Nebulizer aerosol size

Since the 1970s laser sizers have offered convenient and rapid estimation of the optical size distributions of nebulized aerosol size distributions. However, just as weight loss as a measure of aerosol output is confounded by evaporation, droplet size distributions are now clearly understood also to be affected by evaporation once the aerosol cloud is mixed with drier ambient air. The methodology adopted within the European standard was inevitably a compromise but may arguably present the most representative clinical compromise. 

The primary aerosol droplets become smaller as the nebulizer gas flow rate is increased (Fig. 3.7). Often, the average aerosol size is described by the Sauter... 

Aspiration rate is only a small part of the overall transport process in flame spectrometry. The production of aerosol and its transport through the spray chamber are also of great importance. The size distribution of aerosol produced depends upon the surface tension, density, and viscosity of the sample solution. An empirical equation relating aerosol size distribution to these parameters and to nebulizer gas and solution flow rates was first worked out by Nukiyama and Tanasawa,5 who were interested in the size distributions in fuel sprays for rocket motors. Their equation has been extensively exploited in analytical flame spectrometry.2,6-7 Careful matrix matching is therefore essential not only for matching aspiration rates of samples and standards, but also for matching the size distributions of their respective aerosols. Samples and standards with identical size distributions will be transported to the flame with identical efficiencies, a key requirement in analytical flame spectrometry. 

There are many commercially available nebulizers with differing mass output rates and aerosol size distributions which will be a function of operating conditions, such as compressed air flow rate. As described above, for maximum efficacy, the drug-loaded droplets need to be less than 5 pm. In the treatment or prophylaxis of P.carinii pneumonia with nebulized pentamidine where the target is the alveolar space it is preferable to use nebulizers capable of generating droplets of less than 2 pm. 

Numerous investigators have compared the aerosol droplet size of nebulized aerosols from ultrasonic and air-jet devices. " Because droplet size is inversely proportional to the acoustic frequency, smaller droplets are generated from ultrasonic devices with higher frequencies. Ultrasonic nebulizers with high operating frequencies (2-3 MHz) are capable of... 

For aerosols in which the particle velocity is determined by the inspiratory flow rate and the particle size is not sensitive to it, it is expected that the increase in flow rate increases the upper and central airway deposition. For example, Ryan et al. [90] found that fast vital capacity inhalation resulted in a greater proportion of nebulizer aerosol depositing in the central airways than when the aerosol was inhaled slowly. However, the dependence on the inspiratory flow rate becomes more subtle when the particles have intrinsic velocity (such as droplets generated by propellant-driven metered-dose inhalers that need to be entrained into the inhaled air) or the particle size is inspiratory flow dependent (as in the case of passive dry powder inhalers). 

Van Borm W., Broekaert J. A. C., Klockenkamper R., Tschopel P. and Adams F. C. (1991) Aerosol sizing and transport studies with slurry nebulization in inductively coupled plasma spectrometry, Spectrochim Acta, Part B 46 1033-1049. 

Berg E, Svensson JO, Asking L. Determination of nebulizer droplet size distribution a method based on impactor refrigeration. J Aerosol Med 2007 20 97-104. 

Palmer F, Kingsbury SS. Particle size in nebulized aerosols. Am J Pharm 1952 124 112-124. 

There are only two experimental strategies that have the potential to yield reliable predictive results for nebulized aerosols. The first is to measure the droplets in their fully hydrated state. This can be done either immediately as they exit the mouthpiece, using a real-time sizing instrument, or by reducing the evaporation kinetics sufficiently to allow measurement downstream with an offline techniqne snch as inertial cascade impaction. The second is to completely dry the aerosol, size the dry particles, and then calculate back to obtain the original size distribntion. Measuring the aerosol at intermediate hydration states between these two extremes is obviously problematic because the hydration state would have to be measured in order to correct the size distribution back to the original inhaled size. 

Portstendorfer J, Gebhart J, Robig G. Effect of evaporation on the size distribution of nebulized aerosols. J Aerosol Sci 1977 8 371-380. 

Newman SP, PeUow PGD, Clarke SW. Droplet size distributions of nebulized aerosols for inhalation therapy. Chn Phys Physiol Meas 1986 7 139-146. 

The small amounts of aerosol generated by a system such as Halolite are produced over relatively short time period (< 1 s) in a discrete bolus. This bolus is entrained with ambient air during patient inhalation and one would expect a considerable amount of mixing to occur. As ambient air has a significant capacity to absorb water vapor from nebulized aerosol (relative humidity normally <70%), evaporation of aqueous aerosol would be inevitable and rapid. The reduction in droplet size would be expected to be inconsistent, as the rate of evaporation will depend on the speed of inhalation which defines degree of dilution as well as temperature and humidity of ambient air. In contrast, aerosol-laden air inhaled from the Circulaire nebulizer system will entrain little ambient air and is therefore relatively less sensitive to any reduction in droplet size due to evaporation. To what extent evaporation reduces droplet size from Halolite is not known and deserves further investigation. 

A draft European Nebulizer Standard (30) has been submitted for formal approval to CEN (Comite Europeen de Normalisation European Committee for Standardization). CEN is responsible for European standardization in all fields except Electrotechnical (CENELEC) and Telecommunications (ETSl). Publication of the European Nebulizer Standard is expected during 2001. Included within the European standard are detailed descriptions of two test methods for (1) assessing nebulizer aerosol output inhaled using breath simulation similar to that described previously and (2) assessing nebulized aerosol droplet size using low-flow cascade impaction. Because this standard is expected to be adopted throughout Europe (and possibly more widely), a summary of its contents may be useful to readers. 

A cascade impactor operating at 15 L/min would provide an ideal instrument to employ in this standard. Unfortunately, no such device is available. Furthermore, even it were, an impactor operating at 15 L/min would not be able to cope with extension smdies requiring lower airflow rates in, for example, pediatric applications. There are a limited number of devices which operate at lower flows of 1, 2, or 3 L/min of these, the Graseby Anderson 290 series impactor was selected and, in collaboration with the manufacturer, was modified to accommodate nebulized aerosol. This low-flow impactor has additional physical features that help to produce a meaningful estimate of nebulized droplet size, including... 

Figure 14 In vitro assessment of droplet size measurement in the European Standard. Simulated patient inhalation at 15 L/min draws air over (or through) the nebulizer where entrained ambient air mixes with nebulized aerosol. A sample of the air at 2 L/min is drawn into a Marple Series 290 cascade impactor, which sizes aerosol droplets in relation to aerodynamic diameter. Impacted aerosol solute (e.g., NaF or drug) can be subsequently desorbed and quantified from each impaction stage.

During development of the European standard, an interlaboratory trial was organized involving six laboratories within Europe to follow a defined protocol to assess aerosol output and size from two fundamentally different nebulizer systems. Results demonstrated that the methods were repeatable within +/- 10% of mean return for both aerosol output and aerosol size (unpublished data). Results of preliminary research investigating the correlation between in vivo response and in vitro estimate of aerosol output and size show a promising correlation (33), though further work is needed in this area. 

The European Standard presents a set of in vitro methods that are expected to reflect in vivo deposition and have been shown to provide repeatable and consistent results. It is clear that some nebulizer designs cannot easily be adapted into this or any other standard and that some flexibility is required in interpreting and applying such to these systems. In particular, obtaining a realistic profile of aerosol size distribution from the small aerosol boluses mixed with entrained ambient air from the Halolite, Circulaire, and AERx is particularly problanatic. However, such technical difficulties can be overcome and realistic measures of... 

Denyer J. Breathing patterns in adult patients. J Aerosol Med 1997 10(1) 99. Stapleton KW, Finlay WH. Errors in characterizing nebulized particle size Distributions with cascade impactors. J Aerosol Med 1998 ll(Suppl l) 80-83. 

A dramatic resonance effect among the multiple horns is transformed on a medicinal liquid layer to facilitate the ejection of mono-disperse droplets with a size of 2-5 [xm at a low electrical drive power smaller than 1.0 W. The small nozzle size requires a low drive power, which allows the ultrasonic nebulizer device to be pocket-size. A variety of pulmonary drugs have been nebulized with this device. Desirable aerosol sizes and output rate could be achieved (35). 

An example of the measurement of a commercial nebulizer aerosol is shown in Figure 9. The histogram of size and velocity is shown in Figure 9a with the associated mean sizes and velocities. Figure 9b shows the histogram and cumulative distribution of number and volume, while Figure 9c portrays the size-velocity correlation of the flow. 

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