On the Feasibility of Rugose Lipid Microparticles in Pressurized Metered Dose Inhalers with Established and New Propellants.

Pressurized metered dose inhalers (pMDIs) require optimized formulations to provide stable, consistent lung delivery. This study investigates the feasibility of novel rugose lipid particles (RLPs) as potential drug carriers in pMDI formulations. The physical stability of RLPs was assessed in three different propellants: the established HFA-134a and HFA-227ea and the new low global-warming-potential (GWP) propellant HFO-1234ze. A feedstock containing DSPC and calcium chloride was prepared without pore forming agent to spray dry two RLP batches at inlet temperatures of 55 °C (RLP55) and 75 °C (RLP75). RLPs performance in pMDI formulations was compared to two reference samples that exhibit significantly different performance when suspended in propellants: well-established engineered porous particles and particles containing 80% trehalose and 20% leucine (80T20L). An accelerated stability study at 40 °C and relative humidity of 7% ± 5% was conducted over 3 months. At different time points, a shadowgraphic imaging technique was used to evaluate the colloidal stability of particles in pMDIs. Field emission electron microscopy with energy dispersive X-ray spectroscopy was used to evaluate the morphology and elemental composition of particles extracted from the pMDIs. After 2 weeks, all 80T20L formulations rapidly aggregated upon agitation and exhibited significantly inferior colloidal stability compared to the other samples. In comparison, both the RLP55 and RLP75 formulations, regardless of the propellant used, retained their rugose structure and demonstrated excellent suspension stability comparable with the engineered porous particles. The studied RLPs demonstrate great potential for use in pMDI formulations with HFA propellants and the next-generation low-GWP propellant HFO-1234ze.

Variability in low-flow oxygen delivery by nasal cannula evaluated in neonatal and infant airway replicas.

BACKGROUND: The nasal cannula is considered a trusted and effective means of administering low-flow oxygen and is widely used for neonates and infants requiring oxygen therapy, despite an understanding that oxygen concentrations delivered to patients are variable. METHODS: In the present study, realistic nasal airway replicas derived from medical scans of children less than 3 months old were used to measure the fraction of oxygen inhaled (FiO2) through nasal cannulas during low-flow oxygen delivery. Parameters influencing variability in FiO2 were evaluated, as was the hypothesis that measured FiO2 values could be predicted using a simple, flow-weighted calculation that assumes ideal mixing of oxygen with entrained room air. Tidal breathing through neonatal and infant nasal airway replicas was controlled using a lung simulator. Parameters for nasal cannula oxygen flow rate, nasal airway geometry, tidal volume, respiratory rate, inhalation/exhalation, or I:E ratio (ti/te), breath waveform, and cannula prong insertion position were varied to determine their effect on measured FiO2. In total, FiO2 was measured for 384 different parameter combinations, with each combination repeated in triplicate. Analysis of variance (ANOVA) was used to assess the influence of parameters on measured FiO2. RESULTS: Measured FiO2 was not appreciably affected by the breath waveform shape, the replica geometry, or the cannula position but was significantly influenced by the tidal volume, the inhalation time, and the nasal cannula flow rate. CONCLUSIONS: The flow-weighted calculation overpredicted FiO2 for measured values above 60%, but an empirical correction to the calculation provided good agreement with measured FiO2 across the full range of experimental data.

Using Filters to Estimate Regional Lung Deposition with Pressurized Metered Dose Inhalers.

PURPOSE: To evaluate the suitability of a recently proposed apparatus that uses filters to directly fractionate the in vitro lung dose into regional deposition estimates for use with pressurized metered dose inhaler (pMDI) devices as a less resource intensive alternative to cascade impaction. METHODS: Using three commercially available pMDI devices (Asmanex HFA, Ventolin HFA, QVAR), regional deposition estimates were measured directly using the filter-based apparatus (FBA). Regional deposition estimates were also generated for the same inhalers by performing cascade impaction measurements and inputting the results to an in silico regional deposition model. Regional deposition for each inhaler was evaluated at an inhalation flow rate of 30 and 60 L/min. RESULTS: Total recovery of active pharmaceutical ingredient and extrathoracic deposition was independent of method used. The regional deposition estimates provided by each method were similar and captured the same trends. CONCLUSIONS: The direct measurement of estimated regional deposition is possible when using the FBA. This method is far less resource intensive than existing methods and so may be useful both for comparison of generic alternatives and the development of innovative products.

Spray Dried Rugose Lipid Particle Platform for Respiratory Drug Delivery.

PURPOSE: To develop a new lipid-based particle formulation platform for respiratory drug delivery applications. To find processing conditions for high surface rugosity and manufacturability. To assess the applicability of the new formulation method to different lipids. METHODS: A new spray drying method with a simplified aqueous suspension feedstock preparation process was developed for the manufacture of rugose lipid particles of 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC). A study covering a wide range of feedstock temperatures and outlet temperatures was conducted to optimize the processing conditions. Aerosol performance was characterized in vitro and in silico to assess the feasibility of their use in respiratory drug delivery applications. The applicability of the new spray drying method to longer-chain phospholipids with adjusted spray drying temperatures was also evaluated. RESULTS: Highly rugose DSPC lipid particles were produced via spray drying with good manufacturability. A feedstock temperature close to, and an outlet temperature lower than, the main phase transition were identified as critical in producing particles with highly rugose surface features. High emitted dose and total lung dose showed promising aerosol performance of the produced particles for use as a drug loading platform for respiratory drug delivery. Two types of longer-chain lipid particles with higher main phase transition temperatures, 1,2-diarachidoyl-sn-glycero-3-phosphocholine (DAPC) and 1,2-dibehenoyl-sn-glycero-3-phosphocholine (22:0 PC), yielded similar rugose morphologies when spray dried at correspondingly higher processing temperatures. CONCLUSIONS: Rugose lipid particles produced via spray drying from an aqueous suspension feedstock are promising as a formulation platform for respiratory drug delivery applications. The new technique can potentially produce rugose particles using various other lipids.

Comparison of airway pressures and expired gas washout for nasal high flow versus CPAP in child airway replicas.

BACKGROUND: For children and adults, the standard treatment for obstructive sleep apnea is the delivery of continuous positive airway pressure (CPAP). Though effective, CPAP masks can be uncomfortable to patients, contributing to adherence concerns. Recently, nasal high flow (NHF) therapy has been investigated as an alternative, especially in CPAP-intolerant children. The present study aimed to compare and contrast the positive airway pressures and expired gas washout generated by NHF versus CPAP in child nasal airway replicas. METHODS: NHF therapy was investigated at a flow rate of 20 L/min and compared to CPAP at 5 cmH2O and 10 cmH2O for 10 nasal airway replicas, built from computed tomography scans of children aged 4-8 years. NHF was delivered with three different high flow nasal cannula models provided by the same manufacturer, and CPAP was delivered with a sealed nasal mask. Tidal breathing through each replica was imposed using a lung simulator, and airway pressure at the trachea was recorded over time. For expired gas washout measurements, carbon dioxide was injected at the lung simulator, and end-tidal carbon dioxide (EtCO2) was measured at the trachea. Changes in EtCO2 compared to baseline values (no intervention) were assessed. RESULTS: NHF therapy generated an average positive end-expiratory pressure (PEEP) of 5.17 ± 2.09 cmH2O (mean ± SD, n = 10), similar to PEEP of 4.95 ± 0.03 cmH2O generated by nominally 5 cmH2O CPAP. Variation in tracheal pressure was higher between airway replicas for NHF compared to CPAP. EtCO2 decreased from baseline during administration of NHF, whereas it increased during CPAP. No statistical difference in tracheal pressure nor EtCO2 was found between the three high flow nasal cannulas. CONCLUSION: In child airway replicas, NHF at 20 L/min generated average PEEP similar to CPAP at 5 cm H2O. Variation in tracheal pressure was higher between airway replicas for NHF than for CPAP. The delivery of NHF yielded expired gas washout, whereas CPAP impeded expired gas washout due to the increased dead space of the sealed mask.

Using Filters to Estimate Regional Lung Deposition with Dry Powder Inhalers.

PURPOSE: To develop an in vitro method to rapidly evaluate regional lung doses delivered by pharmaceutical inhalers. Currently, cascade impactor measurements are used, but these are resource intensive and require significant post processing of in vitro data to arrive at regional deposition estimates. METHODS: We present a specialized filter apparatus that mimics tracheobronchial (TB) deposition of pharmaceutical aerosols emitted by commercially available dry powder inhalers (DPIs). The filter housing includes an electrostatic neutralizer to eliminate artificial electrostatic filtration effects. Regional deposition (tracheobronchial and alveolar) for four DPIs (Onbrez Breezhaler, Flovent Diskus, Pulmicort Turbuhaler, and Asmanex Twisthaler) was estimated using cascade impactor measurements and an in silico regional deposition model. These estimates were compared to direct measurements of regional deposition as provided by the TB filter mimic and an absolute filter placed downstream of the TB filter housing, representing the alveolar dose. RESULTS: The two methods were shown to provide similar estimates of extrathoracic, tracheobronchial, and alveolar deposition, as well as total recovery of active pharmaceutical ingredients. CONCLUSIONS: Because of its design, the TB filter apparatus makes it possible to estimate regional deposition with inhalers directly using variable inhalation profiles without any additional equipment or changes to the experimental configuration. This method may be useful to expedite development of both innovative and generic drug products as it provides regional respiratory tract deposition estimates using fewer resources than exisiting methods.

Combined in Vitro-in Silico Approach to Predict Deposition and Pharmacokinetics of Budesonide Dry Powder Inhalers.

PURPOSE: A combined in vitro - in silico methodology was designed to estimate pharmacokinetics of budesonide delivered via dry powder inhaler. METHODS: Particle size distributions from three budesonide DPIs, measured with a Next Generation Impactor and Alberta Idealized Throat, were input into a lung deposition model to predict regional deposition. Subsequent systemic exposure was estimated using a pharmacokinetic model that incorporated Nernst-Brunner dissolution in the conducting airways to predict the net influence of dissolution, mucociliary clearance, and absorption. RESULTS: DPIs demonstrated significant in vitro differences in deposition, resulting in large differences in simulated regional deposition in the central conducting airways and the alveolar region. Similar but low deposition in the small conducting airways was observed with each DPI. Pharmacokinetic predictions showed good agreement with in vivo data from the literature. Peak systemic concentration was tied primarily to the alveolar dose, while the area under the curve was more dependent on the total lung dose. Tracheobronchial deposition was poorly correlated with pharmacokinetic data. CONCLUSIONS: Combination of realistic in vitro experiments, lung deposition modeling, and pharmacokinetic modeling was shown to provide reasonable estimation of in vivo systemic exposure from DPIs. Such combined approaches are useful in the development of orally inhaled drug products.

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.

An injection and mixing element for delivery and monitoring of inhaled nitric oxide.

BACKGROUND: Inhaled nitric oxide (NO) is a selective pulmonary vasodilator used primarily in the critical care setting for patients concurrently supported by invasive or noninvasive positive pressure ventilation. NO delivery devices interface with ventilator breathing circuits to inject NO in proportion with the flow of air/oxygen through the circuit, in order to maintain a constant, target concentration of inhaled NO. METHODS: In the present article, a NO injection and mixing element is presented. The device borrows from the design of static elements to promote rapid mixing of injected NO-containing gas with breathing circuit gases. Bench experiments are reported to demonstrate the improved mixing afforded by the injection and mixing element, as compared with conventional breathing circuit adapters, for NO injection into breathing circuits. Computational fluid dynamics simulations are also presented to illustrate mixing patterns and nitrogen dioxide production within the element. RESULTS: Over the range of air flow rates and target NO concentrations investigated, mixing length, defined as the downstream distance required for NO concentration to reach within ±5 % of the target concentration, was as high as 47 cm for the conventional breathing circuit adapters, but did not exceed 7.8 cm for the injection and mixing element. CONCLUSION: The injection and mixing element has potential to improve ease of use, compatibility and safety of inhaled NO administration with mechanical ventilators and gas delivery devices.

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.

Characterizing regional drug delivery within the nasal airways.

INTRODUCTION: The nose has been receiving increased attention as a route for drug delivery. As the site of deposition constitutes the first point of contact of the body with the drug, characterization of the regional deposition of intranasally delivered droplets or particles is paramount to formulation and device design of new products. AREAS COVERED: This review article summarizes the recent literature on intranasal regional drug deposition evaluated in vivo, in vitro and in silico, with the aim of correlating parameters measured in vitro with formulation and device performance. We also highlight the relevance of regional deposition to two emerging applications: nose-to-brain drug delivery and intranasal vaccines. EXPERT OPINION: As in vivo studies of deposition can be costly and time-consuming, researchers have often turned to predictive in vitro and in silico models. Variability in deposition is high due in part to individual differences in nasal geometry, and a complete predictive model of deposition based on spray characteristics remains elusive. Carefully selected or idealized geometries capturing population average deposition can be useful surrogates to in vivo measurements. Continued development of in vitro and in silico models may pave the way for development of less variable and more effective intranasal drug products.

High-Flow and Low-Flow Oxygen Delivery by Nasal Cannula Evaluated in Infant and Adult Airway Replicas.

BACKGROUND: The nasal cannula is widely regarded as a safe and effective means of administering low- and high-flow oxygen to patients irrespective of their age. However, variability in delivered oxygen concentration (FDO2 FDO2 ) via nasal cannula has the potential to pose health risks. The present study aimed to evaluate predictive equations for FDO2 over a large parameter space, including variation in breathing, oxygen flow, and upper-airway geometry representative of both young children and adults. METHODS: Realistic nasal airway geometries were previously collected from medical scans of adults, infants, and neonates. Nasal airway replicas based on these geometries were used to measure the FDO2 for low-flow oxygen delivery during simulated spontaneous breathing. The present study extends previously published data sets to include higher oxygen flows. The extended data sets included nasal cannula oxygen flows that ranged from 6 to 65 L/min for the adult replicas, and from 0.5 to 6 L/min for the infant replicas. For both age groups, FDO2 was measured over a range of breathing frequencies, inspiratory to expiratory time ratios, and tidal volumes. Measured FDO2 values were compared with values predicted by using a previously derived flow-weighted equation. RESULTS: For both age groups, FDO2 was observed to increase nonlinearly with the ratio between oxygen flow supplied to the nasal cannula and the average inhalation flow. The previously derived flow-weighted equation over-predicted FDO2 at higher oxygen flows. A new empirical equation, therefore, was proposed to predict FDO2 for either age group as a function of nasal cannula flow, tidal volume, and inspiratory time. Predicted FDO2 values matched measured values, with average relative errors of 2.4% for infants and 4.3% for adults. CONCLUSIONS: A new predictive equation for FDO2 was obtained that accurately matched measured data in both adult and infant airway replicas for low- and high-flow regimens.

Improving Breath Detection From Pulsed-Flow Oxygen Sources Using a New Nasal Interface.

BACKGROUND: Patients with COPD and other lung diseases are treated with long-term oxygen therapy (LTOT). Portable oxygen sources are required to administer LTOT while maintaining patient autonomy. Existing portable oxygen equipment has limitations that can hinder patient mobility. A novel nasal interface is presented in this study, aiming to enhance breath detection and triggering efficiency of portable pulsed-flow oxygen devices, thereby improving patient mobility and independence. METHOD: To examine the effectiveness of the new interface, 8 respiratory therapists participated in trials using different oxygen sources (tank with oxygen-conserving device, SimplyGo Mini portable oxygen concentrator [POC], and OxyGo NEXT POC) and breathing types (nasal and oral) while using either the new nasal interface or a standard cannula. Each trial was video recorded so participant breaths could be retroactively matched with a pulse/no-pulse response, and triggering success rates were calculated by dividing the number of oxygen pulses by the number of breaths in each trial. After each trial, volunteers were asked to rate their perceived breathing resistance. RESULTS: Nasal breathing consistently resulted in higher triggering success rates compared to oral breathing for pulsed-flow oxygen devices. POCs exhibited higher triggering success rates than did the oxygen tanks with conserving device. However, there were no significant differences in triggering success rates between the two POC models. The new nasal interface demonstrated improved triggering success rates compared to the standard cannula. Whereas the new nasal interface was associated with a slight increase in perceived breathing resistance during nasal breathing trials, participants reported manageable resistance levels when using the interface. CONCLUSIONS: This study demonstrates that the new nasal interface can improve triggering success rates of pulsed-flow oxygen devices during both nasal and oral breathing scenarios. Further research involving patient trials is recommended to understand the clinical implications of improved pulse triggering.

Immunogenicity and safety of an Entamoeba histolytica adjuvanted protein vaccine candidate (LecA+GLA-3M-052 liposomes) in rhesus macaques.

Entamoeba histolytica, the causative agent of amebiasis, is one of the top three parasitic causes of mortality worldwide. However, no vaccine exists against amebiasis. Using a lead candidate vaccine containing the LecA fragment of Gal-lectin and GLA-3M-052 liposome adjuvant, we immunized rhesus macaques via intranasal or intramuscular routes. The vaccine elicited high-avidity functional humoral responses as seen by the inhibition of amebic attachment to mammalian target cells by plasma and stool antibodies. Importantly, antigen-specific IFN-γ-secreting peripheral blood mononuclear cells (PBMCs) and IgG/IgA memory B cells (BMEM) were detected in immunized animals. Furthermore, antigen-specific antibody and cellular responses were maintained for at least 8 months after the final immunization as observed by robust LecA-specific BMEM as well as IFN-γ+ PBMC responses. Overall, both intranasal and intramuscular immunizations elicited a durable and functional response in systemic and mucosal compartments, which supports advancing the LecA+GLA-3M-052 liposome vaccine candidate to clinical testing.

Association between sarcopenia and the risk of serious infection among adults undergoing liver transplantation.

Although sarcopenia (muscle loss) is associated with increased mortality after liver transplantation, its influence on other complications is less well understood. We examined the association between sarcopenia and the risk of severe posttransplant infections among adult liver transplant recipients. By calculating the total psoas area (TPA) on preoperative computed tomography scans, we assessed sarcopenia among 207 liver transplant recipients. The presence or absence of a severe posttransplant infection was determined by a review of the medical chart. The influence of posttransplant infections on overall survival was also assessed. We identified 196 episodes of severe infections among 111 patients. Fifty-six patients had more than 1 infection. The median time to the development of an infection was 27 days (interquartile range = 13-62 days). When the patients were grouped by TPA tertiles, patients in the lowest tertile had a greater than 4-fold higher chance of developing a severe infection in comparison with patients in the highest tertile (odds ratio = 4.6, 95% confidence interval = 2.25-9.53). In a multivariate analysis, recipient age (hazard ratio = 1.04, P = 0.02), pretransplant TPA (hazard ratio = 0.38, P < 0.01), and pretransplant total bilirubin level (hazard ratio = 1.05, P = 0.02) were independently associated with the risk of developing severe infections. Patients with severe posttransplant infections had worse 1-year survival than patients without infections (76% versus 92%, P = 0.003). In conclusion, among patients undergoing liver transplantation, a lower TPA was associated with a heightened risk for posttransplant infectious complications and mortality. Future efforts should focus on approaches for assessing and mitigating vulnerability in patients undergoing transplantation.

Size-specific filtration efficiency and pressure drop of school-aged children's woven and nonwoven masks at varying face velocities.

BACKGROUND: Differences in physiology and breathing patterns between children and adults lead to disparate responses to aerosols of varying sizes. No standardized method exists for measuring the filtration efficiency (FE) of children's masks to reflect such differences. METHODS: Using an adult N95 mask as a control and two different face velocities (vf) (9.3 cm/s representing adults and 4.0 cm/s representing school-aged children), we tested the pressure drop (ΔP) through children's nonwoven masks (surgical and KN95) and children's woven masks (100% cotton and partially-cotton-based masks), as well as their size-specific FE between aerodynamic particle diameters of 0.02 and 2.01 µm. RESULTS: All three types of mask showed a 1 to 9% absolute increase in minimum FE at the lower vf and a significant decrease in ΔP. For children's surgical masks the increase in FE was significant for most of the examined particle sizes, but for children's woven masks the increase was limited to particles smaller than 0.04 µm. CONCLUSIONS: Lower vf for children is likely to lead to a higher FE, lower ΔP, and consequently higher filter qualities in children's masks. For woven masks, the FE for particles larger than 0.04 µm was low (typically <50%) for both vf's studied.

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.

Empirical Deposition Correlations.

Traditionally, empirical correlations for predicting respiratory tract deposition of inhaled aerosols have been developed using limited available in vivo data. More recently, advances in medical image segmentation and additive manufacturing processes have allowed researchers to conduct extensive in vitro deposition experiments in realistic replicas of the upper and central branching airways. This work has led to a collection of empirical equations for predicting regional aerosol deposition, especially in the upper, nasal and oral airways. The present section reviews empirical correlations based on both in vivo and in vitro data, which may be used to predict total and regional deposition. Equations are presented for predicting total respiratory deposition fraction, mouth-throat fraction, nasal, and nose-throat fractions for a large variety of aerosol sizes, subject age groups, and breathing maneuvers. Use of these correlations to estimate total lung deposition is also described.