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PubMed1982

Inhaled aerosols: lung deposition and clinical applications.

Although aerosol deposition in the lungs is often considered in the context of industrial hygiene, aerosols also play an important clinical role. Three principal mechanisms (inertial impaction, gravitational sedimentation and Brownian diffusion) account for the majority of aerosol deposition in the lungs. Deposition depends upon the mode of inhalation, the nature of the particles and physical characteristics of the subject inhaling the particles. Radioaerosols are widely employed in measurements of total and regional deposition, and topographical distribution may also be determined. Aerosols play an important role in the treatment of various forms of respiratory disease, with bronchodilators for the therapy of asthma being particularly important. On average only 10% of the therapeutic aerosol dose actually reaches the lungs. The rate of removal of insoluble radioaerosols deposited in the lungs may be used as an index of mucociliary transport. Aerosols are also used in a variety of other diagnostic and research procedures, particularly for ventilation scanning, alveolar clearance, measurement of alveolar permeability, and for measuring the size of pulmonary air space.

Aerosols↗
PubMed1982

Quantitative comparison of 99Tcm-aerosol and 81Krm ventilation images.

Quantitative indices are described for assessing the distribution of ventilation imaging agents (radioaerosols, in particular) within the lung. They have been applied to images obtained with 99Tcm aerosol particles (0.5-2.0 micrometer diameter) and with 81Krm gas in 12 patients with a wide range of lung function. In patients with normal lung function aerosol distribution was similar to that of 81Krm. In patients with airways obstruction, the aerosol tended to penetrate less well than 81Krm to the lung periphery and to show a less homogeneous distribution there. Quantitative analysis confirms that the aerosol technique is an effective substitute for 81Krm in patients with normal lung function. When lung function is impaired aerosol images may still be valuable particularly in confirming a diagnosis of pulmonary embolism though they must be interpreted with caution in attempting to exclude that diagnosis. We conclude that small particle radioactive aerosols provide a readily available ventilation technique for clinical ventilation-perfusion imaging.

Adult↗
PubMed2001

Aerosolized protein delivery in asthma: gamma camera analysis of regional deposition and perfusion.

Bioavailability of an aerosolized anti-inflammatory protein, soluble interleukin-4 receptor (IL-4R), was measured in patients with asthma using two different aerosol delivery systems, a prototype aerosol delivery system (AERx tethered model, Aradigm, Hayward, CA) and PARI LC STAR nebulizer (Pari, Richmond, VA). Regional distribution of the drug in the respiratory tract obtained by planar imaging using gamma camera scintigraphy was utilized to explain the differences in bioavailability. The drug, an experimental protein being developed for asthma, was mixed with radiolabel 99mTechnetium diethylene triaminepentaacetic acid (99mTc-DTPA). Aerosols were characterized in vitro using cascade impaction (mass median aerodynamic diameter [MMAD] and geometric standard deviation [GSD]); the AERx MMAD 2.0 microm (GSD 1.35), the PARI 3.5 microm (GSD 2.5). Four patients with asthma requiring maintenance aerosolized steroids were studied. First, regional volume was determined utilizing equilibrium 133Xe scanning. Then, after a brief period of instruction, patients inhaled four breaths of protein using AERx (0.45 mg in total) followed 1 week later by inhalation via PARI (3.0 mg nebulized until dry). Each deposition image was followed by a measurement of regional perfusion using injected 99mTc albumin macroaggregates. Deposition of 99mTc-DTPA in the subjects was determined by mass balance. Regional analysis was performed using computerized regions of interest. The regional distribution of deposited drug was normalized for regional volume and perfusion. Following each single inhalation, serial blood samples were drawn over a 7-day period to determine area under the curve (AUC) of protein concentration in the blood. Median AUC(AERx)/AUC(PARI) was 7.66/1, based on the amount of drug placed in each device, indicating that AERx was 7.66 times more efficient than PARI. When normalized for total lung deposition (AUC per mg deposited) the ratio decreased to 2.44, indicating that efficiencies of the drug delivery system and deposition were major factors. When normalized for sC/P and (pU/L)xe ratios (central to peripheral and upper to lower ratios are parameters of regional distribution of deposited particles and regional per- fusion ['p']), AUC(AER)x/AUC(PARI) further decreased to 1.35, demonstrating that peripheral sites of deposition with the AERx affected the final blood concentration of the drug. We conclude that inhaled bioavailability of aerosolized protein, as expressed by AUC, is a quantifiable function of lung dose and regional deposition as defined by planar scintigraphy.

Administration, Inhalation↗
PubMed2001

The Sophia Anatomical Infant Nose-Throat (Saint) model: a valuable tool to study aerosol deposition in infants.

Relatively little is known about the variables that influence lung deposition of inhaled aerosols in children. A model of the upper airways of an infant could be a useful tool to study these variables in vitro. The objective of this study was to construct an anatomically correct model of the upper airways of a young child. A routine three-dimensional (3D) CT scan of the skull and neck of a child was selected that included the airway from the nasal cavity down to the subglottic region. The CT scan was edited to obtain an anatomically correct distinction between air and mucosa. Next, a model was constructed with a stereolithographic technique using a UV-sensitive resin. To validate the model, a 3D CT scan of the model was made and compared to the anatomy of the original image. To study aerosol deposition, the model was connected to a breathing simulator. Medical aerosols were delivered to the model by MDI/spacer during stimulated breathing. An upper airway model was made of a 9-month-old child that needed reconstructive surgery for a skull deformity and with normal anatomy of the upper airways. The nasal airway of the model was open for air passage and the oral airway was closed. The CT scan of the model matched the original in vivo CT scan closely. Aerosol deposition measurements showed that dose passing the model, or lung dose, was comparable with in vivo lung deposition data. We have constructed an anatomically correct model of the upper airways of a child, using a stereolithographic method for in vitro studies of aerosol deposition in young children. This model will be used to obtain insight in aerosol treatment that cannot be obtained in vivo.

Aerosols↗
PubMed1997

Optimization of formulations and conditions for the aerosol delivery of functional cationic lipid:DNA complexes.

We have examined several variables inherent in aerosolizing cationic lipid:DNA complexes using a jet nebulizer and thereby have optimized the delivery of functional complexes. Maximal aerosol transfer efficiency of cationic lipid:pDNA complexes was quantitated and shown to require the presence of at least 25 mM NaCL as an excipient. This is possibly related to effects on the measured zeta potentials of the complex, which indicate that the complexes are more highly charged in solutions of physiological ionic strength than in solutions of low ionic strength. Inclusion of saline also resulted in retention of the starting lipid to plasmid DNA (pDNA) ratio following nebulization. These data were used to design in vitro aerosolization experiments with tissue culture cells that resulted in the identification of a cationic lipid:pDNA ratio of 0.75:1 (mol:mol) as being optimal for aerosolization. This formulation largely protected pDNA from shear degradation during nebulization and produced a respirable aerosol droplet size (1-3 microns). It was tested further in a mouse model and shown to result in the dose-dependent transfection of mouse lungs, generating the equivalent of several picograms of reporter gene activity per mouse lung. The results of these experiments have provided a set of optimal conditions for nebulizing cationic lipid:pDNA complexes that can be used as a starting point for the further evaluation of aerosol delivery of these nonviral gene delivery vectors in vivo.

Administration, Intranasal↗
PubMed1991

Measurement of particle size characteristics of metered dose inhaler (MDI) aerosols.

Measurement of the aerodynamic size of an aerosol allows a prediction of its deposition efficiency and behaviour in the lung. The dynamics of volatile or pressurized (MDI) aerosols presents problems not encountered in the characterization of solid or liquid particles alone. For example, the data obtained in real-time sampling as opposed to measuring an aged aerosol provide a truer representation of circumstances during actual clinical use, yet this may be difficult to achieve due to propellent evaporation. A number of particle sizing systems have been developed based upon light scattering techniques and aerodynamic principles. Each method has its limitations; in general, they successfully measure the aerodynamic size distributions of MDI aerosols. Cascade impactors, the "gold standard" of the industry have the advantage that they allow analysis of drug mass as well as other tracers within the aerosol, but the process as a whole is labour intensive, with limited resolution. Highly automated laser-based systems developed over the past 10 years measure the surface characteristics of the aerosol rather than the direct measurement of mass. Because of different values obtained from various sizing systems, it is suggested that all MDI drugs be sized using cascade impactors but that parallel data be obtained using an alternative sizing system.

Administration, Inhalation↗
PubMed1996

In vivo measurements of aerosol dose and distribution: clinical relevance.

Mathematical and in vitro models, that incorporate particle diameter, normal breathing frequencies and tidal volumes, have been used to predict the deposition fraction of respirable aerosols within the lungs. Although very useful in drug development, determinations of dose and the distribution of dose based solely on such models may be less accurate than in vivo measurements, which are performed under conditions that combine the effects of all the factors that determine aerosol deposition, including the effect of disease. Gammascintigraphy provides a method for in vivo quantification of the total deposited fraction and the distribution of the dose within the lower respiratory tract. Using this technology, it has been shown that deposition fraction in the lower respiratory tract may vary between 1-30% of the dose actuated from an MDI or nebulizer. This wide range in deposited dose suggests that variations in the clinical response to inhaled aerosols may be explained by alterations in the dose delivered, especially if the aerosolized medication has a narrow therapeutic range. Alterations in the distribution of inhaled drugs within the lungs may also affect the clinical response, such that some disorders may best be treated by targeting drug to specific locations of the lung, while others may respond best to homogeneous distribution of aerosolized drug. In vivo measurements would provide confirmation of the dose deposited as well as the pattern of distribution, which should improve the therapeutic outcome of most aerosolized medications.

Administration, Inhalation↗
PubMed1999

A mathematical model of aerosol holding chambers.

A mathematical model of aerosol delivery from holding chambers (spacers) was developed incorporating tidal volume (VT), chamber volume (Vch), apparatus dead space (VD), effect of valve insufficiency and other leaks, loss of aerosol by immediate impact on the chamber wall, and fallout of aerosol in the chamber with time. Four different spacers were connected via filters to a mechanical lung model, and aerosol delivery during "breathing" was determined from drug recovery from the filters. The formula correctly predicted the delivery of budesonide aerosol from the AeroChamber (Trudell Medical, London, Ontario, Canada), NebuChamber (Astra, Södirtälje, Sweden) and Nebuhaler (Astra) adapted for babies. The dose of fluticasone proportionate delivered by the Babyhaler (Glaxco Wellcome, Oxbridge, Middlesex, UK) was 80% of that predicted, probably because of incomplete priming of this spacer. Of the above-mentioned factors, initial loss of aerosol by impact on the chamber wall is most important for the efficiency of a spacer. With a VT of 195 mL, the AeroChamber and Babyhaler were emptied in two breaths, the NebuChamber in four breaths, and the Nebuhaler in six breaths. Insufficiencies of the expiratory valves were demonstrated by comparison of pressure flow curves during "inspiratory" flow with and without occluded expiratory openings. Insufficient inspiratory valves were demonstrated by comparison of "expiratory" pressure flow curves with and without occluded inspiratory openings. With children breathing through the spacers, mask pressure variations were generally on the same order as that seen with the mechanical respiratory, supporting the clinical relevance of the in vitro findings.

Aerosols↗
PubMed2005

Gamma scintigraphic evaluation of a miniaturized AERx pulmonary delivery system for aerosol delivery to anesthetized animals using a positive pressure ventilation system.

The purpose of this study was to characterize performance of a miniaturized AERx((R)) Pulmonary Delivery System designed for aerosol administration to large animal models. The miniaturized AERx System was developed through a systematic scaling down of the AERx System used for humans to allow for operation in certain animal models with lower inspiratory flow rates and inhaled volumes than those used for humans. We used gamma scintigraphy to characterize the in vivo particle deposition achieved with the miniaturized AERx System in two dogs. The dogs were 3-4 years old, and weighed 10.4 kg and 13.6 kg. Acepromazine was used as pre-anesthetic medication. Anesthesia was induced with 5% isoflurane. The trachea was intubated using an endotracheal tube (internal diameter 8.5 mm), and the dogs were ventilated using positive pressure during the exposure using the LRRI puff generator. An inhalation of aerosol was initiated by activation of the puff generator though the computer-controlled interface. Each dog inhaled approximately 0.8 L per puff, of which the aerosol volume comprised approximately 0.25 L, at a target flow rate of 15 L/min. The dogs were exposed to 10 AERx Strips in 10 puffs. The mass median aerodynamic diameter of the aerosolized formulation was approximately 1.25 microm with a fine particle fraction <3.5 microm of 0.976. The scintigraphic images showed uniform bilateral lung deposition following aerosol delivery with the AERx System. Total lung deposition for the two dogs was 10.7% and 18% of the loaded dose from the AERx Strip. The corresponding peripheral lung: inner lung (P/I) ratios were 0.83 and 0.75, suggestive of deposition in the deep lung. Only 0.1% to 0.2% of the loaded dose was exhaled. These results show the miniature AERx System can efficiently deliver aerosols to the deep lung of dogs. The miniaturized AERx System would be a valuable tool for conducting proof-of-concept studies as well as safety and tolerability analysis of inhaled drug candidates in large animal models.

Administration, Inhalation↗
PubMed2006

Comparison of SPECT aerosol deposition data with a human respiratory tract model.

Three-dimensional (3D) radionuclide imaging provides detailed information on the distribution of inhaled aerosol material within the body. Analysis of the data can provide estimates of the deposition per airway generation. In this study, two different nebulizers have been used to deliver radiolabeled aerosols of different particle size to 12 human subjects. Medical imaging has been used to assess the deposition in the body. The deposition pattern has also been estimated using the International Commission on Radiological Protection (ICRP) empirical model and compared to values obtained by experiment. The results showed generally good agreement between model and experiment for both aerosols for the deposition in the extrathoracic and conducting airways. However, there were significant differences in the fate of the remainder of the aerosol between the amount deposited in the alveolar region and that exhaled. The inter-subject variability of deposition predicted by the model was significantly less than that measured, for all regions of the body. The model predicted quite well the differences in deposition distribution pattern between the two aerosols. In conclusion, this study has shown that the ICPR model of inhaled aerosol deposition shows areas of good agreement with results from experiment. However, there are also areas of disagreement, which may be explained by hygroscopic particle growth and individual variation in airway anatomy.

Administration, Inhalation↗
PubMed2002

The variability of delivered dose of aerosols with the same respirable concentration but different size distributions.

The influences of aerosol size distribution and breath tidal volume on respirable dose estimates were examined for mouth breathing using the ACGIH/ISO/CEN criterion for respirable-equivalent aerosols. Actual tissue doses predicted from a set of pulmonary empirical deposition equations, the Heyder-Rudolf equations, were compared with deposition assumed to occur under the penetration-based respirable dust sampling criterion. Deposition estimate errors ranged from approximately 1/10- to 10-fold, with aerosol mass median aerodynamic equivalent diameter and geometric standard deviation as well as tidal volume each showing a substantial influence under appropriate conditions. These findings demonstrate that reliance on respirable aerosol sampling data obtained with devices performing on a penetration-based sampling criterion may lead to erroneous dose-response relationships in exposure standard development as well as exposure misclassification errors during epidemiological studies. A more reliable dose estimate would be obtained using devices with collection efficiency performance closely matching the alveolar deposition prediction curves of Heyder and Rudolf. We believe that if it is not currently required, the development of a deposition-based aerosol sampling methodology will soon be required for the determination and quantification of inhaled aerosol-induced adverse health effects.

Aerosols↗
PubMed2002

Investigation of the aerosols produced by a high-speed, hand-held grinder using various substrates.

Mechanical processes such as grinding are classically thought to form micrometer scale aerosols through abrasion and attrition. High-speed grinding has been used as the basis for testing the hypothesis that ultrafine particles do not form a substantial component of mechanically generated aerosols. A wide variety of grinding substrates were selected for evaluation to represent the broad spectrum of materials available. To characterize the particle size distribution over particle sizes ranging from 4.2 nm to 20.5 microm, the aerosol-laden air collected from an enclosed chamber was split and directed to three aerosol instruments operated in parallel. Transmission electron microscope samples of the various grinding substrates were also collected. The results demonstrate that ultrafine particles do have the potential to form a significant component of a grinding aerosol for a number of substrates. It appears that the ultrafine aerosols were formed by the following processes: (i) from within the grinding motor, (ii) from the combustion of amenable grinding substrates and (iii) from volatilization of amenable grinding materials at the grinding wheel/substrate interface.

Aerosols↗
PubMed2006

Mechanims of aerosol particle deposition in the Oro-pharynx under non-steady airflow.

Comparison of experimental and computational results of aerosol deposition in the oro-pharyngeal cast of human published recently (Sosnowski TR, Moskal A, Gradoń L. (2006) Inhal Toxicol; 18: 773-780) demonstrated the applicability and relevance of considering realistic breathing patterns in analysis of aerosol flow and deposition within the human head airways. This issue is extended in the current paper, focused on a detailed analysis of spatial and temporal distribution of particle deposition in the oro-pharynx during inspiration. CFD modeling was used to determine both the 3D airflow structure and the local particle deposition fluxes at two different inspiratory patterns. Behavior of aerosol (particle size: 0.3-10 micro m, material density: 2200 kg m(-3)) was analyzed applying Lagrangian approach and considering Brownian effects for submicron particles. Results indicate that particles of different sizes are deposited in different parts of the oro-pharynx, depending on the point in the inspiration cycle. Larger particles (3-10 micro m) are separated efficiently in the naso-pharyngeal bend due to inertia, which predominate in the middle phase of inspiration. Submicron particles are deposited more uniformly in the oro-pharyngeal space, and their separation from the air is enhanced in a short transition period between inspiration and expiration. It suggests the importance of mixing of inspired and expired air streams for particle deposition pattern. Comparison of our computational results of deposition to the approximation derived from the in vivo data (Stahlhofen W, Rudolf G, James AC. (1989) J Aerosol Med; 2: 285-308) shows a good agreement for particles, for which the inertia is a predominant mechanism of deposition. The results of this work lead to a more detailed description of the dynamics of oro-pharyngeal aerosol deposition during inspiratory part of the breathing cycle. The recognition of that problem is essential for prediction of toxic or pharmacological local effects of inhaled aerosols.

Aerosols↗
PubMedDate not supplied

Immunization against measles by aerosol.

About 20 years ago, Japanese and American investigators found that inhalation of relatively small amounts of aerosolized, partly attenuated measles vaccines was consistently immunogenic in nearly all susceptible children. The resulting modified measles was not transmissible to susceptible children. In 1965-1966, Japanese investigators showed that levels of neutralizing antibody produced by killed measles virus vaccine, which prevented subsequent immunization when live vaccine was given subcutaneously, did not prevent the immunogenic effect of the same vaccine given by aerosol. This raised the possibility that aerosolized vaccine may be immunogenic in infants with residual maternal antibody, in whom subcutaneously injected vaccine is ineffective. In 1971, Soviet investigators reported the high effectiveness and complete lack of febrile and other clinical reactions in 3,306 children who were exposed in large groups in large tents or chambers to aerosols of the more-attenuated measles vaccines that were currently available. An inexpensive nebulizer and the procedure for administration of aerosolized vaccine to individual children are here described. If the good results reported from the USSR can also be obtained with this simple method of vaccination by aerosol, it may be possible to carry out mass vaccinations against measles with thousands of nonprofessional personnel and thereby quickly eliminate measles in countries where it is still a serious public health problem.

Adolescent↗
PubMed1980

Heightened lung bactericidal activity in mice after aerosol immunization with Re 595 Salmonella minnesota: importance of cellular rather than humoral factors.

Intrapulmonary bactericidal activity was enhanced against aerosolized Serratia marcescens, Escherichia coli, Klebsiella pneumoniae, and Staphylococcus aureus two weeks after aerosol immunization with Re 595 Salmonella minnesota. To define better this nonspecific stimulation of antibacterial lung defenses, mice were simultaneously challenged with S. aureus and S. marcescens up to 30 days after aerosol immunization with Re. Enhanced bactericidal activity against both organisms was noted, although activity against Serratia was more pronounced during the first week after immunization. Repetitive aerosol immunization with Re also resulted in enhanced bactericidal activity. Macrophages harvested from mice after aerosol immunization were "activated" by ultrastructural criteria and had enhanced intracellular bactericidal activity against S. aureus. Aerosol immunization also caused an increase in polymorphonuclear leukocytes in lung lavage fluid, which may have been important in activity against Serratia. Mice systemically immunized with Re developed high antibody titers in serum and lung washings but had no stimulation of lung antibacterial activity.

Aerosols↗
PubMed1988

Aerosol administration of antiviral agents to treat lung infection due to murine cytomegalovirus.

Cytomegalovirus (CMV) pneumonia causes significant morbidity and mortality in bone marrow transplant recipients and in patients with AIDS. 9-(1,3-Dihydroxy-2-propoxymethyl) guanine (ganciclovir) and phosphonoformic acid (PFA) demonstrate activity against CMV in human infections, although recurrent CMV and systemic drug toxicity frequently develop. We examined the efficacy of aerosol administration of antiviral agents against murine CMV (MCMV) infection. Animals were inoculated with MCMV intranasally and were treated with oral ganciclovir; with aerosolized ganciclovir, PFA, or ribavirin; or with buffer. MCMV in lung and salivary gland homogenates was quantified by plaque assay. Oral ganciclovir (200 mg/kg per day) reduced titers of MCMV in both tissues by greater than 95%. Aerosolized ganciclovir, 100 and 200 mg/kg per day, reduced lung titers of MCMV by 93% and 97%, respectively. Aerosolized PFA, 20 and 200 mg/kg per day, reduced lung titers of MCMV by 60% and 68%, respectively. Aerosolized ganciclovir and PFA inhibited replication of MCMV in salivary glands substantially less than did oral administration of either agent. Our results suggest that aerosol administration of antiviral agents can potently and selectively inhibit replication of MCMV in the lung.

Acyclovir↗
PubMed1993

Antibiotic treatment of experimental Pseudomonas aeruginosa pneumonia in guinea pigs: comparison of aerosol and systemic administration.

Pseudomonas aeruginosa pneumonia is associated with high mortality despite appropriate systemic antibacterial therapy. To examine the effects of aerosolized tobramycin on experimental P. aeruginosa pneumonia, guinea pigs were assigned to two main groups: a study group, in which P. aeruginosa was instilled into the tracheal lumen, and a control group, in which normal saline was instilled. Each group was then subdivided according to treatment: normal saline or tobramycin by intramuscular injection, normal saline or tobramycin by aerosol, or normal saline or tobramycin via both aerosol and intramuscular injection. Compared with either intramuscular or aerosolized tobramycin, the combination of aerosol plus intramuscular tobramycin achieved slightly higher survival, total eradication of P. aeruginosa from lungs, and a significant further reduction of lung inflammatory changes. Adding aerosolized tobramycin to systemic tobramycin in the treatment of experimental P. aeruginosa pneumonia enhanced eradication of P. aeruginosa and mitigated pulmonary inflammatory changes.

Aerosols↗
PubMed2003

Measuring aerosols generated inside armoured vehicles perforated by depleted uranium ammunition.

In response to questions raised after the Gulf War about the health significance of exposure to depleted uranium (DU), the US Department of Defense initiated a study designed to provide an improved scientific basis for assessment of possible health effects on soldiers in vehicles struck by these munitions. As part of this study, a series of DU penetrators were fired at an Abrams tank and a Bradley fighting vehicle, and the aerosols generated by vehicle perforation were collected and characterised. A robust sampling system was designed to collect aerosols in this difficult environment and monitor continuously the sampler flow rates. The aerosol samplers selected for these tests included filter cassettes, cascade impactors, a five-stage cyclone and a moving filter. Sampler redundancy was an integral part of the sampling system to offset losses from fragment damage. Wipe surveys and deposition trays collected removable deposited particulate matter. Interior aerosols were analysed for uranium concentration and particle size distribution as a function of time. They were also analysed for uranium oxide phases, particle morphology and dissolution in vitro. These data, currently under independent peer review, will provide input for future prospective and retrospective dose and health risk assessments of inhaled or ingested DU aerosols. This paper briefly discusses the target vehicles, firing trajectories, aerosol samplers and instrumentation control systems, and the types of analyses conducted on the samples.

Aerosols↗