Dose variability of supplemental oxygen therapy with open patient interfaces based on in vitro measurements using a physiologically realistic upper airway model.

BACKGROUND: Supplemental oxygen therapy is widely used in hospitals and in the home for chronic care. However, there are several fundamental problems with the application of this therapy such that patients are often exposed to arterial oxygen concentrations outside of the intended target range. This paper reports volume-averaged tracheal oxygen concentration measurements (FtO2) from in vitro experiments conducted using a physiologically realistic upper airway model. The goal is to provide data to inform a detailed discussion of the delivered oxygen dose. METHODS: A baseline FtO2 dataset using a standard, straight adult nasal cannula was established by varying tidal volume (Vt), breathing frequency (f), and continuous oxygen flow rate (QO2) between the following levels to create a factorial design: Vt = 500, 640, or 800 ml; f = 12, 17, or 22 min- 1; QO2 = 2, 4, or 6 l/min. Further experiments were performed to investigate the influence on FtO2 of variation in inspiratory/expiratory ratio, inclusion of an inspiratory or expiratory pause, patient interface selection (e.g. nasal cannula versus a facemask), and rapid breathing patterns in comparison with the baseline measurements. RESULTS: Oxygen concentration measured at the trachea varied by as much as 60% (i.e. from 30.2 to 48.0% of absolute oxygen concentration) for the same oxygen supply flow rate due to variation in simulated breathing pattern. Among the baseline cases, the chief reasons for variation were 1) the influence of variation in tidal volume leading to variable FiO2 and 2) variation in breathing frequency affecting volume of supplemental oxygen delivered through the breath. CONCLUSION: For oxygen administration using open patient interfaces there was variability in the concentration and quantity of oxygen delivered to the trachea over the large range of scenarios studied. Of primary importance in evaluating the oxygen dose is knowledge of the breathing parameters that determine the average inhalation flow rate relative to the oxygen flow rate. Otherwise, the oxygen dose cannot be determined.

Phase-contrast helium-3 MRI of aerosol deposition in human airways.

One of the key challenges in the study of health-related aerosols is predicting and monitoring sites of particle deposition in the respiratory tract. The potential health risks of ambient exposure to environmental or workplace aerosols and the beneficial effects of medical aerosols are strongly influenced by the site of aerosol deposition along the respiratory tract. Nuclear medicine is the only current modality that combines quantification and regional localization of aerosol deposition, and this technique remains limited by its spatial and temporal resolutions and by patient exposure to radiation. Recent work in MRI has shed light on techniques to quantify micro-sized magnetic particles in living bodies by the measurement of associated static magnetic field variations. With regard to lung MRI, hyperpolarized helium-3 may be used as a tracer gas to compensate for the lack of MR signal in the airways, so as to allow assessment of pulmonary function and morphology. The extrathoracic region of the human respiratory system plays a critical role in determining aerosol deposition patterns, as it acts as a filter upstream from the lungs. In the present work, aerosol deposition in a mouth-throat phantom was measured using helium-3 MRI and compared with single-photon emission computed tomography. By providing high sensitivity with high spatial and temporal resolutions, phase-contrast helium-3 MRI offers new insights for the study of particle transport and deposition.

Determination of regional lung air volume distribution at mid-tidal breathing from computed tomography: a retrospective study of normal variability and reproducibility.

BACKGROUND: Determination of regional lung air volume has several clinical applications. This study investigates the use of mid-tidal breathing CT scans to provide regional lung volume data. METHODS: Low resolution CT scans of the thorax were obtained during tidal breathing in 11 healthy control male subjects, each on two separate occasions. A 3D map of air volume was derived, and total lung volume calculated. The regional distribution of air volume from centre to periphery of the lung was analysed using a radial transform and also using one dimensional profiles in three orthogonal directions. RESULTS: The total air volumes for the right and left lungs were 1035 +/- 280 ml and 864 +/- 315 ml, respectively (mean and SD). The corresponding fractional air volume concentrations (FAVC) were 0.680 +/- 0.044 and 0.658 +/- 0.062. All differences between the right and left lung were highly significant (p < 0.0001). The coefficients of variation of repeated measurement of right and left lung air volumes and FAVC were 6.5% and 6.9% and 2.5% and 3.6%, respectively. FAVC correlated significantly with lung space volume (r = 0.78) (p < 0.005). FAVC increased from the centre towards the periphery of the lung. Central to peripheral ratios were significantly higher for the right (0.100 +/- 0.007 SD) than the left (0.089 +/- 0.013 SD) (p < 0.0001). CONCLUSION: A technique for measuring the distribution of air volume in the lung at mid-tidal breathing is described. Mean values and reproducibility are described for healthy male control subjects. Fractional air volume concentration is shown to increase with lung size.

Bench and mathematical modeling of the effects of breathing a helium/oxygen mixture on expiratory time constants in the presence of heterogeneous airway obstructions.

BACKGROUND: Expiratory time constants are used to quantify emptying of the lung as a whole, and emptying of individual lung compartments. Breathing low-density helium/oxygen mixtures may modify regional time constants so as to redistribute ventilation, potentially reducing gas trapping and hyperinflation for patients with obstructive lung disease. In the present work, bench and mathematical models of the lung were used to study the influence of heterogeneous patterns of obstruction on compartmental and whole-lung time constants. METHODS: A two-compartment mechanical test lung was used with the resistance in one compartment held constant, and a series of increasing resistances placed in the opposite compartment. Measurements were made over a range of lung compliances during ventilation with air or with a 78/22% mixture of helium/oxygen. The resistance imposed by the breathing circuit was assessed for both gases. Experimental results were compared with predictions of a mathematical model applied to the test lung and breathing circuit. In addition, compartmental and whole-lung time constants were compared with those reported by the ventilator. RESULTS: Time constants were greater for larger minute ventilation, and were reduced by substituting helium/oxygen in place of air. Notably, where time constants were long due to high lung compliance (i.e. low elasticity), helium/oxygen improved expiratory flow even for a low level of resistance representative of healthy, adult airways. In such circumstances, the resistance imposed by the external breathing circuit was significant. Mathematical predictions were in agreement with experimental results. Time constants reported by the ventilator were well-correlated with those determined for the whole-lung and for the low-resistance compartment, but poorly correlated with time constants determined for the high-resistance compartment. CONCLUSIONS: It was concluded that breathing a low-density gas mixture, such as helium/oxygen, can improve expiratory flow from an obstructed lung compartment, but that such improvements will not necessarily affect time constants measured by the ventilator. Further research is required to determine if alternative measurements made at the ventilator level are predictive of regional changes in ventilation. It is anticipated that such efforts will be aided by continued development of mathematical models to include pertinent physiological and pathophysiological phenomena that are difficult to reproduce in mechanical test systems.

Bench experiments comparing simulated inspiratory effort when breathing helium-oxygen mixtures to that during positive pressure support with air.

BACKGROUND: Inhalation of helium-oxygen (He/O2) mixtures has been explored as a means to lower the work of breathing of patients with obstructive lung disease. Non-invasive ventilation (NIV) with positive pressure support is also used for this purpose. The bench experiments presented herein were conducted in order to compare simulated patient inspiratory effort breathing He/O2 with that breathing medical air, with or without pressure support, across a range of adult, obstructive disease patterns. METHODS: Patient breathing was simulated using a dual-chamber mechanical test lung, with the breathing compartment connected to an ICU ventilator operated in NIV mode with medical air or He/O2 (78/22 or 65/35%). Parabolic or linear resistances were inserted at the inlet to the breathing chamber. Breathing chamber compliance was also varied. The inspiratory effort was assessed for the different gas mixtures, for three breathing patterns, with zero pressure support (simulating unassisted spontaneous breathing), and with varying levels of pressure support. RESULTS: Inspiratory effort increased with increasing resistance and decreasing compliance. At a fixed resistance and compliance, inspiratory effort increased with increasing minute ventilation, and decreased with increasing pressure support. For parabolic resistors, inspiratory effort was lower for He/O2 mixtures than for air, whereas little difference was measured for nominally linear resistance. Relatively small differences in inspiratory effort were measured between the two He/O2 mixtures. Used in combination, reductions in inspiratory effort provided by He/O2 and pressure support were additive. CONCLUSIONS: The reduction in inspiratory effort afforded by breathing He/O2 is strongly dependent on the severity and type of airway obstruction. Varying helium concentration between 78% and 65% has small impact on inspiratory effort, while combining He/O2 with pressure support provides an additive reduction in inspiratory effort. In addition, breathing He/O2 alone may provide an alternative to pressure support in circumstances where NIV is not available or poorly tolerated.

The influence of flowrate and gas density on positive airway pressure for high flow nasal cannula applied to infant airway replicas.

High flow nasal cannula (HFNC) therapy has been previously shown to produce positive upper airway pressures in adult and child patients. This work aimed to evaluate and quantify the effects of HFNC flowrate and gas type on airway pressures measured in vitro in infant airway replicas. Ten realistic infant airway replicas, extending from nares to trachea, were connected in turn to a lung simulator and were supplied gas flows through HFNC. Air and heliox were each provided at two weight-indexed flowrates, 1 l/min/kg and 2 l/min/kg. Pressure and lung volume were continuously measured during simulated breathing. For constant simulated patient effort, no statistically significant change in tidal volume was measured between baseline and lower or higher HFNC flowrates, nor was there any significant difference in tidal volume between air and heliox. Tracheal pressure increased with increasing HFNC flow rate, and was highly variable between airway replicas. Higher pressures were measured for air versus heliox. For air supplied at 2 l/min/kg, average airway pressures in excess of 4 cm H2O were generated, with positive end-expiratory pressure (PEEP) ranging from 2.5 to nearly 12 cm H2O across the replicas. A predictive correlation for PEEP was proposed based on supplied gas density and flow velocities exiting the cannula and nares, and was able to account for a portion of variability between airway replicas (R2 = 0.913). Additionally, PEEP was well correlated with, and predictive of, expiratory peak pressure (R2 = 0.939) and average inspiratory pressure (R2 = 0.944).

Correlation of high flow nasal cannula outlet area with gas clearance and pressure in adult upper airway replicas.

BACKGROUND: Primary benefits of high flow nasal cannula therapy include washout of carbon dioxide rich exhaled gas and increased airway pressures during tidal breathing. This work reports on the influence of high flow nasal cannula outlet area on upper airways gas clearance and tracheal pressures using measurements in five realistic adult nose-throat airway replicas. METHODS: Two commercial high flow nasal cannulas and one generic nasal cannula of varying size were compared. 100% oxygen was supplied via cannulas at flow rates ranging from 30 to 90l/min to replicas originally filled with air, and oxygen concentrations at the larynx and trachea were compared over time. Additionally, and separately, replicas were connected to a mechanical lung simulator to simulate tidal breathing while undergoing high flow nasal cannula therapy, with tracheal pressure-time waveforms recorded. FINDINGS: Faster gas clearance corresponded with higher flow rates (P<0.001), and with smaller cannula outlet area (P<0.001). Observed pressures were in approximate agreement with limited available in-vivo data in the literature. Between 0 and 60L/min cannula flow rates, tracheal positive end expiratory pressures increase was greater with the smallest cannula (∆PPEEP=785SD(185) Pa) compared to the largest cannula (∆PPEEP=380SD(120)Pa). Regression analysis indicates that positive end expiratory pressure is proportional to the square of flow velocities exiting the cannula and nares (R2=0.906). INTERPRETATION: Since increased pressure and clearance rate have been associated with improved clinical outcomes in previous studies, our results suggest that smaller cannula outlet area may be preferable.

In Vitro-In Silico Comparison of Pulsed Oxygen Delivery From Portable Oxygen Concentrators Versus Continuous Flow Oxygen Delivery.

BACKGROUND: Portable oxygen concentrators (POCs) deliver oxygen in intermittent pulses. The challenge of establishing equivalence between continuous flow oxygen and nominal pulse flow settings on different POCs is well known. In vitro bench measurements and in silico mathematical modeling were used to compare the performance of 4 POCs versus continuous flow oxygen by predicting the FIO2 at the trachea and entering the acini. METHODS: Each of the 4 POCs was connected to a 3-dimensional printed replica of a human adult nasal airway via nasal cannula. A test lung simulated 3 breathing patterns representative of a patient with COPD at rest, during exercise, and while asleep. POCs were tested for each breathing pattern at all integer pulse flow settings. Volume-averaged FIO2 was calculated by analyzing oxygen concentrations and inhalation flow over time. In vitro oxygen waveforms were then combined with a single-path mathematical model of the lungs to assess oxygen transport through the conducting airways. In vitro experiments and mathematical modeling were repeated for continuous flow oxygen. RESULTS: Continuous flow oxygen consistently delivered more (>2% absolute) oxygen in terms of volume-averaged FIO2 for all nominally equivalent pulse flow settings of >2. Differences were also observed when comparing performances between different POCs, particularly at high device settings (5 and 6). Simulations showed that efficiency of delivery to the acinar region of the lungs was higher in pulse flow than in continuous flow oxygen but that continuous flow oxygen generally delivered a higher absolute volume of oxygen. Differences in absolute oxygen delivery per breath between continuous flow oxygen and pulse flow were smaller for acinar delivery than for tracheal delivery. CONCLUSIONS: Significant differences in POC performance based on volume-averaged FIO2 were found between pulse flow and continuous flow oxygen, and among pulse flow modes in different POCs. Although pulse flow was a more efficient mode of delivery than continuous flow oxygen, continuous flow oxygen delivered a greater absolute volume of oxygen per breath.

In vitro validation of computational fluid dynamic simulation in human proximal airways with hyperpolarized 3He magnetic resonance phase-contrast velocimetry.

Computational fluid dynamics (CFD) and magnetic resonance (MR) gas velocimetry were concurrently performed to study airflow in the same model of human proximal airways. Realistic in vivo-based human airway geometry was segmented from thoracic computed tomography. The three-dimensional numerical description of the airways was used for both generation of a physical airway model using rapid prototyping and mesh generation for CFD simulations. Steady laminar inspiratory experiments (Reynolds number Re = 770) were performed and velocity maps down to the fourth airway generation were extracted from a new velocity mapping technique based on MR velocimetry using hyperpolarized (3)He gas. Full two-dimensional maps of the velocity vector were measured within a few seconds. Numerical simulations were carried out with the experimental flow conditions, and the two sets of data were compared between the two modalities. Flow distributions agreed within 3%. Main and secondary flow velocity intensities were similar, as were velocity convective patterns. This work demonstrates that experimental and numerical gas velocity data can be obtained and compared in the same complex airway geometry. Experiments validated the simulation platform that integrates patient-specific airway reconstruction process from in vivo thoracic scans and velocity field calculation with CFD, hence allowing the results of this numerical tool to be used with confidence in potential clinical applications for lung characterization. Finally, this combined numerical and experimental approach of flow assessment in realistic in vivo-based human airway geometries confirmed the strong dependence of airway flow patterns on local and global geometrical factors, which could contribute to gas mixing.

The effect of disease and respiration on airway shape in patients with moderate persistent asthma.

Computational models of gas transport and aerosol deposition frequently utilize idealized models of bronchial tree structure, where airways are considered a network of bifurcating cylinders. However, changes in the shape of the lung during respiration affect the geometry of the airways, especially in disease conditions. In this study, the internal airway geometry was examined, concentrating on comparisons between mean lung volume (MLV) and total lung capacity (TLC). A set of High Resolution CT images were acquired during breath hold on a group of moderate persistent asthmatics at MLV and TLC after challenge with a broncho-constrictor (methacholine) and the airway trees were segmented and measured. The airway hydraulic diameter (Dh) was calculated through the use of average lumen area (Ai) and average internal perimeter (Pi) at both lung volumes and was found to be systematically higher at TLC by 13.5±9% on average, with the lower lobes displaying higher percent change in comparison to the lower lobes. The average internal diameter (Din) was evaluated to be 12.4±6.8% (MLV) and 10.8±6.3% (TLC) lower than the Dh, for all the examined bronchi, a result displaying statistical significance. Finally, the airway distensibility per bronchial segment and per generation was calculated to have an average value of 0.45±0.28, exhibiting high variability both between and within lung regions and generations. Mixed constriction/dilation patterns were recorded between the lung volumes, where a number of airways either failed to dilate or even constricted when observed at TLC. We conclude that the Dh is higher than Din, a fact that may have considerable effects on bronchial resistance or airway loss at proximal regions. Differences in caliber changes between lung regions are indicative of asthma-expression variability in the lung. However, airway distensibility at generation 3 seems to predict distensibility more distally.

Comparison of pulsed versus continuous oxygen delivery using realistic adult nasal airway replicas.

BACKGROUND: Portable oxygen concentrators (POCs) typically include pulse flow (PF) modes to conserve oxygen. The primary aims of this study were to develop a predictive in vitro model for inhaled oxygen delivery using a set of realistic airway replicas, and to compare PF for a commercial POC with steady flow (SF) from a compressed oxygen cylinder. METHODS: Experiments were carried out using a stationary compressed oxygen cylinder, a POC, and 15 adult nasal airway replicas based on airway geometries derived from medical images. Oxygen delivery via nasal cannula was tested at PF settings of 2.0 and 6.0, and SF rates of 2.0 and 6.0 L/min. A test lung simulated three breathing patterns representative of a chronic obstructive pulmonary disease patient at rest, during exercise, and while asleep. Volume-averaged fraction of inhaled oxygen (FiO2) was calculated by analyzing oxygen concentrations sampled at the exit of each replica and inhalation flow rates over time. POC pulse volumes were also measured using a commercial O2 conserver test system to attempt to predict FiO2 for PF. RESULTS: Relative volume-averaged FiO2 using PF ranged from 68% to 94% of SF values, increasing with breathing frequency and tidal volume. Three of 15 replicas failed to trigger the POC when used with the sleep breathing pattern at the 2.0 setting, and four of 15 replicas failed to trigger at the 6.0 setting. FiO2 values estimated from POC pulse characteristics followed similar trends but were lower than those derived from airway replica experiments. CONCLUSION: For the POC tested, PF delivered similar, though consistently lower, volume-averaged FiO2 than SF rates equivalent to nominal PF settings. Assessment of PF oxygen delivery using POC pulse characteristics alone may be insufficient; testing using airway replicas is useful in identifying possible cases of failure and may provide a better assessment of FiO2.

Modelling levels of nitrous oxide exposure for healthcare professionals during EMONO usage.

BACKGROUND: Computational fluid dynamics (CFD) has been used to compute nitrous oxide (N2O) levels within a room during the administration of an equimolar mix of N2O/oxygen (EMONO) in the clinical setting. This study modelled realistic scenarios of EMONO usage in hospital or primary care, in order to estimate the potential N2O exposure of healthcare professionals (HCP) with routine EMONO use and to provide guidance for EMONO users. METHODS: Sixteen scenarios were defined by carrying out a survey of practitioners. CFD simulations were performed for each scenario and N2O concentrations over time were calculated. N2O exposures (time-weighted average of concentration over 8 h [TWA-8 h]) were calculated at the HCPs' mouth to be compared with a predefined occupational exposure limit (OEL). RESULTS: Administration duration and ventilation type were the main factors influencing N2O levels; ventilation type also influenced wash-out time between EMONO administrations. N2O concentration showed a plume distribution towards the ceiling and was highly heterogeneous, highlighting the importance of measurement location. Although estimated TWA-8 h varied widely, 13 of the 16 scenarios had an N2O TWA-8 h of <100 parts per million. CONCLUSIONS: Data demonstrate that EMONO usage in well ventilated rooms - as recommended - helps to ensure that N2O exposure does not exceed the OEL and does not signal any major risks for HCPs when recommendations are followed. Although these data are numerical simulations and should be considered as such, they can provide guidance for EMONO users.

The Creation and Statistical Evaluation of a Deterministic Model of the Human Bronchial Tree from HRCT Images.

A quantitative description of the morphology of lung structure is essential prior to any form of predictive modeling of ventilation or aerosol deposition implemented within the lung. The human lung is a very complex organ, with airway structures that span two orders of magnitude and having a multitude of interfaces between air, tissue and blood. As such, current medical imaging protocols cannot provide medical practitioners and researchers with in-vivo knowledge of deeper lung structures. In this work a detailed algorithm for the generation of an individualized 3D deterministic model of the conducting part of the human tracheo-bronchial tree is described. Distinct initial conditions were obtained from the high-resolution computed tomography (HRCT) images of seven healthy volunteers. The algorithm developed is fractal in nature and is implemented as a self-similar space sub-division procedure. The expansion process utilizes physiologically realistic relationships and thresholds to produce an anatomically consistent human airway tree. The model was validated through extensive statistical analysis of the results and comparison of the most common morphological features with previously published morphometric studies and other equivalent models. The resulting trees were shown to be in good agreement with published human lung geometric characteristics and can be used to study, among other things, structure-function relationships in simulation studies.

Gas transport during in vitro and in vivo preclinical testing of inert gas therapies.

New gas therapies using inert gases such as xenon and argon are being studied, which require in vitro and in vivo preclinical experiments. Examples of the kinetics of gas transport during such experiments are analyzed in this paper. Using analytical and numerical models, we analyze an in vitro experiment for gas transport to a 96 cell well plate and an in vivo delivery to a small animal chamber, where the key processes considered are the wash-in of test gas into an apparatus dead volume, the diffusion of test gas through the liquid media in a well of a cell test plate, and the pharmacokinetics in a rat. In the case of small animals in a chamber, the key variable controlling the kinetics is the chamber wash-in time constant that is a function of the chamber volume and the gas flow rate. For cells covered by a liquid media the diffusion of gas through the liquid media is the dominant mechanism, such that liquid depth and the gas diffusion constant are the key parameters. The key message from these analyses is that the transport of gas during preclinical experiments can be important in determining the true dose as experienced at the site of action in an animal or to a cell.

An in silico analysis of oxygen uptake of a mild COPD patient during rest and exercise using a portable oxygen concentrator.

Oxygen treatment based on intermittent-flow devices with pulse delivery modes available from portable oxygen concentrators (POCs) depends on the characteristics of the delivered pulse such as volume, pulse width (the time of the pulse to be delivered), and pulse delay (the time for the pulse to be initiated from the start of inhalation) as well as a patient's breathing characteristics, disease state, and respiratory morphology. This article presents a physiological-based analysis of the performance, in terms of blood oxygenation, of a commercial POC at different settings using an in silico model of a COPD patient at rest and during exercise. The analysis encompasses experimental measurements of pulse volume, width, and time delay of the POC at three different settings and two breathing rates related to rest and exercise. These experimental data of device performance are inputs to a physiological-based model of oxygen uptake that takes into account the real dynamic nature of gas exchange to illustrate how device- and patient-specific factors can affect patient oxygenation. This type of physiological analysis that considers the true effectiveness of oxygen transfer to the blood, as opposed to delivery to the nose (or mouth), can be instructive in applying therapies and designing new devices.

Airflow modeling of steady inspiration in two realistic proximal airway trees reconstructed from human thoracic tomodensitometric images.

Detailed description of the flow field in human airways is highly important to better understand human breathing and provide a patient's customized diagnosis. An integrated numerical simulation platform is presently proposed in order to incorporate medical images into a numerical software to calculate flow field and to analyze it in terms of fluid dynamics. The platform was set up to compute steady inspiratory airflow in realistic human airways reconstructed from tomodensitometric medical images at resting breathing conditions. This morpho-functional simulation platform has been tested retrospectively with two CT-scanned patient airway morphological models: (i) a normal airway model (subject A) with no evidence of morphological alteration and (ii) a highly altered airway model (subject B) exhibiting a severe stenosis in the right main bronchus. First, various morphological aspects proper to each airway model are provided to show the performance and interest of the reconstruction method. Second, we describe the three-dimensional flow patterns associated to the global morphological features, which are mainly shared by the present realistic models and previous idealistic airway models. Finally, the flow characteristics associated to local morphological features specific to realistic airway models are discussed. The results demonstrate that the morpho-functional simulation platform is able to capture the main features of airway velocity patterns but also more specific airflow patterns which are related to customized patient morphological features such as laminar vortex formation. The present results suggest that the proposed airway functional imaging platform is adequate to provide most of functional information related to airflow and enable a patient to patient diagnosis.

Pharmacokinetic analysis of the chronic administration of the inert gases Xe and Ar using a physiological based model.

BACKGROUND: New gas therapies using inert gases such as xenon and argon are being studied, which would require chronically administered repeating doses. The pharmacokinetics of this type of administration has not been addressed in the literature. METHODS: A physiologically based pharmacokinetics (PBPK) model for humans, pigs, mice, and rats has been developed to investigate the unique aspects of the chronic administration of inert gas therapies. The absorption, distribution, metabolism and excretion (ADME) models are as follows: absorption in all compartments is assumed to be perfusion limited, no metabolism of the gases occurs, and excretion is only the reverse process of absorption through the lungs and exhaled. RESULTS: The model has shown that there can be a residual dose, equivalent to constant administration, for chronic repeated dosing of xenon in humans. However, this is not necessarily the case for small animals used in pre-clinical studies. CONCLUSIONS: The use of standard pharmacokinetics parameters such as area under the curve would be more appropriate to assess the delivered dose of chronic gas administration than the gas concentration in the delivery system that is typically reported in the scientific literature because species and gas differences can result in very different delivered doses.

Controlled, Parametric, Individualized, 2-D and 3-D Imaging Measurements of Aerosol Deposition in the Respiratory Tract of Asthmatic Human Subjects for Model Validation.

BACKGROUND: Computer modeling is used to predict inhaled aerosol deposition in the lung based on definition of the aerosol characteristics and the breathing pattern and airway anatomy of the subject. Validation of the models is limited by the lack of detailed experimental data. Three-dimensional imaging provides an opportunity to address this unmet need. METHODS: Radioactive aerosol was administered to six male asthmatic subjects on two occasions under carefully monitored input conditions. Input parameters varied in particle size, depth of breathing, and carrier gas. The aerosol distribution was measured by combined single photon emission computed tomography and x-ray computer tomography (SPECT/CT) and airway anatomy by high resolution CT. The deposition distribution was measured by both a 2D and 3D analysis and described in terms of the percentage of inhaled aerosol deposited in sections of the respiratory tract and in both spatial and anatomical subdivisions within each lung. The percentage deposition in the conducting airways was also assessed by 24 h clearance. RESULTS: A set of imaging data of aerosol deposition has thus been produced in which the input parameters of inhalation are well described. The results in asthmatics were compared to previous measurements in healthy controls using an identical inhalation protocol. The percentages of deposition in extra-thoracic and thoracic compartments of the airways were not significantly affected by disease, but the regional pulmonary deposition pattern was, with asthma leading to increased deposition in the conducting airways. CONCLUSIONS: The dataset acquired in this study will be useful in validating computer models of aerosol deposition in asthmatic subjects. Asthma did not affect the fraction of inhaled aerosol depositing in the lungs, but gave rise to a more central deposition pattern. The use of 3D SPECT imaging in combination with 24 h clearance measurements enables differentiation of deposition between bronchial and bronchiolar airways.

Realistic glottal motion and airflow rate during human breathing.

The glottal geometry is a key factor in the aerosol delivery efficiency for treatment of lung diseases. However, while glottal vibrations were extensively studied during human phonation, the realistic glottal motion during breathing is poorly understood. Therefore, most current studies assume an idealized steady glottis in the context of respiratory dynamics, and thus neglect the flow unsteadiness related to this motion. This is particularly important to assess the aerosol transport mechanisms in upper airways. This article presents a clinical study conducted on 20 volunteers, to examine the realistic glottal motion during several breathing tasks. Nasofibroscopy was used to investigate the glottal geometrical variations simultaneously with accurate airflow rate measurements. In total, 144 breathing sequences of 30s were recorded. Regarding the whole database, two cases of glottal time-variations were found: "static" or "dynamic" ones. Typically, the peak value of glottal area during slow breathing narrowed from 217 ± 54 mm(2) (mean ± STD) during inspiration, to 178 ± 35 mm(2) during expiration. Considering flow unsteadiness, it is shown that the harmonic approximation of the airflow rate underevaluates the inertial effects as compared to realistic patterns, especially at the onset of the breathing cycle. These measurements provide input data to conduct realistic numerical simulations of laryngeal airflow and particle deposition.

Inhalation pressure distributions for medical gas mixtures calculated in an infant airway morphology model.

A numerical pressure loss model previously used for adult human airways has been modified to simulate the inhalation pressure distribution in a healthy 9-month-old infant lung morphology model. Pressure distributions are calculated for air as well as helium and xenon mixtures with oxygen to investigate the effects of gas density and viscosity variations for this age group. The results indicate that there are significant pressure losses in infant extrathoracic airways due to inertial effects leading to much higher pressures to drive nominal flows in the infant airway model than for an adult airway model. For example, the pressure drop through the nasopharynx model of the infant is much greater than that for the nasopharynx model of the adult; that is, for the adult-versus-child the pressure differences are 0.08 cm H2O versus 0.4 cm H2O, 0.16 cm H2O versus 1.9 cm H2O and 0.4 cm H2O versus 7.7 cm H2O, breathing helium-oxygen (78/22%), nitrogen-oxygen (78/22%) and xenon-oxygen (60/40%), respectively. Within the healthy lung, viscous losses are of the same order for the three gas mixtures, so the differences in pressure distribution are relatively small.