HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:
Guest Access | Sign In via User Name/Password

This Article Abstract Full Text (PDF) Free Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Add to My Personal Article Archive Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (15) Citing Articles via Google Scholar Google Scholar Articles by Coates, A. L. Articles by Lands, L. C. Search for Related Content PubMed PubMed Citation Articles by Coates, A. L. Articles by Lands, L. C.

Effect of Size and Disease on Estimated Deposition of Drugs Administered Using Jet Nebulization in Children With Cystic Fibrosis^*

^* From the Division of Respiratory Medicine (Dr. Coates and Ms. Ho), Hospital for Sick Children, University of Toronto, Toronto; and Division of Respiratory Medicine (Mr. Allen, Ms. MacNeish, and Dr. Lands), Montreal Children’s Hospital McGill University, Montreal, Canada.

Correspondence to: Allan L. Coates, MD, Division of Respiratory Medicine, Hospital for Sick Children, 555 University Ave, Toronto, Ontario, Canada M5G 1X8; e-mail: allan.coates{at}sickkids.on.ca

	Abstract

TOP Abstract Introduction Theory Materials and Methods Results Discussion Appendix 1 References

 
Study objectives: To develop a model that quantified the nebulizer output that was inhaled by subjects with cystic fibrosis (CF) in order to predict the amount of drug likely to enter the upper airway contained in particles small enough to be deposited in the lower respiratory tract of individual patients.

Design: Forty-three patients (age, 6 to 18 years) with CF, with FEV₁ of 26 to 124% of predicted, breathed through a nebulizer circuit with a pneumotachograph in place at the distal end. Algorithms were developed from the measured flows through the pneumotachograph, allowing partitioning of inspiration into undiluted aerosol and fresh gas. In order to validate the algorithms, argon was added to the nebulizing gas flow and then its concentration was analyzed at the mouth by mass spectrometry.

Results: Predictions of the concentration of argon at the mouth were concordant with that measured by mass spectrometry, thus validating the model. Combining data from the model with in vitro nebulizer performance data, predictions for estimates for lung deposition for individuals were possible. Total estimate was independent of patient size or FEV₁. The respiratory duty cycle was 0.44 ± 0.05 (mean ± SD) and correlated (r = 0.91, p < 0.001) with estimated deposition and minute ventilation (r = 0.60, p < 0.01). However, when expressed in milligrams per kilogram of body weight, the estimated deposition in smaller children was fourfold higher than in larger children.

Conclusions: If the effect of patient size and pattern of breathing on estimated drug deposition are not considered when prescribing drugs given by nebulization, the result may be overdosing younger children, underdosing older children, or both.

Key Words: cystic fibrosis • inhaled antibiotics • nebulization

	Introduction

TOP Abstract Introduction Theory Materials and Methods Results Discussion Appendix 1 References

 
The administration of nebulized medication for the treatment of lung disease in children has a number of attractions. It requires minimal cooperation, and it delivers medication directly to the organ of concern. Furthermore, medications that may not be formulated specifically for inhalation therapy can be administered this way in an "off-label" usage. Of particular interest has been the use of inhaled antibiotics for the treatment of cystic fibrosis (CF).^{1 2 3 4 5} However, there are disadvantages of using this method. Less than 10% of the initial dose of medication that is placed in the nebulizer is likely to be deposited in the lung; of that amount, the fraction deposited is highly variable.^{6 7} Fortunately, the inhaled medications currently used are relatively nontoxic, so that huge doses can be placed in a nebulizer in order to ensure adequate deposition to achieve a therapeutic effect.¹ However, for economic reasons as well as the concern that future medications may not have this margin of safety, better methods of ensuring the delivery of an appropriate dose that will provide clinical efficacy are desirable.

Scientific data to support the choice of pediatric drug dosages for nebulization are frequently lacking. Doses for parenterally or enterally administered medications are commonly based on the patient’s body weight (milligrams per kilogram), and sometimes aerosolized medications are also prescribed in this manner.^{8 9} At other times, the same dose is given to all patients.^{1 2 10} In both these situations, the amount of drug that actually reaches the targeted area of the lung will remain highly variable from patient to patient. During aerosol administration using a conventional jet nebulizer, the concentration of the aerosol contained in the inspired gas will be determined by the output of the nebulizer. The aerosol contained in each breath may be diluted by ambient air if the patient’s inspiratory flow exceeds the flow driving the nebulizer (N). The aerosol will remain undiluted only if a small child’s peak inspiratory flow is less than the N. Uniquely, under these circumstances alone, the amount of medication that will be received for a given nebulizer will be directly proportional to the minute ventilation (E) of the child, which is dependent on size or, more specifically, metabolic demand.

Older (larger) children will have an inspiratory flow that well exceeds the N and will significantly dilute the aerosol with ambient air. This phenomenon of less dilution in infants may account for their seemingly increased sensitivity to histamine inhalation.¹¹ An eloquent description of the theory of this process was put forward by Collis et al.¹² Based on radionuclear inhalational studies, the same group of investigators¹³ suggested that the nebulizer drug dose be dramatically reduced for children less than a year and a half of age compared to that for older children. However, while the concept is known, to date there has never been a quantification of the influence of size, breathing pattern, and the degree of lung disease on estimated pulmonary deposition of nebulized medications. The purposes of this study were as follows: (1) to develop a model that would allow the prediction of the inhaled mass (the mass of aerosol that would enter the airway^{14 15} ); and (2) to evaluate the effect of the individual pattern of breathing on the quantity of tobramycin carried in particles small enough to deposit in the lower respiratory tract of children breathing through a mouthpiece, using an unvented, good quality, disposable jet nebulizer.

	Theory

TOP Abstract Introduction Theory Materials and Methods Results Discussion Appendix 1 References

 
When the Bain anesthetic circuit was first introduced,¹⁶ there was concern that rebreathing expired gas would lead to hypercapnia. To investigate this, in 1983, Meakin and Coates¹⁷ developed a model that allowed partitioning of each inspiration into the volume of rebreathed gas, and the volume of fresh anesthetic gas. They justified their model by using the respiratory pattern, measured by a pneumotachograph placed at the distal end of the circuit, to predict the concentration of CO₂ that would appear at the endotracheal tube. Concordance between the predicted and the directly measured values validated the model. For jet nebulization, this model was adapted to determine the fraction of each breath that would contain undiluted aerosol, which, coupled with the output of the nebulizer, could be used to calculate inhaled mass. The fraction of the inhaled mass expected to deposit in the lungs of that specific CF patient could then be calculated from the particle size distribution.

The model was based on the mechanics of a patient breathing through a mouthpiece/T-piece connection to an unvented jet nebulizer (Hudson 1730 Updraft II; Hudson; Temecula, CA). A pneumotachograph was placed on the distal end of the T-piece (Fig 1 ). The nebulizer was run without solution (to prevent wetting the pneumotachograph) with a gas containing 5% Ar. A respiratory mass spectrometer (MS) [model MGA-1100; Marquette; Milwaukee, WI] was used to sample the concentration of Ar at the mouth. In order to align the signals from the pneumotachograph with those from the MS accurately, with respect to time, the time of each digitized flow data point was shifted to account for the delay between the point where gas was sampled at the mouthpiece, and the time of digitization of the electrical output from the MS. If the nebulizer output entering the mouth was undiluted, then the measured Ar concentration would be 5%. It would be less with dilution by entrained room air. Because the N was known from the flow through the pneumotachograph (_pnt[t]), the flow to the patient (_p[t]) could be calculated: P(t) = _PNT(t) + N. The _pnt(t) was calibrated, digitized, and sampled at 200 Hz so that each 5-ms increment of _p(t) represented a tiny volume made up of a fraction of aerosol and a fraction of ambient air.

View larger version (18K): [in this window] [in a new window] [Download PPT slide]   Figure 1. Schematic diagram of the apparatus using the symbols described in the text.

View larger version (24K): [in this window] [in a new window] [Download PPT slide]   Figure 2. Schematic diagram of an inspiration. The stippled area is the amount of flow of undiluted aerosol that enters the mouth and the white area under the curve is the ambient air that is inspired. Area 1 from t0 to t1 is the undiluted aerosol that enters when nebulizing flow is greater than inspiratory flow. Area 2 is the apparatus dead space that contains the undiluted aerosol that filled the space between t0 and t1. Area 3 is the nebulizer output between t1 and t2, and area 4 is the region between t2 and TI when N is again greater than the patient’s inspiratory flow.

	Materials and Methods

TOP Abstract Introduction Theory Materials and Methods Results Discussion Appendix 1 References

The subject was then seated comfortably, familiarized with the nebulizer, and asked to breathe quietly and regularly through the device with nose clips in place. N was set at 6 L/min using a flowmeter that was specifically calibrated for the nebulizer to avoid problems of inadequate back-pressure compensation of the flowmeter.^{22 23 24} For analysis, the operator selected epochs that contained 10 consecutive breaths, indistinguishable from each other (by inspection). Data from patients who could not breathe regularly were not analyzed.

Data analysis was performed, first by comparing the calculated concentration of Ar at the mouth to that measured by MS, to validate the model using the Bland and Altman²⁵ limits of agreement. Once the model was validated, the fraction of inspired ventilation that contained undiluted aerosol was calculated from the combination of the data provided from the model, coupled with the measured E of the patient. The rate of output for an 80-mg dose of tobramycin with 2 mL normal saline solution, using the Hudson 1730 and 6 L/min driving flow had been previously reported.²⁴ Similarly, total aerosol output and output contained within the respirable fraction (RF)^{22 26} have been reported for this nebulizer and are 51 mg total with 21 mg in the RF, with a mass median diameter (± 1 geometric SD) of 5.7 ± 0.26 µm. The inhaled mass per breath can be calculated by combining the rate of output,²⁶ and data from the model. This, when multiplied by the RF,^{22 26} gives an estimate of pulmonary deposition per breath. The ratio of the estimated deposition per breath to the total output per breath is essentially the in vivo efficiency of the device. By multiplying this ratio by the total output of the device,²² the amount (in milligrams) of tobramycin estimated to deposit in the lungs of each patient per nebulization session could be calculated. The definition of the RF was the fraction of aerosol contained in particles 5 µg that, if inhaled, are expected to deposit below the vocal cords.^{27 28 29} Inherent in this definition is the assumption that the RF will be the same for children with disease as it is for normal adults, although it is recognized that there are theoretical reasons why this may not be the case.^{30 31}

Multiple regression analysis was used to explore the factors that would correlate with the estimated pulmonary deposition, including the pattern of breathing, the E, height, and the degree of lung disease (FEV₁ and RV/TLC).

	Results

TOP Abstract Introduction Theory Materials and Methods Results Discussion Appendix 1 References

 
Forty-three patients from 6 to 18 years of age participated in the study. They ranged in height from 108 to 173 cm, and their FEV₁ values ranged from 26 to 124% predicted. Figure 3 shows the Bland and Altman²⁵ plot of limits of agreement for the measured signal from the MS, and the calculated concentration for Ar. The bias ± 2 SDs indicates that the mathematical model successfully defined the pattern of ventilation and the dilution of the aerosol with ambient air. Based on the validity of the model, the subsequent analysis calculated the estimated deposition of aerosol for each individual patient.

View larger version (17K): [in this window] [in a new window] [Download PPT slide]   Figure 3. Bland and Altman25 limits of agreement between the difference in the Ar concentration recorded at the mouth and that predicted from the model, plotted against the recorded concentration (which was considered the true value). The 95% confidence limits are also shown.

View larger version (16K): [in this window] [in a new window] [Download PPT slide]   Figure 4. Relationship between the estimated deposition of tobramycin in milligrams and TI/TTOT. The correlation coefficient is 0.91 with a p < 0.0001.

View larger version (18K): [in this window] [in a new window] [Download PPT slide]   Figure 5. Scattergram of the estimated deposition normalized for weight (milligrams per kilogram) plotted against height.

	Discussion

TOP Abstract Introduction Theory Materials and Methods Results Discussion Appendix 1 References

The Bland and Altman²⁵ plot (Fig 3) shows that the model accurately predicts the concentration of Ar that appears at the mouth. This model is not perfect because there is a tendency to slightly underestimate the inhaled Ar concentration in the smaller children who have the highest concentration of Ar (Fig 3) . Because these children have small VTs, any error in the estimation of the apparatus dead space will cause a proportionately larger error in the calculated concentration of Ar. The single-value entry for apparatus dead space assumes plug flow, in other words, no mixing of aerosol output and ambient (or expired) air within the dead space. Hence, it is assumed that the dead space will be filled with undiluted aerosol during the early phase of inspiration (Fig 2 : t₀ to t₁). Any discrepancy between these assumptions in reality would give rise to the greatest errors when VT is small and the dilution of the inhaled Ar is least. Another factor is the time delay for the MS to sample and read the Ar concentration compared to any signal delay from the pneumotachograph. Again, little children with relatively rapid respiratory rates would magnify the effect on any inaccuracy of the time delay, compared to the slower respiratory pattern of the older children. Despite these constraints, the errors because of such factors appear, from the limits of agreement (Fig 3) , to be small. In order to calculate the concentration of Ar at the mouth, the model must be able to accurately partition the inspired gas into the component of undiluted aerosol and the component of fresh ambient air. Given that this partitioning is the basis for the calculation of the estimated deposition ^(Appendix), similar accuracy can be obtained for estimated deposition calculations.

Given the theoretical results of Collis et al,¹² the results presented here follow the expected pattern. However, Collis et al¹² used patterns of breathing derived from other studies to illustrate their point, whereas the present study used actual patients with CF breathing from the same type of nebulizer that they use in the clinical setting. Furthermore, unlike Collis et al,¹² these results provide a quantitative analysis of the factors that would influence estimated pulmonary deposition of tobramycin, and hence can act as a specific guide to individualizing doses of nebulized medication. The lack of a significant relationship between size of the child and estimated deposition was because of the predominant role played by TI/TTOT, which is independent of size, and the less significant role played by E, which is related to size. For unvented nebulizers, where the output is constant and independent of the respiratory cycle, drug is inhaled during inspiration and lost to the environment during expiration, explaining the very significant relationship between estimated deposition and TI/TTOT. Where E does play a role is in the smaller children. With lower peak inspiratory flows, and hence a longer period where the inspiratory flow, after the onset of inspiration, is less than N, more aerosol is lost to the environment during inspiration. This happens at the start and end of inspiration (Fig 2) . For larger children with a high E and the accompanying high inspiratory flow, inspiratory flow is less than N for very short periods of time, so little aerosol is lost during inspiration. With estimate of deposition independent of size, it is not surprising that there is as much as a fourfold difference in estimated deposition (expressed in terms of milligrams drug per kilogram of body weight) between the smaller and the larger children. Because clinical studies² have shown both beneficial effects of 80 mg of tobramycin administered three times daily² and a lack of toxic effects of doses of tobramycin several-fold higher,¹ it is clear that the drug is potent and safe when given by inhalation (presumably because little is absorbed through the pulmonary epithelium, and that which is expectorated and swallowed has little GI absorption). On the other hand, newer treatments such as gene therapy using either liposome or viral vectors may not be as innocuous and may have a significantly narrower therapeutic index. In such situations, it will be important to be able to estimate the dose required to deliver a prescribed amount of drug by aerosol, based on body weight. If the output of an unvented jet nebulizer driven at 6 L/min is known, the data in Figure 4 can be used to derive a rough estimate of the pulmonary deposition. If further accuracy is required, it will be necessary to make the appropriate measurement on an individual patient using a model similar to that described.

There are two types of limitations and cautions in the interpretation of these data, as there are with all in vitro data, which are assumed to represent the real events in vivo. First, other than the pattern of breathing, the model does not take any other factor concerning disease severity or size into consideration. Of particular concern is the extrapolation of the definition of the RF that was established primarily in studies of normal adults rather than in children with CF. The primary mechanisms of deposition of inhaled particles in the airway are by inertial impaction and sedimentation,³³ with Brownian diffusion playing lesser role. Inertial impaction can be roughly defined as the lack of ability to follow the air carrying the particle around a curve, such as in the posterior pharynx or bifurcation of a bronchus. Hence, it is quite possible that differences in anatomy and size of the upper airway as well as velocity of inspiratory flow may effect the RF. With regard to sedimentation, retention time and airway size (eg, distance for the particle to fall) may also play a role³¹ and would be expected to differ according to size and disease state.³⁴ Furthermore, airway lining liquid viscosity, a factor frequently abnormal in CF, has also been shown to play a role in determining deposition.³⁵ However, errors because of the inappropriate definition of RF cannot be excessively large because the current study used a very efficient unvented nebulizer and found a mean estimated deposition of the nebulizer charge of 10.6%. This compares to values between 5% and 10% found in deposition studies^{6 32 36} in children with CF. Part of this discrepancy may have occurred because the present model estimated total deposition below the cords, while many studies^{6 32 36} exclude the trachea from the regions of interest. Compared to frequent clinical practice, in this study, all subjects breathed through a mouthpiece with a nose clip in place. It is clear that the nose is very effective in removing inhaled particulate matter, and values approximately half of that calculated here would be expected in older children when breathing through a face mask.¹³

A second issue is equipment. The nebulizer used in this study is an unvented disposable device with an output not influenced by any respiratory effort of the subject.²⁶ It is clear that reusable vented or "breath-enhanced" nebulizers will increase their output of tobramycin in relation to the inspiratory flow drawn through them.²⁶ Intuitively, this would increase output for increasing E, and this would be expected to reduce the discrepancies seen between the smaller and the larger children (who have larger values for E). Hence, the breath-enhanced nebulizers are becoming popular for home use, but the much less expensive disposable unvented devices are commonly used in a hospital or clinic environment. The values calculated for estimated deposition are based on measurement of the actual drug output³⁷ (not just weight change) and particle size distribution of this drug output determined by laser diffraction techniques (which do not dry the aerosol cloud^{37 38} ) for this particular nebulizer charged with 80 mg of tobramycin in a 4-mL volume. There are wide variations of nebulizer performance,^{39 40} so to apply this information to any other nebulizer driven at 6 L/min, it would be necessary to characterize the output of the nebulizer while nebulizing the particular drug of interest with the intended fill volume.²² For nebulizing flows different from 6 L/min, the analysis would have to be repeated as the dilution of aerosol with ambient air depends on the patient’s inspiratory flow in relation to the N. The data for the parameters of the Hudson 1730 nebulizer are derived specifically for a N of 6 L/min measured at the exit of the nebulizer, rather than what is indicated by the flowmeter. While standard flowmeters are stated by the manufacturer to be "back-pressure compensated," in reality, this is not the case, and a specific calibration curve is required for each brand and type of nebulizer to be evaluated.^{22 26 40} There are other techniques to calculate inhaled mass, the most popular of which is to place a filter between the patient and the nebulizer and then quantify the drug on the filter.¹⁴ Chemical analysis of the drug on filter is not simple for drugs like tobramycin that do not contain a chromophore for easy ultraviolet spectrophotometric analysis.⁴¹ Alternative techniques⁴¹ are possible but labor intensive and would result in fewer subjects being studied. The present model is sufficiently automated to allow many patients to be tested. With the limitations of the assumption of the RF as mentioned earlier, before any estimate of pulmonary deposition, the inhaled mass must be known. The agreement with predicted and measured concentration of Ar seen in this study would suggest that the model is capable of predicting inhaled mass. If more data become available to improve the definition of RF in this patient group, estimates of deposition could easily be recalculated from the inhaled mass.

In conclusion, we have developed a model that can be used to calculate the inhaled mass allowing the estimation of deposition of aerosol below the vocal cords in children with CF. The results indicate that smaller children breathing through a mouthpiece from an unvented jet nebulizer are likely to receive four times the dose of tobramycin on a per kilogram of weight basis, compared to older and bigger children. The notion that the dose of drugs to be given by aerosol does not have to be individualized for the size of the child is applicable only when giving relatively large doses of nontoxic medication. Taking into consideration the limitations discussed above, this approach can be extended to other therapeutic agents and other devices to estimate pulmonary deposition of an inhaled agent.

	Appendix 1

TOP Abstract Introduction Theory Materials and Methods Results Discussion Appendix 1 References

 
Volume areas 1 to 4 (Fig 2) , when summed together, represent the total nebulizer output (aerosol). The equations for each subvolume are as follows:

(1)

(2)

(3)

(4)

Also, note that at times t₁ and t₂, N = _p(t₁) and _p(t₂). Now,

% Aerosol

(1A)

Defining _pnt(t) as positive for inspiratory flow when _pnt(t) > N, then:

or:

then, from (1a) we get:

(1B)

(1C)

(1D)

In order to determine the Ar concentration at the mouth at discrete times during the VT, consider the following three equations.

At some time between t₀ and t₁:

(2A)

At some time between t₁ and t₂:

(2B)

(2C)

At some time between t₁ and TI:

(2D)

where FAr_a = concentration of Ar in ambient air.

Putting (2a) and (2d) together over the whole excursion of

(2E)

or using an MS (and thereby measuring at the sample port):

(5)

Now if theory and practice agree, values for (2e) should be the same as (3).

	Footnotes

 
Abbreviations: CF = cystic fibrosis; MS = mass spectrometer; RF = respirable fraction; RV/TLC = residual volume/total lung capacity ratio; TI = inspiratory time; TI/TTOT = respiratory duty cycle; VT = tidal volume; E = minute ventilation; N = flow driving the nebulizer; _p(t) flow to the patient; _pnt(t) = flow through the pneumotachograph

Supported by the Canadian Cystic Fibrosis Foundation.

Received for publication April 20, 2000. Accepted for publication November 3, 2000.

	References

TOP Abstract Introduction Theory Materials and Methods Results Discussion Appendix 1 References

 

1. Ramsey, BW, Dorkin, HL, Eisenberg, JD, et al (1993) Efficacy of aerosolized tobramycin in patients with cystic fibrosis. N Engl J Med 328,1740-1746[Abstract/Free Full Text]
2. MacLusky, IB, Gold, R, Corey, ML, et al (1989) Long-term effects of inhaled tobramycin in patients with cystic fibrosis colonized with Pseudomonas aeruginosa. Pediatr Pulmonol 7,42-48[ISI][Medline]
3. Stead, RJ, Hodson, ME, Batten, JC (1987) Inhaled ceftazadime compared with gentamicin and carbenicillin in older patients with cystic fibrosis infected with Pseudomonas aeruginosa. Br J Dis Chest 81,272-279[CrossRef][ISI][Medline]
4. Littlewood, JM, Miller, MG, Ghoneim, AT, et al (1985) Nebulized colomycin for early Pseudomonas colonization in cystic fibrosis [letter]. Lancet 1,865[ISI][Medline]
5. Hodson, ME, Penketh, ARL, Batten, JC (1981) Aerosol carbenicillin and gentamicin treatment of Pseudomonas aeruginosa infection in patients with cystic fibrosis. Lancet 2,1137-1139[ISI][Medline]
6. Ilowite, JS, Gorvoy, JD, Smaldone, GC (1987) Quantitative deposition of aerosolized gentamycin in cystic fibrosis. Am Rev Respir Dis 136,1445-1449[ISI][Medline]
7. Alderson, PO, Secker-Walker, RH, Strominger, DB, et al (1974) Pulmonary deposition of aerosols in children with cystic fibrosis. J Pediatr 84,479-484[CrossRef][ISI][Medline]
8. Schuh, S, Johnson, DW, Callahan, S, et al (1995) Efficacy of frequent nebulized ipratropium bromide added to frequent high-dose albuterol therapy in severe asthma. J Pediatr 126,639-645[CrossRef][ISI][Medline]
9. Kerem, E, Levison, H, Schuh, S, et al (1993) Efficacy of albuteral administered by nebulizer versus spacer device in children with acute asthma. J Pediatr 123,313-317[CrossRef][ISI][Medline]
10. Steinkamp, G, Tummler, B, Gappa, M, et al (1989) Long-term tobramycin aerosol therapy in cystic fibrosis. Pediatr Pulmonol 6,91-98[ISI][Medline]
11. LeSouëf, PN, Geelhoel, GC, Turner, DJ, et al (1989) Response of the normal infants to inhaled histamine. Am Rev Respir Dis 139,62-66[ISI][Medline]
12. Collis, GG, Cole, CH, LeSouëf, PN (1990) Dilution of nebulised aerosols by air entrainment in children. Lancet 336,341-343[CrossRef][ISI][Medline]
13. Chua, HL, Collis, GG, Newbury, AM, et al (1994) The influence of age on aerosol deposition in children with cystic fibrosis. Eur Respir J 7,2185-2191[Abstract]
14. Smaldone, GC (1996) Aerosolized drug delivery in the 90s. Chest 110,316-317[Free Full Text]
15. Smaldone, GC (1994) Drug delivery by nebulization: "reality testing." J Aerosol Med 7,213-216[ISI][Medline]
16. Bain, JA, Spoerel, WE (1972) A streamlined anesthetic system. Can Anesth Soc J 25,30-36
17. Meakin, G, Coates, AL (1983) An evaluation of rebreathing with the Bain circuit system during anesthesia with spontaneous respiration. Br J Anaesth 55,487-496[Abstract/Free Full Text]
18. . for the Cystic Fibrosis Foundation Consensus PanelRosenstein, BJ, Cutting, GR (1998) The diagnosis of cystic fibrosis: a consensus statement. J Pediatr 132,589-595[CrossRef][ISI][Medline]
19. . American Thoracic Society. (1995) Standardization of spirometry: 1994 update. Am J Respir Crit Care Med 152,1107-1136[ISI][Medline]
20. Coates, AL, Peslin, R, Rodenstein, DO, et al (1997) Measurement of lung volumes by plethysmography. Eur Respir J 10,1415-1427[CrossRef][ISI][Medline]
21. Knudson, RJ, Lebowitz, MD, Holberg, CJ, et al (1983) Changes in the normal maximal expiratory flow-volume curve with growth and aging. Am Rev Respir Dis 127,725-734[ISI][Medline]
22. Coates, AL, MacNeish, CF, Meisner, D, et al (1997) The choice of jet nebulizer, nebulizing flow, and the addition of albuterol affects the output of tobramycin aerosols. Chest 111,1206-1212[Abstract/Free Full Text]
23. MacNeish, CF, Meisner, D, Thibert, R, et al (1997) A comparison of pulmonary availability between Ventolin (albuterol) nebules and Ventolin (albuterol) Respirator Solution. Chest 111,204-208[Abstract/Free Full Text]
24. Coates, AL, MacNeish, CF, Lands, LC, et al (1998) Factors influencing the rate of drug output during the course of wet nebulization. J Aerosol Med 11,101-111
25. Bland, JM, Altman, DG (1986) Statistical methods for assessing agreement between two methods of clinical measurement. Lancet 8,307-310
26. Coates, AL, MacNeish, CF, Lands, LC, et al (1998) A comparison of the availability of tobramycin for inhalation from vented vs unvented nebulizers. Chest 113,951-956[Abstract/Free Full Text]
27. Gerrity, TM, Lee, PS, Hass, FJ, et al (1979) Calculated deposition of inhaled particles in the airway generation of normal subjects. J Appl Physiol 47,867-873[Abstract/Free Full Text]
28. Newman, SP, Clarke, SW (1983) Therapeutic aerosols: 1. Physical and practical considerations. Thorax 38,881-886[ISI][Medline]
29. Newman, SP, Pellow, PGD, Clay, MM, et al (1985) Evaluation of jet nebulisers for use with gentamycin solution. Thorax 40,671-676[Abstract]
30. Taulbee, DB, Yu, CP (1975) A theory of aerosol deposition in the human respiratory tract. J Appl Physiol 38,77-85[Abstract/Free Full Text]
31. Goldberg, IS, Lourenço, RV (1973) Deposition of aerosols in pulmonary disease. Arch Intern Med 131,88-91[CrossRef][ISI][Medline]
32. Mukhopadhyay, S, Staddon, GE, Eastman, C, et al (1994) The quantitative distribution of nebulized antibiotic in the lung in cystic fibrosis. Respir Med 88,203-211[ISI][Medline]
33. Yeh, H, Phalen, RF, Raabe, OG (1976) Factors influencing the deposition of inhaled particles. Environ Health Perspect 15,147-152[ISI][Medline]
34. Kim, CS, Lewars, GA, Sackner, MA (1988) Measurement of total lung aerosol deposition as an index of lung abnormality. J Appl Physiol 64,1527-1536[Abstract/Free Full Text]
35. Kim, CS, Abraham, WM, Chapman, GA, et al (1985) Influence of two-phase gas-liquid interaction on aerosol deposition in airways. Am Rev Respir Dis 131,618-623[ISI][Medline]
36. Thomas, SHL, O’Doherty, MJ, Graham, A, et al (1991) Pulmonary deposition of nebulised amiloride in cystic fibrosis: comparison of two nebulisers. Thorax 46,717-721[Abstract]
37. Dennis, JH (1995) Standardisation in drug nebulisers: BS7711; part 3. J Aerosol Med 8,313-315
38. Clark, AR (1995) The use of laser diffraction for the evaluation of the aerosol clouds generated by medical nebulizers. Int J Pharm 115,69-78[CrossRef]
39. Hollie, MC, Malone, RA, Skufea, RM, et al (1991) Extreme variability in aerosol output of the DeVilbiss 646 nebulizer. Chest 100,1339-1344[Abstract/Free Full Text]
40. Ho, SL, Coates, AL (1999) The effect of dead volume on the efficiency and the cost to deliver medications in cystic fibrosis with four disposable nebulizers. Can Respir J 6,253-260[Medline]
41. Kwong, E, MacNeish, CF, Meisner, D, et al (1998) The use of osmometry as a means of determining changes in drug concentration during jet nebulization. J Aerosol Med 11,89-100

This article has been cited by other articles:

				M. R. Miller, J. Hankinson, V. Brusasco, F. Burgos, R. Casaburi, A. Coates, R. Crapo, P. Enright, C. P. M. van der Grinten, P. Gustafsson, et al. Standardisation of spirometry Eur. Respir. J., August 1, 2005; 26(2): 319 - 338. [Abstract] [Full Text] [PDF]

				G. Reychler, A. Keyeux, C. Cremers, C. Veriter, D. O. Rodenstein, and G. Liistro Comparison of Lung Deposition in Two Types of Nebulization: Intrapulmonary Percussive Ventilation vs Jet Nebulization Chest, February 1, 2004; 125(2): 502 - 508. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Free Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Add to My Personal Article Archive Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (15) Citing Articles via Google Scholar Google Scholar Articles by Coates, A. L. Articles by Lands, L. C. Search for Related Content PubMed PubMed Citation Articles by Coates, A. L. Articles by Lands, L. C.