Metered-dose Inhalers Actuation Research Articles

Count- and mass-based dosimetry of MDI spray droplets with polydisperse and monodisperse size distributions

Most previous numerical studies of inhalation drug delivery used monodisperse aerosols or quantified deposition as the ratio of deposited particle number over the total number of released particles (i.e., count-based). These practices are reasonable when the aerosols have a sufficiently narrow size range. However, spray droplets from metered-dose inhalers (MDIs) are often polydisperse with a wide size range, so using monodisperse aerosols and/or count-based deposition quantification may lead to significant errors. The objective of this study was to develop a mass-based dosimetry method and evaluate its performance in lung delivery in a mouth-lung (G9) geometry with an albuterol-CFC inhaler. The conventional practices (monodisperse and polydisperse-count-based) were also simulated for comparison purposes. The MDI actuation in the open space was studied using both high-speed imaging and LES-Lagrangian simulations. Experimentally measured spray velocities and size distribution were implemented in the computational model as boundary conditions. Good agreement was achieved between recorded and simulated spray plume evolution spatially and temporally. The polydisperse-mass-based predictions of MDI doses compared favorably with the measurements in all three regions considered (device, mouth-throat, and lung). Significant errors in MDI regional deposition were predicted using the monodisperse and count-based methods. The new polydisperse-mass-based method also predicted local deposition hot spots that were one order of magnitude higher in intensity than the two conventional methods. The results of this study highlighted that a presentative polydisperse size distribution and appropriate deposition quantification method should be applied to reliably predict the MDI drug delivery in the human respiratory tract.

Effect of MDI Actuation Timing on Inhalation Dosimetry in a Human Respiratory Tract Model.

Accurate knowledge of the delivery of locally acting drug products, such as metered-dose inhaler (MDI) formulations, to large and small airways is essential to develop reliable in vitro/in vivo correlations (IVIVCs). However, challenges exist in modeling MDI delivery, due to the highly transient multiscale spray formation, the large variability in actuation–inhalation coordination, and the complex lung networks. The objective of this study was to develop/validate a computational MDI-releasing-delivery model and to evaluate the device actuation effects on the dose distribution with the newly developed model. An integrated MDI–mouth–lung (G9) geometry was developed. An albuterol MDI with the chlorofluorocarbon propellant was simulated with polydisperse aerosol size distribution measured by laser light scatter and aerosol discharge velocity derived from measurements taken while using a phase Doppler anemometry. The highly transient, multiscale airflow and droplet dynamics were simulated by using large eddy simulation (LES) and Lagrangian tracking with sufficiently fine computation mesh. A high-speed camera imaging of the MDI plume formation was conducted and compared with LES predictions. The aerosol discharge velocity at the MDI orifice was reversely determined to be 40 m/s based on the phase Doppler anemometry (PDA) measurements at two different locations from the mouthpiece. The LES-predicted instantaneous vortex structures and corresponding spray clouds resembled each other. There are three phases of the MDI plume evolution (discharging, dispersion, and dispensing), each with distinct features regardless of the actuation time. Good agreement was achieved between the predicted and measured doses in both the device, mouth–throat, and lung. Concerning the device–patient coordination, delayed MDI actuation increased drug deposition in the mouth and reduced drug delivery to the lung. Firing MDI before inhalation was found to increase drug loss in the device; however, it also reduced mouth–throat loss and increased lung doses in both the central and peripheral regions.

A scintigraphy study of budesonide/glycopyrrolate/formoterol fumarate metered dose inhaler in patients with moderate-to-very severe chronic obstructive pulmonary disease

BackgroundTriple therapy with inhaled corticosteroids/long-acting muscarinic antagonists/long-acting β2-agonists (ICS/LAMA/LABA) is recommended for patients with chronic obstructive pulmonary disease (COPD) with continued symptoms or exacerbations, despite treatment with LAMA/LABA or ICS/LABA. The pulmonary, extrathoracic, and regional lung deposition patterns of a radiolabeled ICS/LAMA/LABA triple fixed-dose combination budesonide/glycopyrrolate/formoterol fumarate (BGF 320/18/9.6 μg), delivered via a single Aerosphere metered dose inhaler (MDI) were previously assessed in healthy volunteers and showed good deposition to the central and peripheral airways (whole lung deposition: 37.7%). Here, we report the findings assessing BGF in patients with moderate-to-very severe COPD.MethodsThis phase I, single-dose, open-label gamma scintigraphy imaging study (NCT03906045) was conducted in patients with moderate-to-very severe COPD. Patients received two actuations of BGF MDI (160/9/4.8 μg per actuation) radiolabeled with technetium‑99‑pertechnetate, not exceeding 5 MBq per actuation. Immediately following each inhalation, patients performed a breath-hold of up to 10 s, then exhaled into an exhalation filter. Gamma scintigraphy imaging of the anterior and posterior views of the lungs and stomach, and a lateral head and neck view, were performed immediately after exhalation. The primary objective of the study was to assess the pulmonary deposition of BGF. Secondary objectives assessed the deposited dose of radiolabeled BGF in the oropharyngeal and stomach regions, on the actuator, and on the exhalation filter in addition to regional airway deposition patterns in the lungs.ResultsThe mean BGF emitted dose deposited in the lungs was 32.1% (standard deviation [SD] 15.6) in patients with moderate-to-very severe COPD, 35.2% (SD 12.8) in patients with moderate COPD, and 28.7% (SD 18.4) in patients with severe/very severe COPD. Overall, the mean normalized outer/inner ratio was 0.55 (SD 0.19), while the standardized central/peripheral ratio was 2.21 (SD 1.64).ConclusionsRadiolabeled BGF 320/18/9.6 μg was efficiently delivered and deposited throughout the entire lung, including large and small airways, in patients with moderate-to-very severe COPD, with similar deposition in patients with moderate COPD and patients with severe/very severe COPD.Trial registration: ClinicalTrials.gov, NCT03906045. Registered 8 April 2019, https://clinicaltrials.gov/ct2/show/NCT03906045

Factors DeterminingIn VitroLung Deposition of Albuterol Aerosol Delivered by Ventolin Metered-Dose Inhaler

The effectiveness of metered-dose inhalers (MDIs) in delivering medication to the lungs highly depends on its correct usage technique. Current guidelines state optimal technique for high lung deposition should include a slow inhalation (>5 seconds) at an inspiratory flow rate of 30 L/min and inhaler actuation at the start of inhalation. However, these recommendations were based on clinical studies using CFC (chlorofluorocarbon)-MDIs and in vitro studies of HFA (hydrofluoroalkane)-MDIs using idealized MDI techniques of uniform inhalation and actuation, disregarding the nonuniform techniques of actual patients. To better understand the effects of time-varying MDI usage parameters on lung deposition of aerosol delivered by an HFA-MDI, we conducted an in vitro study modeled on real-life variable inspiratory flow and actuation techniques recorded from 15 subjects with asthma/chronic obstructive pulmonary disease (COPD). We developed a model representing the time-varying inspiratory flow waveforms and actuation timings based on 43 MDI techniques recorded from patients. Furthermore, we constructed an in vitro experimental setup using a mouth-throat cast, programmable MDI actuator, and breath simulator to evaluate lung deposition for the MDI techniques derived from our model. High inspiratory flow rates, 60-90 L/min, consistently resulted in high in vitro lung deposition (>40%) of aerosol (albuterol delivered from Ventolin HFA-MDI) compared to 30 L/min when MDI actuation occurred in the first half of inhalation. Also, positive coordination resulted in higher in vitro lung deposition compared with negative or zero coordination (actuating before or at the start of inspiration). Furthermore, variation in coordination affected lung deposition more significantly (23%) than flow rate or duration of inspiration (≤5%). In an in vitro experimental model based on inhalation data from patients with asthma and COPD, we demonstrated that aerosol lung deposition emitted from Ventolin HFA-MDI is most optimal for MDI actuation in the first half of inspiration at high flow rates (60-90 L/min).

Does It Really Matter What Volume to Exhale Before Using Asthma Inhalation Devices?

Correct use of inhalation devices is one essential component of optimal management of asthma. Several longstanding controversies regarding specific steps to correct use of metered dose inhalers (MDI) include the lung volume when the MDI should be actuated. As a primary objective, literature was reviewed examining this one step in MDI use. Results from six of nine investigations support the need to gently exhale either to functional residual capacity (FRC) or residual volume (RV) before MDI actuation. Literature is also summarized regarding the need to exhale to FRC or RV before inhaling from MDI plus valved holding chambers or other extension devices and from dry powder inhalers. Numerous studies indicate that many patients as well as health care professionals either do not know or forget to exhale to RV or FRC before inhaling asthma medications. Both patients and health care professionals need education to help ensure correct use of MDI and other asthma inhalation devices, including instruction to first exhale gently to RV or FRC before inhaling the medication.

Simplified administration of aerosolized drugs to small animals using metered dose inhalers

Rationale Animal studies involving administration of aerosolized drugs are complicated by the difficulties of generating and delivering the aerosol to the lungs effectively and reproducibly. A method utilizing a metered dose inhaler (MDI) would allow simplification and standardization of aerosol dosing. Methods 18 adult BN rats were sensitized to ragweed. A spacer chamber was modified with a latex face mask that allowed insertion of an awake rat's nose and mouth into the chamber opposite the MDI. After MDI actuation, rats breathed either placebo or fluticasone 220 aerosol from the chamber for 60s, once daily X7d prior to and 1d after aerosolized ragweed challenge. Others were treated with s.c. dexamethasone X3d for comparison. Body and thymus weights were indicators of systemic steroid effect, and lung volumes, forced expiratory maneuvers and BAL cells were indicators of pulmonary allergic responses at 48h after allergen challenge. Results Fluticasone MDI treatment caused body weight loss and thymus weight loss compared with placebo treatment, indicating sufficient pulmonary delivery to obtain systemic effects. Body weight loss was greater with systemic dexamethasone treatment. Fluticasone also protected the rats from pulmonary allergic responses, with preservation of total lung capacity, FEV 0.2 and FVC, and reduced BAL inflammatory cells, compared with placebo treatment (p<0.03). The fluticasone and dexamethasone groups were similar for FVC, FEV 0.2 and BAL eosinophils, and both the fluticasone and dexamethasone groups showed small within-group variability. Conclusion This method of administering MDI aerosols to rats is simple, effective, and reproducible.

Inhalation Delivery of Anticancer Agents via HFA-Based Metered Dose Inhaler Using Methotrexate as a Model Drug

In the present study, the feasibility of delivering anticancer drugs via metered dose inhaler (MDI) was demonstrated using methotrexate (MTX) as a model anticancer drug. MDI formulations of MTX were prepared using hydrofluoroalkane-134a containing 0.67% MTX and 10% ethyl alcohol. The particle size of MTX was reduced by cryo milling with or without a surfactant (Pluronic F77) and the milled drug was employed for MDI formulations, which were subsequently evaluated for their medication delivery, mass median aerodynamic diameter (MMAD) and geometric standard deviation (GSD). Further, the efficacy of aerosolized MTX was evaluated by determining the in-vitro cytotoxicity of MTX against HL-60 cells using a six-stage viable impactor and the induction of apoptosis in HL-60 cells by acridine orange staining. Our results indicate that MTX aerosols having an MMAD varying between 2.2 and 3.2 microm (GSD 2.6-3.7) with a respirable fraction varying between 14.2 and 17.1% could be obtained by using MTX, which was cryo milled either alone or in combination with Pluronic F77. Exposure of HL-60 cells plated in third, fourth, fifth, and sixth stages of viable impactor to two actuations of MDI showed a cell kill of greater than 50%. Further, aerosolized MTX was found to induce apoptosis in HL-60 cells, as assessed by the morphological examination of the cells with fluorescent and confocal microscopy. Our results demonstrate that it is possible to deliver cytotoxic concentrations of MTX in an in vitro system simulating the lower respiratory tract (by using a six-stage viable impactor) via MDI and the cytotoxicity of the aerosolized MTX could be further improved by the optimization of the aerodynamic size.

Selecting an accessory device with a metered-dose inhaler: variable influence of accessory devices on fine particle dose, throat deposition, and drug delivery with asynchronous actuation from a metered-dose inhaler.

Accessory devices reduce common problems with metered-dose inhalers (MDIs), namely high oropharyngeal deposition of aerosol and incoordination between actuation and inhalation by the patient. The objective of this study was to systematically compare the performance of various accessory devices in vitro. MDIs were tested alone or in combination with four spacers (Toilet paper roll, Ellipse, Optihaler, Myst Assist) and five holding chambers (Aerochamber, Optichamber, Aerosol Cloud Enhancer, Medispacer, and Inspirease). An Anderson cascade impactor was used to measure aerosol mass median aerodynamic diameter (MMAD) and fine particle dose (MMAD < 4.7 microm). In separate experiments, the influence of asynchronous MDI actuation on drug delivery was determined with a simulated spontaneous breathing model. Compared with the MDI alone, all of the accessory devices reduced aerosol MMAD and increased lung-throat ratio (fine particle dose/throat impaction; p < 0.05 for both parameters). The fine particle dose of albuterol was 40% higher with the Ellipse (p < 0.01), was equivalent with the Toilet Paper Roll, Aerochamber, Optichamber, and Medispacer, and was 33-56% lower with the Optihaler, Myst Assist, Aerosol Cloud Enhancer, and Inspirease (p < 0.03). MDI actuation in synchrony with inspiration produced highest drug delivery; when MDI actuation occurred 1-sec before inspiration or during exhalation, decrease in drug delivery with holding chambers (10-40% reduction) was less than that with spacers (40-90% reduction). Accessory device selection is complicated by variability in performance between devices, and in the performance of each device in different clinical settings. In vitro characterization of a MDI and accessory device could guide appropriate device selection in various clinical settings.

Unpredictability of Deception in Compliance With Physician-Prescribed Bronchodilator Inhaler Use in a Clinical Trial

To identify subject characteristics that may be predictive of intentional dumping of metered-dose inhalers (MDIs) during a clinical trial. Nebulizer Chronologs (NCs; Medtrac Technologies; Lakewood, CO), which record the date and time of each MDI actuation, were attached to the MDIs of participants who were given a prescribed medication schedule to follow in a clinical trial. Participants were not informed of the function of the NC or that their medication use was being monitored. The Lung Health Study, a 5-year clinical trial to evaluate the effect of intensive smoking cessation counseling and regular use of an inhaled bronchodilator on the progression of COPD. One hundred one smokers, 35 to 60 years of age, with mild to moderate airways obstruction enrolled in The Lung Health Study. Thirty of these 101 participants (30%) actuated their inhalers > 100 times within a 3-h interval on at least one occasion during the first year of this 5-year trial. Only 1 of an additional 135 participants who had full foreknowledge of the MDI monitoring capability of the NC did so. Most of these dumping episodes occurred shortly before a clinic follow-up visit, suggesting an active attempt to hide noncompliance from the clinic staff. Whereas self-reported inhaler usage and canister weights were similar for the "dumpers" and "nondumpers," NC data indicated significantly lower compliance rates for dumpers (chi(2); p < 0.05). When demographic variables, treatment and clinic assignments, smoking status, pulmonary function test results, respiratory symptoms, and disease history of dumpers and nondumpers were analyzed, no predictors of dumping could be found. Deception among noncompliers occurs frequently in clinical trials, is often not revealed by the usual methods of monitoring, and cannot be predicted by data readily available in clinical trials.

Demonstration of In Vivo Bioequivalence of a Generic Albuterol Metered-Dose Inhaler to Ventolin

To use histamine bronchoprovocation and bioassay statistical procedures to evaluate the in vivo bioequivalence of a generic albuterol metered-dose inhaler (MDI). A randomized, double-blind, balanced, crossover design was used to determine the potency of each generic albuterol MDI actuation relative to Ventolin (Glaxo Wellcome; Research Triangle Park, NC) administration. One treatment was administered on each of 4 study days. A histamine bronchoprovocation procedure was initiated 1.25 h before and 15 min after administration of the study treatment. Twenty-four nonsmoking subjects with mild-to-moderate asthma were studied (18 to 65 years of age; FEV(1), > 60% of predicted; and provocative concentration of histamine causing a 20% fall in FEV(1) [PC(20)], < or = 8 mg/mL at screening). One and four actuations (90 and 360 microg, respectively) of the generic MDI and of Ventolin MDI. Placebo inhalers were used to maintain blinding of inhaler and doses. The primary outcome variable was histamine PC(20) measured after study treatment administration. A significant dose-effect relationship was present (p < 0.0001). Deviation from parallelism of the generic and Ventolin dose-response curves (p = 0.95) and differences in overall mean response between the two formulations (p = 0.68) were not significant. Using Finney 2 x 2 bioassay statistical procedures, we estimated that one actuation of the generic albuterol MDI was equivalent to 1.01 puffs of Ventolin (90% confidence interval, 0.69 to 1.50). The generic albuterol MDI delivers a quantity of albuterol to the beta(2)-receptor site in the lung that is the bioequivalent to Ventolin. Further, this study reinforces the validity of this statistical methodology for determining in vivo bioequivalence.

Reservoir design and dose availability with long-term metered dose inhaler corticosteroid use.

The effect of reservoir design and long-term use with inhaled metered dose inhaler (MDI) corticosteroids on aerosol dose availability was examined. Beclomethasone dipropionate (Vanceril) was delivered by MDI with three brands of available reservoir devices: the AeroChamber, the OptiHaler, and the Aerosol Cloud Enhancer (ACE). An in vitro lung model simulated inspiration. Long-term use was simulated by exhausting five MDI canisters of beclomethasone through each sample of reservoir tested. Each canister exhausted through a reservoir represented approximately 1 month of use with one drug. Total inhaled dose was collected at the reservoir mouthpiece and measured using a spectrophotometric assay. Dose delivery was measured before simulated use and after each MDI canister was exhausted through the reservoir. Three samples of each brand were tested with cleaning and three samples were tested without cleaning. With cleaning, the AeroChamber, OptiHaler, and ACE delivered significantly different average doses of 16.6, 10.3, and 8.7 micrograms per MDI actuation, respectively, (P = 0.0017) over time of use. Changes in dose delivery over time of use were not significant (P = 0.2011). Without cleaning, the same three brands averaged 21.1, 9.7, and 7.8 micrograms per MDI actuation, respectively, (P = 0.0019), and changes in dose delivery over time were not significant (P = 0.3265). Reservoir design can affect the delivery of an inhaled corticosteroid, although the delivery over 4 to 5 months remained stable.

Evaluation of Aerosol Drug Output from the OptiChamberTM and AeroChamberTM Spacers in a Model System

Metered-dose inhalers (MDIs) are an effective means of generating drug-containing aerosols targeted for delivery to intrapulmonary airways. Many problems associated with incorrect patient use of MDIs are mitigated by adding a valved spacer device to the inhaler mouthpiece. This in vitro study compared the efficiency of drug output through a new spacer device, OptiChamber® (HealthScan Products Inc., Cedar Grove, NJ), to that of a device commercially available since the 1980s, AeroChamber® (Monaghan Medical, Pittsburgh, NY). Testing utilized MDI formulations of albuterol, beclomethasone dipropionate, and cromolyn sodium. OptiChamber equaled or, in the majority of cases, exceeded AeroChamber in output of the three drugs at two simulated inspiratory flow rates. Drug output from OptiChamber was found to be less sensitive to changes in flow rate than that from AeroChamber. OptiChamber also showed less decrease in drug output than AeroChamber when time delays were introduced between MDI actuation and the start of a simulated inhalation. Mass median aerodynamic diameters of drugs exiting the two spacers were generally similar to those of drugs exiting the MDI alone. However, spacers were shown to nearly eliminate the output of large-size drug particles (<5.8 μm), which can result in oropharyngeal drug deposition. Emitted fine-particle drug (<5.8 μm) doses from OptiChamber were greater than those from AeroChamber with or without a delay between canister actuation and the start of a simulated inhalation. The results suggest that OptiChamber may provide more efficacious aerosol drug delivery than AeroChamber under both ideal and suboptimal conditions.

Trends in Compliance With Bronchodilator Inhaler Use Between Follow-up Visits in a Clinical Trial

To assess objectively measured, long-term trends in compliance with physician-prescribed metered-dose inhaler (MDI) use during a clinical trial. A prospective study. The Lung Health Study, a 5-year clinical trial to determine the effect of special intervention with an intensive smoking cessation program and bronchodilator therapy in cigarette smokers 35 to 60 years of age with minimal to moderate airflow limitation due to COPD. Two hundred thirty-one participants who were issued an MDI with an attached Nebulizer Chronolog (NC) (Forefront Technologies Inc; Lakewood, Colo) which electronically records the date and time of each MDI actuation. One hundred two participants were not informed of the recording capabilities of the attached NC, while 129 participants were aware of the NC's monitoring function. Following an initial 12-week period of counseling, participants returned to the clinic every 4 months. Analysis of the data from the NC collected over a period of 2 years indicates that compliance with the prescribed medication regimen was best immediately following each follow-up visit and gradually declined during the interval between follow-up visits. The level of compliance after each visit was lower for each successive follow-up. These trends could not be observed from self-report or weighting the medication canisters at follow-up visits. The participants who were informed of the NC's function and who were provided with detailed feedback about their inhaler use generally showed better compliance.

Bronchodilator delivery with metered-dose inhalers in mechanically-ventilated patients.

Metered-dose inhalers (MDIs) provide several advantages over nebulizers, including ease of administration, decreased cost, reliability of dosing, and freedom from contamination. However, this method of aerosol delivery has been considered ineffective in mechanically-ventilated patients because most of the aerosol deposits in the endotracheal tube and ventilator circuit. A smaller amount of aerosol from a MDI is deposited in the lower respiratory tract of mechanically-ventilated patients than in ambulatory patients, although recent studies show that a significant bronchodilator effect can still be achieved. When employed optimally, significant bronchodilation occurs with as little as 4 puffs of a sympathomimetic aerosol. Multiple factors influence the efficacy of MDIs in mechanically-ventilated patients. The method of connecting the MDI canister to the ventilator circuit has a marked effect on aerosol delivery, and other factors include the timing of MDI actuation, ventilator mode, tidal volume, circuit humidity, and duty cycle. With a proper technique of administration, a MDI serves as an effective, convenient, and safe method for delivering bronchodilator aerosols in mechanically-ventilated patients.

Physicians' metered dose inhaler technique after a single teaching session.

It is known that many housestaff physicians are unable to demonstrate perfect metered dose inhaler (MDI) technique. This study assessed whether a single teaching session for house staff physicians would significantly improve their MDI technique. Thirty-eight pediatric house staff physicians were asked to demonstrate MDI technique with a placebo MDI. The physicians were evaluated on the following seven steps: (1) shaking the MDI and removing the cap, (2) exhaling prior to MDI use, (3) holding the MDI upright, (4) proper timing of actuation, (5) a slow inspiratory effort, (6) one MDI actuation per breath, and (7) holding the breath > or = 5 seconds. A 20-minute teaching session and demonstration of proper MDI technique was then given. At the end of this session all residents were eventually able to demonstrate proper technique. Two months following this educational session the same house staff physicians were re-evaluated on their MDI technique. Initially, ten participants (26%) demonstrated perfect technique. Two months postinstruction the same number of physicians (ten) demonstrated perfect technique. Only six physicians demonstrated perfect technique at both evaluations. Three of the seven steps showed enough change from the first evaluation to the second to permit statistical analysis. Step 4 (timing of actuation) had 11 Physicians' performances improve while three worsened (P=.03). Step 5 (a slow inspiratory effort) had nine physicians' performances improve while three worsened (P=.073). For step 7 (holding the breath > or = 5 seconds), 11 physicians improved while 2 worsened (P=.006). Comparing global performance, there were 17 physicians that improved, 8 that worsened, and 13 with no change (P=.054). This study confirmed that many housestaff physicians do not demonstrate optimal MDI technique. While one educational session may somewhat improve their future performance, it is not sufficient to guarantee perfect technique. This suggests that repeated education needs to be given to housestaff physicians.

Albuterol delivery in a model of mechanical ventilation. Comparison of metered-dose inhaler and nebulizer efficiency.

Using an in vitro model, we compared efficiencies of jet nebulizers and metered-dose inhalers (MDI) with actuator devices to deliver albuterol in various conditions of mechanical ventilation. Factors tested included influence of humidification, MDI actuator device (Aerovent spacer or Marquest 172275 MDI adaptor), and synchronization of MDI to the respiratory cycle. With the nebulizer (AeroTech II) filled with 2.5 mg albuterol sulfate in 3 ml water and run until dry, inhaled mass was 42 +/- 2.6% and mass median aerodynamic diameter (MMAD) was 1.3 microns on a nonhumidified circuit. With the MDI+ Aerovent, the inhaled mass percentage per 90 microgm puff was 15.4 +/- 0.2% with humidification and 25.1 +/- 3.7% without humidification, actuations being synchronized with the beginning of inspiration and separated by a 1-min pause. Failure to synchronize actuations with inspiration or to pause 1 min resulted in significant reductions in inhaled mass (by 35 and 72%, respectively). The Marquest adaptor was less efficient, with an inhaled mass of 7.2 +/- 0.7% under optimal conditions. Metered-dose inhaler actuation during expiration resulted in relatively large particles (MMAD = 2.0 microns). All other MDI actuations led to essentially biphasic distributions, with particles greater than 1 micron following a distribution similar to the nebulizer and the overall MMAD estimated to be 0.22 microns. The AeroTech II delivered a cumulative 1,000 micrograms of drug (2,500 x 0.40) over 40 min. To achieve that amount, the MDI connected to the Aerovent and used in its most efficient sequence would require 45 timed puffs (90 micrograms per puff, 25.1% mean inhaled mass) and take 45 min of an experienced therapist's time.(ABSTRACT TRUNCATED AT 250 WORDS)

Metered-dose inhaler usage in subjects with asthma: Comparison of Nebulizer Chronolog and daily diary recordings

The Nebulizer Chronolog (NC) is a portable electronic device that attaches to standard metered-dose inhalers (MDIs) and records and stores the date and time of each MDI actuation. We evaluated the long-term performance of the NC and compared its data to concurrent recordings of self-administered MDI usage in daily diaries. Eighty-three subjects with asthma were evaluated during a 7 1 2 -month panel study of air pollution effects. Although 44 (53%) of the NCs developed a malfunction during the study, the average total (±SD) percentage of useful days with functioning NCs was still 86 ± 18% (median 93%). The agreement between the daily diary and NC recordings was very high, that is, 50 (67%) of 75 subjects had perfect agreement. Eighteen subjects with over or under diary reporting were detected. We conclude that the NC is an effective, objective, accurate, and continuous monitor of daily MDI usage despite some remediable technical problems. The NC can facilitate the evaluation of short- and long-term medication usage patterns and compliance issues in MDI-related research and clinical settings.

Use of Bronchodilator Aerosols

Despite initial fears associated with its safety, aerosol administration by metered dose inhaler (MDI) is rapidly becoming the preferred form of bronchodilator therapy, as it has a number of advantages over oral agents. To enhance aerosol delivery and bronchodilator response, several important steps in the optimal use of an MDI have been characterized. Because many physicians are unaware of the optimal technique in employing an MDI, it is not surprising that patients frequently receive little or no instructions in its use. Furthermore, patients who have received instruction display great difficulty in adhering to the steps in the ideal use of an MDI and frequently cannot coordinate MDI actuation with inspiration. A number of auxiliary delivery systems have recently been developed and show varying success in circumventing the problems involved in patient use of MDIs.

Response to bronchodilator drug administration by a new reservoir aerosol delivery system and a review of other auxiliary delivery systems.

Response to bronchodilator aerosols delivered by metered dose inhalers (MDI) depends in part upon the amount of drug depositing on the airways. Ideally, the MDI should be actuated during a slow deep inhalation followed by a breathholding pause, an impossible maneuver for many patients. We developed a new reservoir aerosol delivery system (RADS) consisting of a 700-ml collapsible bag in which aerosol could be injected. The mouthpiece-canister was filtered with a reed that vibrated at inspiratory flows greater than 0.3 L/s to produce a noise. Patients were instructed to keep inhalation silent while breathing from RADS. One puff of metaproterenol (650 microgram) administered via RADS (with one breath rebreathed) was compared with one puff of metaproterenol (650 micrograms) from usual MDI using serial measurements of body plethysmography and spirometry. Respiratory inductive plethysmography measured the point of MDI actuation, volume of inhalation, inspiratory flow, and breathholding pause. Ten patients with chronic airflow limitation caused by asthma or chronic bronchitis were given typed instructions on MDI usage and trained shortly before the study. Metaproterenol via RADS produced significantly greater maximal increase in SGaw (195 +/- 52% SE) compared with metaproterenol via conventional MDI (101 +/- 24%, p less than 0.003). Bronchodilator response in 4 patients unable to coordinate actuation of the MDI with inspiration was significantly less than in 6 patients with good MDI technique (p less than 0.005). The mean flow rates were 0.54 +/- 0.16 L/s during inhalation of metaproterenol compared with 0.19 +/- 0.02 L/s and 0.24 +/- 0.03 L/s during the first and second inhalations, respectively, using RADS. This reservoir aerosol delivery system, which was well accepted by the patients, promotes more effective bronchodilation than the conventional metered dose inhaler.