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Laboratory and Animal Investigations |

The Effect of Heliox on Nebulizer Function Using a β-Agonist Bronchodilator* FREE TO VIEW

Dean R. Hess, PhD, RRT, FCCP; Frank L. Acosta, BS; Ray H. Ritz, RRT; Robert M. Kacmarek, PhD, RRT, FCCP; Carlos A. Camargo, Jr, MD, DrPH, FCCP
Author and Funding Information

*From the Departments of Respiratory Care (Drs. Hess, Ritz, and Kacmarek), and Emergency Medicine (Dr. Camargo and Mr. Acosta), Massachusetts General Hospital, Channing Laboratory (Dr. Camargo), Department of Medicine, Brigham and Women’s Hospital, and Harvard Medical School, Boston, MA.



Chest. 1999;115(1):184-189. doi:10.1378/chest.115.1.184
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Published online

Objective: To evaluate nebulizer performance when heliox was used to power the nebulizer.

Methods: Conventional and continuous nebulizer designs were evaluated. The conventional nebulizer was used with 5 mg albuterol and flows of 8 L/min air, 8 L/min heliox, and 11 L/min heliox; it was also used with 10 mg albuterol and a heliox flow of 8 L/min. The continuous nebulizer was set to deliver 10 mg of albuterol over 40 min at flows of 2 L/min air, 2 L/min heliox, and 3 L/min heliox; it was also used with 20 mg albuterol and a heliox flow of 2 L/min. A cotton plug at the nebulizer mouthpiece was used to trap aerosol during simulated spontaneous breathing. The amount of albuterol deposited on the cotton plug was determined spectrophotometrically. Particle size was determined using an 11-stage cascade impactor.

Results: For both nebulizer designs, particle size and inhaled mass of albuterol decreased significantly (p < 0.001) when the nebulizer was powered with heliox rather than air. When powered with heliox, the reduction in inhaled mass of albuterol was less for the conventional nebulizer (16%) than the continuous nebulizer (67%). The nebulization time, however, was more than twofold greater with heliox (p < 0.001). Increasing the flow of heliox increased the particle size (p < 0.05), inhaled mass of albuterol (p < 0.05), and inhaled mass of particles 1 to 5 μm (p < 0.05) to levels similar to powering the nebulizer with air at the lower flow. Increasing the albuterol concentration in the nebulizer and using the lower heliox flow increased the inhaled mass of albuterol (p < 0.05) while maintaining the smaller particle size produced with that flow.

Conclusions: The use of heliox to power a nebulizer affects both the inhaled mass of medication and the size of the aerosol particles. The flow to power the nebulizer should be increased when heliox is used.

Abbreviations: GSD = geometric SD; MMAD = mass median aerodynamic diameter

Figures in this Article

Heliox is a mixture of helium and oxygen, the most common blend being 80% helium and 20% oxygen. Because heliox is less dense than air, resistance is reduced in airways with turbulent flow. In recent years, heliox has been used increasingly in the treatment of severe acute asthma to delay inspiratory muscle fatigue until bronchodilator and corticosteroid therapy is effective. That heliox decreases airway resistance during asthma has been demonstrated indirectly by Manthous et al.1In that study, pulsus paradoxus and peak expiratory flow were significantly improved during heliox therapy. Similar improvements in lung function during acute asthma have been reported by others,2,,3,,4 although this has not been a universal finding.5Several studies have reported greater pulmonary penetration of aerosols in patients with stable asthma and with acute airway constriction during heliox breathing.6,,7,,8,,9,,10 Because of the lower density and greater viscosity of heliox, gas flow becomes less turbulent, which improves the transport of aerosols through constricted airways to more peripheral lung regions.

Although heliox therapy may be effective for selected patients with severe acute asthma, it is not needed in the treatment of most patients with acute asthma. When heliox therapy is used, jet nebulizers are typically powered with heliox rather than air or oxygen. The nebulizer may be one of a conventional design or one designed for continuous nebulization.11,,12,,13,,14,,15,,16,,17 Although many evaluations of nebulizer function have been published,18,,19,,20,,21 the effect of heliox on nebulizer function has not been described. In this study, we evaluated the effect of heliox on the performance of a conventional nebulizer and one designed for continuous nebulization.

Nebulizers Evaluated

We evaluated two nebulizer designs. The Hudson Micro-Mist (Hudson Respiratory Care; Temucula, CA) was chosen to represent a conventional nebulizer. This nebulizer was evaluated with air powering the nebulizer at 8 L/min, heliox (80% helium and 20% oxygen) powering the nebulizer at 8 L/min, and heliox powering the nebulizer at 11 L/min. For each of these flows, 5 mg (1 mL of 0.5%) of albuterol (Proventil; Schering; Kenilworth, NJ) was placed into the nebulizer and diluted with saline solution to a total fill volume of 5 mL. This nebulizer also was evaluated using a heliox flow of 8 L/min and 10 mg of albuterol diluted to a total fill volume of 5 mL. For heliox, the flowmeter (Timeter; Lancaster, PA) was adjusted to account for the effect of heliox (eg, an indicated flow of 4.5 L/min for an actual flow of 8 L/min).22 For each of these experimental conditions, three new nebulizers were evaluated in triplicate (n = 9). Nebulization time was determined by stopwatch and was considered complete when there was not audible or visible evidence of nebulization for 30 s.

The miniHEART (Vortran Medical Technology; Sacramento, CA) was chosen to represent a continuous nebulizer. It was evaluated with air powering the nebulizer at 2 L/min, heliox powering the nebulizer at 2 L/min, and heliox powering the nebulizer at 3 L/min. For each of these flows, 15 mg of albuterol was placed into the nebulizer and diluted to 8 mL with saline solution. The nebulizer was operated for 40 min to produce an output of 10 mg per manufacturer’s specifications. The miniHEART was also evaluated using a heliox flow of 2 L/min with 30 mg of albuterol placed into the nebulizer and diluted to 8 mL with saline solution. All flows (air and heliox) were confirmed using a calibrated bubble flowmeter (Fisher Scientific; Hampton, NH). For each experimental condition, three new nebulizers were evaluated in triplicate (n = 9).

The nebulizers were provided by the manufacturers from their saleable stock. None were prototypes or otherwise prepared specifically for this study.

Particle Size Determination

The experimental setup used to determine particle size is shown in Figure 1, top, and is similar to that used in previous experiments in our laboratory.19 Particle size was determined for each nebulizer, flow, driving gas, and drug concentration listed above. For each of these experimental conditions, three new nebulizers were evaluated in triplicate (n = 9). As determined by pilot studies, the aerosol was sampled for 2 min within 5 min of establishing flow from the nebulizer.

Aerosol particle size was determined by an 11-stage cascade impactor (Intox; Albuquerque, NM) with cutoff stages of 12, 9.52, 7.56, 6, 5, 4, 3, 1.8, 1, 0.4, and 0.25 μm. Aerosol was sampled 5 cm from the outlet of the nebulizer (approximate position of the mouthpiece in the patient’s mouth when the nebulizer is used clinically) at a flow of 2 L/min. The albuterol deposited on each stage of the impactor was collected on stainless steel plates, washed with saline solution, and the amount of albuterol was determined spectrophotometrically. The cascade impactor was calibrated by the manufacturer and used per manufacturer’s specifications. For heliox, the impactor was calibrated to account for the density and viscosity of heliox:

where ECD is the effective cutoff diameter, N is the number of stage jets, η is the gas viscosity, W is the diameter of the stage jets, and Q is the gas flow.23

Mass median aerodynamic diameter (MMAD) and geometric SD (GSD) were determined from the calibration curves of the cascade impactor. Cumulative deposition data were plotted against stage cutoff diameter and fitted with a logarithmic regression curve to determine the particle size at 50% of the accumulated deposition (MMAD). This relationship was unimodal for all nebulizers and R2 for this relationship is typically >0.9 in our laboratory (unpublished data). GSD was calculated as the MMAD divided by the particle size at 16% deposition. In addition to MMAD and GSD, the percentage of particles in the respirable range of 1 to 5 μm was determined.

Evaluation of Aerosol Available to the Patient

The experimental system was similar to that used previously in our laboratory19 and is shown in Figure 1, bottom. It was designed to simulate clinical use of a nebulizer and allowed us to measure the inhaled mass of albuterol.,24 The nebulizer was placed in a clamp and attached to a ring stand in the vertical position. A double-sided test lung (Michigan Instruments; Grand Rapids, MI) was used to simulate spontaneous breathing at 12 breaths/min, inspiratory flow of 0.3 to 0.4 L/s with a sine wave pattern, and tidal volume of 0.45 to 0.5 L. The mouthpiece of the nebulizer was replaced with an adapter and a cotton plug was placed into the adapter to trap aerosol. The lung model was attached to the adapter containing the cotton plug. Pilot studies showed that the cotton plug trapped all aerosol leaving the nebulizer and that albuterol can be recovered from the cotton (unpublished data). At the end of each trial, the drug present in the cotton plug was extracted using 20 mL of saline solution and gentle agitation by vortex. The resulting solution was centrifuged at 5,000 g for 10 min to remove all cotton fibers from the solution and the amount of albuterol was then determined spectrophotometrically. We also calculated the inhaled mass of particles in the respirable range of 1 to 5 μm (respirable mass). The respirable mass available to the patient was calculated by multiplying the inhaled mass times the percentage of particles in the respirable range.

Spectrophotometric Analysis of Albuterol

A stock solution of albuterol (0.05 mg/mL) was prepared from powdered drug (Sigma; St. Louis, MO) and a standard curve was constructed from serial dilutions. All absorbance measurements were made at a wavelength of 278 nm. The spectrophotometric absorbance was adjusted to zero with a saline solution solvent (or saline solution solvent treated with cotton as appropriate) before each measurement was made. The amount of drug in the test solutions was determined from the standard curve.

Statistical Analysis

Summary statistics are reported as mean ± SD. Differences between groups were determined by one-way analysis of variance. Post hoc analysis was conducted using the Scheffé procedure. Statistical significance was set at p < 0.05 (two tailed). All statistical analysis was performed using commercially available software (SPSS; Chicago, IL).

Conventional Nebulizer

There was a significant difference in particle sizes produced for the four test conditions (p < 0.001) (Table 1). The particle size decreased significantly when it was powered at 8 L/min with heliox rather than air (p < 0.05 by post hoc Scheffé analysis). The particle size was significantly greater when the nebulizer was powered with 11 L/min of heliox rather than 8 L/min of heliox (p < 0.05 by post hoc Scheffé analysis). There was no difference in particle size between the two albuterol concentrations when the nebulizer was powered with 8 L/min of heliox (p > 0.05 by post hoc Scheffé analysis). The GSDs for the conventional nebulizer (5-mg dose) were 3.17 ± 0.26μ m for air at 8 L/min, 3.25 ± 0.28 μm for heliox at 11 L/min, and 2.12 ± 0.11 μm for heliox at 8 L/min (p < 0.001).

There was a significant difference between the test conditions for the mass of albuterol inhaled (p < 0.001). Compared with powering the nebulizer with air at 8 L/min, there was a significantly lower inhaled mass of albuterol when the nebulizer was powered with heliox at 8 L/min (p < 0.05 by post hoc Scheffé analysis) (Table 1). When the heliox flow was increased to 11 L/min, there was no significant difference in the mass of albuterol inhaled compared with an air flow of 8 L/min (p > 0.05 by post hoc Scheffé analysis). The inhaled mass of albuterol was greater when 10 mg of albuterol was placed into the nebulizer cup compared with the other test conditions (p < 0.05 in each case by post hoc Scheffé analysis). Although there were significant differences for inhaled mass of particles in the respirable range of 1 to 5 μm among the four experimental conditions (p < 0.001) (Table 1), there was no difference between air powering the nebulizer at 8 L/min and heliox powering the nebulizer at 11 L/min (p > 0.05 by Scheffé analysis).

There was a significant difference between nebulization times for the test conditions (p < 0.001). The nebulization time was shorter when the nebulizer was powered with air at 8 L/min or heliox at 11 L/min as compared with heliox at 8 L/min (p < 0.05 in each case by post hoc Scheffé analysis) (Table 1).

Continuous Nebulizer

There was a significant difference in particles sizes produced for the four test conditions (p < 0.001) (Table 1). The particle size decreased significantly when it was powered with heliox at 2 L/min rather than air at 2 L/min (p < 0.05 by post hoc Scheffé analysis). The particle size was significantly greater when the nebulizer was powered with 3 L/min of heliox rather than 2 L/min of heliox (p < 0.05 by post hoc Scheffé analysis). There was no difference in particle size between the two albuterol concentrations when the nebulizer was powered with 2 L/min of heliox (p > 0.05 by post hoc Scheffé analysis). The GSDs for the continuous nebulizer (10-mg dose) were 2.71 ± 0.23 μm for air at 2 L/min, 2.54 ± 0.11 μm for heliox at 3 L/min, and 3.85 ± 0.59 μm for heliox at 3 L/min (p < 0.001).

There was a significant difference between the test conditions for the inhaled mass of albuterol (p < 0.001) (Table 1). Compared with powering the nebulizer with air at 2 L/min, there was a significantly lower mass of albuterol inhaled when the nebulizer was powered with heliox at 2 L/min (p < 0.05 by post hoc Scheffé analysis). When the heliox flow was increased from 2 to 3 L/min, there was a significant increase in the mass of albuterol inhaled (p < 0.05 by post hoc Scheffé analysis). When 20 mg of albuterol was placed into the nebulizer, the inhaled mass of albuterol was significantly different than each of the other test conditions (p < 0.05 in each case by post hoc Scheffé analysis). There were significant differences for inhaled mass of particles in the respirable range of 1 to 5 μm among the four experimental conditions (p < 0.001) (Table 1). The greatest mass of respirable particles occurred when powering the nebulizer with 3 L/min of heliox (p < 0.05 by Scheffé analysis).

The results of this study demonstrate that nebulizer performance was affected if the nebulizer was powered by heliox rather than air. For both nebulizers, the inhaled mass of albuterol was significantly reduced when the nebulizer was powered with heliox. The reduction in inhaled mass of albuterol was less for the conventional nebulizer (16%) than the continuous nebulizer (67%) when powered with heliox. However, there was a greater than twofold increase in nebulization time with heliox and the conventional nebulizer. For both nebulizers, an increased flow with heliox produced a respirable mass (inhaled mass of particles 1 to 5 μm) similar to that produced when the nebulizer was powered with air.

Nebulizers use Bernoulli’s principle to produce an aerosol.24 A high-pressure gas is directed through a jet orifice, creating a low lateral pressure. This low pressure draws the solution up a capillary tube, where the gas stream shatters it into small particles. The aerosol is then thrown against a baffle, which further reduces the size of the particles. Bernoulli’s principle can be described mathematically as follows:

where P1 is the gas pressure before the jet orifice, P2 is the gas pressure after the jet orifice, m is the mass of the gas, v2 is the gas velocity after the jet orifice, and v1 is the gas velocity before the jet orifice. If the mass of the gas decreases (eg, by using heliox rather than air), the pressure drop across the jet orifice (P1 − P2) is less. The rate at which the solution is drawn up the capillary tube thus decreases with heliox, accounting for a lower inhaled mass (eg, continuous nebulizer) or a longer nebulization time (eg, conventional nebulizer). Furthermore, if the mass of the gas decreases, there is a greater velocity change as the gas passes through the jet orifice (v22 − v12). Therefore, use of heliox (rather than air) increases the velocity at which the solution impacts the baffle and results in a smaller particle size with heliox.

Increasing the heliox flow increased the inhaled mass of albuterol from both nebulizers. However, this also increased the particle size, most likely due to the Bernoulli principle discussed above. Increasing the albuterol concentration without increasing the heliox flow produced a greater inhaled mass of albuterol while maintaining a smaller particle size. However, the inhaled mass of respirable particles from the conventional nebulizer was virtually the same powering it with 8 L/min of air or 11 L/min of heliox. This suggests that the flow should be increased when a nebulizer of this design is used. For the continuous nebulizer design, the inhaled mass of respirable particles was greatest when powering it with 3 L/min of heliox rather than 2 L/min of air, which again supports a recommendation of higher flows when using heliox. Because this study measured the inhaled mass of albuterol, which corresponds to the amount taken in at the mouth of the patient and not to lung deposition, the actual effect on lung deposition is not known from our study.

For both nebulizers, the inhaled mass of albuterol was <30% of the nominal dose placed into the nebulizer. These results are consistent with other previous studies that have shown that medication nebulizers provide an inhaled mass that is a fraction of the dose placed into the nebulizer.13,,19 This is the result of the dead volume of the nebulizer and the loss of drug during the expiratory phase. The particle size was greater for the continuous nebulizer than for the conventional nebulizer, suggesting that the conventional nebulizer may be advantageous for aerosol delivery in patients with constricted airways.

Although these data show that nebulizer performance is affected when the nebulizer is powered with heliox rather than air, the clinical implications of this remain to be determined. However, the effect of heliox on nebulizer performance must be recognized in clinical studies evaluating inhaled medication delivery during heliox therapy. The effects of heliox on aerosol penetration and clinical outcomes might be due to either the effect of heliox on aerosol penetration in the lung or aerosol generation in the nebulizer. Ideally, nebulizer performance with heliox should be characterized before proceeding to clinical studies that evaluate aerosol delivery during heliox therapy.

The use of heliox to power a medication nebulizer affects both the inhaled mass of drug available to the patient and the size of the aerosol particles. Thus, pulmonary deposition of aerosols during heliox therapy may be due to the effect of heliox on aerosol generation in the nebulizer or aerosol penetration within the lungs. The flow to power the nebulizer should be increased when heliox is used.

This work was conducted in the Respiratory Care Laboratory and the Henry K. Beecher Laboratory at the Massachusetts General Hospital.

Financial support was provided for Mr. Acosta from the Massachusetts General Hospital Summer Research Trainee Program, Boston, MA. Dr. Camargo is supported by grant HL-03533 from the National Institutes of Health, Bethesda, MD.

Correspondence to: Dean Hess, Respiratory Care, Ellison 401, Massachusetts General Hospital, 55 Fruit St, Boston, MA 02114; e-mail: dhess@partners.org

Figure Jump LinkFigure 1. Top: experimental setup used to evaluate particle size output of the nebulizer. Bottom: experimental setup used to evaluate inhaled mass of albuterol.Grahic Jump Location
Table Graphic Jump Location
Table 1. Summary of Results

We wish to thank the staff of the Henry K. Beecher Anesthesia Laboratory, Massachusetts General Hospital, Boston, for their assistance with this project.

Manthous, CA, Hall, JB, Schmidt, G, et al (1995) The effect of heliox on pulsus paradoxus and peak flows in patients with severe asthma.Am J Respir Crit Care Med151,310-314. [PubMed]
 
Kass, JE, Castriotta, RJ Heliox therapy in acute severe asthma.Chest1995;107,757-760. [PubMed] [CrossRef]
 
Kudukis, T, Mathous, CA, Schmidt, G, et al Inhaled helium-oxygen (heliox) revisited: the effect of inhaled heliox during the treatment of acute status asthmaticus in children.J Pediatr1996;130,217-224
 
Shiue, ST, Gluck, EH The use of helium-oxygen mixtures in the support of patients with status asthmaticus and respiratory acidosis.J Asthma1989;26,177-180. [PubMed]
 
Carter, ER, Webb, CR, Moffitt, DR Evaluation of heliox in children hospitalized with acute severe asthma.Chest1996;109,1256-1261. [PubMed]
 
Anderson, M, Svartengren, M, Philipson, K, et al Deposition in man of particles suspended in air or in helium-oxygen mixture at different flow rates.J Aerosol Med1990;3,209-216
 
Anderson, M, Svartengren, M, Bylin, G, et al Deposition in asthmatics of particles inhaled in air or in helium-oxygen.Am Rev Respir Dis1993;147,524-528. [PubMed]
 
Esch, JL, Specktor, DM, Lippman, M Effect of lung airway branching pattern and gas composition on particle deposition: II. Experimental studies in human and canine lungs.Exp Lung Res1988;14,321-348. [PubMed]
 
Svartengren, M, Anderson, M, Philipson, K, et al Human lung deposition of particles suspended in air or in helium/oxygen mixture.Exp Lung Res1989;15,575-585. [PubMed]
 
Swift, DL, Carpin, JC, Mitzner, W Pulmonary penetration and deposition of aerosols in different gases.Ann Occup Hyg1982;26,109-117. [PubMed]
 
Chipps, BE, Blackney, DA, Blacke, LE, et al Vortran high output extended aerosol respiratory therapy (HEART) of delivery of continuously nebulized terbutaline for the treatment of acute bronchospasm.Pediatr Asthma Allergy Immunol1990;4,271-277
 
Lin, RY, Suater, D, Newman, T, et al Continuous versus intermittent albuterol nebulization in the treatment of acute asthma.Ann Emerg Med1993;22,1847-1853. [PubMed]
 
McPeck, M, Tandon, R, Hughes, K, et al Aerosol delivery during continuous nebulization.Chest1997;111,1200-1205. [PubMed]
 
Moler, FW, Johnson, CE, Van Laanen, C, et al Continuous versus intermittent nebulized terbutaline: plasma levels and effects.Am J Respir Crit Care Med1995;151,602-606. [PubMed]
 
Reisner, C, Kotch, A, Dworkin, G Continuous versus frequent intermittent nebulization of albuterol in acute asthma: a randomized, prospective study.Ann Allergy Asthma Immunol1995;75,41-47. [PubMed]
 
Rudnitsky, GS, Eberlein, RS, Schoffstall, JM, et al Comparison of intermittent and continuously nebulized albuterol for treatments of asthma in an urban emergency room.Ann Emerg Med1993;22,1842-1846. [PubMed]
 
Shestra, M, Bidali, K, Gourlay, S, et al Continuous vs intermittent albuterol, at high and low doses, in the treatment of severe acute asthma in adults.Chest1996;110,42-47. [PubMed]
 
Alvine, GF, Rodgers, P, Fitzsimmons, KM, et al Disposable jet nebulizers: how reliable are they?Chest1992;101,316-319. [PubMed]
 
Hess, D, Fisher, D, Williams, P, et al Medication nebulizer performance: effects of diluent volume, nebulizer flow, and nebulizer brand.Chest1996;110,498-505. [PubMed]
 
Loffert, DT, Ikle, D, Nelson, HS A comparison of commercial jet nebulizers.Chest1994;106,1788-1793. [PubMed]
 
Phipps, PR, Gonda, I Droplets produced by medical nebulizers: some factors affecting their size and solute concentration.Chest1990;97,1327-1332. [PubMed]
 
Hess, DR, Branson, RD, Chatburn, RL. Respiratory care equipment. 1995; JB Lippincott. Philadelphia, PA:.
 
Newton, GJ, Carpender, RL, Cheng, YS, et al High-temperature-high-pressure cascade impactor design, performance, and data analysis methods.J Colloid Interface Sci1982;87,279-290
 
Smaldone, GC Drug delivery via aerosol systems: concept of ‘aerosol inhaled.’J Aerosol Med1991;4,229-235. [PubMed]
 

Figures

Figure Jump LinkFigure 1. Top: experimental setup used to evaluate particle size output of the nebulizer. Bottom: experimental setup used to evaluate inhaled mass of albuterol.Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1. Summary of Results

References

Manthous, CA, Hall, JB, Schmidt, G, et al (1995) The effect of heliox on pulsus paradoxus and peak flows in patients with severe asthma.Am J Respir Crit Care Med151,310-314. [PubMed]
 
Kass, JE, Castriotta, RJ Heliox therapy in acute severe asthma.Chest1995;107,757-760. [PubMed] [CrossRef]
 
Kudukis, T, Mathous, CA, Schmidt, G, et al Inhaled helium-oxygen (heliox) revisited: the effect of inhaled heliox during the treatment of acute status asthmaticus in children.J Pediatr1996;130,217-224
 
Shiue, ST, Gluck, EH The use of helium-oxygen mixtures in the support of patients with status asthmaticus and respiratory acidosis.J Asthma1989;26,177-180. [PubMed]
 
Carter, ER, Webb, CR, Moffitt, DR Evaluation of heliox in children hospitalized with acute severe asthma.Chest1996;109,1256-1261. [PubMed]
 
Anderson, M, Svartengren, M, Philipson, K, et al Deposition in man of particles suspended in air or in helium-oxygen mixture at different flow rates.J Aerosol Med1990;3,209-216
 
Anderson, M, Svartengren, M, Bylin, G, et al Deposition in asthmatics of particles inhaled in air or in helium-oxygen.Am Rev Respir Dis1993;147,524-528. [PubMed]
 
Esch, JL, Specktor, DM, Lippman, M Effect of lung airway branching pattern and gas composition on particle deposition: II. Experimental studies in human and canine lungs.Exp Lung Res1988;14,321-348. [PubMed]
 
Svartengren, M, Anderson, M, Philipson, K, et al Human lung deposition of particles suspended in air or in helium/oxygen mixture.Exp Lung Res1989;15,575-585. [PubMed]
 
Swift, DL, Carpin, JC, Mitzner, W Pulmonary penetration and deposition of aerosols in different gases.Ann Occup Hyg1982;26,109-117. [PubMed]
 
Chipps, BE, Blackney, DA, Blacke, LE, et al Vortran high output extended aerosol respiratory therapy (HEART) of delivery of continuously nebulized terbutaline for the treatment of acute bronchospasm.Pediatr Asthma Allergy Immunol1990;4,271-277
 
Lin, RY, Suater, D, Newman, T, et al Continuous versus intermittent albuterol nebulization in the treatment of acute asthma.Ann Emerg Med1993;22,1847-1853. [PubMed]
 
McPeck, M, Tandon, R, Hughes, K, et al Aerosol delivery during continuous nebulization.Chest1997;111,1200-1205. [PubMed]
 
Moler, FW, Johnson, CE, Van Laanen, C, et al Continuous versus intermittent nebulized terbutaline: plasma levels and effects.Am J Respir Crit Care Med1995;151,602-606. [PubMed]
 
Reisner, C, Kotch, A, Dworkin, G Continuous versus frequent intermittent nebulization of albuterol in acute asthma: a randomized, prospective study.Ann Allergy Asthma Immunol1995;75,41-47. [PubMed]
 
Rudnitsky, GS, Eberlein, RS, Schoffstall, JM, et al Comparison of intermittent and continuously nebulized albuterol for treatments of asthma in an urban emergency room.Ann Emerg Med1993;22,1842-1846. [PubMed]
 
Shestra, M, Bidali, K, Gourlay, S, et al Continuous vs intermittent albuterol, at high and low doses, in the treatment of severe acute asthma in adults.Chest1996;110,42-47. [PubMed]
 
Alvine, GF, Rodgers, P, Fitzsimmons, KM, et al Disposable jet nebulizers: how reliable are they?Chest1992;101,316-319. [PubMed]
 
Hess, D, Fisher, D, Williams, P, et al Medication nebulizer performance: effects of diluent volume, nebulizer flow, and nebulizer brand.Chest1996;110,498-505. [PubMed]
 
Loffert, DT, Ikle, D, Nelson, HS A comparison of commercial jet nebulizers.Chest1994;106,1788-1793. [PubMed]
 
Phipps, PR, Gonda, I Droplets produced by medical nebulizers: some factors affecting their size and solute concentration.Chest1990;97,1327-1332. [PubMed]
 
Hess, DR, Branson, RD, Chatburn, RL. Respiratory care equipment. 1995; JB Lippincott. Philadelphia, PA:.
 
Newton, GJ, Carpender, RL, Cheng, YS, et al High-temperature-high-pressure cascade impactor design, performance, and data analysis methods.J Colloid Interface Sci1982;87,279-290
 
Smaldone, GC Drug delivery via aerosol systems: concept of ‘aerosol inhaled.’J Aerosol Med1991;4,229-235. [PubMed]
 
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