High flow nasal cannula: Influence of gas type and flow rate on airway pressure and CO2 clearance in adult nasal airway replicas.

BACKGROUND: High flow nasal cannula therapy is a form of respiratory support which delivers high flow rates of heated, humidified gas to the nares via specialized cannula. Two primary mechanisms of action attributed to the therapy are the provision of positive airway pressure as well as clearance of CO2-rich exhaled gas from the upper airways. METHODS: Physiologically accurate nose-throat airway replicas were connected at the trachea to a lung simulator, where CO2 was supplied to mimic the CO2 content in exhaled gas. Cannula delivered either air, oxygen or heliox (80/20%volume helium/oxygen) to the replicas at flow rates ranging from 0 to 60 l/min. Five replicas and three cannulas were compared. Tracheal pressure and CO2 concentration were continuously measured. The lung simulator provided breaths with tidal volume of 500 ml and frequency of 18 breaths/min. Additional clearance measurements were conducted for tidal volume and breathing frequency of 750 ml and 27 breaths/min, respectively. FINDINGS: Cannula flow rate was the dominant factor governing CO2 concentration. Average CO2 concentration decreased with increasing cannula flow rate, but above 30 L/min this effect was less pronounced. Tracheal positive end-expiratory pressure increased with flow rate and was lower for heliox than for air or oxygen. A predictive correlation was developed and used to predict positive end-expiratory pressure for a given cannula size as a function of supplied flow rate and occlusion of the nares. INTERPRETATION: Compared with administration of air or oxygen, administration of heliox is expected to result in similar CO2 clearance from the upper airway, but markedly lower airway pressure.

Topical contrast agents to improve soft-tissue contrast in the upper airway using cone beam CT: a pilot study.

The purpose of this study is to explore the topical use of radiographic contrast agents to enhance soft-tissue contrast on cone beam CT (CBCT) images. Different barium sulphate concentrations were first tested using an airway phantom. Different methods of barium sulphate application (nasal drops, syringe, spray and sinus wash) were then tested on four volunteers, and nebulized iodine was tested in one volunteer. CBCT images were performed and then assessed subjectively by two examiners for contrast agent uniformity and lack of streak artefact. 25.0% barium sulphate presented adequate viscosity and radiodensity. Barium sulphate administered via nasal drops and sprays showed non-uniform collection at the nostrils, along the inferior and/or middle nasal meatuses and posterior nasal choana. The syringe and sinus wash showed similar results with larger volumes collecting in the naso-oropharynx. Nebulized iodine failed to distribute into the nasal cavity and scarcely collected at the nostrils. All methods of nasal application failed to adequately reach or uniformly coat the nasal cavity beyond the inferior nasal meatuses. The key factors to consider for optimum topical radiographic contrast in the nasal airway are particle size, flow velocity and radio-opacity.

An in vitro study on the deposition of micrometer-sized particles in the extrathoracic airways of adults during tidal oral breathing.

Deposition of particles in the aerodynamic diameter range of 0.5-6.7 µm was measured in nine replicas of the extrathoracic airways of adults with four sinusoidal patterns and oral breathing. The four chosen breathing patterns are typical of those occurring during natural resting breathing and during nebulization therapy. Additionally, deposition of micrometer-sized particles in the "Alberta Idealized Adult Throat," which was previously found useful in simulating the average deposition of particles during inhalation of constant flow rates, was measured during inhalation of the four sinusoidal patterns in this study. To reduce intersubject scatter in developing predictive correlations, the non-dimensional Reynolds (Re) and Stokes (Stk) numbers are used with the square root of the average cross sectional area of the oral airways as the characteristic diameter being found to reduce intersubject variability to the highest extent. Our best fit to the deposition data is given by η = [1 - 1/(1.51 x 10(5)(Stk(3.03)Re(0.25)) + 1)] x 100. Moreover, the "Alberta Idealized Adult Throat" is found to mimic average deposition, given in past in vivo studies, in the upper airways of adults during natural tidal breathing.

Simulation of enhanced deposition due to magnetic field alignment of ellipsoidal particles in a lung bifurcation.

BACKGROUND: Aerosolized chemotherapy has been recognized as a potential treatment for lung cancer. The challenge of providing sufficient therapeutic effects without reaching dose-limiting toxicity levels hinders the development of aerosolized chemotherapy. This could be mitigated by increasing drug-delivery efficiency with a noninvasive drug-targeting delivery method. The purpose of this study is to use direct numerical simulations to study the resulting local enhancement of deposition due to magnetic field alignment of high aspect ratio particles. METHODS: High aspect ratio particles were approximated by a rigid ellipsoid with a minor diameter of 0.5 µm and fluid particle density ratio of 1,000. Particle trajectories were calculated by solving the coupled fluid particle equations using an in-house micro-macro grid finite element algorithm based on a previously developed fictitious domain approach. Particle trajectories were simulated in a morphologically realistic geometry modeling a symmetrical terminal bronchiole bifurcation. Flow conditions were steady inspiratory air flow due to typical breathing at 18 L/min. Deposition efficiency was estimated for two different cases: [1] particles aligned with the streamlines and [2] particles with fixed angular orientation simulating the magnetic field alignment of our previous in vitro study. RESULTS: The local enhancement factor defined as the ratio between deposition efficiency of Case [1] and Case [2] was found to be 1.43 and 3.46 for particles with an aspect ratio of 6 and 20, respectively. CONCLUSIONS: Results indicate that externally forcing local alignment of high aspect ratio particles can increase local deposition considerably.

In vitro lung delivery of bacteriophages KS4-M and ΦKZ using dry powder inhalers for treatment of Burkholderia cepacia complex and Pseudomonas aeruginosa infections in cystic fibrosis.

AIMS: To determine the feasibility of formulating and aerosolizing powders containing bacteriophages KS4-M and ΦKZ for lung delivery and treatment of pulmonary Burkholderia cepacia complex and Pseudomonas aeruginosa infections. METHODS AND RESULTS: Endotoxin-removed bacteriophages KS4-M and ΦKZ were lyophilized in lactose/lactoferrin 60 : 40 w/w matrix and deagglomerated in a mixer mill (without beads) to formulate respirable powders. The powders were then aerosolized using an Aerolizer(®) capsule inhaler. Mass median aerodynamic diameter (MMAD) of this inhalable aerosol was determined using Andersen cascade impactor at 60 l min(-1). Measured MMAD for both types of powders was 3·4 µm, and geometric standard deviation was 1·9-2·0. Viability of bacteriophages delivered distal to an idealized mouth-throat replica was determined from bioassays of samples collected on filters placed after the idealized replica. As a percentage of inhaler load, amount of powder delivered distal to the mouth-throat replica, which is a measure of lung delivery, was 33·7 ± 0·3% for KS4-M and 32·7 ± 0·9% for ΦKZ. Titres collected downstream of the mouth throat were (3·4 ± 2·5) × 10(6) PFU for KS4-M with an Aerolizer capsule load of (9·8 ± 4·8) × 10(6) and (1·9 ± 0·6) × 10(7) for ΦKZ with an Aerolizer capsule load of (6·5 ± 1·9) × 10(7). CONCLUSIONS: Bacteriophages KS4-M and ΦKZ can be lyophilized without significant loss of viability in a lactose/lactoferrin 60 : 40 w/w matrix. The resulting powders can be aerosolized to deliver viable bacteriophages to the lungs. SIGNIFICANCE AND IMPACT OF THE STUDY: Development of lactoferrin-based bacteriophage aerosol powders solidifies the ground for future research on developing novel formulations as an alternative to inhaled antibiotic therapy in patients with cystic fibrosis.

Changes in collection efficiency in nylon net filter media through magnetic alignment of elongated aerosol particles.

Fiber aerosols tend to align parallel to surrounding fluid streamlines in shear flows, making their filtration more difficult. However, previous research indicates that composite particles made from cromoglycic acid fibers coated with small nanoscaled magnetite particles can align with an applied magnetic field. The present research explored the effect of magnetically aligning these fibers to increase their filtration. Nylon net filters were challenged with the aerosol fibers, and efficiency tests were performed with and without a magnetic field applied perpendicular to the flow direction. We investigated the effects of varying face velocities, the amount of magnetite material on the aerosol particles, and magnetic field strengths. Findings from the experiments, matched by supporting single-fiber theories, showed significant efficiency increases at the low face velocity of 1.5 cm s(-1) at all magnetite compositions, with efficiencies more than doubling due to magnetic field alignment in certain cases. At a higher face velocity of 5.12 cm s(-1), filtration efficiencies were less affected by the magnetic field alignment being, at most, 43% higher for magnetite weight compositions up to 30%, while at a face velocity of 10.23 cm s(-1) alignment effects were insignificant. In most cases, efficiencies became independent of magnetic field strength above 50 mT, suggesting full alignment of the fibers. The present data suggest that fiber alignment in a magnetic field may warrant applications in the filtration and detection of fibers, such as asbestos.

Formulation and in vivo evaluation of effervescent inhalable carrier particles for pulmonary delivery of nanoparticles.

The purpose of this study was to evaluate the safety of a new inhalable effervescent carrier preparation containing model nanoparticles. Spray-freeze drying was used to prepare inhalable powders containing butylcyanoacrylate nanoparticles. The particle size of the nanoparticles before incorporation into the effervescent carrier and after dissolving the carrier powder was measured using laser light scattering. The particle size distribution of the effervescent carrier aerosol particles was measured using a cascade impactor. The prepared powder was tested in vivo using five Balb/c nude mice. The animals were treated with 1 mg of inhalable powder every week for 4 weeks. The body weight and morbidity score of the mice were observed over an 8-week period. The effervescent activity of the inhalable nanoparticle powder was observed when the powder was exposed to humidity. The particle size of the nanoparticles did not change significantly after spray-freeze drying. The mass median aerodynamic diameter (MMAD) of the prepared powder was 4.80 +/- 2.12 microm, which is suitable for lung delivery. The animals that were treated with effervescent powder tolerated the administration without any changes in their morbidity scores. Our pilot study demonstrates that pulmonary nanoparticle delivery via effervescent carrier particles appears safe in the present animal model.

Modeling of aerosol deposition with interface devices.

Various approaches can be used to mathematically model the performance of different masks, mouthpieces, and aerosol delivery devices. The sophistication of such models can vary widely, from the use of simple algebraic empirical correlations to advanced computational fluid dynamics simulations. Bench-top testing is also often used to model aspects of devices, since it is difficult to capture certain aspects of device behavior with mathematical models. These various approaches to modeling differ in their limitations. Empirical correlations exist for predicting the effects of varying mouthpiece diameter and mouth-throat dimensions on extrathoracic losses, but are restricted to stable, nonballistic aerosols in certain flow rate ranges. Computational fluid dynamics (CFD) simulations that solve the Reynolds-averaged Navier-Stokes (RANS) equations typically require near-wall turbulence corrections in order to adequately model mouth-throat deposition, while Large Eddy Simulation (LES) removes this deficiency. Bench-top models that use replicas of the extrathoracic airways vary in their accuracy and generality in replicating the filtering properties of these airways. Choosing and using these various modeling approaches for evaluating patient-device interfaces requires knowledge of their merits and pitfalls, a brief discussion of which is given here.

A dry powder inhaler with reduced mouth-throat deposition.

A novel, compact, and highly efficient dry powder inhaler (DPI) with low mouth-throat deposition is described. The performance of this DPI was evaluated by measuring both (1) the total aerosol deposition in and distal to an idealized mouth-throat cast and (2) the fine particle fraction (FPF) using a standard Mark II Anderson impactor. Ultraviolet (UV) spectroscopy techniques were used in the aerosol deposition measurements. Two inhalation aerosol powders, namely budesonide (extracted from a Pulmicort/Turbuhaler multi-dose device, 200 microg/dose) and ciprofloxacin + lipid + lactose (in-house), were dispersed by the DPI at a steady inhalation flow rate of 60 L/min. The newly developed DPI had a total aerosol delivery distal to the mouth-throat cast of 50.5% +/- 3.04% and 69.7% +/- 1.5% for the budesonide and ciprofloxacin + lipid + lactose aerosols, respectively. This is a significant improvement over the Turbuhaler original device delivery of 34.5% +/- 5.2%, particularly considering that in vitro mouth-throat deposition dropped from 27.5% +/- 5.4% with the budesonide Turbuhaler to 11.0% +/- 3.5% with the present inhaler. The different lung deliveries from the same inhaler for the two formulations above also confirm that the overall performance of an inhaler is optimizable via powder formulations.

Medical and pharmaceutical nanoengineering conference/International conference on MEMS, nano and smart systems.

Researchers representing all the northern hemispheric continents gathered for 3 days in Banff, Canada, to hear a wide range of talks on the application of micro- and nanotechnology to drug delivery. Topics included nanotubes, nanoparticles, liposomes, micelles, novel inhaled aerosols, antibody engineering and vaccines. Also featured were talks on the application of micro- and nanotechnology to diagnostics, including microfluidics, as well as biomolecular computing. The conference showcased the first demonstration of preliminary concepts for "smart particle aerosols", in which nanofabrication methods are used to produce inhaled aerosol particles with "intelligent" features. The conference provided an excellent forum for cross-fertilisation and discussion between disciplines, with attendees covering a broad range of areas in engineering and the physical and life sciences that are not often found together at a single conference. This breadth of attendees and topics provided a highly stimulating environment. An invitation to next year's conference (24-29 July 2005, Banff, Alberta, Canada) was extended, as listed at the conference website [101].

The effect of breathing pattern on nebulizer drug delivery.

The significance of using breathing patterns with simplified functional shapes in vented jet nebulizer research is examined. This study is comprised of three parts: (1) The measurement and analysis of human breathing patterns, (2) the subsequent in vitro testing of the effects of breathing pattern differences using a consistent bench test method, and (3) a computer modeling of these effects on the estimated regional drug deposition in the human lung. Breathing through a Pari LC-Star nebulizer caused statistically significant changes (p < or = 0.05) in measured human breathing patterns when compared to normal breathing. Observed changes included an increase in the tidal volume (34%) and period (39%). Additionally, the average duty cycle shifted 12% towards a more symmetrical breath due to the unequal increase in the inhalation and exhalation times (55% and 28%, respectively). The position of the point of maximum flow in each breath phase shifted towards the beginning and end of the breath for the inhale and exhale by 28% and 48%, respectively. The bench testing revealed that breathing pattern shape variation caused statistically significant differences in nebulizer output only in two cases. Decreasing duty cycles and shifting the point of maximum flow towards the beginning of the breath both result in a decrease in output efficiency. Square flow patterns produced slight but consistently higher output efficiencies (average 2.1% higher) and a constant output particle size over the course of each breath, different from the other non-square patterns. Numerical simulations revealed no significant dosage differences resulting from breathing pattern shape variations. However, square wave patterns consistently produced slight overpredictions in comparison with real nebulizer patterns. In contrast, sine wave patterns were found to produce essentially the same results as nebulizer patterns in both the bench tests and in the deposition simulations. This suggests that sine wave shapes are preferable for simulating breathing when bench testing drug delivery using vented jet nebulizers.

In vitro aerosol delivery and regional airway surface liquid concentration of a liposomal cationic peptide.

A liposome encapsulation was optimized for the entrapment and aerosol delivery of an alpha-helical cationic peptide, CM3, which had shown good antimicrobial and antiendotoxin activity in vitro. The encapsulation procedure and the phospholipids used were selected to maximize both the encapsulation and nebulization efficiencies, without compromising liposomal integrity during nebulization. The best compromise was found with dimyristoyl phosphatidylcholine and dimyristoyl phosphatidylglycerol (3:1 molar ratio), which allowed for peptide encapsulation levels of 730 microg/mL using 30 mM lipid concentration. The aerosol produced with the selected liposomal formulation was subsequently analyzed for determination of size distribution and nebulizer efficiencies. These quantities were used as input for a mathematical lung deposition model, which predicted local lung depositions of the liposomal peptides for three models of lung geometry and breathing patterns: an adult, an 8-year-old child, and a 4-year-old child. The deposition results were then applied to a novel model of airway surface liquid in the lung to assess the concentration of the deposited peptide. The resulting concentration estimates indicate that the minimum inhibitory levels of CM3 can be reached over most part of the tracheobronchial region in the adult model, and can be exceeded throughout the same region in both pediatric model subjects, using a valved jet nebulizer with a 2.5mL volume fill.

In vitro monodisperse aerosol deposition in a mouth and throat with six different inhalation devices.

Experiments were performed to determine the effect of different pharmaceutical aerosol inhalation devices on the deposition of monodisperse aerosols in an idealized mouth and throat geometry. The devices included two dry powder inhalers (Diskus and Turbuhaler), two nebulizers (Pari LC STAR and Hudson T-Updraft), and a metered dose inhaler with attached holding chamber (Aerochamber), in addition to a straight tube (1.7 cm inner diameter). Aerosol particles (DL-alpha tocopheryl acetate) of diameters of 2.5, 5, and 7 microm generated by a vibrating orifice generator were inhaled at steady air flow rates of Q = 5-90 L/min through the devices and into the mouth-throat. Deposition in the mouth-throat and after-filter were determined by ultraviolet (UV) spectrophotometric assay. The amount of deposition in the mouth and throat region was found to depend on the type of device that the aerosol entered through. Deposition in the extrathoracic region with the two types of jet nebulizers did not differ significantly (p > 0.1) from that of a straight tube or each other over their entire tested range of 590 > or = pd2Q > or = 11,375, where p is particle density (in g/cm3), d is particle diameter (in microm), and Q is flow rate (in cm3/s). The metered dose inhaler with attached holding chamber was found to differ from the straight tube only at two intermediate values of pd2Q = 5,145 and 16,033. The deposition occurring for the dry powder inhalers was found to be significantly greater than for the straight tube for all values of pd2Q > or = 10,954 for the Diskus and pd2Q > or = 9,435 for the Turbuhaler. Deposition with the dry powder inhalers was found to be up to 14 times greater than that with the straight tube. Thus, the inhaler geometry that the aerosol passes through prior to entering the mouth and throat region can greatly affect the deposition in the mouth-throat.

Determination of surface free energy of interactive dry powder liposome formulations using capillary penetration technique.

The surface free energy of interactive dry powder formulations consisting of varying ratios of lactose plus liposomal ciprofloxacin were determined using capillary penetration technique. Powder is produced by jet-milling after mixing with lyophilized liposomal ciprofloxacin with inhalation grade lactose powder (Pharmatose 325M). Measurement of the weight gained during intrusion of different liquids in a packed column of powder is combined with dynamic considerations to give the surface free energy, gamma(sv). Confidence in methodology was gained by determining gamma(sv) for PMMA microspheres and comparing to literature values. Values of gamma(sv) are then obtained for unmilled Pharmatose 325M powder (gamma(sv)=54.2 mJ m(-2)), milled Pharmatose 325M (gamma(sv)=54.2 mJ m(-2)) and lipid:lactose formulations with weight ratios of 1:5, 1:10 and 1:20. All the powder liposomal formulations are found to have the same gamma(sv)=48.0 mJ m(-2), suggesting that adhesive forces in the three interactive powders should be similar barring any confounding roughness effects.

Mapping PET-measured triamcinolone acetonide (TAA) aerosol distribution into deposition by airway generation.

The three dimensional (3D) distribution of inhaled drugs was measured using Positron Emission Tomography (PET) (Berridge, M.S, Muswick, G.J., Lee, Z., Leisure, G.L., Nelson, A.D., Muzic, R.F. Jr., Miraldi, F., Heald, D.L., 1997. PET evaluation of Azmacort(R) ([C-11]triamcinolone acetonide) dose administration. J. Nucl. Med. 38 (5) Suppl., 4-5). Data analysis was based upon regional ratios or penetration indices. To improve the analytical usefulness and objectivity, labeled drug from dynamic PET images was mapped into 23 airway generations following a general framework from a SPECT-based methodology (Fleming, J.S., Nassim, M.A., Hashish, A.H., Bailey, A.G. , Conway, J., Holgate, S., Halson, P., Moore, E., Martonen, T.B., 1995. Description of pulmonary deposition of radiolabeled aerosol by airway generation using a conceptual three dimensional model of lung morphology. J. Aerosol Med. 8, 341-356). A recently developed airway network model was used in this study. Quantitative PET scans of [C-11]triamcinolone acetonide distribution in the lung were determined following administration of Azmacort(R), a commercial metered dose inhaler with an integrated spacer device. Distributions at varying time periods after drug administration were investigated to explore the dynamics and kinetics of the aerosolized drug. Initially, deposition of labeled drug on conducting airways (generations 1-14) was found to be higher than those on acinar airways (generation 15-23), 64% versus 36%. The distribution pattern changed slowly with time. By 47 min, 51% of the dose remaining in the lung was found on conducting airways while 49% was on acinar airways. This study illustrates the value of PET imaging for the evaluation and design of drug formulations.

Overcoming the adverse effect of humidity in aerosol delivery via pressurized metered-dose inhalers during mechanical ventilation.

The well-known problem of reduced drug delivery that occurs when heated, humid air is used with pressurized metered-dose inhalers (pMDIs) and spacers in intubated settings is carefully studied with Airomir using an in vitro model under controlled conditions of temperature and humidity. A better understanding of the physical processes leading to the aforementioned drop in performance is obtained, and a method is devised to circumvent the problem without having to reduce the temperature or humidity of the ventilator circuit. The present study shows that the mole fraction of water vapor in the ventilation air (and not the temperature) is the major factor behind the sharp drop in the amount of drug delivered to the lung. However, the presence of water vapor does not affect performance because of hygroscopic growth. Instead, it influences the initial atomization process and the early stages of aerosol generation. Removal of these negative effects can be achieved by using a larger spacer that allows longer times for the aerosol to evaporate, as is demonstrated in the present study.

Lung delivery of aerosolized dextran.

The ability of nebulizers to deliver dextran (nominal molecular mass, 4,000 g/mol) to the lung as an inhaled aerosol is evaluated by in vitro experimental methods and mathematical models. Dextran in isotonic saline was aerosolized by four nebulizer types (Pari LC STAR, Hudson T-Updraft II, Acorn II, and Sonix 2000) at dextran concentrations

Inertial sizing of aerosol inhaled from two dry powder inhalers with realistic breath patterns versus constant flow rates.

A procedure is developed that allows particles inhaled with realistic breath patterns to be sized by cascade impaction at a constant flow rate. This procedure is then used to examine the difference between particle sizes obtained with constant flow rate (step profile) versus actual-subject breath patterns for two dry powder inhalers DPIs: the Ventodisk and Spiros inhalers (delivering salbutamol sulphate). Aerosol inhaled from the DPIs by a breath simulator was combined with make-up air to provide 300 l/min. to a pair of virtual impactors. These impactors separate out particles in the nominal diameter range of 1-10 microm for sizing at 30 l/min. by a MOUDI cascade impactor, with filter collection of particles outside this range. Breathing patterns of ten subjects ranging in age from 6 to 17 years of age were measured and recorded using whole-body plethysmography while these volunteers inhaled through Ventodisk and Spiros inhalers. Particle sizes with four of these breath patterns, as well as several constant flow rate step profiles, were then obtained using the sizing apparatus with a realistic mouth throat intake. Our results show that as long as the constant flow rates were near typical values occurring in the actual-subject breaths, particle sizes obtained with constant flow rates were not significantly different (P > 0.01) from those occurring with actual-subject breath patterns. Significant differences are present if constant flow rates unrepresentative of those expected during particle uptake with the actual-subject patterns are used with the Ventodisk. These results show that judiciously chosen constant flow rates give rise to inertial particle size measurements that are equivalent to those obtained during actual-subject inhalation for the two types of DPIs tested.

Validating deposition models in disease: what is needed?

To develop theoretical deposition models, assumptions are introduced to make the models computationally affordable. For this reason, experimental (in vivo) validation of such models is needed to give confidence to the assumptions being made. However, for an in vivo deposition experiment to be considered useful for validation of a model, a number of parameters must be measured in the experiment for input to the model. Ideally, these parameters would include time-dependent breathing flow rates during aerosol exposure, properties of the inhaled aerosol as a function of time during the breath (including particle size distribution, aerosol mass fraction, as well as hygroscopic properties, inhaled temperature and humidity if hygroscopicity is important), in addition to anatomical regional deposition data and detailed lung geometry measurements. Furthermore, because of the dependence of extrathoracic filtering on the inlet conditions at the mouth and the complexity of modeling deposition in this region, experimental data on the filtering properties of the mouth-throat are needed. Although some of the above parameters are impractical to measure with current experimental techniques, it would greatly aid the development of deposition models if as many of these parameters as possible were measured in future in vivo deposition experiments. Data exemplifying the importance of measuring the above parameters is discussed.

In vitro comparison of salbutamol hydrofluoroalkane (Airomir) metered dose inhaler aerosols inhaled during pediatric tidal breathing from five valved holding chambers.

Amounts of salbutamol delivered from chlorofluorocarbon (CFC)-free metered dose inhalers (MDIs) (Airomir; 3M, St. Paul, MN) in particle sizes appropriate for inhalational treatment with five common holding chambers (NES [or Nebuchamber] spacer [Astra Draco AB, Lund, Sweden], AeroChamber [Trudell Medical, London, Ontario, Canada], OptiChamber [Health-scan Products, Cedar Grove, NJ], Vent170 spacer [Nordac Design, Waterloo, Ontario, Canada], and E-Z Spacer [WE Pharmaceuticals, Ramona, CA]) when used under simulated pediatric tidal breathing conditions were determined. Five devices of each type were tested with Airomir hydrofluoroalkane (HFA) inhalers (100 micrograms of salbutamol). Each device was connected to face replicas representative of 7-month-old (infant) and 2-year-old (toddler) children, and aerosol was also inhaled into an Andersen cascade impactor (Graseby Andersen, Smyrna, GA) using a valve system and simulated tidal breathing patterns representative of children of these ages. Amounts of drug inhaled in fine particles with the HFA formulation are significantly less (up to 46% less) with the E-Z Spacer (P < 0.01) compared with amounts inhaled in previous studies with the CFC formulation but are nearly the same with other holding chamber types (e.g., differing by < 6% for the AeroChamber). With the HFA formulation, the metal NES spacer delivered significantly more salbutamol in fine particles (P < 0.01) than any of the other holding chambers. Amounts of salbutamol inhaled in fine particles during pediatric tidal breathing from valved holding chambers with Airomir varies considerably between holding chamber types.