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.

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.

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.

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.

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.

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.

Characterization of dry powder inhaler performance through experimental methods.

Experimental methods provide means for the quality control of existing DPIs and for exploring the influence of formulation and device parameters well in advance of clinical trials for novel devices and formulations. In this review, we examine the state of the art of in vitro testing of DPIs, with a focus primarily on the development of accurate in vitro-in vivo correlations. Aspects of compendial testing are discussed, followed by the influence of flow profiles on DPI performance, the characterization of extrathoracic deposition using mouth-throat geometries, and the characterization of regional thoracic deposition. Additional experimental methods that can inform the timing of bolus delivery, the influence of environmental conditions, and the development of electrostatic charge on aerosolized DPI powders are reviewed. We conclude with perspectives on current in vitro methods and identify potential areas for future investigation, including the estimation of variability in deposition, better characterization of existing compendial methods, optimization of formulation and device design to bypass extrathoracic deposition, and the use of novel tracheobronchial filters that aim to provide more clinically relevant measures of performance directly from in vitro testing.

Intranasal delivery of a synthetic Entamoeba histolytica vaccine containing adjuvant (LecA + GLA-3 M-052 liposomes): In vitro characterization.

Amebiasis, a disease caused by the parasite Entamoeba histolytica, is estimated to cause millions of infections and at least 55,000 deaths globally each year. With no vaccine currently available, there is an urgent need for an accessible means of stimulating protective mucosal immunity. The objective of this study was to characterize the nasal spray of a novel amebiasis vaccine candidate from a syringe-based liquid atomization device, the Teleflex MAD Nasal™, in both adult and infant nasal airways. Human ergonomic testing was completed to determine realistic actuation parameters. Spray pattern, plume geometry, and droplet size distribution were measured to evaluate reproducibility of free plume characteristics. The Alberta Idealized Nasal Inlet (AINI) and three realistic infant nasal airways were used to determine the in vitro deposition profile in adult and infant airways, respectively. Collectively, in vitro results demonstrated the feasibility of delivering the vaccine candidate to target sites within the nasal airways. Penetration through the nasal airways that could lead to deposition in the lungs was below the limit of quantification for both adult and infant geometries, indicating a low likelihood of adverse events due to lung exposure. These results support continued investigation of intranasal delivery of the synthetic Entamoeba histolytica vaccine.

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.

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.

Size-Specific Filtration Performance of N95 Respirators After Decontamination by Moist Heat Incubation.

Background: Decontamination and reuse of respirators have been proposed to mitigate the shortage of respirators during pandemics. The U.S. National Institute for Occupational Safety and Health (NIOSH)'s respirator filtration efficiency (FE) test has been used to confirm that decontamination procedures maintain minimum FE above 95% for N95s and similar respirators. However, it was hypothesized that the limited range of test particle sizes may not include the most penetrating particle size (MPPS) for all respirators, especially after decontamination by moist heat incubation (MHI). Materials and Methods: A custom-designed apparatus was used to measure size-specific FE for respirators across particle size bins between aerodynamic diameter of 0.07 and 1.97 µm using an electrical low-pressure impactor. FEs were measured for two N95 respirator models before and after 10 cycles of MHI. In addition, pressure drop through the respirator materials and scanning electron microscope (SEM) images of respirator layers were obtained before and after MHI. Results: For Kimtech™ brand N95 respirators, FE was not reduced at any size after MHI. For Safe Life brand N95s, FE was below 95% before MHI and decreased significantly after MHI. The MPPS for this respirator was outside the range defined in NIOSH test protocol, and increased after MHI. There was no appreciable change to the pressure drop through the two respirator models after MHI, nor was any deterioration in fiber integrity visible in SEM images. Conclusions: Based on the results of the present study and other studies in the literature, MHI can be used to decontaminate respirators without significant decrease in FE. However, potential effects of MHI on FE need to be assessed for each respirator model. The ability to evaluate size-specific FE across a wide range of particle sizes is important in identifying the MPPS and associated FE of respirators before and after MHI.

Pulsatile Bi-Directional Aerosol Flow Affects Aerosol Delivery to the Intranasal Olfactory Region: A Patient-Specific Computational Study.

The nasal olfactory region is a potential route for non-invasive delivery of drugs directly from the nasal epithelium to the brain, bypassing the often impermeable blood-brain barrier. However, efficient aerosol delivery to the olfactory region is challenging due to its location in the nose. Here we explore aerosol delivery with bi-directional pulsatile flow conditions for targeted drug delivery to the olfactory region using a computational fluid dynamics (CFD) model on the patient-specific nasal geometry. Aerosols with aerodynamic diameter of 1 µm, which is large enough for delivery of large enough drug doses and yet potentially small enough for non-inertial aerosol deposition due to, e.g., particle diffusion and flow oscillations, is inhaled for 1.98 s through one nostril and exhaled through the other one. The bi-directional aerosol delivery with steady flow rate of 4 L/min results in deposition efficiencies (DEs) of 50.9 and 0.48% in the nasal cavity and olfactory region, respectively. Pulsatile flow with average flow rate of 4 L/min (frequency: 45 Hz) reduces these values to 34.4 and 0.12%, respectively, and it mitigates the non-uniformity of right-left deposition in both the cavity (from 1.77- to 1.33-fold) and the olfactory region (from 624- to 53.2-fold). The average drug dose deposited in the nasal cavity and the olfactory epithelium region is very similar in the right nasal cavity independent of pulsation conditions (inhalation side). In contrast, the local aerosol dose in the olfactory region of the left side is at least 100-fold lower than that in the nasal cavity independent of pulsation condition. Hence, while pulsatile flow reduces the right-left (inhalation-exhalation) imbalance, it is not able to overcome it. However, the inhalation side (even with pulsation) allows for relatively high olfactory epithelium drug doses per area reaching the same level as in the total nasal cavity. Due to the relatively low drug deposition in olfactory region on the exhalation side, this allows either very efficient targeting of the inhalation side, or uniform drug delivery by performing bidirectional flow first from the one and then from the other side of the nose.

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.

A simple HEPA filtering facepiece.

Shortages of efficient filtering facepiece respirators leave the public vulnerable to transmission of infectious diseases in small particle aerosols. This study demonstrates that a high-filtration-efficiency facepiece capable of filtering out >95% of 0.05µm particles while being worn can be simply produced with available materials.

Feasibility of three-dimensional facial imaging and printing for producing customised nasal masks for continuous positive airway pressure.

RATIONALE: Delivery of continuous positive airway pressure (CPAP) is the standard treatment for obstructive sleep apnoea in children and adults. Treatment adherence is a major challenge, as many patients find the CPAP mask uncomfortable. The study aim was to demonstrate the feasibility of delivered CPAP through customised nasal masks by assessing mask leak and comfort of customised masks compared to commercially available CPAP masks. METHODS: Six healthy adult volunteers participated in a crossover study including commercial masks in three different sizes (petite, small/medium and large) from the same supplier and a customised mask fabricated for each subject using three-dimensional facial scanning and modern additive manufacturing processes. Mask leak and comfort were assessed with varying CPAP levels and mask tightness. Leak was measured in real time using an inline low-resistance Pitot tube flow sensor, and each mask was ranked for comfort by the subjects. RESULTS: Mask leak rates varied directly with CPAP level and inversely with mask tightness. When ranked for comfort, three subjects favoured the customised mask, while three favoured a commercial mask. The petite mask yielded the highest mask leaks and was ranked least comfortable by all subjects. Relative mask leaks and comfort rankings for the other commercial and customised masks varied between individuals. Mask leak was comparable when comparing the customised masks with the highest ranked commercial masks. CONCLUSION: Customised masks successfully delivered target CPAP settings in all six subjects, demonstrating the feasibility of this approach.

Regional Deposition: Targeting.

Patterns of regional aerosol deposition within the lungs are known to vary in a predictable manner with a number of factors, most notably aerodynamic particle size and inhalation pattern. Targeting deposition involves the intentional manipulation of one or more of these factors to promote aerosol deposition in certain locations within the respiratory tract. This section will begin by exploring existing evidence supporting the need to target regional deposition. Thereafter, various approaches to targeting will be introduced. In addition to control of aerodynamic particle size and inhalation pattern, a collection of approaches are available through which to passively target deposition to more central or peripheral lung regions. These include the delivery of short aerosol boluses at prescribed time points in inhalation, control of transient hygroscopic aerosol size changes during transport through the respiratory tract, and use of alternative carrier gas mixtures such as helium/oxygen mixtures. Comparatively, targeting aerosol deposition locally to very precise, spatially-defined lung regions is in its infancy. Early, exploratory techniques used for local targeting will be described. The continued evolution of deposition targeting towards ever more specific locations within the lungs is required to explore fundamental research questions in aerosol medicine: namely, how precise does targeting need to be before additional refinement fails to produce appreciably different therapeutic effects, and which nascent applications of aerosols in medicine might benefit from more selective regional targeting?

Inhaled Nitric Oxide: In Vitro Analysis of Continuous Flow Noninvasive Delivery via Nasal Cannula.

BACKGROUND: Inhaled nitric oxide (NO) is most frequently delivered to mechanically ventilated patients in critical care, but it can also be administered noninvasively. The delivered dose and efficiency of continuous flow NO supplied through a nasal cannula has yet to be established. This study aimed to determine the influence of nasal cannula type, supply flow, and breathing pattern on delivered NO using a realistic adult airway replica and lung simulator. METHODS: Simulated breathing patterns were selected to represent rest, sleep, and light exercise, and were varied to investigate the effects of tidal volume and breathing frequency independently. Supplied gas flows targeted tracheal concentrations at rest of 5 or 20 ppm NO and were supplied with 2 L/min O2. Three different cannulas were tested. Tracheal NO concentrations and NO mass flow past the trachea were evaluated. RESULTS: Cannula type had a minor influence on delivered dose. Tracheal NO concentrations differed significantly based on breathing pattern (P < 0.01); for a target NO concentration of 20 ppm at rest, average inhaled NO concentrations were 23.3 ± 0.5 ppm, 36.5 ± 1.4 ppm, and 17.2 ± 0.3 ppm for the rest, sleep, and light exercise breathing patterns, respectively. For the same test conditions, mass flow of NO past the trachea was less sensitive to breathing pattern: 20.3 ± 0.5 mg/h, 19.9 ± 0.8 mg/h, and 24.3 ± 0.4 mg/h for the rest, sleep, and light exercise breathing patterns, respectively. Mass flow and delivery efficiency increased when minute volume increased. CONCLUSIONS: These results indicate that inhaled NO concentration is strongly influenced by breathing pattern, whereas inhaled NO mass flow is not. NO mass flow may therefore be a useful dose metric for continuous flow delivery via nasal cannula.