Bronchiectasis is a disease characterized by hypersecretion and retention of mucus requiring physical and pharmacologic treatment. Recently we reported that inhalation of dry powder mannitol markedly increases mucociliary clearance (MCC) in asthmatic and in healthy subjects (Daviskas, E., S. D. Anderson, J. D. Brannan, H. K. Chan, S. Eberl, and G. Bautovich. 1997. Inhalation of dry-powder mannitol increases mucociliary clearance. Eur. Respir. J. 10:2449–2454). In this study we investigated the effect of mannitol on MCC in patients with bronchiectasis. Eleven patients 40 to 62 yr of age inhaled mannitol (approximately 300 mg) from a Dinkihaler. MCC was measured over 90 min, in the supine position, on three occasions involving: mannitol or control or baseline, using a radioaerosol technique. On the control day patients reproduced the breathing maneuvers and the number of coughs induced by the mannitol. Mannitol significantly increased MCC over the 75 min from the start of the intervention compared with control and baseline in the whole right lung, central, and intermediate region. Mean ( ± SEM) clearance with mannitol was 34.0 ± 5.0% versus 17.4 ± 3.8% with control and 11.7 ± 4.4% with baseline in the whole right lung (p < 0.0001). The mean number of coughs induced by mannitol was 49 ± 11. In conclusion, inhalation of dry powder mannitol increased clearance of mucus and thus has the potential to benefit patients with bronchiectasis.
Bronchiectasis is a disease characterized by an abnormal and permanent dilatation of one or more bronchi. It is generally a result of previous lung infections and results in an impairment of the mucociliary system (1-3). Impaired mucociliary clearance (MCC) may be due to abnormal ciliary activity, abnormal load and rheology of mucus, or abnormal interaction between cilia and mucus. Failure of the mucociliary system to clear the airways may lead to mucus retention and plugging, recurrent infection, severe airflow limitation, and chronic cough. Clinical findings of bronchiectasis include an increased and persistent mucus production and all the features associated with an impairment or failure of the mucociliary system. Cough is a reserve mechanism to clear the airways when the mucociliary system fails and is effective mainly in the central airways.
The treatment of the mucociliary dysfunction in patients with bronchiectasis consists mainly of physical and pharmacologic therapy. The aim of the treatment is to reduce the mucus production and (or) to increase the clearance of mucus by stimulating the ciliary activity, by improving the interaction between cilia and mucus, and by rendering the rheology of mucus to be more favorable. Pharmacologic therapy includes glucocorticosteroids, β2-adrenergic agonists, antibiotics, and mucoactive agents. Physical therapy includes postural drainage and forced breathing maneuvers (4). Patients should combine physical and pharmacologic therapy, as neither of these treatments is as effective alone (4).
An osmotic stimulus in the lower airways is receiving attention as a treatment to increase MCC. Inhalation of hypertonic saline does increase MCC in patients with bronchitis (5), asthma (6), or cystic fibrosis (7) and in healthy subjects (6). We have recently shown that a preparation of the osmotic agent mannitol, suitable for inhalation as a dry powder (8), increases MCC in asthmatic and in healthy subjects (9).
Inhalation of dry powder mannitol may be an efficient method to clear excessive secretions of the airways in patients with bronchiectasis. Our aim in this study was to investigate if inhalation of dry powder mannitol increases clearance of mucus in patients with bronchiectasis.
The study was approved by the Ethics Review Committee of Central Sydney Area Health Service, Protocol No. 93 0061, and informed consent was obtained in writing from all subjects before they participated in the study. It was performed under the Clinical Trial Notification Scheme of the Therapeutic Goods Administration of Australia (No. 94-492).
Eleven patients 40 to 62 yr of age with bronchiectasis took part in the study (Table 1). Patients were introduced to the study by their physician. The diagnosis of bronchiectasis was confirmed with either a high resolution computed tomography (CT) scan or with bronchography. None of the patients had cystic fibrosis and none was known to have any ciliary defects. All but one patient had had the clinical symptoms of bronchiectasis since childhood, and all but two needed a daily intervention (physical or pharmacologic therapy or both) (Table 1) to help clear some of their secretions. All patients had productive cough. Two patients had had a lobectomy of the left lower lobe and one had had a lobectomy of right lower lobe. Five patients were receiving inhaled β2-adrenergic agonists and glucocorticosteroids regularly, whereas five were not receiving any medication. All had recurrent infections treated with antibiotics. Two were receiving nebulized gentamicin regularly. All patients withheld their medication, postural drainage, and exercise for at least 12 h before beginning the protocol on each day. None of the patients had a history of smoking and none had an acute lower respiratory tract infection for at least 3 wk prior to each study. The majority of the patients had airflow limitation (FEV1/FVC < 79% and FEF25–75 < 70%) (Table 1). However, only five patients had a reduced FEV1 (< 80% predicted), and the majority of them had a FVC that was in the normal range (> 80% predicted).
|Subjects No.||Sex||Age (yr)||Height (cm)||FEV1(% pred )||FEV1/FVC (%)||FVC (% pred )||FEF25–75(% pred )||Maximal Fall in FEV1(%)||Mannitol (mg)||Treatment||Surgical History|
|6||F||56||157||86||76||95||68||0||300||S, I, FL, G||Nil||Nil|
|11||F||51||159||87||85||86||89||0||300||S, BEC, TH, G||NIL||LLL lobectomy|
Ten patients had their airways challenged with the aerosol of dry powder mannitol on a separate day, and one was found to have an asthmatic response. This patient had developed bronchiectasis after aspergillosis, which affected both upper lobes. The airway narrowing in response to mannitol was prevented when this patient was premedicated with nedocromil sodium aerosol (16 mg). The remaining patient, who had severe airflow limitation, was also premedicated with nedocromil sodium (16 mg) before the delivery of mannitol.
The mannitol powder (Mannitol BP; Rhône Poulenc Chemicals Pty Ltd., Brookvale, NSW, Australia) was prepared, in the Department of Pharmacy at the University of Sydney by spray-drying a solution of mannitol containing 50 mg/ml (Buchi 190 Mini Spray Drier; Buchi, Flawil, Switzerland). The dried powder was irradiated at Steritech (Wetherill Park, NSW, Australia) (absorbed dose: approximately 4.7 kGy) and a bioburden analysis was carried out at Stanford Laboratories (Rydalmere, NSW, Australia). The results for both yeast and mould showed a value less than 10 cfu/g, and no coliforms or other pathogens were detected.
The particle size of the dry powder mannitol was measured using a multistage liquid impinger (Astra Pharmaceuticals, Lund, Sweden) and assayed by vapor pressure osmometry (Knauer, Berlin, Germany). Gelatin capsules (Parke-Davis, Sydney, Australia) were hand-filled with 5, 10, 20, and 40 (± 0.2) mg using an analytical balance (Sartorius BA11OS; Sartorius, Gottingen, Germany) kept at 40% relative humidity and 20 ± 1° C. The capsules were stored in a container with silica gel that was kept in a dry cabinet. The mannitol was inhaled with a vital capacity maneuver and an inspiratory flow rate between 60 and 120 L/min followed by a breathhold of 5 s using a Dinkihaler (Rhône Poulenc Rorer, Collegeville, PA). Forty-five percent of particles by mass were less than 5.6 μm at 90 L/min.
In our previous studies of the effect of mannitol on MCC (9), the mean (± SD) dose of mannitol loaded in the device that induced a significant increase in MCC in asthmatic and healthy subjects was 267 ± 171 and 400 mg, respectively. On the basis of these results (9) it was decided that a dose of mannitol of approximately 300 mg would be likely to induce an effect on MCC in patients with bronchiectasis. This was delivered by approximately nine capsules, the majority of them containing 40 mg mannitol. The capsules were emptied well and there was no obvious residual amount of mannitol left in the device. The inhaled dose of mannitol was approximately 85 to 90% of the loaded dose.
Spirometry was measured using a hot wire anemometer (AS-500; Minato, Osaka, Japan), before and after inhalation of dry powder mannitol, on the first visit and before the radioaerosol inhalation on the MCC study days. All subjects were clinically stable and had reproducible spirometry. Predicted values were taken from Quanjer and colleagues for adults (10).
Inhalation of radioaerosol. Mucociliary clearance was measured using a radioaerosol technique and imaging with a gamma camera. Approximately 1 GBq 99mTc-sulphur colloid (Chedoke-McMaster Hospitals, Hamilton, ON, Canada) was diluted in 5 ml of isotonic saline. The radioaerosol (MMAD: 6 μm; span: 1.8), determined by laser diffraction technique on a Malvern Mastersizer X (Malvern Instruments Ltd, Malvern, Worcestershire, UK), was generated by an Acorn jet nebulizer (Medic-Aid; Peckham, Sussex, UK) at 8 L/min. The radioaerosol was mildly polydisperse as indicated by the span value (a measure of the width of the droplet distribution). The droplet characteristics were kept constant by humidifying the dilution air supplementing the flow to the mouthpiece. Patients inhaled the radioaerosol with a controlled breathing pattern following a target volume and a target inspiratory time on a computer screen in order to maximize deposition in the conducting airways (11). The target volume was set to be 450 ml and the inspiratory time was set so that the peak inspiratory flow rate was around 40 L/min. This rate was appropriate for this group of patients who had airflow limitation. The patients inhaled the radioaerosol for approximately 2 min. This delivery time was chosen so that the lung counts were about 2,000 counts/s. Upon finishing inhaling the radioaerosol, the subjects removed the deposited radioactivity from their oropharynx and the esophagus by rinsing and gargling with water and expectorating, and by swallowing some bread and water.
Imaging. Anterior and posterior lung images were obtained, with the patient in the supine position, using a single-head rotating gamma camera (Philips Diagnost Tomo, Hamburg, Germany), in a matrix 64 × 64 linked to an on-line computer (PDP11; Digital Equipment Corp., Maynard, MA). The lung fields of the subjects were delineated using anterior and posterior transmission images (12) taken with a moving line source (13). In order to align the lung fields between the transmission and emission images and between the dynamic emission images, images of markers placed on premarked positions on the subject's body were also collected. Care was taken that all emission images were collected at the same time after the midinhalation of the radioaerosol for the three study days.
All images were decay-corrected to the time of midinhalation of the radioaerosol. Geometric mean (GM) images were obtained from the anterior and posterior emission images (14). GM images provide counts that are largely independent of the depth of the activity and thus are insensitive to anterior/posterior movements of activity over the study duration (14).
The outline of the right lung was obtained using the GM of the transmission image. The right lung was further divided into three regions of interest: central, intermediate, peripheral (15). The initial lung radioaerosol distribution (penetration index) was defined by the ratio of the counts per pixel in the peripheral to the counts per pixel in the central region in the first GM emission image obtained 10 min after the mid-inhalation of the radioaerosol.
A monoexponential or biexponential function was fitted to each curve obtained from the dynamic GM images, using a nonlinear least- squares method (IDL 5.0; Research Systems Inc., Boulder, CO). The total counts of the whole right lung and defined regions in the first emission GM image were taken as the initial counts expressed as 100% retention. The counts of the whole right lung and defined regions in the dynamic emission GM images, measured before and after the intervention, were expressed as percentages of the initial counts. Data from the best fit were used to calculate the initial baseline percent clearance, the percent clearance during and post intervention, and over 75 min from the start of intervention.
The study involved four visits, which were at least 48 h apart. The procedure on each visit was as follows. Visit 1. Assessment of airway responsiveness to dry powder mannitol. Visits 2, 3, and 4 each involved (1) Spirometry; (2) Radioaerosol inhalation; (3) Transmission/emission anterior/posterior images (1 min each) 10 min after the midinhalation time of the radioaerosol; (4) Dynamic emission anterior/posterior images (20 s each) for 10 min; (5) Intervention: inhalation of dry powder mannitol or control or resting nasal breathing (baseline study); (6) Dynamic emission anterior/posterior images (20 s each) for 60 min. The choice of the baseline or mannitol study was random. The mannitol always preceded the control study.
The number of coughs were counted at all times of MCC measurements for each of the three study days. The control study day involved the same inhalation maneuvers and the same number of inhalations through the Dinkihaler loaded with an empty capsule. Also, on the control day all subjects were asked to cough as many times as they coughed spontaneously on the mannitol day. For the two patients who were premedicted with nedocromil sodium before the inhalation of mannitol, nedocromil sodium was also given on the control day.
A one-factor analysis of variance (ANOVA) with repeated measures was performed on the calculated clearance with mannitol, its control, and at baseline level. Post-hoc analysis was performed using Fisher's PLSD test (16). Probability values less than 0.05 were considered statistically significant. All statistical analyses were performed using a computerized statistical package (Statview; Abacus Concepts Inc., Berkeley, CA). Results are reported as mean ± SEM. Ninety-five percent confidence intervals (95% CI) were calculated when appropriate.
Inhalation of dry powder mannitol when compared with the control and baseline, markedly improved the clearance of mucus over the 75 min from the start of intervention in patients with bronchiectasis (Figure 1). In the whole right lung mean mucociliary clearance in response to mannitol was almost doubled when compared with control (34.0 ± 5.0 versus 17.4 ± 3.8%) (p < 0.0001). A majority of the patients (seven out of 11) had a baseline clearance of less than 11% (mean, 11.7 ± 4.4%) (Figure 2a) over this time, and in the majority of patients this was increased twofold to threefold in response to mannitol (Figure 2a) (p < 0.0001). The effect of mannitol on clearance was immediate as most of the increase in clearance occurred during the intervention time (15 min) (Figure 1) (p < 0.0002). Cough and inspiratory maneuvers alone (control) did not alter the clearance significantly when compared with baseline in the whole right lung (Figures 1 and 2a) (p > 0.05).
Regional analysis showed that, in the central region, cough and inspiratory maneuvers alone (control) improved clearance by a factor of 2 when compared with baseline (Figure 2b) (p < 0.0001). However, in the presence of mannitol, clearance was improved close to fourfold when compared with baseline in this region (Figure 2b) (p < 0.0001). In a few patients baseline clearance was quite poor in the central region to the extent that there was a net accumulation of mucus over the time of measurement (Figure 2b). Mannitol also increased the clearance in the intermediate region (Figure 2c) (p < 0.001). When compared with control and baseline, mannitol improved clearance by a factor of 2 in most patients in this region (Figure 2c). By contrast to the enhanced clearance in the central and intermediate region, the clearance in the peripheral region was not affected significantly by either the control or the mannitol in most patients (Figure 2d).
There was no significant difference in the initial baseline clearance measured over 15 min before the start of the intervention in the whole right lung between study days (5.3 ± 1.8, 7.7 ± 2.5, and 5.3 ± 1.8% for baseline, control, and mannitol study day, respectively) (p > 0.15) (Figure 1). The mean baseline clearance over 60 min from the midinhalation time of the radioaerosol, measured on the baseline study day, was 13.5% (± 4.7).
The mean (± SD) inhaled dose of mannitol was 320 (± 81) mg (Table 1). Mannitol was well tolerated by all patients. The recorded number of coughs at all intervals for the three study days is shown in Table 2. The number of coughs during the intervention interval on the mannitol and the control study day were reproduced as closely as possible (p > 0.2). Also, there was no significant difference in the number of coughs during the initial baseline clearance (p > 0.2) or the postintervention (p > 0.2) period for the three study days.
The pattern of the radioaerosol deposition and penetration indices were similar on all study days (p > 0.3) (Table 3). The radioaerosol was inhaled at a similar inspiratory flow rate, 41 ± 2, 40 ± 2, and 42 ± 3 L/min for the baseline, mannitol, and control study day, respectively (p > 0.5).
This study in patients with bronchiectasis showed that mannitol inhaled as a dry powder markedly improves the clearance of mucus, when compared with the control and baseline, over the 75 min from the start of intervention. Mannitol almost doubled the clearance of mucus in the whole right lung when compared with the control over the 75 min of measurement. The increase in clearance was evident in the central and intermediate region.
Mucociliary clearance has been found to be impaired in patients with bronchiectasis (1-3), and our data of the baseline MCC are in agreement with these findings. Using the same technique for the measurement of MCC, we have found the mean MCC in young healthy subjects 18 to 46 yr of age (n = 29) to be 29.1 ± 1.8% over 60 min (6, 17, and unpublished data). Puchelle and colleagues (18), using a similar technique, have reported a similar mean MCC (34.1 ± 4.9%) in young subjects 21 to 37 yr of age. A lower value of clearance (21.8 ± 3.5%) was found in older healthy subjects (older than 54 yr), which is 62% of the clearance found in young subjects (18). This suggests that MCC decreases with age. The patients with bronchiectasis in this study (mean age, 52 yr; range, 40 to 62 yr) were found to have a mean MCC of 13.5 ± 4.7% over 60 min, which is about 46% of the MCC value seen in our young normal subjects measured with our technique. Therefore, the clearance achieved in response to mannitol in this group of patients was similar to the baseline clearance in young healthy subjects, which suggests that it must be well above the expected baseline clearance in older healthy subjects.
The impairment of the mucociliary system in patients with bronchiectasis most likely relates to the load and the rheologic properties of the mucus, both of which can affect the interaction between the cilia and the mucus. The incidence of ciliary abnormalities in patients with bronchiectasis, not caused by primary ciliary dyskinesia, is not different from that in healthy subjects (19). The ciliary beat frequency has been found to be in the normal range (19); however, it can be decreased as a consequence of chronic infection (20).
The effect of mannitol on mucus clearance was clearly evident in the majority of patients. Only one patient (Patient 2) showed no effect on clearance. However, this patient had reasonably good baseline clearance (> 20%) in all regions and had the right lower lobe removed a year before, although he still had clinical symptoms of mild bronchiectasis. Cough, on the control day, appeared to have a big effect on clearance on one patient (Patient 7), thus minimizing the measured effect of mannitol in this patient.
Mannitol improved clearance markedly in the central and intermediate region of the lung in the majority of patients. The reason for the lack of any effect of mannitol in the peripheral region is not clear. It is possible that very little mannitol was deposited in that region, which could have been due to the particle size distribution in the particular preparation of mannitol used. A similar particle size distribution of mannitol was found to increase MCC in the peripheral region in patients with mild asthma and in healthy subjects, although the increase was of a smaller magnitude in the healthy subjects and possibly had no biologic significance (9). Inhalation of mannitol containing smaller particles could give a greater effect on clearance in all lung regions because the lung dose would increase. The optimal lung dose and deposition of mannitol for effective mucus clearance needs to be investigated.
The magnitude and the duration of the acute effect of inhaling dry powder mannitol on mucociliary clearance in patients with bronchiectasis was similar to that found in subjects with mild asthma and in healthy subjects (9). Similar results were also found with hypertonic saline in patients with bronchitis (5) or mild asthma, and in healthy subjects (6). The advantage of using a dry powder of mannitol over the wet aerosol of hypertonic saline is that it does not require an ultrasonic nebulizer for delivery and potentially could be used anywhere. Further, it is likely that mannitol is retained in the airway lumen for longer periods than the sodium and chloride ions as the permeability of mannitol is low by comparison (21). It may be expected that any agent capable of increasing osmolarity could potentially be used. However, osmotic agents vary in their potency per weight and their hygroscopic characteristics. Mannitol delivered as a powder meets the essential requirements of resisting moisture resorption at relatively high humidities and being effective at low doses.
The mechanism whereby inhalation of dry powder mannitol increases the clearance of mucus in patients with bronchiectasis is not clear and cannot be obtained from this study. It is likely that a combination of factors may be responsible for the increased mucus clearance with the osmotic agent mannitol. An increase in the osmolarity of the airway fluid with hypertonic saline or impermeable ions has been shown to increase the mucus movement per ciliary beat (22). Additionally, an increase in the osmolarity of the airway fluid has been found to release mediators from epithelial (23) and mast cells (24) and neuropeptides from sensory nerves (25), which may stimulate the ciliary beat frequency (26, 27). There is recent evidence that the number of activated mast cells is increased in patients with bronchiectasis compared with that in healthy subjects (28). Therefore, mannitol could have caused an increase in the ciliary activity or it could have caused an improvement in the interaction between cilia and mucus, which may have helped the system to eliminate excessive secretions.
More importantly, mannitol could have changed the rheology of the mucus. This view is supported by experiments showing an increase in the transportability of mucus from patients with cystic fibrosis and bronchiectasis in the mucus-depleted bovine trachea when incubated overnight with dry powders of hyperosmotic agents, including mannitol (29). The work of King (30) has also suggested that ionic and nonionic osmotic agents improve the rheology of mucus by reducing the number of entanglements that mucin polymers form. Although ionic agents such as salt may achieve this by shielding the fixed charges along the mucin macromolecule, nonionic agents such as sugar derivatives may achieve this by disrupting the hydrogen bonds between mucins (30). As patients with bronchiectasis commonly have viscous mucus, the major effect of mannitol in these patients could have been an improvement in the rheology of mucus. An improvement in the rheology of mucus accompanied by an increase in the ciliary activity and optimal interaction between cilia and mucus would result in an effective clearance of mucus.
An osmotic stimulus is also expected to increase the water in the airway lumen, and this may also have an effect on the transportability of mucus in these patients. Increasing the hydration in the airway lumen by inhaling humidified air has been shown to improve clearance in patients with bronchiectasis (31).
In addition, mannitol induced cough in all patients, and in this study most of the increase in clearance occurred during the mannitol inhalation time when most of the cough occurred. However, cough alone did not increase clearance above the baseline level, except in the central region. Therefore, the increase in clearance observed in response to mannitol cannot be explained by cough alone. However, cough clearance could have been more effective in the presence of mannitol if the rheology of the mucus was more favorable.
Mannitol may stimulate mucus secretion at the same time it increases clearance. This could be a direct effect of mannitol on the mucus secretory cells. Additionally, it could happen indirectly through the mediators released in response to hyperosmolarity, which are known to stimulate mucus secretion (32). Although stimulation of mucus secretion is not desirable for this group of patients, the increase in the clearance of mucus may outbalance the production of mucus. This study reports only the acute effect of mannitol on MCC, and there are no adverse effects of mannitol reported by this group of patients. On the contrary most patients commented that they felt their lungs were “light and clear” for 24 to 48 h after inhalation of mannitol only. The long term potential clinical benefit of mannitol in association with the current pharmacologic and physical treatment needs to be investigated.
Inhalation of mannitol could potentially induce airway narrowing in sensitive subjects. The prevalence of asthma in this group of patients with bronchiectasis was very low. However, it is suggested that an airway challenge test for asthma is performed before it is given for the benefit of mucociliary clearance. If patients are asthmatic, then they should be premedicated with an appropriate protective drug.
In conclusion, inhalation of dry powder mannitol significantly increased clearance of mucus in patients with bronchiectasis. The mechanism of this increase in clearance remains unclear. Inhalation of dry powder mannitol has the potential to minimize retention of mucus and thus benefit patients with bronchiectasis who require a daily intervention to clear their secretions.
The writers would like to thank the technical staff of the Department of Nuclear Medicine for their help and the patients for taking part in the study. They would also like to thank the physicians of the Royal Prince Alfred and Concord Hospital and Dr. Keay Foster from Gosford Hospital for referring their patients.
Supported by a grant from the National Health and Medical Research Council of Australia.
|1.||Lourenço R. V., Loddenkemper R., Carton R. W.Patterns of distribution and clearance in patients with bronchiectasis. Am. Rev. Respir. Dis.1061972857866|
|2.||Currie D. C., Pavia D., Agnew J. E., Lopez-Vidriero M. T., Diamond P. D., Cole P. J., Clarke S. W.Impaired tracheobronchial clearance in bronchiectasis. Thorax421987126130|
|3.||Isawa T., Teshima T., Hirano T., Anazawa Y., Miki M., Konno K., Motomiya M.Mucociliary clearance and transport in bronchiectasis: global and regional assessment. J. Nucl. Med.311990543548|
|4.||Salathe M., O'Riordan T. G., Wanner A.Treatment of mucociliary dysfunction. Chest110199610481057|
|5.||Pavia D., Thomson M. L., Clarke S. W.Enhanced clearance of secretions from the human lung after the administration of hypertonic saline aerosol. Am. Rev. Respir. Dis.1171978199203|
|6.||Daviskas E., Anderson S. D, Gonda I., Eberl S., Meikle S., Seale J. P., Bautovich G.Inhalation of hypertonic saline aerosol enhances mucociliary clearance in asthmatic and healthy subjects. Eur. Respir. J.91996725732|
|7.||Robinson M., Regnis J. A., Bailey D. L., King M., Bautovich G., Bye P. T. P.Effect of hypertonic saline, amiloride and cough on mucociliary clearance in patients with cystic fibrosis. Am. J. Respir. Crit. Care Med.153199615031509|
|8.||Anderson S. D., Brannan J. D., Spring J., Spalding N., Rodwell L. T., Chan H. K., Gonda I., Walsh A., Clark A. R.A new method for bronchial provocation testing in asthmatic subjects using a dry powder of mannitol. Am. J. Respir. Crit. Care Med.1561997758765|
|9.||Daviskas E., Anderson S. D., Brannan J. D., Chan H. K., Eberl S., Bautovich G.Inhalation of dry-powder mannitol increases mucociliary clearance. Eur. Respir. J.10199724492454|
|10.||Quanjer, P. H., G. J. Tammeling, J. E. Cotes, O. F. Pederson, R. Peslin, and J. C. Yernault. 1993. Lung volumes and forced ventilatory flows. Eur. Respir. J. 6(Suppl. 16):5–40.|
|11.||Phipps P. R., Gonda I., Anderson S. D.Apparatus for the control of breathing during aerosol inhalation. J. Aerosol Med.51992155170|
|12.||Bailey D. L., Hutton B. F., Walker P. J.Improved SPECT using simultaneous emission and transmission tomography. J. Nucl. Med.281987844851|
|13.||Bailey D. L., Robinson M., Meikle S. R., Bye P. T. P.Simultaneous emission and transmission measurements as an adjunct to dynamic planar gamma camera studies. Eur. J. Nucl. Med.31996326331|
|14.||Bailey D. L., Fulton R. R., Jackson C. B., Hutton B. F.Dynamic geometric mean studies using a single headed rotating gamma camera. J. Nucl. Med.30198918651869|
|15.||Phipps P. R., Gonda I., Bailey D. L., Borham P., Bautovich G., Anderson S. D.Comparisons of planar and tomographic gamma scintigraphy to measure the penetration index of inhaled aerosols. Am. Rev. Respir. Dis.139198915161523|
|16.||Altman, D. 1992. Practical Statistics for Medical Research, 1st ed. Chapman & Hall, London. 205–212, 325–333.|
|17.||Daviskas E., Anderson S. D., Gonda I., Chan H. K., Cook P., Fulton R.Changes in mucociliary clearance during and after isocapnic hyperventilation in asthmatic and healthy subjects. Eur. Respir. J.81995742751|
|18.||Puchelle E., Zahm J. M., Bertrand A.Influence of age on bronchial mucociliary transport. Scand. J. Respir. Dis.601979307313|
|19.||de Iongh R. U., Rutland J.Ciliary defects in healthy subjects, bronchiectasis and primary ciliary dyskinesia. Am. J. Respir. Crit. Care Med.151199515591567|
|20.||Wanner A., Salathé M., O'Riordan T. G.Mucociliary clearance in the airways. Am. J. Respir. Crit. Care Med.154199618681902|
|21.||Yankaskas J. R., Gatzy J. T., Boucher R. C.Effects of raised osmolarity on canine tracheal epithelial ion transport function. J. Appl. Physiol.62198722412245|
|22.||Winters S. L., Yeates D. B.Roles of hydration, sodium and chloride in regulation of canine mucociliary transport system. J. Appl. Physiol.83199713601369|
|23.||Assouline G., Leibson V., Danon A.Stimulation of prostaglandin output from rat stomach by hypertonic solutions. Eur. J. Pharmacol.441977271273|
|24.||Jongejan R. C., de Jongste J. C., Raatgee R. C., Stijnen T., Bonta I. L., Kerrebijn K. F.Effect of hyperosmolarity on human isolated central airway. Br. J. Pharmacol.1021991931937|
|25.||Silber G., Proud D., Warner J., Naclerio R., Kagey-Sobotka A., Lichtenstein L., Eggleston P.In vivo release of inflammatory mediators by hyperosmolar solutions. Am. Rev. Respir. Dis.1371988606612|
|26.||Wanner A., Sielczak M., Mella J. F., Abraham W. M.Ciliary responsiveness in allergic and nonallergic airways. J. Appl. Physiol.60198619671971|
|27.||Wong L. B., Miller I. F., Yeates D. B.Pathways of substance P stimulation of canine tracheal ciliary beat frequency. J. Appl. Physiol.701991267273|
|28.||Sepper R., Konttinen Y. T., Kemppinen P., Sorsa T., Eklund K. K.Mast cells in bronchiectasis. Ann. Med.301998307315|
|29.||Wills P., Hall R., Chan W.-m., Cole P. J.Sodium chloride increases the ciliary transportability of cystic fibrosis and bronchiectasis sputum on the mucus-depleted bovine trachea. J. Clin. Invest.991997913|
|30.||King M.Mucoactive therapy: what the future holds for patients with cystic fibrosis. Pediatr. Pulmonol.241997122123|
|31.||Conway J. H., Fleming J. S., Perring S., Holgate S. T.Humidification as an adjunct to chest physiotherapy in aiding tracheo-bronchial clearance in patients with bronchiectasis. Respir. Med.861992109114|
|32.||Tavakoli, S., S. J. Levine, and J. H. Shelhamer. 1997. Airway mucus secretion. In P. J. Barnes, M. M. Grunstein, A. R. Leff, and A. J. Woolcock, editors. Asthma. Lippincott-Raven Publishers, Philadelphia. 843– 857.|
The application for the use of mannitol described in the paper is covered by a U.S. Patent No. 5817028, an Australian Patent No. 682756 and an International Patent PCT/AU 95/00086 held by Central Sydney Area Health Service.