Airway cross section strongly influences alveolar plateau slope of capnograms for smaller tidal volumes.

We compared the predictions of the single path convection-diffusion model (SPM) and the well-mixed single acinus model (SAM) with the normalized slopes (NS) of experimentally measured volumetric capnograms in which VT was varied in three healthy spontaneously breathing adults. For values of VT greater than 15 ml/kg, the tidal volume penetrates deep into the acinar airways, mixing by molecular diffusion is rapid and the predictions of the SAM and SPM both agree with the experiment. The SPM however shows much better agreement with the experimental NS data than does the SAM for values of VT less than 10 ml/kg. The explanation for the departure of the SAM from the observed experimental data, at small VT, is that it represents the limiting case (of well-mixed alveolar gas) for the SPM, only at large VT, where the assumption of rapid mixing is most accurate. We conclude that in general, gas phase diffusivity and total acinar airway cross sectional area variation with cumulative volume into the lung are essential to realistically model airway gas exchange between VT and FRC and to obtain agreement with experimental data under the widest range of breathing conditions.

A numerical model of nasal odorant transport for the analysis of human olfaction.

The transport and uptake of inspired odorant molecules in the human nasal cavity were determined using an anatomically correct three-dimensional finite element model. The steady-state equations of motion and continuity were first solved to determine laminar flow patterns of odorous air at quiet breathing flow rates. The air stream entering the ventral tip of the naris traveled to the olfactory slit, and then passed through the slit in nearly a straight path without forming separated recirculating zones. The fraction of volumetric flow passing through the olfactory airway was about 10%, and remained nearly constant with variation in flow rate. The three-dimensional inspiratory velocity field was used in the solution of the uncoupled steady convective-diffusion equation to determine the concentration field in the airways and odorant mass flux at the nasal walls. The mass-transfer boundary condition used at the nasal cavity wall included the effects of solubility and diffusivity of odorants in the mucosal lining, and the thickness of the mucus layer. The total olfactory flux of odorants, that is highly correlated with perceived odor intensity, was determined as a function of all transport parameters in our model. Increase in nasal flow rate at a constant inlet concentration resulted in an increase in total olfactory uptake for all odorants. However, with increase in flow rate, the fractional uptake, i.e., total olfactory flux normalized by convective flux at the inlet, decreased for poorly soluble odorants, while it increased for highly soluble odorants. The pattern of flux (or imposed patterning) across the olfactory mucosa, that carries information concerning odor identity, was also determined as a function of transport parameters. There was an overall decrease in odorant flux as the location on the olfactory surface was varied from the anterior towards the posterior and from the inferior towards the superior ends. The flux pattern became more uniform, i.e., the steepness of the flux gradients across the olfactory surface decreased, as the mucus solubility of the odorants decreased. Different odorants generated discernibly different flux patterns across the olfactory mucosa that may contribute to the encoding of odor quality. Variation of total olfactory flux with time after cessation of airflow was determined by solving the unsteady diffusion equation in the air-phase. The flux decreased approximately exponentially with time. The rate of decay decreased as solubility and diffusivity decreased, but was very rapid over a wide range of the parameters, with time constants of less than 0.5 s for most odorants, implying a rapid decrease in perceived odor intensity with cessation of nasal airflow.

Pulmonary delivery of beclomethasone liposome aerosol in volunteers. Tolerance and safety.

STUDY OBJECTIVE: To test the tolerance and safety of single doses of beclomethasone dipropionate (Bec)-dilauroylphosphatidylcholine (DLPC) liposome aerosol in volunteers. DESIGN: Single-dose inhalations of liposome preparations of Bec-DLPC and DLPC alone were administered for 15 min from a jet nebulizer (Puritan-Bennett, modified twin jet; mass median aerodynamic diameter of 1.6 microns) under close clinical and laboratory surveillance. Two dose levels (0.5 mg Bec/12.5 mg DLPC per milliliter, and 1.0 mg Bec and 25 mg DLPC per milliliter in the reservoirs, respectively) were administered. The Bec doses were selected to approximate the dosages of this glucocorticoid used with metered-dose inhalers (MDIs). First, four volunteers were exposed to an initial low dose; the mean (+/-SD) inhaled doses were 0.56 +/- 0.07 mg of Bec and/or 14.0 +/- 1.8 mg of DLPC. Subsequently, a second group of six volunteers was exposed to a higher dose; the mean (+/-SD) inhaled doses were 1.29 +/- 0.14 mg of Bec and/or 34.6 +/- 6.8 mg of DLPC. SETTING: Outpatient and inpatient. PATIENTS: Normal male (n = 6) and female (n = 4) adult volunteers. INTERVENTIONS: Inhalation of Bec-DLPC and DLPC liposome aerosols in a single-dose tolerance study involving 10 normal volunteers. MEASUREMENTS AND RESULTS: Spirometry, clinical observations, clinical chemistry, and hematology were monitored. No adverse clinical or laboratory events were observed. CONCLUSIONS: Bec-DLPC liposome aqueous aerosol was well tolerated in doses equivalent to those currently administered by MDIs and dry powder inhalers for treatment of asthma.

Predicted combustion product deposition in the human airway.

Fires involving modern polymeric materials produce toxic vapours and particles of widely varying composition and size depending on available oxygen and localized temperatures. Adverse health effects of inhaled combustion-generated particles depend on physiological interactions at the airway deposition site. The present work is a theoretical investigation into the importance of airway humidity and temperature profiles, initial particle size, particle size distribution and ionic concentration on airway particle deposition. A modified numerical model accounting for hygroscopic particle growth was used to predict airway deposition of 0.1-10.0 microm mass median aerodynamic diameter (MMAD) particles. Dynamic humidity profiles were generated with an unsteady state model of heat and water vapour transport. Results suggest that for hygroscopic particles < 2.0 microm, MMAD dynamic end-inspiratory humidity profiles produce up to 250% greater predicted nasopharyngeal deposition than steady state humidity profiles. Assuming combustion products are hygroscopic, these results also suggest that less pulmonary deposition will occur than previously predicted. In addition, higher upper airway concentrations of combustion products may have significant health consequences independent of pulmonary deposition patterns.

The importance of a source term in modeling multibreath inert gas washout.

The single path model (SPM) of airway gas transport with a distributed blood source term was used to simulate multiple breath inert lung gas washout of N2, He, and SF6 after total body equilibration with these gases. Normalized phase III inert gas washout slopes were computed for each breath and compared with published experimental data obtained under similar conditions on human subjects. The model predicts a normalized slope asymptote which agrees with experimental results within two standard deviations or less of the mean, depending on the lengths and diameters assumed in the acinar airways of the SPM. In the model and in the human subject data, the asymptote represents the development of a quasi-steady state in which the volume of inert gas exhaled at the mouth is equal to the volume transported into the acinar airways by the pulmonary blood during each breath. The present study indicates that at least in the steady state, airway inhomogeneity is not essential to model lung washout data, and that a distributed blood source term in the SPM yields good agreement with experiment.

Numerical simulation of airflow in the human nasal cavity.

An anatomically correct finite element mesh of the right human nasal cavity was constructed from CAT scans of a healthy adult nose. The steady-state Navier-Stokes and continuity equations were solved numerically to determine the laminar airflow patterns in the nasal cavity at quiet breathing flow rates. In the main nasal passages, the highest inspiratory air speed occurred along the nasal floor (below the inferior turbinate), and a second lower peak occurred in the middle of the airway (between the inferior and middle turbinates and the septum). Nearly 30 percent of the inspired volumetric flow passed below the inferior turbinate and about 10 percent passed through the olfactory airway. Secondary flows were induced by curvature and rapid changes in cross-sectional area of the airways, but the secondary velocities were small in comparison with the axial velocity through most of the main nasal passages. The flow patterns changed very little as total half-nasal flow rate varied between resting breathing rates of 125 m/s and 200 ml/s. During expiration, the peaks in velocity were smaller than inspiration, and the flow was more uniform in the turbinate region. Inspiratory streamline patterns in the model were determined by introducing neutrally buoyant point particles at various locations on the external naris plane, and tracking their path based on the computed flow field. Only the stream from the ventral tip of the naris reached the olfactory airway. The numerically computed velocity field was compared with the experimentally measured velocity field in a large scale (20x) physical model, which was built by scaling up from the same CAT scans. The numerical results showed good agreement with the experimental measurements at different locations in the airways, and confirmed that at resting breathing flow rates, airflow through the nasal cavity is laminar.

Volumetric capnography in children. Influence of growth on the alveolar plateau slope.

BACKGROUND: Lung growth in children is associated with dramatic increases in the number and surface area of alveolated airways. Modelling studies have shown the slope of the alveolar plateau (phase III) is sensitive to the total cross-sectional area of these airways. Therefore, the influence of age and body size on the phase III slope of the volumetric capnogram was investigated. METHODS: Phase III slope (alveolar dcCO2/dv) and airway deadspace (VDaw) were derived from repeated single-breath carbon dioxide expirograms collected on 44 healthy mechanically ventilated children (aged 5 months-18 yr) undergoing minor surgery. Ventilatory support was standardized (VT = 8.5 and 12.5 ml/kg, f = 8-15 breaths/min, inspiratory time = 1 s, end-tidal partial pressure of carbon dioxide = 30-45 mmHg), and measurements were recorded by computerized integration of output from a heated pneumotachometer and mainstream infrared carbon dioxide analyzer inserted between the endotracheal tube and anesthesia circuit. Experimental data were compared to simulated breath data generated from a numeric pediatric lung model. RESULTS: An increased VDaw, a smaller VDaw/VT, and flatter phase III slope were found at the larger tidal volume (P < 0.01). Strong relationships were seen at VT = 12.5 ml/kg between airway deadspace and age (R2 = 0.77), weight (R2 = 0.93), height (R2 = 0.78), and body surface area (R2 = 0.89). The normalized phase III slopes of infants were markedly steeper than that of adolescents and were reduced at both tidal volumes with increasing age, weight, height, and body surface area. Phase III slopes and VDaw generated from modelled carbon dioxide washout simulations closely matched the experimental data collected in children. CONCLUSIONS: Morphometric increases in the alveolated airway cross-section with lung growth is associated with a decrease of the phase III slope. During adolescence, normalized phase III slopes approximate those of healthy adults. The change in slope with lung growth may reflect a decrease in diffusional resistance for carbon dioxide transport within the alveolated airway resulting in diminished acinar carbon dioxide gradients.

Noninvasive recovery of acinar anatomic information from CO2 expirograms.

A numerical single path model of respiratory gas exchange with distributed alveolar gas sources was used to estimate the anatomical changes in small peripheral airways such as occur in chronic obstructive pulmonary diseases (COPD). A previous sensitivity analysis of the single path model showed that decreasing total acinar airway cross-sectional area by an area reduction factor, R, results in computed gas expirograms with Phase III steepening similar to that observed in COPD patients. From experimental steady state CO2 washout data recorded from six healthy subjects and six COPD patients, optimized area reduction factors for the single path model were found that characterize peripheral airway anatomy for each subject. Area reduction factors were then combined with measured functional residual capacity data to calculate the normalized peripheral airspace diameters in a given subject, relative to the airspace diameters in the generations of an idealized standard lung. Mean area reduction factors for the patient subgroup were 63% of those for the healthy subgroup, which is related to the gas transport limitation observed in disease. Mean airspace sizes for the patient subgroup were 235% of the healthy subgroup, which characterizes the increase in size and reduction in number of peripheral airspaces due to tissue erosion in emphysema. From these results, the air-phase diffusive conductance in COPD patients was calculated to be 32% of the mean value in the healthy subjects. These findings correlated well with standard pulmonary function test data for the patients and yield the recovery of acinar airway information from gas washout by combining the single path model with experimental measurements.

A mass transport model of olfaction.

A theoretical model of olfaction involving all the major mechanisms in the mass transport of odorant molecules from inspired air to the olfactory receptors is developed. The mechanisms included are: (i) convective bulk flow of odorant molecules to the olfactory region of the nasal cavity by inhaled air, (ii) lateral transport of odorant molecules from the flowing gas stream in the olfactory region onto the olfactory mucus surface, (iii) sorption of odorant molecules into the mucus at the air-mucus interface, (iv) diffusion of odorant molecules through the mucus layer, and (v) interaction of odorant molecules with the olfactory receptor cells. The model is solved to yield the olfactory response as a function of various physical variables such as the inspiratory flow rate, the mass transfer coefficient, the initial concentration of odorant molecules in the inhaled air, the length of the olfactory mucosa, the thickness of the olfactory mucosa, and the air-mucus partitioning (or solubility in the mucus) of odorant molecules. It was determined that the flow rate of the odorant carrier gas, length of the olfactory mucus surface, and the solubility of odorant molecules in the olfactory mucus should play important roles in determining the odor intensity for these odorants. The model predicts that, given adequate mucus surface for sorption, increase in the flow rate results in an increase in perceived odor intensity for the readily sorbed or highly soluble odorants (such as carvone) and a decrease in odor intensity for the poorly sorbed or insoluble odorants (such as octane). With a substantial decrease in the mucus surface for sorption, increase in the flow rate results in a decrease in perceived odor intensity for all odorants. The theoretical results show good agreement with various experimental data obtained from both psychophysical and electrophysiological studies of olfaction using animals and human subjects.

Velocity profiles measured for airflow through a large-scale model of the human nasal cavity.

An anatomically accurate, x20 enlarged scale model of a healthy right human adult nasal cavity was constructed from computerized axial tomography scans for the study of nasal airflow patterns. Detailed velocity profiles for inspiratory and expiratory flow through the model and turbulence intensity were measured with a hot-film anemometer probe with 1 mm spatial resolution. Steady flow rates equivalent to 1,100, 560, and 180 ml/s through one side of the real human nose were studied. Airflows were determined to be moderately turbulent, but changes in the velocity profiles between the highest and lowest flow rates suggest that for normal breathing laminar flow may be present in much of the nasal cavity. The velocity measurements closest to the model wall were estimated to be inside the laminar sublayer, such that the slopes of the velocity profiles are reasonably good estimates of the velocity gradients at the walls. The overall longitudinal pressure drop inside the nasal cavity for the three inspiratory flow rates was estimated from the average total shear stress measured at the central nasal wall and showed good agreement with literature values measured in human subjects.

Microemboli reduce phase III slopes of CO2 and invert phase III slopes of infused SF6.

We investigated the effect of increasing doses of intravenously infused glass microspheres (mean diameter 125 microns) on gas exchange in anesthetized, heparinized, mechanically ventilated goats (VT = 16-18 ml/kg). Breath-by-breath CO2 expirograms were collected using a computerized system (Study A) during the infusion of a total of 15 g of microspheres. We found a 50% decrease in extravascular lung water by indicator dilution with a corresponding doubling of alveolar dead space (VDalv). Airways deadspace (VDaw) decreased by 13 ml (10%) and mean normalized phase III slope for CO2 decreased from 0.23 to -0.08 L-1 becoming negative in 3 of 5 animals. In a second study (Study B), simultaneous breath-by-breath CO2 and infused SF6 expirograms were collected using an infrared CO2 analyzer and a mass spectrometer. Under baseline conditions VDaw for CO2 was smaller than for SF6 and the ratio of the phase III slope for SF6 to the phase III slope for CO2 was 1.39. Following embolization there were no differences in VDaw between the two gases, however, the phase III slope for CO2 became either slightly negative or extremely flat, while the phase III slope for SF6 became negative in 73% of the breaths (-0.17 L-1, P < 0.05). Negative phase III slopes have been predicted by a single path model when blood flow is confined to the most mouthward generations of the acinus (Schwardt et al., Ann. Biomed. Engin, 19: 679-697, 1991). The agreement between the numerical model and the experimental data is consistent with a serial distribution of blood flow within the acinus.

Modelling steady state pulmonary elimination of He, SF6 and CO2: effect of morphometry.

We studied the influence of acinar morphometry on the shape of simulated expirograms computed from a single path convection-diffusion model that includes a source term for gas evolution from the blood (Scherer et al., J. Appl. Physiol. 64: 1022-1029, 1988). Acinar structure was obtained from published data of 3 different lung morphometries. The simulations were performed over a range of tidal volumes (VT) and breathing frequencies (f) comparable to those observed in a previously reported human study. Airways dead space (VDaw) increased with VT in all the morphometric models tested and in the experimental data. The increase in VDaw with VT was inversely related to the diffusivity of the evolving gas and to the rate of increase in airway cross-section of the most mouthward (proximal) alveolated generations of the models. Normalized phase III slope for all the gases decreased with increasing VT in all the models as was previously reported for healthy human subjects. In the model simulations, the greatest sensitivity of phase III slope to VT was seen with the least diffusible gas using the airway morphometry with the smallest cross-sectional areas in the proximal alveolated generations. We conclude that both VDaw and phase III slope of an evolving gas are sensitive to the geometry of the proximal acinar airways and that this is manifest by their dependence on tidal volume, breathing frequency, molecular diffusivity and alveolar/blood source emission rate. The model simulations indicate that heterogeneity of gas washout is not required to explain the magnitude of the phase III slope in healthy human subjects.

Diffusivity, respiratory rate and tidal volume influence inert gas expirograms.

We modified, and developed software for, a computer-controlled quadrupole mass spectrometer to measure complete breath-by-breath expirograms of helium (He) and sulfur hexafluoride (SF6) exhaled during the infusion of saline saturated with the inert gases. He and SF6 have similar blood solubilities but very different gas phase diffusivities allowing examination of the influence of gas phase diffusivity on steady state inert gas expirograms. We studied six normal human volunteers in nine separate studies and examined the influence of tidal volume (VT) and breathing frequency (f) on the airways dead space (VDaw) and alveolar plateau slope (phase III) for the inert gases and CO2. The experimental data showed a reduction in VDaw with rapid shallow breathing, while phase III slope increased by a factor of two to three. We critically evaluated the data and methodology of these and previously reported studies of continuous and single breath washout of He and SF6. In general the 15 to 20 ml differences in VDaw between He and SF6 were in keeping with previous studies by others. The ratio of phase III slopes of SF6 to He reported by us previously (Scherer et al., J. Appl. Physiol. 64: 1022-1029, 1988) was 3.13. In the current study, which includes the analysis of more than 400 He and SF6 breaths, the ratio of SF6 to He slope was 1.85. The difference between the two studies was largely related to the improved methodology of the current study, particularly for the measurement of He. The results support the conclusion that diffusivity is an important component of both phase II and phase III of the expirogram. However, the difference in phase III between He and SF6 is somewhat less than previously reported.

Sensitivity of CO2 washout to changes in acinar structure in a single-path model of lung airways.

A numerical solution of the convection-diffusion equation with an alveolar source term in a single-path model (SPM) of the lung airways simulates steady state CO2 washout. The SPM is used to examine the effects of independent changes in physiologic and acinar structure parameters on the slope and height of Phase III of the single-breath CO2 washout curve. The parameters investigated include tidal volume, breathing frequency, total cardiac output, pulmonary arterial CO2 tension, functional residual capacity, pulmonary bloodflow distribution, alveolar volume, total acinar airway cross sectional area, and gas-phase molecular diffusivity. Reduced tidal volume causes significant steepening of Phase III, which agrees well with experimental data. Simulations with a fixed frequency and tidal volume show that changes in blood-flow distribution, model airway cross section, and gas diffusivity strongly affect the slope of Phase III while changes in cardiac output and in pulmonary arterial CO2 tension strongly affect the height of Phase III. The paper also discusses differing explanations for the slope of Phase III, including sequential emptying, stratified inhomogeneity, and the issue of asymmetry, in the context of the SPM.

A model of cigarette smoke particle deposition.

A computer model of aerosol deposition has been extended to cover particle sizes representative of cigarette mainstream and sidestream smoke particles. The model is the first to theoretically predict total airway depositions of mainstream particles in a range which agrees with experimentally determined literature values by including effects of hygroscopicity and normal smoking breathing patterns. The hygroscopic characteristics of cigarette smoke particles are modeled as if they were saturated sodium chloride droplets. A discussion is included showing that this assumption is consistent with presently available data on the hygroscopic characteristics of cigarette smoke. Detailed regional depositions are provided. Though most of the particles are shown to deposit in the periphery, the surface concentrations of deposited particles are not necessarily much greater there than in centrally located airways. A peak in surface concentration at the third generation is exhibited, despite low total depositions there. Central airway surface concentrations are shown to be relatively independent of breathing pattern and airway geometry, implying that the effects of cigarette smoke particle deposition cannot be greatly reduced by changing the pattern of smoke inhalation. For sidestream smoke particles, total percent depositions agree with literature values of 7%-20% for both nonhygroscopic and hygroscopic particles. Deposition is seen to be favored in the periphery of the lung, though surface concentrations of the deposited material can be greater in Weibel Generations 3-6. Peak surface concentrations are again seen to occur in Generation 3. The increased toxicity of sidestream smoke particles may make them as unhealthy as mainstream smoke particles, despite the higher depositions observed for mainstream smoke.

Studies of wall shear and mass transfer in a large scale model of neonatal high-frequency jet ventilation.

The problem of endotracheal erosion associated with neonatal high-frequency jet ventilation (HFJV) is investigated through measurement of air velocity profiles in a scaled up model of the system. Fluid mechanical scaling principles are applied in order to construct a model within which velocity profiles are measured by hot-wire anemometry. The effects of two different jet geometries are investigated. Velocity gradients measured near the tracheal wall are used to measure the shear stresses caused by the jet flow on the wall. The Chilton-Colburn analogy between the transport of momentum and mass is applied to investigate tracheal drying caused by the high shear flow. Shear forces are seen to be more than two times higher for jets located near the endotracheal tube wall than for those located axisymmetrically in the center of the tube. Since water vapor fluxes are dependent on these shears, they are also higher for the asymmetric case. Fluxes are shown to be greatly dependent on the temperature and relative humidity of the inspired gas. Water from the tracheal surface may be depleted within one second if inspired gases are inadequately heated and humidified. It is recommended that the design of neonatal HFJV devices include delivery of heated (near body temperature), humidified (as close to 100% humidity as possible) gases through an axisymmetric jet to best avoid the problem of endotracheal erosion.

The biophysics of nasal airflow.

The biophysics of nasal airflow involve the measurement, analysis, and understanding of bulk airflow or momentum transport through the nasal cavity and of the exchange of mass and heat laterally between the air stream and the walls. In both of these areas, optimal progress depends on judicious, combined, and continuous use of physical models, mathematical calculations, and measurements made on human subjects. The progress that has been made to date is both fascinating and encouraging and suggests that great improvement in understanding, diagnosis, and treatment of nasal and upper airway disease will be possible in the future through closer contact and cooperation between clinicians and physical and biological scientists.