| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Guest Access | Sign In via User Name/Password
|
|
|
|||||||
Guest Access | Sign In via User Name/Password |
|||||||||
* From the Departments of Respiratory Medicine (Drs. Daviskas, Anderson, and Young) and PET & Nuclear Medicine (Mr. Eberl), Royal Prince Alfred Hospital, Camperdown; and Department of Pharmacy (Dr. Chan), University of Sydney, Sydney, Australia.
Correspondence to: Evangelia Daviskas, MBiomedE, PhD, Department of Respiratory Medicine, Level 9, Page Chest Pavilion, Royal Prince Alfred Hospital, Missenden Rd, Camperdown, NSW 2050, Australia; e-mail: lily{at}nucmed.rpa.cs.nsw.gov.au
 |
Abstract |
|---|
 TOP Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Design: Clearance of mucus was measured on 3 consecutive days using 99mTc-sulfur colloid radioaerosol and a gamma camera.
Interventions: Mannitol, 330 ± 68 mg (mean± SD), was inhaled using a dry powder inhaler only on day 2.
Patients: Eight patients with bronchiectasis (age range, 29 to 70 years).
Measurements and results: On each day, lung images were collected over 2 h and at 24 h. Key findings of the study are as follows: (1) the 24-h retention of mucus was reduced the day after mannitol had been inhaled, compared to the day without mannitol (day 1) in the whole right lung (57.6 ± 6.2% vs 68.1 ± 5.9%), central (47.5 ± 6.7% vs 56.9 ± 6.5%), intermediate (61.7 ± 5.6% vs 73.8 ± 5.5%), and peripheral regions (70.9 ± 4.3% vs 86.6 ± 4.6%)(p < 0.02); and (2) mannitol helped patients clear mucus within 2 h that might otherwise take up to 24 h, from the whole right lung and defined regions. However, clearance over 60 min measured 24 h after mannitol inhalation was not significantly different to baseline clearance without mannitol (8.7 ± 1.9% on day 1 vs 9.7 ± 3.7% 24 h after mannitol; p > 0.8). The patients maintained the same lung function the day before and after mannitol had been inhaled: FEV1 (percent predicted), 79 ± 5 on day 1 vs 80 ± 5 on day 3; and forced expiratory flow, midexpiratory phase (percent predicted), 50 ± 6 on day 1 vs 51 ± 6 on day 3; p > 0.6).
Conclusions: Mannitol inhalation acutely increases clearance of mucus, and this effect extends beyond the acute study period, resulting in decreased mucus retention at 24 h.
Key Words: bronchiectasis • hyperosmolarity • mannitol • mucus clearance
|
Introduction |
|---|
|
TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Osmotic agents, such as ionic hypertonic saline solution, and nonionic mannitol, dextran, and lactose, have been found to increase clearance of mucus5 6 7 8 9 10 and are regarded as promising mucoactive agents.11 The mechanism whereby osmotic agents increase clearance of mucus remains unclear. A combination of factors, which include changes in the rheology of mucus favoring ciliary and cough clearance,11 12 may be responsible. Osmotic agents may change the viscoelastic properties of the mucus by reducing the number of entanglements that mucin polymers form. While ionic agents may achieve this by shielding the fixed charges along the mucin macromolecules, the nonionic agents may achieve this by disrupting the hydrogen bonds between mucins.11 Osmotic agents also have the potential to increase the amount of water in the airway lumen.13 14 Thus, increased hydration may also contribute to an increase in the transportability of mucus.14 Additionally, osmotic agents may increase clearance of mucus by stimulating mucus secretion. The effect of osmolarity on mucus secretion could be direct15 or indirect via release of mediators from epithelial16 and mast cells17 and neuropeptides from sensory nerves,18 19 which are known to be secretagogues.20 Although an increase in mucus secretion is not a desirable effect for the patient with bronchiectasis, this stimulation of mucus secretion may help increase clearance of viscous and stagnated mucus.
We have recently shown21 that inhalation of dry powder mannitol increases clearance of mucus acutely in patients with bronchiectasis. In that study,21 subjects had commented that the subjective benefits of a single dose of mannitol extended well beyond the acute study period. As the single dose of mannitol could be retained in the airways for some time because of its low permeability,22 the duration of its effect on the clearance of mucus remained in question. Mannitol may benefit patients by reducing the mucus load acutely, or it may have a prolonged effect on mucociliary clearance. Also, as excessive mucus in the airways may result in some limitation of airflow, a reduction in the mucus load may also improve airway function especially in the small airways. Thus, the present study investigated, in addition to the acute effect of mannitol, (1) the 24-h retention of mucus, and (2) the clearance rate and lung function close to 24 h following inhalation of a single dose of mannitol in patients with bronchiectasis.
|
Materials and Methods |
|---|
|
TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Subjects
Eight patients with bronchiectasis (age range, 29 to 70 years;
Table 1 ) took part in the study. Patients were introduced to the study by their
physician. Bronchiectasis was diagnosed with either a high-resolution
CT scan or with bronchography. Five patients had bronchiectasis in both
the right and left lung, one in the right lung only and two in the left
lung only. None of the patients had a diagnosis of cystic fibrosis, and
none had immotile cilia syndrome. All had long-standing symptoms of
bronchiectasis arising from some infection in the past. Four patients
were receiving regular pharmacologic treatment with a
{beta}2-adrenergic agonist (short- or long-acting)
and the glucocorticoid drug budesonide. Two patients were receiving
salmeterol, a long-acting {beta}2-adrenergic
agonist. All but two were having postural drainage and/or exercise
daily to help clear excessive secretions. All had recurrent infections
treated with antibiotics. All patients withheld their short-acting
{beta}2-adrenergic agonist and budesonide for at
least 12 h before beginning the protocol on each day. The two
patients receiving salmeterol stopped treatment from 48 h before
the study until the end of the study. Nonsteroidal anti-inflammatory
medication was stopped 72 h before the study. None of the patients
had a history of smoking, and none were being treated with an
antibiotic at the time of the study.
|
Dry Powder Mannitol
The mannitol powder (Mannitol BP; Rhône Poulenc Chemicals
Pty., Ltd.; Brookvale, NSW, Australia) was prepared by spray
drying a solution containing 50 mg/mL (Büchi 190 Mini Spray
Drier; Büchi Labortechnik AG; Flawil, Switzerland). Before
being used for inhalation, it was irradiated at Steritech (Wetherill
Park NSW, Australia), absorbed dose of approximately 4.7 kGy, and a
bioburden analysis was carried out at Stanford Laboratories (Rydalmere
NSW, Australia). The results for both yeast and mold showed a value
< 10 cfu g-1, 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 a Waters high-performance liquid chromatography system using a refractive index detector (model 410; Waters; Milford, MA). Gelatin capsules (Parke-Davis; Sydney, Australia) were hand filled with approximately 5, 10, 20, and 40 mg using an analytical balance (model BA11OS; Sartorius; Gottingen, Germany) kept at 40% relative humidity and 20 ± 1°C. Patients inhaled the mannitol with a vital capacity maneuver and a fast inspiratory flow rate followed by a breath hold of 5 s using an inhaler (Inhalator; Boehringer Ingelheim; Ingelheim, Germany). Sixty-five percent of mannitol particles by mass in the aerosol clouds generated from the inhaler at 60 L min-1 were < 7µm as measured by the multiple-stage liquid impinger.
In our previous study on the effect of mannitol on mucociliary clearance in patients with bronchiectasis,20 the mean ( ± SD) inhaled dose of mannitol was 320 ± 81 mg. Based on these20 and previous results,8 it was decided to deliver a similar dose of mannitol, 400 mg, in the present study. The inhaled dose was determined by weighing the mannitol capsules before and after inhalation using an analytical balance (model BA11OS; Sartorius).
Measurement of Lung Function
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 mucociliary clearance study days. All subjects were clinically
stable and had reproducible spirometry. Predicted values were taken
from Quanjer et al,24
for adults.
Measurement of Mucociliary Clearance
Mucociliary clearance was measured using a radioaerosol
technique and imaging with a gamma camera. The method for delivering
the radioaerosol, the image collection and analysis have been published
in detail previously.6
21
Inhalation of Radioaerosol
In brief, the radioaerosol,
99mTc-sulfur colloid (Chedoke-McMaster Hospitals;
Hamilton, Ontario) was generated (mass median aerodynamic diameter, 6
µm; span, 1.8 µm) by an Acorn jet nebulizer (Medic-Aid;
Peckham, Sussex, UK) at 8 L/min. Patients inhaled the radioaerosol with
a controlled breathing pattern following a target volume (450 mL) and a
target inspiratory time on a computer screen for maximum deposition in
the conducting airways.21
25
The breathing pattern aimed
at a peak inspiratory flow rate of around 40 L/min. The patients
inhaled the radioaerosol for approximately 2 min.
Imaging
Anterior and posterior lung images were obtained, with the
patient in the supine position, using a single-head rotating gamma
camera (Diagnost Tomo; Philips; Hamburg, Germany). The lung fields of
the subjects were delineated with anterior and posterior transmission
images26
taken with a moving line source.27
Protocol
Assessment Study:
An airway challenge with dry powder
mannitol was performed in all patients, at least 48 h prior to the
mucociliary clearance studies, in order to assess airway responsiveness
to mannitol and to establish safety.
Mucociliary Clearance Studies:
Clearance was studied
on 3 consecutive days, which started at least 48 h after the
assessment study. On day 1, the day before mannitol was administered,
clearance was measured without any intervention, over 2 h and at
24 h following the radioaerosol. On day 2, mannitol was
administered and clearance was measured over 2 h and at 24 h
following the radioaerosol. On day 3, clearance was measured as on day
1 in order to investigate if there were changes as a consequence of the
mannitol administered the previous day.
The procedure on days 1 to 3 were as follows: (1) spirometry; (2) radioaerosol inhalation; (3) emission anterior/posterior images (1-min each), 10 min after the mid-inhalation time of the radioaerosol, in order to assess initial deposition of the radioaerosol; (4) dynamic emission anterior/posterior images (20-s each) for 30 min, in order to assess initial baseline clearance; (5) intervention (inhalation of dry powder mannitol [day 2] or resting nasal breathing [day 1 and day 3]); (6) dynamic emission anterior/posterior images (20-s each) for 60 min, in order to assess clearance with and without the effect of mannitol; and (7) emission anterior/posterior images (10-min each), approximately 24 h after the mid-inhalation time of the radioaerosol (day 2 and day 3 only, performed before spirometry), in order to assess the 24-h retention of radioactivity with and without the effect of mannitol.
The number of spontaneous coughs were counted by the investigator at all times of mucociliary clearance measurements for each of the 3 study days. For the two patients who were premedicated with nedocromil sodium before the inhalation of mannitol, nedocromil sodium was also given on the other mucociliary clearance study days.
Data Image Analysis
All images were decay corrected to the time of mid-inhalation of
the radioaerosol. Geometric mean (GM) images were obtained from the
anterior and posterior transmission and emission images.28
The right lung was divided into three regions of interest: central,
intermediate, and peripheral.29
The initial lung
radioaerosol distribution (penetration index) was characterized by the
ratio of the counts per pixel in the peripheral to the counts per pixel
in the central region in the GM emission image obtained 10 min after
the mid-inhalation of the radioaerosol.
A mono- or bi-exponential function was fitted to each curve obtained from the dynamic GM images, using a nonlinear least squares method (IDL 5.0; Research Systems; 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, and of the emission image taken at 24 h were expressed as percentage of the initial counts. Data from the best fit were used to calculate the baseline percent clearance (initial and at 60 min), the percent clearance during and after intervention, over 75 min from the start of intervention, percent clearance over total time (approximately 120 min), and percent retention and clearance at 24 h.
Statistical Analysis
A one-factor analysis of variance, with repeated measures, was
performed on the calculated clearance at the same specified intervals
on the three study days and on the 24-h retention of study day 1 and
day 2. Post hoc analysis was performed using Fisher PLSD
test.30
Spearman’s correlation analysis was performed between the changes in the 24-h percent retention and the changes in the penetration indexes. Probability values < 0.05 were considered statistically significant. Statistical analyses were performed using a computerized statistical package (Statview; Abacus Concepts; Berkeley, CA). Results are reported as mean ± SEM. Ninety-five percent confidence intervals were calculated where appropriate.
|
Results |
|---|
|
TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
|
The reduction in the 24-h retention of mucus is a likely consequence of the acute increase in clearance. As shown in Figure 1 , most of the total increase in clearance within 24 h in response to mannitol occurred acutely in all lung regions. The acute increase in clearance after mannitol was such that most patients had cleared a similar or an increased amount of mucus at 120 min as they had cleared at 24 h without mannitol. The mean percent clearance at 120 min and at 24 h with mannitol compared to the clearance without mannitol for each of these intervals are shown in Figure 2 .
|
Mannitol Dose, Lung Function, and Cough
The mean ( ± SD) inhaled dose of mannitol was 330 ± 68 mg.
The clearance of mucus induced by this single daily dose had no effect
on the FEV1 (p > 0.3) or on the forced
expiratory flow, midexpiratory phase (FEF25–75%;
p > 0.6). The lung function remained similar on all
consecutive study days: mean ( ± SEM) percent predicted
FEV1, 79 ± 5, 80 ± 5, and 80 ± 5; FVC,
93 ± 4, 93 ± 4, and 93 ± 5; and
FEF25–75%, 50 ± 6, 50 ± 7, and 51 ± 6.
Mannitol was well tolerated by all patients despite the induction of cough. The cough occurred with a greater frequency during and after the inhalation of mannitol, compared to the cough that occurred spontaneously on day 1 and day 3 when no mannitol was given (p < 0.05; Table 2 ). The number of coughs on the day before and the day after inhalation of mannitol was not significantly different (p > 0.2).
|
|
|
Discussion |
|---|
|
TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
The acute increase of the clearance of mucus over 75 min from the start of inhalation of mannitol is in agreement with the effect reported previously in a separate group of patients with bronchiectasis in the whole right lung, central, and intermediate region.21 In the patients in the current study, a significant increase in clearance was also observed in the peripheral region, a finding not observed in the previous study.21 The failure to find a significant effect in clearance in response to mannitol in the peripheral region in the previous study21 is unclear. It possibly relates either to the differences in the patient group in relation to baseline clearance or it may relate to the different dry powder inhaler device used. It is possible that a greater quantity of mannitol was deposited in the smaller airways in this group of patients as a result of the lower inspiratory flow rate through the inhaler used (Inhalator, 60 L/min) in this study vs 90 L/min (Dinkihaler; Rhone-Poulenc Rorer; Collegeville, PA) as used in the previous study.21
The majority of patients had a poor clearance in the whole right lung (< 11% over 60 min) and defined regions, which was quite reproducible over the occasions it was measured in this study. Healthy individuals, 18 to 46 years of age, are expected to clear close to 30%, and individuals > 54 years old are expected to clear close to 22% over 60 min.21 31 The low value of clearance in these patients is in agreement with the findings of other workers1 2 3 and with the increased and persistent mucus production that characterizes the disease.
Measurement of the 24-h retention of radioactivity showed that total clearance of mucus was increased when mannitol had been inhaled. This would suggest that the mucus load 24 h after mannitol was decreased, a finding that supports the subjective comments of the patients. While retention was less at 24 h, repeat measurements of the clearance rate itself 24 h after inhalation of a single dose of mannitol did not show an increase compared with the pretreatment day. This is difficult to explain without knowing the state of mucus, in terms of load and properties at baseline and 24 h after mannitol.
The radioaerosol technique measures the clearance of the radioactivity deposited on or intermixed with mucus. It does not provide an indication of the total amount of mucus in the airways or the production rate of mucus. Mannitol, being a hyperosmotic agent, will stimulate mucus secretion.15 How much of the old stagnated and new mucus is cleared in response to mannitol cannot be deduced from this study. However, as the radioaerosol is inhaled before the inhalation of mannitol, the radioactivity is initially deposited on the old stagnated mucus. It is likely that any newly secreted mucus, in response to mannitol, is mixed with the radioactive stagnated mucus and in some way facilitates its clearance. Nonetheless, the data suggest that a single dose of mannitol does not have a measurable effect on clearance rate 24 h after it was inhaled; for this reason, it is not surprising that mannitol had no measurable effect on lung function. The results of the present study suggest that dosing should be twice daily if mannitol is to have a significant effect in the long term on rate of clearance of mucus and lung function.
Dry powder mannitol induced coughing during and after the administration with a frequency that was higher, compared to the spontaneous coughing that occurred on day 1 and day 3, and this was consistent with previous observations.21 Our previous study21 showed that the increase in cough frequency alone does not account for the improvement in mucus clearance. It is possible that clearance induced by coughing was greatly improved in the presence of mannitol in these patients. Cough clearance in response to mannitol was actually shown to be increased in patients with cystic fibrosis in a cough controlled study.32 It is possible that an important effect of mannitol in patients with bronchiectasis is an improvement in cough clearance. The increase in the clearance of mucus in the peripheral region over 75 min and the reduction in the 24-h retention of mucus observed in this study is unlikely to be primarily due to cough because it is mainly effective in the large airways.
Mannitol has a pleasant taste and the increase in cough frequency induced by the mannitol was well tolerated. Most patients with bronchiectasis undergo physiotherapy treatment. This treatment in itself induces cough, aiming to help expectoration of excessive secretions. Therefore mannitol could also be seen as a substitute or a help to physiotherapy treatment in patients with bronchiectasis. The effect of mannitol on the overall mucus clearance in daily life remains to be investigated.
In conclusion, the present study confirms the acute increase in the clearance of mucus in response to inhaled mannitol in patients with bronchiectasis reported previously. This study has extended these findings to show the following: (1) the effect of mannitol on the clearance of mucus extends beyond the acute study time resulting in a reduction in the 24-h retention of mucus; (2) a single dose of mannitol does not have any measurable effect on the clearance rate itself and lung function 24 h after its inhalation; (3) mannitol rapidly clears mucus that without mannitol might take > 24 h to clear; and (4) mannitol inhaled as a dry powder can have an effect on mucus clearance of the lung in the peripheral region in patients with bronchiectasis. These are important findings and suggest that a twice-daily dose of mannitol may provide greater benefit than a single dose. These data provide important guidance to the design of treatment regimens for trials of the long-term clinical effects of mannitol in patients with bronchiectasis.
|
Acknowledgements |
|---|
|
Footnotes |
|---|
The study was supported by a grant from the National Health and Medical Research Council of Australia.
The application for the use of mannitol described in this article is covered by U.S. Patent No. 5817028, Australian Patent No. 682756, and an International Patent, PCT/AU 95/00086, held by Central Sydney Area Health Service.
Received for publication March 20, 2000. Accepted for publication June 29, 2000.
|
References |
|---|
|
TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
This article has been cited by other articles:
|
|
 |
|
  A. Jaques, E. Daviskas, J. A. Turton, K. McKay, P. Cooper, R. G. Stirling, C. F. Robertson, P. T. P. Bye, P. N. LeSouef, B. Shadbolt, et al. Inhaled Mannitol Improves Lung Function in Cystic Fibrosis Chest, June 1, 2008; 133(6): 1388 - 1396. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. Moller, K. Haussinger, R. Winkler-Heil, W. Stahlhofen, T. Meyer, W. Hofmann, and J. Heyder Mucociliary and long-term particle clearance in the airways of healthy nonsmoker subjects J Appl Physiol, December 1, 2004; 97(6): 2200 - 2206. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A P Watt, V Brown, J Courtney, M Kelly, L Garske, J S Elborn, and M Ennis Neutrophil apoptosis, proinflammatory mediators and cell counts in bronchiectasis Thorax, March 1, 2004; 59(3): 231 - 236. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Daviskas, S.D. Anderson, S. Eberl, H-K. Chan, I.H. Young, and J.P. Seale Effects of terbutaline in combination with mannitol on mucociliary clearance Eur. Respir. J., December 1, 2002; 20(6): 1423 - 1429. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
), day 2 (•), and day 3
(
) in the whole right lung (top left,
A), central (top right,
B), intermediate (bottom left,
C), and peripheral (bottom right,
D) regions in eight patients with bronchiectasis.
Clearance is calculated as 100 minus the retained activity at a
specified time. The following are demonstrated in the whole right lung
and defined regions: (1) the poor clearance over 30 min before
intervention; (2) the immediate increase in clearance in response to
mannitol (day 2), compared to clearance without mannitol on day 1; (3)
the decrease in the 24-h retention of radioactivity of day 2, when
mannitol was inhaled, compared to that of day 1; and (4) the lack of
any change in the clearance rate between day 1 and day 3.