Regional deposition of inhaled particles in human lungs: comparison between men and women

We measured detailed regional depositionpatterns of inhaled particles in healthy adult male(n = 11; 25 ± 4 yr of age) and female (n = 11; 25 ± 3 yr of age)subjects by means of a serial bolus aerosol delivery technique formonodisperse fine [particle diameter(D_p) = 1 µm] and coarse aerosols(D_p = 3 and 5 µm). The bolus aerosol (40 ml half-width) was delivered to a specificvolumetric depth (Vp) of the lung ranging from 100 to 500 ml with a50-ml increment, and local deposition fraction (LDF) was assessed for each of the 10 local volumetric regions. In all subjects, the deposition distribution pattern was very uneven with respect to Vp,showing characteristic unimodal curves with respect to particle sizeand flow rate. However, the unevenness was more pronounced in women.LDF tended to be greater in all regions of the lung in women than inmen for D_p = 1 µm. For D_p = 3 and 5 µm, LDF showed a marked enhancement in the shallow region of Vp  200 ml in women compared with men(P < 0.05). LDF in women wascomparable to or smaller than those of men in deep lung regions of Vp > 200 ml. Total lung deposition was comparable between men and womenfor fine particles but was consistently greater in women than men forcoarse particles regardless of flow rates used: the difference rangedfrom 9 to 31% and was greater with higher flow rates(P < 0.05). The results indicatethat 1) particledeposition characteristics differ between healthy men and women undercontrolled breathing conditions and2) deposition in women is greaterthan that in men.

     

Total deposition of ultrafine sodium chloride particles in human lungs

The total deposition of monodisperse, 0.026-0.19 micron (dry volume equivalent diameter) sodium chloride particles in the lungs of five healthy subjects, who breathed orally, was measured. For a tidal volume of 1,000 ml and flow rate of 500 ml/s, the percentages deposited were: 37.2 +/- 8.4% (mean +/- SD) for 0.026 micron, 23.8 +/- 3.3% for 0.051 micron, 22.8 +/- 3.1% for 0.096 micron, and 31.8 +/- 6.2% for 0.19 micron particles. The deposition minimum corresponded to a particle size of approximately 0.08 micron. Deposition did not correlate with measures of lung volume or body size but did correlate with forced expired flow rate after 75% of forced vital capacity (FVC) exhaled (FEF 75%/FVC) and with percent-predicted values for FEF 25-75% and FEF 75%. Lengthening the breathing period from 4 to 8 s/breath while maintaining flow rate at 500 ml/s caused an additional 11.3 +/- 3.1% of the inhaled particles to deposit. Sedimentation and diffusion were found to be the principal deposition mechanisms. These hygroscopic particles deposited according to sizes they would attain in air with a relative humidity between 96 and 100%.     

Respiratory deposition model of an inhaled aerosol bolus

The bolus delivery method is designed to deliver a dose to the desired location in the lung, and it has the advantage of fewer side effects and a more efficient way of delivery. Based upon the lung deposition model developed for continuously inhaling aerosols of constant concentration, a mathematical model of aerosol bolus deposition is proposed. The calculated results show that the recovery depends on the bolus penetration depth, flow rate, particle size, breath holding time and bolus volume. Three sets of published experimental data with different controlling factors (particle size, flow rate and breath holding time) are adopted to make the quantitative comparisons with the calculated results. The predictions and data for the low intrinsic motion particles (～1 μm) have good agreement, as do the coarse particles in the shallow airways region. For females, the recovery was found to be consistently lower than that for males.     

Respiratory deposition model of an inhaled aerosol bolus

The bolus delivery method is designed to deliver a dose to the desired location in the lung, and it has the advantage of fewer side effects and a more efficient way of delivery. Based upon the lung deposition model developed for continuously inhaling aerosols of constant concentration, a mathematical model of aerosol bolus deposition is proposed. The calculated results show that the recovery depends on the bolus penetration depth, flow rate, particle size, breath holding time and bolus volume. Three sets of published experimental data with different controlling factors (particle size, flow rate and breath holding time) are adopted to make the quantitative comparisons with the calculated results. The predictions and data for the low intrinsic motion particles (～1 μm) have good agreement, as do the coarse particles in the shallow airways region. For females, the recovery was found to be consistently lower than that for males.     

A model of regional deposition of aerions in the human lungs

The numerical solution of the equation of airions mass transfer in the human lung is obtained considering diffusional deposition. More than 90% of airions inhaled during breathing are deposited. The deposition occurs in the first 10-12 generations of the lung tree, and therefore the airions do not reach the alveolar region.     

Aerosol particle deposition in human lungs

The pneumoconiosis developing after inhalation of air-borne dusts in the work place depends on the relation between the value of particle deposition in the respiratory tract and the rate of particle clearance from sites of their deposition. For testing the deposition in humans an aerosol of paraffin oil was given to a cohort of healthy persons. The characteristic parameters of the aerosol had been defined. The concentration of particles in 5 channels were measured in both the inhaled and exhaled air samples using the particle counter ROYCO 225. The deposition fraction was calculated from the relation of particle amount in expired air to the amount in inhaled air in each distribution class. In this preliminary report the results comparable with the prediction mathematical curve are discussed.     

Human variation in the peripheral air-space deposition of inhaled particles

Intersubject variability in both peripheral air-space dimensions and breathing pattern [tidal volume (VT) and respiratory frequency (f)] may play a role in determining intersubject variation in the fractional deposition of inhaled particles that primarily deposit in the lung periphery (i.e., distal to conducting airways). In healthy subjects breathing spontaneously at rest, we measured the deposition fraction (DF) of a 2.6-microns monodisperse aerosol by Tyndallometry while simultaneous measurement of VT and f were made. Under these conditions particle deposition occurs primarily in the peripheral air spaces of the lung. As an index of peripheral air-space size, we used measurements of aerosol recovery (RC) as a function of breath-hold time (t) (Gebhart et al. J. Appl. Physiol. 51: 465-476, 1981). In each subject, we measured RC (aerosol expired/aerosol inspired) of a 1.0-micron monodisperse aerosol as a function of breath-hold time for inspiratory capacity breaths of aerosol. The half time (t1/2) (the breath-hold time to reach 50% RC with no breath hold) is proportional to a mean diameter (D) of air spaces filled with aerosol. In the 10 subjects studied, we found a variable DF, range 0.04-0.44 [0.25 +/- 0.12 (SD)]. DF correlated most closely with 1/f, or the period of breathing (r = 0.96, P less than 0.01). There was no significant correlation between DF and t1/2 as an index of peripheral air-space size. In fact there was little deviation in t1/2 in these normal subjects [coefficient of variation (CV) = 0.12].(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of exercise on deposition and subsequent retention of inhaled particles

To investigate the effect of exercise and its associated increase in ventilation on the deposition and subsequent retention of inhaled particles, we measured the fractional and regional lung deposition of a radioactively tagged (99mTc) monodisperse aerosol (2.6 microns mass median aerodynamic diam) in normal human subjects at rest and while exercising on a bicycle ergometer. Breath-by-breath deposition fraction (DF) was measured throughout the aerosol exposures by Tyndallometry. Following each exposure gamma camera analysis was used to 1) determine the regional distribution of deposited particles and 2) monitor lung retention for 2.5 h and again at 24 h. We found that DF was unchanged between ventilation at rest (6-10 l/min) and exercise (32-46 l/min). Even though mouth deposition was enhanced with exercise, it was not large enough to produce a significant difference in the deposition fraction of the lung (DFL) between resting and exercise exposures. The central-to-peripheral distribution of deposited aerosol was larger for the exercise vs. resting exposure, reflecting a shift of particle deposition to more central bronchial airways. Apical-to-basal distribution was not different for the two exposures. Retention at 2.5 h and 24 h (R24) was reduced following the exercise vs. the resting exposure, consistent with greater bronchial deposition during exercise. The product of DFL and R24 gave a measure of fractional burden at 24 h (B24), i.e., the fraction of inhaled aerosol residing in the lungs 24 h after exposure. B24 was not significantly different between rest and exercise exposures.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of exercise on redistribution and clearance of inhaled particles from hamster lungs

Does exercise alter the redistribution and clearance of particles from the lungs? Sedentary hamsters and hamsters that were exercise trained by voluntary wheel running for the previous 5 wk were exposed to a 198Au-labeled aerosol for 25 min. Six trained and 6 sedentary animals were killed within 5 min after the exposure (day 0); the same number were killed 5 days later. The trained hamsters ran ad libitum during those 5 days. The lungs of all animals were excised, dried at total lung capacity, sliced into 1-mm-thick sections, and dissected into pieces that were counted for radioactivity and weighed. On day 0, trained hamsters had 80% more particles per milligram of lung than sedentary hamsters, although both were exposed under identical conditions of restraint. After five days, exercising hamsters cleared 38% of the particles present at day 0, whereas sedentary animals removed only 15%. Significant clearance was observed from the middle lung regions of sedentary hamsters and from all lung regions in exercising hamsters. We conclude that exercise can enhance the redistribution and clearance of particles from the lungs; the mechanisms responsible are as yet unclear.     

Recent advances in pulmonary drug delivery using large, porous inhaled particles

The abilityto deliver proteins and peptides to the systemic circulation byinhalation has contributed to a rise in the number of inhalationtherapies under investigation. For most of these therapies, aerosolsare designed to comprise small spherical droplets or particles of massdensity near 1 g/cm³ and meangeometric diameter between ~1 and 3 µm, suitable for particlepenetration into the airways or lung periphery. Studies performedprimarily with liquid aerosols have shown that these characteristics ofinhaled aerosols lead to optimal therapeutic effect, both for local andsystemic therapeutic delivery. Inefficient drug delivery can stillarise, owing to excessive particle aggregation in an inhaler,deposition in the mouth and throat, and overly rapid particle removalfrom the lungs by mucocilliary or phagocytic clearance mechanisms. Toaddress these problems, particle surface chemistry and surfaceroughness are traditionally manipulated. Recent data indicate thatmajor improvements in aerosol particle performance may also be achievedby lowering particle mass density and increasing particle size, sincelarge, porous particles display less tendency to agglomerate than(conventional) small and nonporous particles. Also, large, porousparticles inhaled into the lungs can potentially release therapeuticsubstances for long periods of time by escaping phagocytic clearancefrom the lung periphery, thus enabling therapeutic action for periodsranging from hours to many days.

     

Determining deposition sites of inhaled lung particles and their effect on clearance

An essential component of lung defense is clearance of particulates and infectious vectors from the mucus membrane of the tracheobronchial tree and the alveolar regions of the lung. To partition clearance between these areas we determined the bronchial branching pattern, the anatomical sites of particle deposition, and subsequent clearance in the same animal. Using a 2.85-microns particle tagged with 57Co for inhalation and deposition in the sheep lung, we followed clearance via a series of computer-stored gamma-scintillation lung images. The same sheep was reinhaled, and the particle distributions for both inhalations were compared. After the animals were killed, the bronchial branching pattern and length of the bronchial tree were documented. The number of particles depositing in all bronchi down to 1 mm diam was determined by scintillation counting, and the number in respiratory bronchioles and alveoli was microscopically counted. We conclude that particles deposited in bronchi greater than or equal to 1 mm diam clear in 2-4 h postdeposition. Bronchi distal to 1-mm-diam bronchi and alveoli clear evenly over 72 h, and the number of particles equal to the tracheobronchial deposition cleared after 45 h.     

Assessment of regional non-linear tissue deformation and air volume change of human lungs via image registration

We evaluate the non-linear characteristics of the human lung via image registration-derived local variables based on volumetric multi-detector-row computed tomographic (MDCT) lung image data of six normal human subjects acquired at three inflation levels: 20% of vital capacity (VC), 60% VC and 80% VC. Local variables include Jacobian (ratio of volume change) and maximum shear strain for assessment of lung deformation, and air volume change for assessment of air distribution. First, the variables linearly interpolated between 20% and 80% VC images to reflect deformation from 20% to 60% VC are compared with those of direct registration of 20% and 60% VC images. The result shows that the linearly-interpolated variables agree only qualitatively with those of registration (P<0.05). Then, a quadratic (or linear) interpolation is introduced to link local variables to global air volumes of three images (or 20% and 80% VC images). A sinusoidal breathing waveform is assumed for assessing the time rate of change of these variables. The results show significant differences between two-image and three-image results (P<0.05). The three-image results for the whole lung indicate that the peak of the maximum shear rate occurs at about 37% of the maximum volume difference between 20% and 80% VC, while the peaks for the Jacobian and flow rate occur at 50%. This is in agreement with accepted physiology whereby lung tissues deform more at lower lung volumes due to lower elasticity and greater compliance. Furthermore, the three-image results show that the upper and middle lobes, even in the recumbent, supine posture, reach full expansion earlier than the lower lobes.     

Assessment of papain-induced lung injury in isolated lungs by measurements of aerosol deposition and mixing.

Aerosol bolus inspirations were used to assess lung injury in 15 isolated dog lungs exposed to low (0-375 units) or high doses (600-1,200 units) of papain. Effective air space size (EAD) was determined from aerosol deposition during a 5-s breath hold. Convective mixing was assessed by the spreading of the expired bolus with respect to expired volume, quantified by a coefficient of dispersion (CD) equal to the square root of the difference in the variances of the expired and inspired boluses divided by the volumetric penetration of the bolus. After exposure, CD measured with deeply penetrating boluses increased by an average of 2.5% in the low-exposure group (P greater than 0.05) and 28.0% in the high-exposure group (P less than 0.0001). CD measured with shallowly penetrating boluses decreased by 4.3% (P less than 0.0001) in the low-exposure group and increased by an average of 18.3% in the high-exposure group (P less than 0.05). Papain exposure caused EAD to increase in some lungs and decrease in others. For deep bolus penetrations, EAD changed by an average of -0.8% in the low-exposure group (P greater than 0.05) and +21.1% in the high-exposure group (P greater than 0.05). Both EAD and CD appeared to be sensitive to lung injury. However, changes in EAD were less consistent than those in CD, possibly due to changes caused by lung injury in the regional distribution of inspired aerosol.     

Bronchial airway deposition and retention of particles in inhaled boluses: effect of anatomic dead space

The fractionaldeposition of particles in boluses delivered to shallow lung depths andtheir subsequent retention in the airways may depend on the relativevolume and size of an individual's airways. To evaluate the effect ofvariable anatomic dead space (ADS) on aerosol bolus delivery we hadhealthy subjects inhale radiolabeled, monodisperse aerosol(^99mTc-iron oxide, 3.5 µm meanmondispersed aerosol diameter) boluses (40 ml) to a volumetric frontdepth of 70 ml into the lung at a lung volume of 70% total lungcapacity end inhalation. By using filter techniques, aerosolphotometry, and gamma camera analysis, we estimated the fraction of theinhaled boluses deposited in intrathoracic airways (IDF). ADS bysingle-breath N₂ washout was alsomeasured from 70% total lung capacity. Results showed that among allsubjects IDF was variable (range = 0.04-0.43, coefficient ofvariation = 0.54) and increased with decreasing ADS(r = 0.76, P = 0.001, n = 16). We found significantlygreater deposition in the left (L) vs. right (R) lungs; mean L/R (ratioof deposition in L lung to R lung, normalized to ratio of L-to-R lungvolume) was 1.58 ± 0.42 (SD; P < 0.001 for comparison with 1.0). Retention of deposited particles at 2 hwas independent of ADS or IDF. There was significant retention ofparticles at 24 h postdeposition (0.27 ± 0.05) andslow clearance of these particles continued through 48 hpostdeposition. Finally, analysis of central-to-peripheral ratios ofinitial deposition and 24-h-retention gamma-camera images suggestsignificant retention of insoluble particles in large bronchial airwaysat 24 h postdeposition (i.e., 24 h central-to-peripheral ratio = 1.40 ± 0.44 and 1.82 ± 0.54 in the R and L lung, respectively; P < 0.02 for comparison with 1.0).These data may prove useful for 1)designing aerosol delivery techniques to target bronchial airways and2) understanding airway retention ofinhaled particles.

     

Regional deposition and retention of particles in shallow, inhaled boluses: effect of lung volume

The regionaldeposition of particles in boluses delivered to shallow lung depths andtheir subsequent retention in the airways may depend on the lung volumeat which the boluses are delivered. To evaluate the effectof end-inspiratory lung volume on aerosol bolus delivery, we hadhealthy subjects inhale radiolabeled, monodisperse aerosol(^99mTc-iron oxide, 3.5-µm massmedian aerodynamic diameter) boluses (40 ml) to a volumetric frontdepth of 70 ml into the lung at lung volumes of 50, 70, and 85% oftotal lung capacity (TLC) end inhalation. By gamma camera analysis, wefound significantly greater deposition in the left (L) vs. right (R)lungs at the 70 and 85% TLC end inhalation; ratio of deposition in Lto R lung, normalized to L-to-R ratio of lung volume (mean L/R), was1.60 ± 0.45 (SD) and 1.96 ± 0.72, respectively(P < 0.001 for comparison to 1.0) for posterior images. However, at 50% TLC, L/R was 1.23 ± 0.37, not significantly different from 1.0. These data suggest that the L andR lungs may be expanding nonuniformly at higher lung volumes. On theother hand, subsequent retention of deposited particles at 2 and 24 hpostdeposition was independent of L/R at the various lung volumes. Thusasymmetric bolus ventilation for these very shallow boluses does notlead to significant increases in peripheral alveolar deposition. Thesedata may prove useful for 1)designing aerosol delivery techniques to target bronchial airways and2) understanding airway retention ofinhaled particles.

     

Assessment of human regional cerebral circulation by venocclusive rheoplethysmoencephalography]

A possibility was shown of using the method of venocclusion rheoplethysmoencephalography (RPEG) for the assessment of the extent of changes in the cerebral circulation (CC) in individual regions of the cerebral hemispheres of a practically healthy man in various functional loads. The changes in the CC was recorded in per cent in respect to its initial background value. Data on the increase (by 114%) of the CC in the centralparietal region of the left cerebral hemisphere in movement with the right hand and on its reduction (by 45%) in sound stimulation. In the adjacent (temporal) region the changes in the CC were of other character.     

Aerosol bolus dispersion and convective mixing in human and dog lungs and physical models.

The dispersion of aerosol boluses in the lung is a probe for convective mixing and has been proposed as a marker for abnormal lung function. To better understand the factors underlying this phenomenon, aerosol dispersion was compared in human subjects, dogs, and various physical models. In all systems, dispersion increased with the volumetric penetration of the aerosol bolus. The rate of this increase was 83% greater in humans compared with dogs. Dispersion in dogs was close to that in a packed bed with beads of 2.5 mm. Aerosol dispersion decreased with increasing flow rate in human subjects. An artificial larynx inserted into the straight tube caused a 33% increase in dispersion. In humans, aerosol dispersion was significantly correlated with forced expired flow between 25 and 75% of vital capacity. A 2-s pause between inspiration and expiration increased dispersion 23-58% in three isolated dog lungs but did not affect dispersion in the packed bed. The data suggest that lung geometry, flow rate, particle mobility, and the larynx all significantly affect aerosol dispersion by influencing the reversibility of aerosol transport between inspiration and expiration.