Maximization of pulmonary hygroscopic aerosol deposition

A newly developed computer model is used to predict the aqueous salt solution concentration, breathing pattern, and inhaled droplet size distribution parameters that will maximize pulmonary deposition of hygroscopic medicinal aerosols. The parameter values providing maximum pulmonary deposition include 1) a NaCl concentration in the aerosolized solution of 0.035 g/ml or higher if the subject can tolerate it, 2) as nearly a monodispersed inhaled aerosol size distribution as possible, 3) an aerosol mass median diameter of 2-3 micron, and 4) slow (7 breaths/min) uninterrupted breathing of 1.5-2 liters of aerosol/breath. With these values, the model predicts that pulmonary deposition can be increased by greater than 100% relative to the deposition achieved in conventional inhalation therapy with isotonic saline-based medications.     

Effect of body size on breathing pattern and fine-particle deposition in children.

Interchild variability in breathing patterns may contribute to variability in fine particle lung deposition and morbidity in children associated with those particles. Fractional deposition (DF) of fine particles (2-microm monodisperse, carnauba wax particles) was measured in healthy children, age 6-13 yr (n = 36), while they followed a resting breathing pattern previously determined by respiratory inductance plethysmography. Interchild variation in DF, measured by photometry at the mouth, was most strongly predicted by their tidal volume (Vt) (r =0.79, P < 0.001). Multiple regression analysis further showed that, for any given height and age, Vt increased with increasing body mass index (BMI) (P < 0.001). The overweight children (> or =95th percentile BMI) (n = 8) had twice the DF of those in the lowest BMI quartile (<25th percentile) (n = 9; 0.28 +/- 0.13 vs. 0.15 +/- 0.06, respectively; P < 0.02). In the same groups, resting minute ventilation was also significantly higher in the overweight children (8.5 +/- 2.2 vs. 5.9 +/- 1.1 l/min; P < 0.01). Consequently, the rate of deposition (i.e., particles depositing/time) in the overweight children was 2.8 times that of the leanest children (P < 0.02). Among all children, the rate of deposition was significantly correlated with BMI (r = 0.46, P = 0.004). These results suggest that increased weight in children may be associated with increased risk from inhalation of pollutant particles in ambient air.     

Computational analysis of micron-particle deposition in a human triple bifurcation airway model

Steady laminar axisymmetric inhalation flow and wall deposition of micron-size particles in representative triple bifurcation airways have been simulated using a commercial finite-volume code with user-enhanced programs. Assuming spherical non-interacting particles (3 microm相似文献   

The effects of therapist breathing style on subject's inhalation volumes

This study explored how the clinicians'/experimenters' breath patterns affected subjects' inhalation volume. 20 volunteer subjects inhaled 20 sequential breaths (10 normal and 10 paced) with their eyes closed. During the paced exhalation, the experimenter audibly exhaled in phase with the subjects' exhalation. The subjects's inhalation volumes significantly increased during the paced as compared to the initial normal breathing phase, F(1,19)=8.82, p<.01, repeated measures ANOVA. These findings confirm that the clinician's breathing style directly affects the client's breath pattern.     

Effects of ventilation on the collection of exhaled breath in humans.

A computerized system has been developed to monitor tidal volume, respiration rate, mouth pressure, and carbon dioxide during breath collection. This system was used to investigate variability in the production of breath biomarkers over an 8-h period. Hyperventilation occurred when breath was collected from spontaneously breathing study subjects (n = 8). Therefore, breath samples were collected from study subjects whose breathing were paced at a respiration rate of 10 breaths/min and whose tidal volumes were gauged according to body mass. In this "paced breathing" group (n = 16), end-tidal concentrations of isoprene and ethane correlated with end-tidal carbon dioxide levels [Spearman's rank correlation test (r(s)) = 0.64, P = 0.008 and r(s) = 0.50, P = 0.05, respectively]. Ethane also correlated with heart rate (r(s) = 0.52, P < 0.05). There was an inverse correlation between transcutaneous pulse oximetry and exhaled carbon monoxide (r(s) = -0.64, P = 0.008). Significant differences were identified between men (n = 8) and women (n = 8) in the concentrations of carbon monoxide (4 parts per million in men vs. 3 parts per million in women; P = 0.01) and volatile sulfur-containing compounds (134 parts per billion in men vs. 95 parts per billion in women; P = 0.016). There was a peak in ethanol concentration directly after food consumption and a significant decrease in ethanol concentration 2 h later (P = 0.01; n = 16). Sulfur-containing molecules increased linearly throughout the study period (beta = 7.4, P < 0.003). Ventilation patterns strongly influence quantification of volatile analytes in exhaled breath and thus, accordingly, the breathing pattern should be controlled to ensure representative analyses.     

Airway deposition of hygroscopic heterodispersed aerosols: results of a computer calculation

A new computer model is developed and used to calculate the deposition of inhaled heterodispersed hygroscopic aerosols for mouth breathing in a Weibel symmetric bronchial tree. The model was first validated by obtaining good agreement with recent experimental and theoretical data on regional and total airway deposition of monodispersed and heterodispersed nonhygroscopic aerosols. The model was then used to obtain predictions of regional and total deposition of heterodispersed hygroscopic aerosol particles (droplets of NaCl solutions). Parameters that were varied in the hygroscopic calculations include initial droplet NaCl concentration, time of inspiration and expiration, volume of aerosol inspired, period of breath holding, and initial inhaled lognormal aerosol mass median diameter and geometric standard deviation. Results of the computer calculations show that increasing heterodispersity tends to flatten and broaden regional deposition curves when fraction of inhaled mass deposited is plotted vs. inhaled mass median aerodynamic particle diameter. Hygroscopicity is shown to increase tracheobronchial and pulmonary airway deposition with hypertonic NaCl solution aerosols showing increases over isotonic and nonhygroscopic aerosols of up to 200%.     

Effects of bronchodilator particle size in asthmatic patients using monodisperse aerosols.

Aerosol particle size influences airway drug deposition. Current inhaler devices are inefficient, delivering a heterodisperse distribution of drug particle sizes where, at best, 20% reaches the lungs. Monodisperse aerosols are the appropriate research tools to investigate basic aerosol science concepts within the human airways. We hypothesized that engineering such aerosols of albuterol would identify the ideal bronchodilator particle size, thereby optimizing inhaled therapeutic drug delivery. Eighteen stable mildly to moderately asthmatic patients [mean forced expiratory volume in 1 s (FEV1) 74.3% of predicted] participated in a randomized, double-blind, crossover study design. A spinning-top aerosol generator was used to produce monodisperse albuterol aerosols that were 1.5, 3, and 6 microm in size, and also a placebo, which were inhaled at cumulative doses of 10, 20, 40, and 100 microg. Lung function changes and tolerability effects were determined. The larger particles, 6 and 3 microm, were significantly more potent bronchodilators than the 1.5-microm and placebo aerosols for FEV1 and for the forced expiratory flow between exhalation of 25 and 75% of forced vital capacity. A 20-microg dose of the 6- and 3-microm aerosols produced FEV1 bronchodilation comparable to that produced by 200 microg from a metered-dose inhaler. No adverse effects were observed in heart rate and plasma potassium. The data suggest that in mildly to moderately asthmatic patients there is more than one optimal beta2-agonist bronchodilator particle size and that these are larger particles in the higher part of the respirable range. Aerosols delivered in monodisperse form can enable large reductions of the inhaled dose without loss of clinical efficacy.     

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.     

Longitudinal distribution of chlorine absorption in human airways: a comparison to ozone absorption.

The bolus inhalation method was used to measure the fraction of inhaled chlorine (Cl(2)) and ozone (O(3)) absorbed during a single breath as a function of longitudinal position in the respiratory system of 10 healthy nonsmokers during oral and nasal breathing at respired flows of 150, 250, and 1,000 ml/s. At all experimental conditions, <5% of inspired Cl(2) penetrated beyond the upper airways and none reached the respiratory air spaces. On the other hand, larger penetrations of O(3) beyond the upper airways occurred as flow increased and during nasal than during oral breathing. In the extreme case of oral breathing at 1,000 ml/s, 35% of inhaled O(3) penetrated beyond the upper airways and approximately 10% reached the respiratory air spaces. Mass transfer theory indicated that the diffusion resistance of the tissue phase was negligible for Cl(2) but important for O(3). The gas phase resistances were the same for Cl(2) and O(3) and were directly correlated with the volume of the nose and mouth during nasal and oral breathing, respectively.     

Computational Analysis of Micron-particle Deposition in a Human Triple Bifurcation Airway Model

Steady laminar axisymmetric inhalation flow and wall deposition of micron-size particles in representative triple bifurcation airways have been simulated using a commercial finite-volume code with user-enhanced programs. Assuming spherical non-interacting particles (3 μm≤ d p ≤7 μm), various inlet Reynolds numbers (Re=500-2000) and Stokes numbers (St=0.02-0.23) were considered. The resulting particle deposition patterns were analyzed and then summarized in terms of deposition efficiencies, i.e. DE=DE(Re,St) Surprisingly high DE-values occur at relatively low Reynolds numbers (e.g., Re=500 ) in the third bifurcation. The quantitative results are of interest to researchers either conducting health risk assessment studies for inhaled particulate pollutants or analyzing drug aerosol inhalation and deposition at desired lung target sites.     

Chemoreflex control of breathing during wakefulness in healthy men and women.

This study used a modified CO(2) rebreathing procedure to examine the effect of gender on the chemoreflex control of breathing during wakefulness in healthy men (n = 14) and women (n = 14). Women were tested in the follicular phase of the menstrual cycle. During rebreathing trials, subjects hyperventilated to reduce the partial pressure of end-tidal CO(2) (Pet(CO(2))) below 25 Torr and were then switched to a rebreathing bag containing a normocapnic hypoxic or hyperoxic gas mixture. During the trial, Pet(CO(2)) increased, while O(2) was maintained at a constant level. The point at which ventilation began to rise as Pet(CO(2)) increased was identified as the ventilatory recruitment threshold (VRT). Ventilation below the VRT was measured, and the slope of the ventilatory response above the VRT was determined. Gender had no effect on the hyperoxic or hypoxic VRT for CO(2). Central chemoreflex sensitivity was significantly greater in men than women but not after correction for forced vital capacity. Measures of peripheral chemoreflex sensitivity were similar between genders. However, the slope of the tidal volume (Vt) response to hyperoxic and hypoxic CO(2) rebreathing (corrected and uncorrected) was greater in men than women, respectively. We conclude that central chemoreflex sensitivity is greater in men compared with women as reflected by differences in ventilatory (uncorrected) and Vt (corrected and uncorrected) responses to CO(2). However, gender has no significant effect on the central chemoreflex VRT for CO(2). The peripheral chemoreflex control of breathing during wakefulness is similar between men and women.     

Influenza virus in human exhaled breath: an observational study

Background

Recent studies suggest that humans exhale fine particles during tidal breathing but little is known of their composition, particularly during infection.

Methodology/Principal Findings

We conducted a study of influenza infected patients to characterize influenza virus and particle concentrations in their exhaled breath. Patients presenting with influenza-like-illness, confirmed influenza A or B virus by rapid test, and onset within 3 days were recruited at three clinics in Hong Kong, China. We collected exhaled breath from each subject onto Teflon filters and measured exhaled particle concentrations using an optical particle counter. Filters were analyzed for influenza A and B viruses by quantitative polymerase chain reaction (qPCR). Twelve out of thirteen rapid test positive patients provided exhaled breath filter samples (7 subjects infected with influenza B virus and 5 subjects infected with influenza A virus). We detected influenza virus RNA in the exhaled breath of 4 (33%) subjects–three (60%) of the five patients infected with influenza A virus and one (14%) of the seven infected with influenza B virus. Exhaled influenza virus RNA generation rates ranged from <3.2 to 20 influenza virus RNA particles per minute. Over 87% of particles exhaled were under 1 µm in diameter.

Conclusions

These findings regarding influenza virus RNA suggest that influenza virus may be contained in fine particles generated during tidal breathing, and add to the body of literature suggesting that fine particle aerosols may play a role in influenza transmission.     

Influence of nicotine in cigarette smoke on acute ventilatory responses in awake dogs

To determine whether the acute ventilatory responses to inhaled cigarette smoke are affected by a difference in nicotine level, control cigarettes (low-nicotine research cigarettes) were laced with nicotine to generate an increase of 330% (mean) in nicotine content with little or no change in the levels of other smoke constituents. Acute ventilatory responses to both control and nicotine-laced cigarettes were determined and compared in six awake chronic dogs. Spontaneous inhalation of nicotine-laced cigarette smoke (10% concn, 750 ml vol) via a tracheostomy tube caused distinct and consistent changes in breathing pattern on the first or second breath of inhaled smoke: an apnea in three dogs, an augmented inspiration in two dogs, and rapid shallow breathing in one dog. No significant change in breathing pattern was found immediately following inhalation of control cigarette smoke. Both types of cigarettes caused a delayed hyperpnea. However, the increase in minute ventilation induced by nicotine-laced cigarettes (from a base line of 2.8 to a peak of 25.7 l/min) was significantly greater than that by control cigarettes (from 2.9 to 5.5 l/min). Results of this study suggest that nicotine is responsible for the elicitation of both the immediate and delayed ventilatory responses to inhaled cigarette smoke generated under our experimental conditions.     

Partitioning of airway responses to inhaled methacholine in the rat

We measured the changes in upper and lower airway resistance after inhalation of aerosols of methacholine (MCh) in doubling concentrations (16, 32, 64, and 128 mg/ml) in 11 anesthetized nonintubated spontaneously breathing rats. Upper airway resistance (Ru) increased from a control value of 0.48 +/- 0.04 cmH2O X ml-1 X s (mean +/- SE) to 0.85 +/- 0.15 after 128 mg/ml MCh, whereas lower airway resistance (Rlo) increased from 0.11 +/- 0.03 to 0.21 +/- 0.04. However, there was no correlation between the magnitudes of the changes in Ru and Rlo. In a further seven anesthetized spontaneously breathing rats aerosols of MCh were delivered into the lower airways via a tracheostomy and resulted in increases in Rlo from a control value of 0.20 +/- 0.03 to 0.66 +/- 0.12 after 128 mg/ml MCh. Ru also increased to approximately double its control value. We conclude that inhaled MCh causes narrowing of both Ru and Rlo in the anesthetized rat, the changes in Ru and Rlo are not correlated, and changes in Ru can occur when MCh deposition occurs only in the lower airways.     

Determination of regional ventilation and perfusion in the lung using xenon and computed tomography.

We propose a model to measure both regional ventilation (V) and perfusion (Q) in which the regional radiodensity (RD) in the lung during xenon (Xe) washin is a function of regional V (increasing RD) and Q (decreasing RD). We studied five anesthetized, paralyzed, mechanically ventilated, supine sheep. Four 2.5-mm-thick computed tomography (CT) images were simultaneously acquired immediately cephalad to the diaphragm at end inspiration for each breath during 3 min of Xe breathing. Observed changes in RD during Xe washin were used to determine regional V and Q. For 16 mm(3), Q displayed more variance than V: the coefficient of variance of Q (CV(Q)) = 1.58 +/- 0.23, the CV of V (CV(V)) = 0.46 +/- 0.07, and the ratio of CV(Q) to CV(V) = 3.5 +/- 1.1. CV(Q) (1.21 +/- 0.37) and the ratio of CV(Q) to CV(V) (2.4 +/- 1.2) were smaller at 1,000-mm(3) scale, but CV(V) (0.53 +/- 0.09) was not. V/Q distributions also displayed scale dependence: log SD of V and log SD of Q were 0.79 +/- 0.05 and 0.85 +/- 0.10 for 16-mm(3) and 0.69 +/- 0.20 and 0.67 +/- 0.10 for 1,000-mm(3) regions of lung, respectively. V and Q measurements made with CT and Xe also demonstrate vertically oriented and isogravitational heterogeneity, which are described using other methodologies. Sequential images acquired by CT during Xe breathing can be used to determine both regional V and Q noninvasively with high spatial resolution.     

Restraining hamsters alters their breathing pattern

Does the restraint required for head or nose-only exposure of rodents to inhaled aerosols or gases alter their breathing pattern? And does prior exercise training, which may increase muscle strength, affect this response to restraint? To answer those questions, we measured breathing pattern in 11 adult male hamsters while they were either 1) free to move in small cages or 2) closely restrained in head-out cones. The measurements were repeated after hamsters spent 6 wk either sedentary in standard cages or in cages with exercise wheels. Hamsters were placed in a plethysmograph to measure respiratory frequency (f) and tidal volume (VT). Their product is minute volume (V). When restrained, f and V were 1.9 and 1.7 times, respectively, greater than when hamsters were free, but VT did not change. After 6 wk, the sedentary group responded differently to restraint; f increased 3-fold, VT decreased by one-half, and V increased 1.6-fold. Exercised hamsters increased f 2.3-fold and decreased VT by one-third; V increased by 1.5-fold. In inhalation studies, changes in breathing pattern would significantly influence the amount of material inhaled, the fraction retained, and thus the amount and distribution of material deposited in the lungs.     

Flow simulation in the human upper respiratory tract

Computer simulations of airflow patterns within the human upper respiratory tract (URT) are presented. The URT model includes airways of the head (nasal and oral), throat (pharyngeal and laryngeal), and lungs (trachea and main bronchi). The head and throat morphology was based on a cast of a medical school teaching model; tracheobronchial airways were defined mathematically. A body-fitted three-dimensional curvilinear grid system and a multiblock method were employed to graphically represent the surface geometries of the respective airways and to generate the corresponding mesh for computational fluid dynamics simulations. Our results suggest that for a prescribed phase of breath (i.e., inspiration or expiration), convective respiratory airflow patterns are highly dependent on flow rate values. Moreover, velocity profiles were quite different during inhalation and exhalation, both in terms of the sizes, strengths, and locations of localized features such as recirculation zones and air jets. Pressure losses during inhalation were 30-35% higher than for exhalation and were proportional to the square of the flow rate. Because particles are entrained and transported within airstreams, these results may have important applications to the targeted delivery of inhaled drugs.     

Acute effects of acrolein on breathing: role of vagal bronchopulmonary afferents.

Spontaneous inhalation of acrolein vapor (350 ppm, 1 ml/100 g body wt) elicited an immediate and transient inhibitory effect on breathing in anesthetized rats, characterized by a prolongation of expiratory duration and accompanied by a bradycardia; ventilation was reduced by 47 +/- 6%, which returned to baseline after three to seven breaths. When both vagi were cooled to 6.6 +/- 0.1 degrees C, the reflex apneic response to lung inflation was completely abolished but the bradypneic response to acrolein was not affected. After perineural capsaicin treatment of both cervical vagi to selectively block the capsaicin-sensitive C-fiber afferents, acrolein no longer evoked an inhibitory effect on breathing; conversely, an augmented inspiration was consistently elicited with the first breath of acrolein inhalation, which was subsequently abolished by cooling both vagi to 6.5 degrees C. The inhibitory effect of inhaling acrolein at a lower concentration (200 ppm) was not detectable, whereas that of a higher concentration (600 ppm) was more intense and prolonged. All these responses were completely eliminated by bilateral vagotomy. These results suggest that inhaled acrolein activated both vagal C-fiber endings and rapidly adapting irritant receptors in the airways, but the acrolein-induced inhibitory effect on breathing was elicited primarily by the C-fiber afferent stimulation.     

Deposition of micrometer particles in pulmonary airways during inhalation and breath holding

We investigated how breath holding increases the deposition of micrometer particles in pulmonary airways, compared with the deposition during inhalation period. A subject-specific airway model with up to thirteenth generation airways was constructed from multi-slice CT images. Airflow and particle transport were simulated by using GPU computing. Results indicate that breath holding effectively increases the deposition of 5μm particles for third to sixth generation (G3-G6) airways. After 10s of breath holding, the particle deposition fraction increased more than 5 times for 5μm particles. Due to a small terminal velocity, 1μm particles only showed a 50% increase in the most efficient case. On the other hand, 10μm particles showed almost complete deposition due to high inertia and high terminal velocity, leading to an increase of 2 times for G3-G6 airways. An effective breath holding time for 5μm particle deposition in G3-G6 airways was estimated to be 4-6s, for which the deposition amount reached 75% of the final deposition amount after 10s of breath holding.