Humidified and Heated Cascade Impactor for Aerosol Sizing.

Aerosol sizing is generally measured at ambient air but human airways have different temperature (37°C) and relative humidity (100%) which can affect particle size in airways and consequently deposition prediction. This work aimed to develop and evaluate a new method using cascade impactor to measure particle size at human physiological temperature and humidity (HPTH) taking into account ambient air conditions. A heated and humidified trachea was built and a cascade impactor was heated to 37°C and humidified inside. Four medical aerosols [jet nebulizer, mesh nebulizer, Presurized Metered Dose Inhaler (pMDI), and Dry Powder Inhaler (DPI)] under ambient conditions and at HPTH were tested. MMAD was lower at HPTH for the two nebulizers; it was similar at ambient conditions and HPTH for pMDI, and the mass of particles smaller than 5 µm decreased for DPI at HPTH (51.9 vs. 82.8 µg/puff). In conclusion, we developed a new method to measure particle size at HPTH affecting deposition prediction with relevance. In vivo studies are required to evaluate the interest of this new model to improve the precision of deposition prediction.

Controlled, Parametric, Individualized, 2-D and 3-D Imaging Measurements of Aerosol Deposition in the Respiratory Tract of Asthmatic Human Subjects for Model Validation.

BACKGROUND: Computer modeling is used to predict inhaled aerosol deposition in the lung based on definition of the aerosol characteristics and the breathing pattern and airway anatomy of the subject. Validation of the models is limited by the lack of detailed experimental data. Three-dimensional imaging provides an opportunity to address this unmet need. METHODS: Radioactive aerosol was administered to six male asthmatic subjects on two occasions under carefully monitored input conditions. Input parameters varied in particle size, depth of breathing, and carrier gas. The aerosol distribution was measured by combined single photon emission computed tomography and x-ray computer tomography (SPECT/CT) and airway anatomy by high resolution CT. The deposition distribution was measured by both a 2D and 3D analysis and described in terms of the percentage of inhaled aerosol deposited in sections of the respiratory tract and in both spatial and anatomical subdivisions within each lung. The percentage deposition in the conducting airways was also assessed by 24 h clearance. RESULTS: A set of imaging data of aerosol deposition has thus been produced in which the input parameters of inhalation are well described. The results in asthmatics were compared to previous measurements in healthy controls using an identical inhalation protocol. The percentages of deposition in extra-thoracic and thoracic compartments of the airways were not significantly affected by disease, but the regional pulmonary deposition pattern was, with asthma leading to increased deposition in the conducting airways. CONCLUSIONS: The dataset acquired in this study will be useful in validating computer models of aerosol deposition in asthmatic subjects. Asthma did not affect the fraction of inhaled aerosol depositing in the lungs, but gave rise to a more central deposition pattern. The use of 3D SPECT imaging in combination with 24 h clearance measurements enables differentiation of deposition between bronchial and bronchiolar airways.

Determination of regional lung air volume distribution at mid-tidal breathing from computed tomography: a retrospective study of normal variability and reproducibility.

BACKGROUND: Determination of regional lung air volume has several clinical applications. This study investigates the use of mid-tidal breathing CT scans to provide regional lung volume data. METHODS: Low resolution CT scans of the thorax were obtained during tidal breathing in 11 healthy control male subjects, each on two separate occasions. A 3D map of air volume was derived, and total lung volume calculated. The regional distribution of air volume from centre to periphery of the lung was analysed using a radial transform and also using one dimensional profiles in three orthogonal directions. RESULTS: The total air volumes for the right and left lungs were 1035 +/- 280 ml and 864 +/- 315 ml, respectively (mean and SD). The corresponding fractional air volume concentrations (FAVC) were 0.680 +/- 0.044 and 0.658 +/- 0.062. All differences between the right and left lung were highly significant (p < 0.0001). The coefficients of variation of repeated measurement of right and left lung air volumes and FAVC were 6.5% and 6.9% and 2.5% and 3.6%, respectively. FAVC correlated significantly with lung space volume (r = 0.78) (p < 0.005). FAVC increased from the centre towards the periphery of the lung. Central to peripheral ratios were significantly higher for the right (0.100 +/- 0.007 SD) than the left (0.089 +/- 0.013 SD) (p < 0.0001). CONCLUSION: A technique for measuring the distribution of air volume in the lung at mid-tidal breathing is described. Mean values and reproducibility are described for healthy male control subjects. Fractional air volume concentration is shown to increase with lung size.

Controlled, parametric, individualized, 2D and 3D imaging measurements of aerosol deposition in the respiratory tract of healthy human volunteers: in vivo data analysis.

BACKGROUND: To provide a validation dataset for aerosol deposition modeling, a clinical trial was performed in which the inhalation parameters and the inhaled aerosol were controlled or characterized. METHODS: Eleven, healthy, never-smokers, male participants completed the study. Each participant performed two inhalations of (99m)Tc-labeled aerosol from a vibrating mesh nebulizer, which differed by a single controlled parameter (aerosol particle size: "small" or "large"; inhalation: "deep" or "shallow"; carrier gas: air or a helium-oxygen mix). The deposition measurements were made by planar imaging, and single photon emission computed tomography-computed tomography (SPECT-CT). RESULTS: The difference between the mean activity measured by two-dimensional imaging and that delivered from the nebulizer was 2.7%, which was not statistically significant. The total activity deposited was significantly lower in the left lung than in the right lung (p<0.0001) with a mean ratio (left/right) of 0.87±0.1 standard deviation (SD). However, when normalized to lung air volume, the left lung deposition was significantly higher (p=0.0085) with a mean ratio of 1.08±0.12 SD. A comparison of the three-dimensional central-to-peripheral (nC/P3D) ratio showed that it was significantly higher for the left lung (p<0.0001) with a mean ratio (left/right) of 1.36±0.20 SD. The effect of particle size was statistically significant on the nC/P3D ratio (p=0.0014), extrathoracic deposition (p=0.0037), and 24-hr clearance (p<0.0001), contrary to the inhalation parameters, which showed no effect. CONCLUSIONS: This article presents the results of an analysis of the in vivo deposition data, obtained in a clinical study designed to provide data for model validation. This study has demonstrated the value of SPECT imaging over planar, the influence of particle size on regional distribution within the lung, and differences in deposition between the left and right lungs.

A technique for determination of lung outline and regional lung air volume distribution from computed tomography.

BACKGROUND: Determination of the lung outline and regional lung air volume is of value in analysis of three-dimensional (3D) distribution of aerosol deposition from radionuclide imaging. This study describes a technique for using computed tomography (CT) scans for this purpose. METHODS: Low-resolution CT scans of the thorax were obtained during tidal breathing in 11 healthy control male subjects on two occasions. The 3D outline of the lung was determined by image processing using minimal user interaction. A 3D map of air volume was derived and total lung air volume calculated. The regional distribution of air volume from center to periphery of the lung was analyzed using a radial transform and the outer-to-inner ratio of air volume determined. RESULTS: The average total air volume in the lung was 1,900±126 mL (1 SEM), which is in general agreement with the expected value for adult male subjects in the supine position. The fractional air volume concentration increased from the center toward the periphery of the lung. Outer-to-inner (O/I) ratios were higher for the left lung [11.5±1.8 (1 SD)] than for the right [10.1±0.8 (1 SD)] (p<0.001). When normalized for the region sizes, these ratios were 1.37±0.16 and 1.20±0.04, respectively. The coefficient of variation of repeated measurement of the normalized O/I ratio was 5.9%. CONCLUSIONS: A technique for outlining the lungs from CT images and obtaining an image of the distribution of air volume is described. The normal range of various parameters describing the regional distribution of air volume is presented, together with a measure of intrasubject repeatability. This technique and data will be of value in analyzing 3D radionuclide images of aerosol deposition.

The use of combined single photon emission computed tomography and X-ray computed tomography to assess the fate of inhaled aerosol.

BACKGROUND: Gamma camera imaging is widely used to assess pulmonary aerosol deposition. Conventional planar imaging provides limited information on its regional distribution. In this study, single photon emission computed tomography (SPECT) was used to describe deposition in three dimensions (3D) and combined with X-ray computed tomography (CT) to relate this to lung anatomy. Its performance was compared to planar imaging. METHODS: Ten SPECT/CT studies were performed on five healthy subjects following carefully controlled inhalation of radioaerosol from a nebulizer, using a variety of inhalation regimes. The 3D spatial distribution was assessed using a central-to-peripheral ratio (C/P) normalized to lung volume and for the right lung was compared to planar C/P analysis. The deposition by airway generation was calculated for each lung and the conducting airways deposition fraction compared to 24-h clearance. RESULTS: The 3D normalized C/P ratio correlated more closely with 24-h clearance than the 2D ratio for the right lung [coefficient of variation (COV), 9% compared to 15% p < 0.05]. Analysis of regional distribution was possible for both lungs in 3D but not in 2D due to overlap of the stomach on the left lung. The mean conducting airways deposition fraction from SPECT for both lungs was not significantly different from 24-h clearance (COV 18%). Both spatial and generational measures of central deposition were significantly higher for the left than for the right lung. CONCLUSIONS: Combined SPECT/CT enabled improved analysis of aerosol deposition from gamma camera imaging compared to planar imaging. 3D radionuclide imaging combined with anatomical information from CT and computer analysis is a useful approach for applications requiring regional information on deposition.

Aerosolized chemotherapy.

Regional chemotherapy has been proposed as a treatment modality in a number of cancer settings. In primary or metastatic lung cancer, administration of chemotherapy via inhalation could increase exposure of lung tumor to the drug, while minimizing systemic side effects. Several proof of concept studies in animal models of metastatic or primary lung cancer have demonstrated the safety, pharmacokinetic advantage, and antitumor effect of aerosol administration of several chemotherapeutic agents including doxorubicin, gemcitabine and liposome-encapsulated formulations of paclitaxel and 9-nitrocamptothecin (9-NC). Recent phase I studies have demonstrated the feasibility of aerosol delivery of doxorubicin and liposomal formulations of 9-NC and cisplatin in patients with primary and metastatic lung cancer with a limited pharmacokinetic profile consistent with the observed low systemic toxicity. Further studies integrating safety, pharmacokinetic, and efficacy considerations are required to determine whether there is a place for local administration of chemotherapy via inhalation in lung cancer.

Lung deposition of HFA beclomethasone dipropionate in an animal model of bronchopulmonary dysplasia.

The best delivery of a drug in ventilated neonates is obtained when using a small particle diameter solution administered via a spacer. Lung deposition of hydrofluoroalkane beclomethasone dipropionate (QVAR, 1.3 microm particles), delivered via an Aerochamber-MV15, was measured in piglets under conditions mimicking ventilated severely ill neonates (uncuffed 2.5 mm endotracheal tube; peak pressure 16 cm H2O; respiratory rate 40/min). After determining the mass and particle size distribution of the 99mTc-labeled and unlabeled drug, three lung deposition studies were performed: after 1 h of ventilation (controls, n = 18), after 48 h aggressive ventilation inducing an acute lung injury (nine piglets out of the controls), and after increasing the pressure to 24 cm H2O during drug delivery (five piglets out of the nine with acute lung injury). All piglets were then killed for lung histology. Results (median, range), expressed as a percentage of the delivered dose, were compared using an inferential or the Friedman test. While lung deposition was low, it was greater (p = 0.003) in controls (2.66%, 0.50-7.70) than in piglets with histologically confirmed acute lung injury (0.26%, 0.06-1.28) or under a high-pressure ventilation (1.01%, 0.30-2.15). Lung deposition of QVAR in an animal model of ventilated neonates is low, variable, and dramatically affected by lung injury.

New ipratropium formulation to decrease nebulization time.

A new anticholinergic aerosol containing 0.5mg ipratropium bromide dissolved in 1mL of solution has been produced with the purpose of decreasing nebulization time for patients compared to the traditional formulation which is twice as voluminal (0.5mg/2mL, Boehringer-Ingelheim, France). The aim of this study was to compare aerosol characteristics (inhaled mass, particle size distribution and nebulization time) of these two formulations of ipratropium bromide, nebulized alone and with terbutaline (5mg/2mL, Astra Zeneca, Sweden), to determine whether the new formulation was equivalent to the old one. Four different jet nebulizers were used: PariLC+, Atomisor NL9M, Sidestream and Mistyneb. Statistical analysis of the results showed that for all types of nebulizer, the inhaled mass of ipratropium bromide 0.5mg/1mL was significantly lower than the inhaled mass of ipratropium bromide 0.5mg/2mL, and that there was no statistical difference between the inhaled mass of ipratropium bromide 0.5mg/1mL+terbutaline 5mg/2mL and the inhaled mass of ipratropium bromide 0.5mg/2mL+terbutaline 5mg/2mL. The study also showed that the new formulation of ipratropium bromide (0.5mg/1mL) mixed with terbutaline allowed a 26% decrease in nebulization time compared to the old formulation (0.5mg/2mL) mixed with terbutaline without changing aerosol characteristics (inhaled mass and particle size distribution). This leads to the conclusion that a 2mL minimum volume is required for nebulization, and that nebulization of ipratropium bromide 0.5mg/1mL alone must be avoided.

Gemcitabine aerosol: in vitro antitumor activity and deposition imaging for preclinical safety assessment in baboons.

AIM: To characterize gemcitabine aerosol, its in vitro activity against lung cancer cells, its deposition, and tolerance in a non-human primate model. METHODS: In vitro cytotoxicity of nebulized gemcitabine against NCI-H460 and A549 lung cancer cells was tested using a growth inhibition assay and compared with non-nebulized gemcitabine. The (99m)Tc-DTPA-radiolabeled gemcitabine aerosol was characterized by cascade impaction and the gemcitabine mass/(99m)Tc activity relationship was established for further quantitative nuclear imaging. Nine weekly inhalations at a target dose of 1 mg/kg body weight of gemcitabine were performed in three baboons using dynamic scintigraphic acquisitions for continuous monitoring of gemcitabine delivery during inhalation. Gemcitabine plasma concentrations were measured during the first inhalation. RESULTS: Growth inhibition assays for both NCI-H460 and A549 cells did not differ between nebulized and non-nebulized gemcitabine. Aerosol characterization showed a particle mass median aerodynamic diameter of 3.7+/-0.8 microm and a linear relationship between gemcitabine mass (y) and (99m)Tc activity (x) (y=0.82x - 10(-5), R (2)=0.88). No toxicity was observed after nine weekly inhalations of a mean dose of gemcitabine of 11.1 mg (88% of the target dose) as assessed from scintigraphic data. A dose-dependent peak plasma concentration of gemcitabine (20-74 ng/ml) was observed by the tenth minute of inhalation. CONCLUSIONS: We have characterized a gemcitabine aerosol suitable for intrathoracic airway deposition and demonstrated that jet nebulization does not alter the cytotoxic properties of the drug. In a primate model, we have developed a scintigraphic procedure for the monitoring of aerosol deposition, and we have demonstrated the safety of nine weekly aerosol administrations of gemcitabine.