to tiotropium in preschool children with persistent asthmatic symptoms (using test VHC) was compared with pooled data from nine Phase 2/3 trials in older children, adolescents, and adults with symptomatic persistent asthma not using test VHC. RESULTS: At fixed inspiratory flow rates, emitted mass and fine particle dose decreased under lower flow conditions; dose reduction was observed when Respimat® was administered by test VHC at paediatric flow rates. In <5-year-old children, such a dose reduction is appropriate. In terms of dose per kg/body weight, in vitro-delivered dosing in children was comparable with adults. Transmission and aerosol holding properties of Respimat® when administered with test VHC were fully sufficient for aerosol delivery to patients. At zero delay, particles <5 µm (most relevant fraction) exhibited a transfer efficacy of ≥60%. The half-time was>10 s, allowing multiple breaths. Standardized tidal inhalation resulted in an emitted mass from the test VHC of approximately one-third of labelled dose, independent of coordination and face mask use, indicating predictable tiotropium administration by test VHC with Respimat®. Tiotropium exposure in 1-5-year-old patients using the test VHC, when adjusted by height or body surface, was comparable with that in older age groups without VHCs; no overexposure was observed. Adverse events were less frequent with tiotropium (2.5 µg, n = 20 [55.6%]; 5 µg, n = 18 [58.1%]) than placebo (n = 25 [73.5%]). CONCLUSIONS: Our findings provide good initial evidence to suggest that tiotropium Respimat® may be administered with AeroChamber Plus® Flow-Vu® VHC in 1-5-year-old patients with persistent asthmatic symptoms. To confirm the clinical efficacy and safety in these patients, additional trials are required. CLINICAL TRIALS REGISTRY NUMBER: The trial was registered under NCT01634113 at http://www.clinicaltrials.gov.

Critical inhaler errors in asthma and COPD: a systematic review of impact on health outcomes.

BACKGROUND: Inhaled drug delivery is the cornerstone treatment for asthma and chronic obstructive pulmonary disease (COPD). However, use of inhaler devices can be challenging, potentially leading to critical errors in handling that can significantly reduce drug delivery to the lungs and effectiveness of treatment. METHODS: A systematic review was conducted to define 'critical' errors and their impact on health outcomes and resource use between 2004 and 2016, using key search terms for inhaler errors in asthma and COPD (Search-1) and associated health-economic and patient burden (Search-2). RESULTS: Search-1 identified 62 manuscripts, 47 abstracts, and 5 conference proceedings (n = 114 total). Search-2 identified 9 studies. We observed 299 descriptions of critical error. Age, education status, previous inhaler instruction, comorbidities and socioeconomic status were associated with worse handling error frequency. A significant association was found between inhaler errors and poor disease outcomes (exacerbations), and greater health-economic burden. CONCLUSIONS: We have shown wide variations in how critical errors are defined, and the evidence shows an important association between inhaler errors and worsened health outcomes. Given the negative impact diminished disease outcomes impose on resource use, our findings highlight the importance of achieving optimal inhaler technique, and a need for a consensus on defining critical and non-critical errors.

Discriminating Ability of Abbreviated Impactor Measurement Approach (AIM) to Detect Changes in Mass Median Aerodynamic Diameter (MMAD) of an Albuterol/Salbutamol pMDI Aerosol.

This article reports on results from a two-lab, multiple impactor experiment evaluating the abbreviated impactor measurement (AIM) concept, conducted by the Cascade Impaction Working Group of the International Pharmaceutical Aerosol Consortium on Regulation and Science (IPAC-RS). The goal of this experiment was to expand understanding of the performance of an AIM-type apparatus based on the Andersen eight-stage non-viable cascade impactor (ACI) for the assessment of inhalation aerosols and sprays, compared with the full-resolution version of that impactor described in the pharmacopeial compendia. The experiment was conducted at two centers with a representative commercially available pressurized metered dose inhaler (pMDI) containing albuterol (salbutamol) as active pharmaceutical ingredient (API). Metrics of interest were total mass (TM) emitted from the inhaler, impactor-sized mass (ISM), as well as the ratio of large particle mass (LPM) to small particle mass (SPM). ISM and the LPM/SPM ratio together comprise the efficient data analysis (EDA) metrics. The results of the comparison demonstrated that in this study, the AIM approach had adequate discrimination to detect changes in the mass median aerodynamic diameter (MMAD) of the ACI-sampled aerodynamic particle size distribution (APSD), and therefore could be employed for routine product quality control (QC). As with any test method considered for inclusion in a regulatory filing, the transition from an ACI (used in development) to an appropriate AIM/EDA methodology (used in QC) should be evaluated and supported by data on a product-by-product basis.

Development and Evaluation of a Family of Human Face and Upper Airway Models for the Laboratory Testing of Orally Inhaled Products.

Many orally inhaled products are supplied with a facemask instead of a mouthpiece, enabling aerosolized medication to be transferred from the inhaler to the lungs when the user lacks the capability to use a mouthpiece. Until recently, laboratory evaluation of an orally inhaled product-facemask was frequently undertaken by removing the facemask, treating the facemask adapter as being equivalent to a mouthpiece. Measurements of delivered drug mass were therefore subject to bias arising from the absence of dead volume, had the facemask been present. We have described the development of the Aerosol Delivery to an Anatomic Model (ADAM) infant, small child, and adult faces and upper airways, and their subsequent evaluation. Each model possesses physical features of appropriate size, and the soft tissues are also simulated. Rudimentary underlying bony structure is also present, because its purpose is only to provide support, enabling the mechanical response of the facial soft tissues when a facemask is applied to be realized. A realistic upper airway (nasopharynx for the infant model, naso- and oropharynx for the child and oropharynx for the adult models) is also incorporated, so that each model can be used to determine the mass of inhaled medication likely to penetrate as far as the lungs where therapy is intended to be applied. Measurements of the mass of pressurized metered-dose inhaler-delivered salbutamol at a filter distal to the upper airway of each model, simulating age-appropriate tidal breathing, were remarkably consistent, almost all being in the range 0.3 to 1.0 µg/kg across the model age ranges, when expressed as a fraction of body weight.

Overuse of short-acting beta-agonist bronchodilators in COPD during periods of clinical stability.

BACKGROUND: Overuse of short-acting beta-agonists (SABA) is described in asthma, but little is known about overuse of SABA in chronic obstructive pulmonary disease (COPD). METHODS: Prospective 3-month cohort study of patients with moderate-to-severe COPD who were provided a portable electronic inhaler sensor to monitor daily SABA use. Subjects wore a pedometer for 3 seven-day periods and were asked to complete a daily diary of symptoms and inhaler use. Overuse was defined as >8 actuations of their SABA per day while clinically stable. RESULTS: Among 32 participants, 15 overused their SABA inhaler at least once (mean 8.6 ± 5.0 puffs/day), and 6 overused their inhaler more than 50% of monitored days. Compared to those with no overuse, overusers had greater dyspnea (modified Medical Research Council Dyspnea Scale: 2.7 vs. 1.9, p = 0.02), were more likely to use home oxygen (67% vs. 29%, p = 0.04), and were more likely to be on maximal inhaled therapy (long-acting beta-agonist, long-acting antimuscarinic agent, and an inhaled steroid: 40% vs. 6%, p = 0.03), and most had completed pulmonary rehabilitation (67% vs. 0%, p < 0.001). However, 27% of overusers of SABA were not on guideline-concordant COPD therapy. CONCLUSIONS: Overuse of SABA was common and associated with increased disease severity and symptoms, even though overusers were on more COPD-related inhalers and more had completed pulmonary rehabilitation. More research is needed to understand factors associated with inhaler overuse and how to improve correct inhaler use.

The Evolution of Pressurized Metered-Dose Inhalers from Early to Modern Devices.

Pressurized metered-dose inhalers (pMDIs) are sometimes viewed as old-fashioned and as having been superseded by dry powder inhalers (DPIs). Here, we review the technological advances that characterize modern pMDIs, and consider how they can influence the effectiveness of drug delivery for patients with asthma and chronic obstructive pulmonary disease. Compared with old chlorofluorocarbon (CFC)-based inhalers, many hydrofluoroalkane (HFA)-driven pMDIs have more favorable plume characteristics such as a reduced velocity and a higher fine particle fraction; together, these advances have resulted in the development of pMDIs with reduced oropharyngeal deposition and increased lung deposition. In addition, the plume from many HFA-pMDIs is warmer, which may facilitate their use by patients; moreover, devices are equipped with dose counters, which improves their reliability. As well as reviewing the technological advances of pMDIs, we also discuss the importance of individualizing inhaler therapies to each patient by accounting for their personal preferences and natural breathing patterns. Because pMDIs and DPIs differ considerably in their handling characteristics, matching the right inhaler to the right patient is key to ensuring effective therapy and good compliance. Finally, the majority of patients can be trained successfully in the correct use of their pMDI; training and regular monitoring of inhalation technique are essential prerequisites for effective therapy. While the 'ideal inhaler' may not exist, pMDIs are an effective device option suitable for many patients. pMDIs, together with other types of devices, offer opportunities for the effective individualization of treatments.

The evolution of spacers and valved holding chambers.

Spacers and valved holding chambers (VHCs) are pressurized metered dose inhaler (pMDI) accessory devices, designed to overcome problems that patients commonly experience when administering aerosol via a pMDI. Spacers were developed in direct response to patient-related issues with pMDI technique, particularly, poor coordination between actuation and inhalation, and local side-effects arising from oropharyngeal deposition. Current clinical guidelines indicate the need for widespread prescription and use of spacers, but, despite their apparent ubiquity, the devices themselves are, unfortunately, all too commonly "disused" by patients. An understanding of the background from which spacers developed, and the key factors influencing the optimization of the spacer and the later VHC, is crucial to developing an appreciation of the potential of these devices, both contemporary and future, for improving the delivery of pressurized aerosols to patients. This review, informed by a full patent search and an extensive scientific literature review, takes into account the clinical and laboratory evidence, commercial developments, and the sometimes serendipitous details of scientific anecdotes to form a comprehensive perspective on the evolution of spacers, from their origins, in the early days of the pMDI, up to the present day.

Use of breath-actuated inhalers in patients with asthma and COPD - an advance in inhalational therapy: a systematic review.

The pressurized metered dose inhalers and dry powder inhalers are the most widely used devices for inhalation therapy in asthma and chronic obstructive pulmonary disease; each of these devices have certain advantages and disadvantages that impact their use. Motivation from the virtues of these devices led to the development of breath-actuated or breath-activated metered dose inhalers. A history of the breath-actuated inhalers, the development and technical aspects, studies about the usability, inhalation technique and patient preference, lung deposition and impact on lung function are presented in this review article. This review presents the use of breath-actuated inhalers in asthma and chronic obstructive pulmonary disease and in children and elderly; and a brief economic evaluation aims to put the clinical efficacy and ease-of-use of the breath-actuated inhaler into perspective by understanding the long-term cost benefits associated with this device.

Twenty years of HFA pMDI patents: facts and perspectives.

OBJECTIVES: Over the past 20 years, the inhalation drug delivery industry has undergone a quiet revolution after the phasing out of the chlorofluorocarbon propellants used to formulate pressure-metered dose inhalers (pMDIs). This review looks back to the creative landscape of those 20 years through a study of patent application trends. To this end, an analysis of the hydrofluoroalkane pMDIs patent landscape was undertaken. METHODS: A statistical analysis demonstrates that 20 years after the introduction of hydrofluoroalkanes in the inhalation delivery field, the original patent applications are coming to the end of their legal life. KEY FINDINGS: Detailed analysis revealed that, from a total of 971 of the patents identified, up to 2.3% will expire within the next 5 years, rising to up to 7.3% in the next 10 years. The UK and USA were the main patent destinations and locations of inventive activity, as measured by patent filing location. Interestingly, the UK was the first destination and location of inventive activity in Europe, largely due to the activity of GlaxoSmithKline, followed by Italy, thanks to the work of Trinity-Chiesi. The analysis also showed that patent assignees are not always major pharmaceutical companies, with suppliers of propellants, as well as companies without major inhalation activity (such as Novadel), making substantial contributions to the landscape. CONCLUSIONS: These developments may have a significant impact on innovation trends and key company activity around novel pMDI formulations, in particular for generics manufacturers.

Aerosol delivery of antimicrobial agents during mechanical ventilation: current practice and perspectives.

Critically ill patients, who develop ventilator-associated pneumonia during prolonged mechanical ventilation, often require antimicrobial agents administered through the endotracheal or the tracheotomy tube. The delivery of antibiotics via the respiratory tract has been established over the past years as an alternative route in order to deliver high concentrations of antimicrobial agents directly to the lungs and avoid systemic toxicity. Since the only formal indications for inhaled/aerosolized antimicrobial agents is for patients suffering from cystic fibrosis, consequently the majority of research and published studies concerns this group of patients. Newer devices and new antibiotic formulations are currently off-label used in ambulatory cystic fibrosis patients whereas similar data for the mechanically ventilated patients do not yet exist.

Closer to an 'ideal inhaler' with the Easyhaler: an innovative dry powder inhaler.

The characteristics of an ideal inhaler are based around the design and formulation of the device, patient use and the clinical effect, together with concordance and patient preference. To ensure consistent drug delivery to the lungs, with regular adherence to the prescribed dosage regimen, it is essential that all these characteristics simultaneously interact to provide smooth and sustained therapeutic control affected only by the clinical status of the patient. The literature highlights that dose emission from an Easyhaler is fairly consistent irrespective of the inhalation technique used by patients of all age groups. Clinical studies have shown equivalence of this device to those frequently prescribed and that it is preferred by many patients. Although further research is required into the development of inhalation devices, the literature describing the Easyhaler dry powder inhaler indicates how an inhaler can closely meet the criteria for an ideal inhaler.

Spray pattern analysis for metered dose inhalers: effect of actuator design.

PURPOSE: This study was conducted to identify the device factors influencing spray pattern and particle size to gain a more complete understanding of spray plume measurements. METHODS: A statistically designed experiment was used to investigate the influence of three actuator features (orifice diameter, expansion chamber depth, and orifice length) on spray pattern and particle size profiles. Custom-built actuators were manufactured and analyzed with laser light sheet illumination methods for spray patterns and laser diffraction for particle size analysis. RESULTS: In addition to orifice size, spray patterns were significantly influenced by the actuator orifice length and sump depth. Particle size analysis of the plumes generated from actuators used in these studies showed that all actuator features (orifice size, length, and sump depth) were significant factors influencing particle size. CONCLUSIONS: The performance of propellant-based metered dose inhaler aerosols seems to be significantly related to sump depth and orifice length, in addition to orifice size. Rational design of propellant-based metered dose inhalers should therefore consider these variables in addition to formulation strategies and simply modifying orifice diameter.