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Original Research: CYSTIC FIBROSIS |

Inhaled Mannitol Improves the Hydration and Surface Properties of Sputum in Patients With Cystic Fibrosis FREE TO VIEW

Evangelia Daviskas, MBiomedE, PhD; Sandra D. Anderson, PhD, DSc; Anna Jaques, BSc, MPH; Brett Charlton, MBBS, PhD
Author and Funding Information

From the Department of Respiratory and Sleep Medicine (Dr Daviskas), Royal Prince Alfred Hospital, Sydney; Central Clinical School (Dr Anderson), School of Medicine, University of Sydney, Sydney; and Pharmaxis Ltd. (Ms Jaques and Dr Charlton), Frenchs Forest, NSW, Australia.

Correspondence to: Evangelia Daviskas, PhD, Department of Respiratory and Sleep Medicine, Royal Prince Alfred Hospital, 11 West, Missenden Rd, Camperdown, Sydney, NSW 2050, Australia; e-mail: daviskas@med.usyd.edu.au


Funding/Support: This study was sponsored by Pharmaxis Ltd.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestpubs.org/site/misc/reprints.xhtml).


© 2010 American College of Chest Physicians


Chest. 2010;137(4):861-868. doi:10.1378/chest.09-2017
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Background:  The airway mucus in patients with cystic fibrosis (CF) is dehydrated and adhesive and accumulates in the airways, resulting in chronic inflammation, infection, and progressive loss of lung function. Inhaled mannitol improves mucus clearance and, when administered over 2 weeks, it improves lung function in CF (Jaques et al. Chest. 2008;133(6):1388-1396). The changes in the physical properties of sputum after a 2-week treatment with mannitol were investigated in the same subjects with CF.

Methods:  Sputum was collected before and at the end of the 2-week treatment period from 28 subjects with CF who participated in the double-blind crossover study. Mannitol or placebo 420 mg bid was inhaled over 2 weeks. The solids content, surface tension, contact angle, and viscoelasticity were measured.

Results:  Two-week treatment with mannitol reduced the solids from 7.3% ± 3.0% to 5.7% ± 3.0% (P = .012), surface tension from 83.1 ± 7.2 to 78.6 ± 8.0 mN/m (P < .039), and contact angle from 52.4 ± 7.7 to 47.9 ± 7.3 degrees. There was no significant change in the viscoelastic properties of sputum (P > .1). Placebo treatment had no significant effect on the sputum properties. The change in solids content correlated with the change in both FEV1 (r = −0.78, P = .004) and forced expiratory flow in the middle half of the FVC (r = −0.80, P = .003), and the percentage change in surface tension and contact angle correlated with the percentage change in the FEV1 (r = −0.73, P = .012 and r = −0.63, P = .03, respectively) in these subjects.

Conclusion:  Treatment with inhaled mannitol over 2 weeks improved the hydration and surface properties of sputum in patients with CF. This effect was sustained and correlated with airway function changes.

Trial registration:  clinicaltrials.gov; Identifier: NCT00455130

Figures in this Article

In cystic fibrosis (CF) failure of the transmembrane regulator to control ion transport across the airway epithelia leads to dehydrated airways with adhesive and tenacious mucus and abnormal mucociliary and cough clearance.1,2 Failure to clear mucus effectively leads to recurrent bacterial infections that fail to resolve causing persistent inflammation and airway wall damage.3 The CF airways are colonized predominantly with Pseudomonas aeruginosa and patients have progressive loss of lung function.3 A major goal in the treatment and management of CF is to improve the airway hydration and sputum properties, facilitate clearance of mucus, improve health-related quality of life, and minimize the progression of the disease.

Inhaled mannitol is an osmotic agent that has been shown to improve airway hydration and clearance of mucus in diseases with excessive secretions, including CF.4-6 In a recent study, when mannitol was administered bid over 2 weeks in patients with CF, it improved the lung function and the health-related quality of life.7 Mannitol treatment increased the FEV1 from baseline by a mean 7% and the forced expiratory flow in the middle half of the FVC (FEF25-75) by 15.5%.7 Part of the study was to investigate the effect of mannitol on the physical properties of sputum collected from these patients. We report the findings of the effect of mannitol when administered over 2 weeks on the physical properties of sputum in patients with CF.

Subjects

Thirty-nine subjects with CF, clinically stable, from Australia and New Zealand were randomized, and 35 subjects completed both treatments of the study.7 Subjects were > 8 years old and had FEV1 between 41% and 91% predicted. Eligible subjects were premedicated with 400 μg of salbutamol prior to having an airway challenge with mannitol (Aridol; Pharmaxis Ltd; Frenchs Forest, NSW, Australia) following a standard protocol8 to exclude subjects with airway hyperresponsiveness to mannitol. Subjects with ≥ 15% decrease in FEV1 from baseline were excluded. The study was approved by the ethics committee at each center, and written informed consent was obtained from all participants prior to screening.7

Study Design and Treatment

This was a double-blind, crossover study. Subjects were randomized to treatment in a 1:1 ratio. The design of the study is shown in Table 1. Subjects were instructed to inhale mannitol or placebo (420 mg bid) over a 2-week period. The first treatment dose was inhaled under supervision in the hospital clinic. Mannitol and placebo were inhaled from a dry powder inhaler.7 Salbutamol (400 μg) from a pressurized metered-dose inhaler and a Volumatic spacer (Allen and Hanburys; West Uxbridge, England) was administered before each treatment.

Table Graphic Jump Location
Table 1 —Design of Study and Sputum Collection
Sample Collection

Sputum was collected after spontaneous expectoration, in the hospital clinic, at specified intervals as shown in Table 1. Twenty-eight subjects (including 12 children < 18 y) were able to expectorate a sample but not necessarily on all occasions. Five of the 12 children (41.7%) and seven of the 16 adult (43.8%) subjects with CF were on regular dornase alfa. Baseline sputum samples were collected before any treatment began. At the end of the 2-week treatment period, sputum was collected approximately 12 h after the last dose of mannitol or placebo was inhaled. A sample was also collected 2 weeks after the last treatment dose was inhaled. The sputum was visualized and the mucus component was selected manually, eliminating saliva, and was stored in 1.2-mL tubes in a −80°C freezer until analyzed.

Measurements
Solids content:

The percentage of solids content in the sputum was calculated by measuring the weight of a 50-μL aliquot of sputum before and after lyophilization to dryness for 24 h using a freeze dryer (Kinetics; Stone Ridge, NY).

Surface Tension:

Surface tension was measured using a semiautomatic tensiometer (Fisher Tensiomat Model no. 21; Fisher Scientific; Pittsburgh, PA) using the du Nouy ring method as described previously.9-11 The tensiometer was calibrated using a 5.94-cm circumference ring and a known mass. The calibration was verified against water of known surface tension (72.0 mN/m). Surface tension of sputum was measured with a custom platinum-iridium ring with a circumference of 1.38 cm. Using a positive displacement pipette, an aliquot of 20 to 25 μL of sputum was placed on a glass slide at room temperature (24°C). The average of three measurements using three 20 to 25 μL aliquots of sputum was taken. Measurements were valid if the ring was completely detached from the sputum sample. As the tensiometer is calibrated with the large circumference ring, the surface tension values of sputum, obtained using the small circumference ring, were multiplied by 4.3 to account for difference in the circumference of the two rings.

Wettability (Contact Angle-Glass):

Wettability of mucus, its ability to spread over a solid planar surface, is characterized by the contact angle (θ).12 The contact angle of a 20-μL aliquot of sputum drop on glass was measured as previously described.10,11 The image of the sputum drop was captured with a camera (AxioCam MRc5; Zeiss; Gottingen, Germany) interfaced to a stereomicroscope (Stemi 2000, Zeiss) and a computer. The contact angle between the sputum drop and the glass at equilibrium was measured using image analysis (Carl Zeiss Vision GmbH; Munich, Germany).

Rheology of Sputum:

The elasticity and viscosity of sputum were measured using a 20-μL aliquot and a controlled stress rheometer with geometry 20 mm, 0.5° aluminum cone and plate (AR 2000; TA Instruments; New Castle, DE) as previously described.10,11 Measurements of elasticity and viscosity were obtained first using the creep procedure at a constant shear stress of 0.20 Pa at 37°C. These were subsequently interconverted to dynamic viscosity and elasticity as a function of angular frequency (AR 2000). The results are reported as dynamic elasticity (storage modulus G′) and dynamic viscosity (loss modulus G″) at angular frequencies of 1 and 100 rad/s. Values for viscosity and elasticity measured at frequency 1 rad/s are more representative of tidal breathing airflow and clearance by ciliary activity, whereas at frequency 100 rad/s the values measured are more representative of those during high airflow and cough clearance.

Statistical Analysis

The effect of each treatment on the sputum properties was assessed using analysis of variance with repeated measures. Post hoc analysis was performed using Fisher-protected least significant difference. Differences from baseline between the two treatments were compared using unpaired t test analysis. A two-tailed P value < .05 was considered to be statistically significant. Data are presented as mean ± SD, and 95% CIs are reported if applicable. Spearman rank correlations were performed between the changes in the sputum properties and the lung function.

There was no significant difference in the sputum properties between mannitol and placebo treatment at baseline and after a 2-week washout period. In addition, the order of treatment did not influence any of the sputum properties (ie, there was no carryover effect).

The solids content and surface properties of sputum were significantly reduced after a 2-week treatment with mannitol inhaled bid in patients with CF. This reduction was observed approximately 12 h after the last dose. The reduction in the solids and surface properties of sputum after 2 weeks’ treatment with mannitol correlated significantly with the increase in lung function reported in the same subjects.7

Solids Content

The solids content was significantly reduced after a 2-week treatment with mannitol from 7.3% ± 3.0% to 5.7% ± 3.0% (P = .012, n = 15) (Fig 1). The mean (95% CI) change from baseline in solids was −1.6% ± 2.2% (−0.4% to −2.8%). In contrast, 2-week treatment with placebo increased the solids from 6.0% ± 3.3% to 6.7% ± 3.2% (P = .34, n = 13) (Fig 1). The mean (95% CI) change from baseline with placebo was 0.7% ± 2.4% (−0.8% to 2.1%). The differences from baseline after 2-week treatment were significantly different between mannitol and placebo (P = .014). Individual data are shown in Figure 2. The solids returned to pretreatment values after 2 weeks’ washout (P > .1).

Figure Jump LinkFigure 1. The significant reduction in solids content after 2 weeks’ treatment with mannitol and the lack of any significant effect with the placebo treatment.Grahic Jump Location
Figure Jump LinkFigure 2. Individual data showing the changes in the solids content after 2 weeks’ treatment with mannitol (A) and placebo (B). The majority of subjects treated with mannitol had a reduction in the solids content indicative of an increase in the hydration of sputum.Grahic Jump Location
Surface Tension

Surface tension was significantly reduced from 83.1 ± 7.2 to 78.6 ± 8.0 mN/m (P < .039, n = 13) after 2-week treatment with mannitol, whereas with placebo treatment it increased from 81.6 ± 12.9 to 83.9 ± 7.7 mN/m (P > .3, n = 12) (Fig 3). The mean (95% CI) change from baseline with mannitol was −4.5 ± 7.0 mN/m (−0.3 to −8.7 mN/m) and the mean (95% CI) change with placebo was 2.3 ± 7.8 mN/m (−2.7 to 7.3 mN/m). The differences from baseline were significantly different between mannitol and placebo (P = .032) (Fig 3).

Figure Jump LinkFigure 3. The significant reduction in the surface tension after 2 weeks’ treatment with mannitol in contrast to the placebo treatment.Grahic Jump Location
Wettability (Contact Angle on Glass)

The contact angle was significantly reduced from 52.4 ± 7.7 to 47.9 ± 7.3 degrees (P = .038, n = 13) after 2-week treatment with mannitol, whereas it increased from 51.5 ± 9.9 to 53.9 ± 9.7 degrees with 2 weeks’ placebo treatment (P > .3, n = 14) (Fig 4). The mean (95% CI) change from baseline with mannitol was −4.5 ± 6.9 degrees (−0.3 to −8.7 degrees) and the mean (95% CI) change with placebo was 2.3 ± 8.8 degrees (−2.7 to 7.4 degrees). The differences from baseline were significantly different between mannitol and placebo (P = .035) (Fig 4).

Figure Jump LinkFigure 4. The significant reduction in the contact angle after 2 weeks’ treatment with mannitol in contrast to the placebo treatment.Grahic Jump Location
Rheology
Elasticity and Viscosity:

The viscoelastic properties before and after 2 weeks’ treatment are shown in Table 2. These values did not change significantly with either mannitol or placebo after 2 weeks’ treatment (P > .1).

Table Graphic Jump Location
Table 2 —Sputum Dynamic Elasticity and Viscosity at 1 rad/s and 100 rad/s, Before and After 2 Weeks of Treatment With Mannitol and Placebo

Values given as mean ± SD. G′ = dynamic elasticity; G″ = dynamic viscosity.

Effect of Dornase Alfa and Age:

Sputum properties at baseline were similar between those on dornase alfa and those not on dornase alfa (P > .3). In addition, there was no difference in the sputum properties between children and adults (P > .5).

Correlations of Sputum Properties With Lung Function:

The change from baseline in the solids content correlated negatively with the change in both FEV1 and FEF25-75 (r = −0.78, P = .004; r = −0.80, P = .003, respectively) (Fig 5). The % change from baseline in the surface tension and the contact angle correlated negatively with the % change in FEV1 measured after 2 weeks’ treatment with mannitol in these subjects (r = −0.73, P = .012; r = −0.63, P = .03, respectively) (Fig 6). In addition, the % change from baseline in contact angle correlated negatively with the % change in FVC (r = −0.63, P = .03). Baseline surface tension and contact angle correlated positively with the solids content (Fig 7).

Figure Jump LinkFigure 5. Significant negative correlation of the change from baseline in the solids content with the change in FEV1 (A) and forced expiratory flow in the middle half of the FVC (FEF25-75) (B) after 2 weeks’ treatment with mannitol. This figure demonstrates that the reduction in the solids content correlates with the increase in lung function following treatment with mannitol.Grahic Jump Location
Figure Jump LinkFigure 6. Significant negative correlation of the change from baseline in the surface tension (A) and contact angle (B) with the % change in FEV1 after 2 weeks’ treatment with mannitol. This figure demonstrates that the reduction in the surface tension and contact angle correlates with the increase FEV1 following treatment with mannitol in subjects with cystic fibrosis.Grahic Jump Location
Figure Jump LinkFigure 7. Surface tension (A) and contact angle (B) correlate positively with the solids content at baseline.Grahic Jump Location

Treatment with inhaled mannitol over 2 weeks improved the hydration and surface properties of sputum in patients with CF. The effect of mannitol on the sputum properties was evident for approximately 12 h after the end of the last treatment dose. This is the first in vivo study to show a sustained effect of mannitol on the sputum properties in CF. In addition, the reduction in solids content and surface properties correlated with the improvement in the lung function in these patients after 2 weeks’ treatment with mannitol.7

Because of the abnormality of the CF transmembrane regulator chloride channel, the airway surface in patients with CF is usually dehydrated with adhesive mucus. Baseline values of the solids content in the patients in this study varied from 3% to 14%, suggesting a range in the hypersecretion and hydration of mucus. Dehydrated mucus is viscous and sticky and mucus transport is significantly decreased as solids increase from 2.5% (normal) to 6%.13,14 Mannitol given as a dry powder by inhalation increases the hydration of the airway surface by creating an osmotic gradient for water efflux into the airway lumen, events that are likely to enhance clearance of mucus. The significant reduction in solids with mannitol treatment in this study is indicative of improved hydration at the airway surface in these subjects. The important finding in this study is that regular treatment with inhaled mannitol may be able to sustain improved hydration of the airway surface and thus reduce the mucus load in patients with CF.

The baseline surface tension of the sputum was high and consistent with a decrease in the hydration of the airways in CF.15,16 This is also supported by the significant correlation between surface properties and solids (Fig 7). The contribution of surface tension to the adhesivity of mucus and impaired cough clearance has been well studied.15,17-19 Regular treatment with mannitol over 2 weeks decreased the surface tension and increased wettability, as shown by the contact angle. Furthermore, mannitol has been reported to increase mucociliary and cough clearance in patients with CF, both consistent with the findings in the present study.6 In addition, our findings are consistent with the improvement in the respiratory symptoms and the increase in lung function following treatment with mannitol bid over 2 weeks in the same subjects.7 Significant correlations were found between the reduction in solids and the improvement in FEV1 and FEF25-75, the reduction in surface tension with the improvement in FEV1, and the reduction in contact angle with the improvement in FEV1 and FVC in the same subjects. These correlations support the notion that stagnated mucus can obstruct the airways or that clearing mucus effectively and regularly can reverse some of the airway obstruction and decrease the resistance to the airflow.

In contrast to the solids content and surface properties there was no reduction in the viscoelastic properties observed. The findings are also in contrast to the in vitro findings showing a reduction in the viscoelastic properties with hypertonic saline and dextran in CF sputum20,21 and of the in vivo sputum changes with mannitol in individuals with asthma.11 However, similar baseline viscoelastic properties in patients with CF have been reported by other workers using similar methods as we used here.22 Viscoelasticity of secretions is determined by the polymeric composition and cross linking of the mucins as well as by the hydration of mucus. However, as the CF sputum has more pus than mucus, the rheological properties of sputum are determined mainly by the DNA and F-actin copolymers that originate from neutrophils that have undergone a necrotic death.23 Hence, an increase in hydration may not have a pronounced effect in the viscoelasticity of the CF sputum consistent with the present findings. Inhaled mannitol was also shown to have a small insignificant effect on the viscoelastic properties of sputum in a pilot study in patients with non-CF bronchiectasis.10

Baseline sputum properties in subjects who were on regular treatment with dornase alfa were similar to the properties of the rest of the group. In addition, there was no difference in the baseline sputum properties between children and adults in this group of subjects with CF. It appears that disease severity establishes early in life in CF consistent with studies comparing sputum properties in children with CF with adult chronic bronchitis and children with non-CF bronchiectasis and with primary ciliary dyskinesia.24,25

To our knowledge, this is the first study to show sustained changes in the sputum properties after the last mannitol treatment had been inhaled, in a cohort of subjects with CF receiving regular treatment over 2 weeks. The significant changes in the sputum properties reported previously in response to mannitol in non-CF bronhiectasis10 and subjects with asthma11 occurred within 1 h after inhalation of a single dose of mannitol. Subjects with non-CF bronchiectasis have not demonstrated a sustained effect on the sputum properties in response to inhaled mannitol.10 The sustained reduction in the solids and surface properties in the subjects with CF after mannitol treatment suggests that either the mannitol was still present in the airways or that the effect was sustained following 2 weeks of treatment with mannitol. The effect of hypertonic saline on the clearance of mucus was found to be sustained after 2 weeks of treatment.26 However, mannitol may not be absorbed from the airways and may be cleared with the mucus and via the paracellular pathway, which is slow, allowing prolonged activity. The sustained benefit of mannitol demonstrated in this study suggests that there is potential to provide some protection against chronic dehydration and poor clearance of mucus and this would likely reduce the recurrent infection rate in patients with CF. Inhaled mannitol bid administered over 3 months was recently reported to increase lung function and improve quality of life.27 The increase in lung function was evident also in the subjects treated with dornase alfa.27

In conclusion, the present study showed that regular treatment with inhaled mannitol increases the hydration and changes the surface properties favorably in patients with CF. The new and important finding in this study is that these changes in the sputum properties were sustained for approximately 12 h after the last treatment and correlated significantly with the improvement in lung function in response to inhaled mannitol in CF. The sustained effect of inhaled mannitol on the sputum properties has only been observed in subjects with CF. The findings provide evidence for mechanistic actions and support that regular treatment with inhaled dry powder mannitol may have significant clinical benefits in CF.

Author contributions:Dr Daviskas: contributed to the study design, measurement and analysis of sputum properties, interpretation of the findings, and writing the manuscript.

Dr Anderson: contributed to the study design, interpretation of the findings, and writing the manuscript.

Ms Jaques: contributed to the study design, interpretation of the findings, and writing the manuscript.

Dr Charlton: contributed to the study design, interpretation of the findings, and writing the manuscript.

Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Dr Daviskas is an employee of the South West Sydney Area Health Service (SSWAHS), which owns the patent relating to the use of mannitol for enhancing clearance of secretions described in the article and may benefit from royalties in the future. Dr Daviskas owns self-funded shares in Pharmaxis Ltd. Dr Daviskas, in her capacity as an employee of the SSWAHS, consults for Pharmaxis. Dr Anderson is the inventor of the mannitol test. The patent is owned by her previous employer, SSWAHS. SSWAHS invoiced Pharmaxis for her time; until March 2009 she had not received personally any monies from Pharmaxis other than to cover traveling expenses. Since March 2009 she has received $2,000 for consulting fees. She owns shares in Pharmaxis that she purchased herself. She receives a share of 10% of the royalties paid to SSWAHS. She has acted in an honorary capacity on the Scientific Board of Pharmaxis. She has spoken for Merk and for Niccomed in the last 3 years, for which she has received an honorarium. Ms Jaques is the Clinical Development Manager of and holds shares and stock options in Pharmaxis Ltd. Dr Charlton is the Medical Director of and holds shares and stock options in Pharmaxis Ltd.

Other contributions: We thank all the patients who participated in this study and all the centers in Australia and New Zealand that participated in the clinical trial and collected the sputum samples. This work was performed at the Royal Prince Alfred Hospital, Sydney, NSW, Australia.

CF

cystic fibrosis

FEF25-75

forced expiratory flow in the middle half of the FVC

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Robinson M, Bye PTB. Mucociliary clearance in cystic fibrosis. Pediatr Pulmonol. 2002;334:293-306. [CrossRef] [PubMed]
 
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Figures

Figure Jump LinkFigure 1. The significant reduction in solids content after 2 weeks’ treatment with mannitol and the lack of any significant effect with the placebo treatment.Grahic Jump Location
Figure Jump LinkFigure 2. Individual data showing the changes in the solids content after 2 weeks’ treatment with mannitol (A) and placebo (B). The majority of subjects treated with mannitol had a reduction in the solids content indicative of an increase in the hydration of sputum.Grahic Jump Location
Figure Jump LinkFigure 3. The significant reduction in the surface tension after 2 weeks’ treatment with mannitol in contrast to the placebo treatment.Grahic Jump Location
Figure Jump LinkFigure 4. The significant reduction in the contact angle after 2 weeks’ treatment with mannitol in contrast to the placebo treatment.Grahic Jump Location
Figure Jump LinkFigure 5. Significant negative correlation of the change from baseline in the solids content with the change in FEV1 (A) and forced expiratory flow in the middle half of the FVC (FEF25-75) (B) after 2 weeks’ treatment with mannitol. This figure demonstrates that the reduction in the solids content correlates with the increase in lung function following treatment with mannitol.Grahic Jump Location
Figure Jump LinkFigure 6. Significant negative correlation of the change from baseline in the surface tension (A) and contact angle (B) with the % change in FEV1 after 2 weeks’ treatment with mannitol. This figure demonstrates that the reduction in the surface tension and contact angle correlates with the increase FEV1 following treatment with mannitol in subjects with cystic fibrosis.Grahic Jump Location
Figure Jump LinkFigure 7. Surface tension (A) and contact angle (B) correlate positively with the solids content at baseline.Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1 —Design of Study and Sputum Collection
Table Graphic Jump Location
Table 2 —Sputum Dynamic Elasticity and Viscosity at 1 rad/s and 100 rad/s, Before and After 2 Weeks of Treatment With Mannitol and Placebo

Values given as mean ± SD. G′ = dynamic elasticity; G″ = dynamic viscosity.

References

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Robinson M, Bye PTB. Mucociliary clearance in cystic fibrosis. Pediatr Pulmonol. 2002;334:293-306. [CrossRef] [PubMed]
 
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