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 99mTc-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&lt;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&lt;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&lt;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.<br/

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

© 2014 Fleming et al.; licensee BioMed Central Ltd. 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.Air Liquid

Métrologie des aérosols dans des conditions physiologiques pour la prédiction de leur dépôt dans les voies respiratoires

L'interprétation des résultats de granulométrie des aérosols obtenus par impaction en cascade peut différer selon la méthode employée. Une méthode de traitement des données de granulométrie a été mise au point pour tenir compte de l'imperfection de l'efficacité de collection des impacteurs. Pour étudier l'effet de la température et de l'humidité, nous avons développé une méthode de mesure par impaction en cascade à 37C-100%HR. Nous avons ensuite réalisé des prédictions de dépôt avec ce modèle. Une étude clinique de Phase I sur la gemcitabine administrée par voie aérosol étant en cours au moment de l'accomplissement de ces travaux, nous avons pu comparer les prédictions aux images de dépôt des patients. Les deux logiciels de simulation de dépôt utilisés ont surestimé la quantité d'aérosol exhalée, alors que l'ERS a prédit un meilleur dépôt. Une prédiction de la masse inhalable a également été réalisée in vitro et a donné des résultats proches de ceux obtenus in vivo.The interpretation of aerosols particle size results obtained by cascade impaction can differ according to the method used. A method for processing cascade impactor data has been developed to take into account imperfect collection efficiency of impactors. In order to study the effect of temperature and relative humidity, we have developed a method for cascade impactor measurements at 37C-100%RH. We then have made deposition predictions with this model. A Phase I clinical study for inhaled gemcitabine administration being in process at the time of this work, we were able to compare the predictions to patients deposition images. The two softwares used to simulate deposition overestimated exhaled aerosol, whereas the ERS predicted better deposition. Inhaled mass was also predicted in vitro, and gave results closed to those obtained in vivo.TOURS-BU Médecine (372612103) / SudocSudocFranceF

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&lt;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.<br/

Controlled, parametric, individualized, 2-D and 3-D imaging measurements of aerosol deposition in the respiratory tract of healthy human subjects: preliminary comparisons with simulations

Preliminary comparisons of simulation results from existing extrathoracic (ET) models and a lung deposition model with individualized, two-dimensional and three-dimensional (3D) imaging measurements of aerosol deposition in the respiratory tract of healthy human subjects have been presented. In general, the ET models did not correspond well with each individual's experimental data. However, there is rather good agreement between simulated and experimental results for regional lung deposition comparable to those previously found in the literature. Comparisons of generational distributions are relatively poor. These preliminary results suggest not only the need for further developments in deposition modeling, but also the need for better methods for analyzing experimentally determined 3D deposition distributions for comparison to simulated results

Aerosolized Chemotherapy

International audienceRegional 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.</p

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?&lt;?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.<br/