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PubMed1996

Optimal particle size for beta 2 agonist and anticholinergic aerosols in patients with severe airflow obstruction.

BACKGROUND: The optimal particle size of a beta 2 agonist or anticholinergic aerosol in patients with severe airflow obstruction is unknown. METHODS: Seven stable patients with a mean forced expiratory volume in one second (FEV1) of 37.9% of the predicted value inhaled three types of monodisperse salbutamol and ipratropium bromide aerosols with particle sizes of 1.5 microns, 2.8 microns, and 5 microns, respectively, and a placebo aerosol. The volunteers inhaled 20 micrograms salbutamol and 8 micrograms ipratropium bromide, after which lung function changes were determined and analysed with repeated measurements analysis of variance (ANOVA). RESULTS: Greater improvements in FEV1, specific airway conductance (sGaw) and maximum expiratory flow at 75%/50% of the forced vital capacity (MEF75/50) were induced by the 2.8 microns aerosol than by the other particle sizes. CONCLUSIONS: In patients with severe airflow obstruction the particle size of choice for a beta 2 agonist or anticholinergic aerosol should be approximately 3 microns.

Adrenergic beta-Agonists↗
PubMed1999

Aerosolized GM-CSF ameliorates pulmonary alveolar proteinosis in GM-CSF-deficient mice.

Surfactant proteins and phospholipids accumulate in the alveolar spaces and lung tissues of mice deficient in granulocyte-macrophage colony-stimulating factor (GM-CSF), with pathological findings resembling the histology seen in the human disease pulmonary alveolar proteinosis (PAP). Previous metabolic studies in GM-CSF-deficient [GM(-/-)] mice indicated that defects in surfactant clearance cause the surfactant accumulation in PAP. In the present study, GM(-/-) mice were treated daily or weekly with recombinant mouse GM-CSF by aerosol inhalation or intraperitoneal injection for 4-5 wk. Lung histology, alveolar macrophage differentiation, and surfactant protein B immunostaining returned toward normal levels in the GM-CSF aerosol-treated mice. Alveolar and lung tissue saturated phosphatidylcholine and surfactant protein B concentrations were significantly decreased after treatment with aerosolized GM-CSF. Cessation of aerosolized GM-CSF for 5 wk resulted in increased saturated phosphatidylcholine pool sizes that returned to pretreatment levels. In contrast, PAP did not improve in GM(-/-) mice treated daily for 5 wk with larger doses of systemic GM-CSF. Aerosolized GM-CSF improved PAP in the GM(-/-) mice, demonstrating that surfactant homeostasis can be influenced by local administration of GM-CSF to the respiratory tract.

Administration, Inhalation↗
PubMed1983

Anesthesia alters the pattern of aerosol retention in hamsters.

General anesthesia was used to produce nonventilated areas of the lung, and aerosol inhalation was used to locate these areas, assuming that no aerosol deposits in a nonventilated region. Male Syrian golden hamsters were anesthetized with pentobarbital sodium (90 mg/kg), which reduced respiratory frequency, tidal volume, minute volume, and O2 consumption to 61, 41, 24, and 36%, respectively, of the corresponding awake levels. Awake and anesthetized hamsters were exposed to the aerosol for 30 min; then the lungs were excised, dried at total lung capacity, sliced into sections, and dissected into pieces. Autoradiographs were made of slices, and the activity and weight of pieces were determined. The evenness index (EI), a measure of the uniformity of retention, was calculated for each piece. With complete uniformity of retention, all EI's would be 1.0. In awake animals, only 0.2% (by wt) of the lungs had little or no retention (EI's less than 0.20). More particles deposited in the apex than in the base of the lungs. General anesthesia for extended periods of time with no deep breaths alters ventilation and therefore the distribution of aerosol retention. Many regions of the lungs in the anesthetized animals received few or no particles (11.6% of lungs had EI less than 0.20); however, no consistent pattern was observed in the location of these areas from animal to animal. The apex-to-base gradient for retention in these animals was also reversed. Radioactive aerosols can be used as probes to indicate the extent and distribution of nonventilated areas in the lungs.

Aerosols↗
PubMed1983

Deposition of aerosol particles and flow resistance in mathematical and experimental airway models.

Aerosol deposition and flow resistance in obstructed airways were determined from five mathematical and experimental airway models. The first three models were theoretical and based upon Weibel's symmetrical lung model with 1) uniform reduction of airway diameter in various groups of airway generations; 2) obstruction of a few major airways such that a severe uneven flow distribution occurs in the lung; 3) focal constriction of selected large airways. In model 3, an empirical formula was utilized to assess deposition and resistance in the constricted airways. The remaining two models were tested experimentally; 4) oscillation of a compliant wall in a straight tube and 5) two-phase gas-liquid flow utilizing human sputum in a rigid branching tube. In models 1, 2, and 3, airway resistance increased to a greater extent than did the increase of aerosol deposition except when small airways were obstructed in model 1. Here, the increase of aerosol deposition was slightly higher than the rise in airway resistance. A sharp increase of aerosol deposition with a minimal increase of flow resistance was demonstrated in models 4 and 5. These data indicate that aerosol deposition may be a more sensitive indicator of airway abnormalities than overall airway resistance in small airways obstruction, during oscillation of large and medium airway walls, and when excessive secretions within the airways move with a wave or slug motion.

Aerosols↗
PubMed1984

Effect of aerosol histamine on lung lymph in awake sheep.

This study examined the effect of aerosol histamine on lung lymph in the awake sheep. Eleven sheep were chronically instrumented for measurement of lung lymph, lung mechanics, and vascular pressures. Aerosol histamine was given by use of a Collison nebulizer and delivered via a tracheostomy tube. Five breaths of a 30 mg/ml histamine solution caused lung lymph flow (QL) to increase from a base line of 5.5 +/- 0.5 (SE) ml/h to 14.3 +/- 1.5 (P less than 0.05) and the lymph-to-plasma protein concentration ratio (L/P) to increase from 0.63 +/- 0.02 to 0.72 +/- 0.02 (P less than 0.05). The concentration of aerosol histamine required to change QL by 30% (ED130QL) was determined by giving increasing concentrations of aerosol histamine every 15 min. The mean ED130QL was 22.2 mg/ml. The dose of histamine required to increase QL by 30% did not correlate (r = 0.04, n = 7) with the dose required to decrease dynamic compliance by 35%. The increase in QL lasted 100 +/- 19 min. Hourly exposure to five breaths of 30 mg/ml for 5 h caused a sustained increase in QL in two sheep and a waning effect in two sheep. The combination of aerosol histamine and elevated microvascular pressure (achieved by inflating a Foley catheter situated in the left atrium) caused changes in QL and L/P not totally consistent with the hypothesis that histamine increased pulmonary vascular permeability. Increased vascular permeability in the bronchial circulation was considered a likely explanation of the data.

Aerosols↗
PubMed1985

Use of aerosols to measure in vivo volume-dependent changes in lung air space dimensions.

Using measurements of aerosol recovery following a 5-s breath hold [NRC(5)] as indices of lung air space dimensions, we evaluated the in vivo changes in these dimensions associated with changes in lung volume (VL). In anesthetized dogs, single breaths of a 1.2-micron monodisperse aerosol were introduced into the respirator's cycle at a number of isovolume points on the inflation and deflation limb of the pressure-volume curve for the dog's lungs. At isovolume, NRC(5) measured off the inflation limb was slightly larger than NRC(5) measured off the deflation limb, implying a larger mean air space dimension for the air space configuration on the inflation vs. the deflation limb. Since a constant aerosol tidal volume (VT) was used for all VL in all dogs, the proportion of the lung filled with aerosol, VT/VL = Pn (where Pn is defined as an index of aerosol penetration into the lung periphery), varied along with VL. In all dogs, we found that, for NRC(5) measurements with Pn less than 0.33, NRC(5) steadily increased with increasing VL, which implies an increasing mean air space dimension as VL increases. However, when we account for the effect that changes in Pn with increasing VL have on NRC(5), we conclude that the observed increase in NRC(5) with VL is primarily due to decreases in Pn and not increases in the mean air space dimension as VL increases.(ABSTRACT TRUNCATED AT 250 WORDS)

Aerosols↗
PubMed1991

Aerosolized surfactant treatment of preterm lambs.

To evaluate the potential for aerosolized surfactant treatments of surfactant deficiency, twin lamb fetuses were delivered at 130-132 days gestational age and received nebulized natural surfactant (Neb NS), nebulized Survanta (Neb Surv), tracheally instilled natural surfactant (Inst NS), or nebulized saline (Neb Saline). Neb NS and Neb Surv groups had significant increases in ventilatory efficiency index and dynamic compliance values (P less than 0.05). Both groups also had pressure-volume curves that were comparable to the Inst NS group. The Neb Saline control group had deterioration of the ventilation efficiency index and dynamic compliance values over time as well as pressure-volume curves that demonstrated smaller lung volumes compared with all three surfactant-treated groups (P less than 0.01). Delivery of aerosolized surfactant to the lung was only approximately 2 mg lipid/kg for the nebulized groups, a dose one-twentieth of that previously noted to be effective in instillation protocols. Distribution histograms of the aerosolized surfactant-treated groups differed from the instilled animals as there was more deposition in the right upper lobes and tracheae in the nebulized groups compared with the instilled group (P less than 0.05). Pulmonary blood flow was not altered by aerosolized surfactant treatment. Administration of aerosolized surfactant to preterm lambs improved lung function at a very low surfactant dose.

Aerosols↗
PubMed1996

Regional deposition of inhaled hygroscopic aerosols: in vivo SPECT compared with mathematical modeling.

The regional deposition patterns of inhaled hygroscopic aerosols obtained in vivo in the studies of Phipps et al. (P. R. Phipps, I. Gonda, D. L. Bailey, P. Borham, G. Bautovich, and S. D. Anderson. Am. Rev. Respir. Dis. 139: 1516, 1989; and P. R. Phipps, I. Gonda, S. D. Anderson, D. L. Bailey, and G. Bautovich. Eur. Respir. J. 7: 1474-1482, 1994) and Chan et al. (H.-K. Chan, P. R. Phipps, I. Gonda, P. Cook, R. Fulton, I. Young, and G. Bautovich. Eur. Respir. J. 7: 1483-1489, 1994) by using single-photon-emission computerized tomography (SPECT) are compared with the regional deposition predicted by the hygroscopic lung deposition model of Finlay and Stapleton (W. H. Finlay and K. W. Stapleton. J. Aerosol Sci. 26: 655-670, 1995). Three pairs of saline aerosols are considered: isotonic with small [2.6-microns mass median aerodynamic diameter (MMAD), geometric standard deviation (GSD) 1.4] vs. large (5.5-microns MMAD, GSD 1.7) droplets; hypotonic (0.3% NaCl) vs. hypertonic (4.5% NaCl) with 3.7- to 3.8-microns MMAD (GSD 1.4), and hypotonic vs. hypertonic (3.7- to 3.8-microns MMAD, GSD 1.5-1.8) with reduced number of droplets per cubic centimeter. For each of the three pairs of aerosols, no significant difference (P > 0.05) was found between the in vivo and computational results for either the mean value or the variance of the difference in peripheral to central deposition. Thus it appears that theoretical calculations can be used to predict the pattern of lung deposition of hygroscopic aerosols in populations of normal subjects.

Administration, Inhalation↗
PubMed1998

Controlled dissolution from wax-coated aerosol particles in canine lungs.

Treatment of pulmonary and systemic diseases may be improved and toxicity reduced by pulmonary deposition of drug-containing aerosols exhibiting delayed dissolution. Aqueous disodium fluorescein and pentamidine aerosols were dried, concentrated, and condensation coated with paraffin wax. The apparent mass median aerodynamic diameters of the coated fluorescein particles were 2.8-4.0 microns. Wax-to-fluorescein ratios were 0.38-1.05. The dissolution half times determined using a single-pass flow system were 1.5 min for uncoated fluorescein and 0.8 min for uncoated pentamidine. These increased over threefold when the aerosols were coated with paraffin wax to maxima of 5.3 and 2.6 min, respectively. Wax-coated aerosols generated from fluorescein mixed with 99mTc-labeled iron oxide colloid delivered to the canine lungs demonstrated a 3.4-fold increase in the absorption half time of disodium fluorescein compared with uncoated fluorescein (11.2 vs. 38.4 min). The absence of changes in pulmonary function on inhalation of these wax-coated aerosols, together with a high drug load and delayed release, establishes a foundation for future therapeutic applications.

Adsorption↗
PubMed1999

A source of experimental underestimation of aerosol bolus deposition.

We examined the measurement error in inhaled and exhaled aerosol concentration resulting from the bolus delivery system when small volumes of monodisperse aerosols are inspired to different lung depths. A laser photometer that illuminated approximately 75% of the breathing path cross section recorded low inhaled bolus half-widths (42 ml) and negative deposition values for shallow bolus inhalation when the inhalation path of a 60-ml aerosol was straight and unobstructed. We attributed these results to incomplete mixing of the inhaled aerosol bolus over the breathing path cross section, on the basis of simultaneous recordings of the photometer with a particle-counter sampling from either the center or the edge of the breathing path. Inserting a 90 degrees bend into the inhaled bolus path increased the photometer measurement of inhaled bolus half-width to 57 ml and yielded positive deposition values. Dispersion, which is predominantly affected by exhaled bolus half-width, was not significantly altered by the 90 degrees bend. We conclude that aerosol bolus-delivery systems should ensure adequate mixing of the inhaled bolus to avoid error in measurement of bolus deposition.

Administration, Inhalation↗
PubMed1981

[Efficacy of theophylline aerosols in obstructive lung diseases (author's transl)].

We investigated aethophylline and aminophylline aerosols using a jet or an ultrasonic nebulizer in 51 patients suffering from NSLD with reversible bronchospasm. FEV1 was controlled in fixed intervals, and the patients were questioned about their subjective statements. A bronchospasmolytic test with isoprenaline spray at the end was performed to demonstrate the actual reversibility of the bronchospasm. Only theophylline aerosols produced by a ultrasonic nebulizer had a subjective and a functional efficacy. Theophylline aerosols of a 2.5% solution were proved to be better than aerosols of a 5% solution, but in comparison with the used sympathicomimetic drug isoprenaline spray, they were less effective. There was a good correlation with the subjective statements of the patients concerning the clinical effects. The concentration of the therapeutic aerosol seemed to be an important factor for the local tolerance and the ventilatory effects, measurable serum levels of theophylline could not be found. Therefore, the topical action of theophylline is considered to be responsible for the clinical effect.

Adult↗
PubMed1984

Mode of inhalation for trained and untrained asthmatics using a pressurized aerosol.

A pressurized inhalation aerosol should be actuated at the beginning of a slow and deep inhalation, followed by a long pause of breathholding. In this study a registration was performed on the mode of inhalation. The flow-volume curve and the moment of actuation were obtained from an aerosol actuator provided with sensors, and the breathholding pause was measured. Data were obtained from 34 asthmatic patients, regularly trained to use the pressurized aerosol, and these data were compared with those from 44 untrained patients. When the subjects used a terbutaline sulfate aerosol in their usual fashion, most of the trained subjects succeeded well. Further improvements could possibly be made regarding the depth of inhalation and, after control with the recording device, regarding the flow rate at actuation. Most of the untrained subjects did not use a deep enough inhalation with respect to their vital capacity, and their breath-holding pause was very short. It only seems possible to improve these parameters by regular training. In order to reach optimal results the asthmatic patients must be regularly controlled and instructed regarding their use of a pressurized inhalation aerosol. A recording device is useful in demonstrating to each subject which parameter can be improved.

Adolescent↗
PubMed1985

Pulmonary deposition of aerosols by different mechanical devices.

With a new method for easy labeling of beta 2-agonists we measured intra- and extrapulmonary aerosol deposition after the administration of a bolus from a metered-dose inhaler at residual volume (RV) inhaling after a pause of 2 s and after immediate administration into the inspiratory flow at functional residual capacity (FRC). Immediate administration during a slow inspiratory vital capacity maneuver gives the highest intrapulmonary deposition (30-40%). Compressed air and ultrasonic nebulizers with a particle distribution pattern of 2-5 micron aerodynamic mass median diameter (AMMD) allow in normal subjects to achieve an intrapulmonary deposition of 30-60% during standardized tidal breathing at rest, the magnitude of the deposition depending mainly on each subject's larynx geometry. The outlet system leads to different deposition patterns in aerosol generators with the same AMMD. Many commercially available aerosol generators do not fulfill the criteria for any intrapulmonary aerosol deposition. For drug administration into the lungs, condensation aerosol generators ('steam boiler nebulizers') are useless as well as compressed-air, ultrasonic and steam driven nebulizers with a particle size of more than 10 micron AMMD.

Adrenergic beta-Agonists↗
PubMed1980

Suppression of anaphylactic reactions in guinea pigs by previous treatment with ragweed aerosol.

Guinea pigs subjected to intranasal dusting with ragweed (RW) pollen or intranasal instillation of RW extract (RWE) showed anaphylactic reactions when subjected to RW extract aerosol (RWE). These animals, however, did not respond to an aerosol of RW whole pollen. Animals which received the RWEA treatment prior to nasal dusting with RW pollen showed no subsequent anaphylactic reactions when exposed to RWEA. Both the aerosol-sensitive and the aerosol-nonresponsive animals exhibited high titers of homocytotropic antibodies to RWE. In addition, the aerosol-nonresponsive animals also had precipitating antibodies of IgG type. The state of nonresponsiveness did not appear to be due to the precipitating antibodies, since this condition could not be passively transferred by sera and blocking antibody activity was not demonstrable.

Administration, Intranasal↗
PubMed1985

Relation between components of the immune response in rats sensitized by aerosol and subcutaneous injections.

Relations between the appearance of various components of the immune response were analyzed in two groups of rats sensitized by aerosol and subcutaneous injections in the neck region, respectively. The relations were expressed by Spearman rank correlation coefficient and studied by cluster analysis. In the aerosol-sensitized animals, there was a close association between IgA and IgG antibody levels in bronchial fluid and these in turn were related to IgG levels in serum and more loosely to IgE levels in bronchial fluid. There was an apparent association between IgE antibody formation and mast cell maturation in cultures of regional lymph node cells and the appearance of mucous cells in the lungs. These variables seemed associated with spontaneous cell proliferation in vitro and the numbers of mast cells in the lungs. This indicates that local stimulation with antigen induces local immune responses and immune-mediated migration of cells. In subcutaneously sensitized animals, formation of IgG antibodies in vitro seemed related to the stimulated proliferation of regional lymph node cells. The levels of IgG and IgE antibodies in bronchial fluid and in serum also appeared to be related. Unlike the findings in aerosol-sensitized animals there was no apparent relation between the differentiation of mast cells and mucous cells. This was possibly due to lack of immune-mediated antigen-induced cell migration. The different immune response patterns in aerosol and subcutaneously sensitized rats should be considered when studies are designed aiming to explore the pathogenesis of allergic inflammatory diseases. The findings also indicate that the various parameters of immunity are more closely related in aerosol than in subcutaneously immunized animals.

Aerosols↗
PubMed1987

Lung nonresponsiveness produced in guinea pigs by aerosolized antigen. I. Nonresponsiveness is not antigen specific.

Nonresponsiveness to aerosolized antigen induced by repeated exposure of guinea pigs to either bovine serum albumin (BSA) or ragweed (RW) aerosols was not antigen specific, since induction of lung sensitization with the same, as well as heterologous antigen, was prevented. However, prior lung sensitization to an antigen was maintained in spite of subsequent treatment with aerosolized antigen. In this case treatment with aerosolized antigen could abrogate sensitization of the lung to all subsequent antigens. Chopped lung pieces could not be passively sensitized by antisera to homologous or heterologous antigens unless they were previously treated at low pH. High levels of conventional and homocytotropic antibody were demonstrated in nonresponder animals. Nonresponsiveness induced by fed antigen, however, was antigen specific, and elevated homocytotropic antibody levels were not present. Aerosol-induced nonresponsiveness appears to be a local phenomenon which involves a blocking of the pulmonary mast cells by immune complexes or other blocking factors so that they can no longer respond to antigen challenge.

Aerosols↗
PubMed1988

Involvement of PAF-acether in anaphylactic bronchoconstriction induced in guinea pigs by aerosolized antigen.

Bronchoconstriction following the aerosolization of PAF-acether or antigen to guinea pigs induces autodesensitization, but the responses to direct spasmogenic substances are not modified. Bronchoconstriction by PAF-acether is not reduced when it is aerosolized to passively sensitized animals previously desensitized by repeated inhalations of the allergen (ovalbumin). In contrast, when passively sensitized animals are initially desensitized to PAF-acether by repeated inhalations of this agonist, ovalbumin aerosolization induces a bronchoconstriction which is significantly reduced when compared with the response obtained in nondesensitized animals though, in this case, the response to aerosolized histamine is not modified. Thus, PAF-acether is released during intrapulmonary anaphylactic shock induced by aerosolized ovalbumin and can be a prime candidate for its development.

Aerosols↗
PubMed1996

Aerosolized cyclosporine in lung recipients with refractory chronic rejection.

This study evaluated aerosolized cyclosporine as rescue therapy for lung transplant recipients with unremitting chronic rejection. Nine patients with histologic active obliterative bronchiolitis and progressively worsening airway obstruction refractory to conventional immune suppression received aerosolized cyclosporine. Improvement in rejection histology was seen in seven of nine patients. We compared the changes in the FVC and FEV1 over time using linear regression analysis in these seven histologic responders and nine historical control patients. During the pretreatment period for both the experimental and control groups, the FVC and FEV1 declined at comparable rates. After aerosolized cyclosporine there was stabilization of pulmonary function, whereas in the controls there was continued decline. Cyclosporine blood levels were less than 50 ng/ml 24 h after an aerosolized dose of 300 mg in five patients receiving oral tacrolimus. Nephrotoxicity, hepatotoxicity, and a greater than expected rate of infection was not observed. This study suggests that aerosolized cyclosporine is safe and may be effective therapy for refractory chronic rejection in lung transplant recipients.

Adult↗