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.

In Vitro Regional Deposition of Nasal Sprays in an Idealized Nasal Inlet: Comparison with In Vivo Gamma Scintigraphy.

PURPOSE: To compare in vitro regional nasal deposition measurements using an idealized nasal airway geometry, the Alberta Idealized Nasal Inlet (AINI), with in vivo regional deposition for nasal drug products. MATERIALS AND METHODS: One aqueous solution formulation (NasalCrom), one aqueous suspension formulation (Nasonex) and one nasal pressurized metered dose spray device (QNASL) were selected. Two spray orientation angles, 60° and 45° from the horizontal, were selected. A steady inhalation flow rate of 7.5 L/min was selected to simulate slow inhalation through a single nostril. After actuation, the AINI was disassembled. The mass of drug deposited in each region and a downstream filter, representing penetration of drug to the lungs, was determined using ultraviolet-visible (UV-Vis) spectrophotometry. RESULTS: No filter (lung) deposition was detected for NasalCrom or Nasonex. Filter deposition ranged from 6 to 11% for QNASL. For NasalCrom, 45% to 69% of the dose deposited in the AINI was deposited in the vestibule and 31% to 55% was deposited in the turbinates; for Nasonex, 66% to 74% (vestibule) and 26% to 34% (turbinates); for QNASL, 90% to 100% (vestibule) and 0% to 10% (turbinates). No statistically significant difference was observed between regional deposition in vivo and in vitro for any of the formulations, except that nasopharyngeal deposition with Nasonex differed by less than 1.56% from in vivo, which while statistically significant, is unlikely to be clinically significant. CONCLUSIONS: The AINI was able to mimic regional in vivo deposition for nasal drug products, permitting differentiation between devices based on regional deposition.

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.

Prophylaxis of Mycobacterium tuberculosis H37Rv Infection in a Preclinical Mouse Model via Inhalation of Nebulized Bacteriophage D29.

Globally, more people die annually from tuberculosis than from any other single infectious agent. Unfortunately, there is no commercially-available vaccine that is sufficiently effective at preventing acquisition of pulmonary tuberculosis in adults. In this study, pre-exposure prophylactic pulmonary delivery of active aerosolized anti-tuberculosis bacteriophage D29 was evaluated as an option for protection against Mycobacterium tuberculosis infection. An average bacteriophage concentration of approximately 1 PFU/alveolus was achieved in the lungs of mice using a nose-only inhalation device optimized with a dose simulation technique and adapted for use with a vibrating mesh nebulizer. Within 30 minutes of bacteriophage delivery, the mice received either a low dose (∼50-100 CFU), or an ultra-low dose (∼5-10 CFU), of M. tuberculosis H37Rv aerosol to the lungs. A prophylactic effect was observed with bacteriophage aerosol pre-treatment significantly decreasing M. tuberculosis burden in mouse lungs 24 hours and 3 weeks post-challenge (p < 0.05). These novel results indicate that a sufficient dose of nebulized mycobacteriophage aerosol to the lungs may be a valuable intervention to provide extra protection to health care professionals and other individuals at risk of exposure to M. tuberculosis.

Multi-Solvent Microdroplet Evaporation: Modeling and Measurement of Spray-Drying Kinetics with Inhalable Pharmaceutics.

PURPOSE: Evaporation and particle formation from multi-solvent microdroplets containing solid excipients pertaining to spray-drying of therapeutic agents intended for lung delivery were studied. Various water and ethanol co-solvent systems containing a variety of actives and excipients (beclomethasone, budesonide, leucine, and trehalose) were considered. METHODS: Numerical methods were used to predict the droplet evaporation rates and internal solute transfers, and their results verified and compared with results from two separate experimental setups. In particular, an electrodynamic balance was used to measure the evaporation rates of multicomponent droplets and a monodisperse droplet chain setup collected dried microparticles for further analytical investigations and ultramicroscopy. RESULTS: The numerical results are used to explain the different particle morphologies dried from solutions at different co-solvent compositions. The obtained numerical data clearly show that the two parameters controlling the general morphology of a dried particle, namely the Péclet number and the degree of saturation, can change with time in a multi-solvent droplet. This fact complicates product development for such systems. However, this additional complexity vanishes at what we define as the iso-compositional point, which occurs when the solvent ratios and other composition-dependent properties of the droplet remain constant during evaporation, similar to the azeotrope of such systems during distillation. CONCLUSIONS: Numerical and experimental analysis of multi-solvent systems indicate that spray-drying near the iso-compositional ratio simplifies the design and process development of such systems.

Correction to: Multi-Solvent Microdroplet Evaporation: Modeling and Measurement of Spray-Drying Kinetics with Inhalable Pharmaceutics.

The Publisher regrets having introduced the following errors into the article when performing proof corrections.

Aerosol drug delivery to the lungs during nasal high flow therapy: an in vitro study.

BACKGROUND: Aerosol delivery through a nasal high flow (NHF) system is attractive for clinicians as it allows for simultaneous administration of oxygen and inhalable drugs. However, delivering a fine particle fraction (FPF, particle wt. fraction < 5.0 µm) of drugs into the lungs has been very challenging, with highest value of only 8%. Here, we aim to develop an efficient nose-to-lung delivery system capable of delivering improved quantities (FPF > 16%) of dry powder aerosols to the lungs via an NHF system. METHODS: We evaluated the FPF of spray-dried mannitol with leucine with a next generation impactor connected to a nasopharyngeal outlet of an adult nasal airway replica. In addition, we investigated the influence of different dispersion (20-30 L/min) and inspiratory (20-40 L/min) flow rates, on FPF. RESULTS: We found an FPF of 32% with dispersion flow rate at 25 L/min and inspiratory flow rate at 40 L/min. The lowest FPF (21%) obtained was at the dispersion flow rate at 30 L/min and inspiratory flow rate at 30 L/min. A higher inspiratory flow rate was generally associated with a higher FPF. The nasal cannula accounted for most loss of aerosols. CONCLUSIONS: In conclusion, delivering a third of inhalable powder to the lungs is possible in vitro through an NHF system using a low dispersion airflow and a highly dispersible powder. Our results may lay the foundation for clinical evaluation of powder aerosol delivery to the lungs during NHF therapy in humans.

Anti-Tuberculosis Bacteriophage D29 Delivery with a Vibrating Mesh Nebulizer, Jet Nebulizer, and Soft Mist Inhaler.

PURPOSE: To compare titer reduction and delivery rate of active anti-tuberculosis bacteriophage (phage) D29 with three inhalation devices. METHODS: Phage D29 lysate was amplified to a titer of 11.8 ± 0.3 log10(pfu/mL) and diluted 1:100 in isotonic saline. Filters captured the aerosolized saline D29 preparation emitted from three types of inhalation devices: 1) vibrating mesh nebulizer; 2) jet nebulizer; 3) soft mist inhaler. Full-plate plaque assays, performed in triplicate at multiple dilution levels with the surrogate host Mycobacterium smegmatis, were used to quantify phage titer. RESULTS: Respective titer reductions for the vibrating mesh nebulizer, jet nebulizer, and soft mist inhaler were 0.4 ± 0.1, 3.7 ± 0.1, and 0.6 ± 0.3 log10(pfu/mL). Active phage delivery rate was significantly greater (p < 0.01) for the vibrating mesh nebulizer (3.3x108 ± 0.8x108 pfu/min) than for the jet nebulizer (5.4x104 ± 1.3x104 pfu/min). The soft mist inhaler delivered 4.6x106 ± 2.0x106 pfu per 11.6 ± 1.6 µL ex-actuator dose. CONCLUSIONS: Delivering active phage requires a prudent choice of inhalation device. The jet nebulizer was not a good choice for aerosolizing phage D29 under the tested conditions, due to substantial titer reduction likely occurring during droplet production. The vibrating mesh nebulizer is recommended for animal inhalation studies requiring large amounts of D29 aerosol, whereas the soft mist inhaler may be useful for self-administration of D29 aerosol.

Production of Inhalation Phage Powders Using Spray Freeze Drying and Spray Drying Techniques for Treatment of Respiratory Infections.

PURPOSE: The potential of aerosol phage therapy for treating lung infections has been demonstrated in animal models and clinical studies. This work compared the performance of two dry powder formation techniques, spray freeze drying (SFD) and spray drying (SD), in producing inhalable phage powders. METHOD: A Pseudomonas podoviridae phage, PEV2, was incorporated into multi-component formulation systems consisting of trehalose, mannitol and L-leucine (F1 = 60:20:20 and F2 = 40:40:20). The phage titer loss after the SFD and SD processes and in vitro aerosol performance of the produced powders were assessed. RESULTS: A significant titer loss (~2 log) was noted for droplet generation using an ultrasonic nozzle employed in the SFD method, but the conventional two-fluid nozzle used in the SD method was less destructive for the phage (~0.75 log loss). The phage were more vulnerable during the evaporative drying process (~0.75 log further loss) compared with the freeze drying step, which caused negligible phage loss. In vitro aerosol performance showed that the SFD powders (~80% phage recovery) provided better phage protection than the SD powders (~20% phage recovery) during the aerosolization process. Despite this, higher total lung doses were obtained for the SD formulations (SD-F1 = 13.1 ± 1.7 × 10(4) pfu and SD-F2 = 11.0 ± 1.4 × 10(4) pfu) than from their counterpart SFD formulations (SFD-F1 = 8.3 ± 1.8 × 10(4) pfu and SFD-F2 = 2.1 ± 0.3 × 10(4) pfu). CONCLUSION: Overall, the SD method caused less phage reduction during the powder formation process and the resulted powders achieved better aerosol performance for PEV2.

Low re-inhalation of the exhaled flow during normal nasal breathing in a pediatric airway replica.

To estimate the fraction of the exhaled airflow that is re-inhaled during normal nasal breathing, experiments were carried out in a water tank with an anatomically accurate respiratory tract model of a 4-year-old child. The velocity of respiratory flow was scaled using similarity laws between air and water. Breath simulation was performed via a computer-controlled piston-cylinder system. Food-dye visualization allows a qualitative analysis of the re-inhaled fraction of this exhaled flow. For the quantitative analysis, neutrally buoyant particles were added to the water medium, and illuminated by the laser which illuminates the whole breathing region of the respiratory model, such that the trajectory and quantity of the re-inhaled particles can be recorded and counted. The experimental results in the pediatric airway replica show that a negligible fraction (<0.06%) of the exhaled airflow is re-inhaled during normal nasal breathing in the absence of the rising thermal plume. The artificial plume generated by a heated aluminium brick at the tank bottom increases the re-inhalation ratio by 4 times under the investigated case (albeit still at a very low value of 0.15%). Our results thus reveal that during normal nasal breathing in the present pediatric subject, the vast majority of human exhaled airflow escapes from the inhalation zone and is not re-inhaled.

Aerosol phage therapy efficacy in Burkholderia cepacia complex respiratory infections.

Phage therapy has been suggested as a potential treatment for highly antibiotic-resistant bacteria, such as the species of the Burkholderia cepacia complex (BCC). To address this hypothesis, experimental B. cenocepacia respiratory infections were established in mice using a nebulizer and a nose-only inhalation device. Following infection, the mice were treated with one of five B. cenocepacia-specific phages delivered as either an aerosol or intraperitoneal injection. The bacterial and phage titers within the lungs were assayed 2 days after treatment, and mice that received the aerosolized phage therapy demonstrated significant decreases in bacterial loads. Differences in phage activity were observed in vivo. Mice that received phage treatment by intraperitoneal injection did not demonstrate significantly reduced bacterial loads, although phage particles were isolated from their lung tissue. Based on these data, aerosol phage therapy appears to be an effective method for treating highly antibiotic-resistant bacterial respiratory infections, including those caused by BCC bacteria.

Comparison of in vitro deposition of pharmaceutical aerosols in an idealized child throat with in vivo deposition in the upper respiratory tract of children.

PURPOSE: Deposition of drug emitted from two commercially available inhalers was measured in an in vitro child oral airway model and compared to existing in vivo data to examine the ability of the child model to replicate in vivo deposition. METHODS: In vitro deposition of drug from a QVAR® pressurized metered dose inhaler (pMDI) and Pulmicort® Turbuhaler® dry powder inhaler (DPI) in an Idealized Child Throat (1) and downstream filter was measured using UV spectroscopy and simulated realistic breathing profiles. Potential effects of ambient relative humidity ranging from 10% to 90% on deposition were also considered. RESULTS: In vitro QVAR pMDI deposition in the idealized mouth-throat at 50% RH (39.2 ± 2.3% of delivered dose) compared well (p>0.05) with in vivo extrathoracic deposition in asthmatic children age 8 to 14 (45.8 ± 12.3%). In vitro Turbuhaler DPI deposition in the idealized mouth-throat at 50% RH (69.0 ± 1.5%) matched in vivo extrathoracic deposition (p>0.05) in 6 to 16 year old children with cystic fibrosis (70.4 ± 21.2%). The effects of ambient humidity were found to be insignificant for Turbuhaler and minor for QVAR. CONCLUSIONS: The Idealized Child Throat successfully mimics in vivo deposition data in school age children for the inhalers tested, and may provide a standard platform for optimizing pediatric treatment with inhaled pharmaceutical aerosols.

Use of a fundamental approach to spray-drying formulation design to facilitate the development of multi-component dry powder aerosols for respiratory drug delivery.

PURPOSE: A fundamental approach incorporating current theoretical models into aerosol formulation design potentially reduces experimental work for complex formulations. A D-amino acid mixture containing D-Leucine (D-Leu), D-Methionine, D-Tryptophan, and D-Tyrosine was selected as a model formulation for this approach. METHODS: Formulation design targets were set, with the aim of producing a highly dispersible D-amino acid aerosol. Particle formation theory and a spray dryer process model were applied with boundary conditions to the design targets, resulting in a priori predictions of particle morphology and necessary spray dryer process parameters. Two formulations containing 60% w/w trehalose, 30% w/w D-Leu, and 10% w/w remaining D-amino acids were manufactured. RESULTS: The design targets were met. The formulations had rugose and hollow particles, caused by deformation of a crystalline D-Leu shell while trehalose remained amorphous, as predicted by particle formation theory. D-Leu acts as a dispersibility enhancer, ensuring that both formulations: 1) delivered over 40% of the loaded dose into the in vitro lung region, and 2) achieved desired values of lung airway surface liquid concentrations based on lung deposition simulations. CONCLUSIONS: Theoretical models were applied to successfully achieve complex formulations with design challenges a priori. No further iterations to the design process were required.

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.