Evangelia Daviskas

Inhalation of hypertonic saline aerosol enhances mucociliary clearance in asthmatic and healthy subjects

Hyperosmolarity of the airway surface liquid (ASL) has been proposed as the stimulus for hyperpnoea-induced asthma. We found previously that mucociliary clearance (MCC) was increased after isocapnic hyperventilation (ISH) with dry air, and we proposed that the increase related to transient hyperosmolarity of the ASL. We investigated the effect of increasing the osmolarity of the ASL on MCC, by administering an aerosol of concentrated salt solution. MCC was measured using 99mTc-sulphur colloid, gamma camera and computer analysis in 12 asthmatic and 10 healthy subjects on three separate days, involving administration of each of the following: 1) ultrasonically nebulized 14.4% saline; 2) ultrasonically nebulized 0.9% saline; and 3) no aerosol intervention (control). The (mean +/- SD) volume of nebulized 14.4% saline was 2.2 +/- 1.2 mL for asthmatics and 3.2 +/- 0.7 mL for healthy subjects. This volume was delivered over a period of 5.4 +/- 1.3 and 6.4 +/- 0.7 min for asthmatic and healthy subjects, respectively. The airway response to 14.4% saline was assessed on a separate visit and the fall in forced expiratory volume in one second (FEV1) was 22 +/- 4% in the asthmatic and 3 +/- 2% in the healthy subjects. Compared to the MCC with the 0.9% saline and control, the hypertonic aerosol increased MCC in both groups. In asthmatic subjects, MCC of the whole right lung in 1 h was 68 +/- 10% with 14.4% saline vs 44 +/- 14% with 0.9% saline and 39 +/- 13% with control. In healthy subjects, MCC of the whole right lung in 1 h was 53 +/- 12% with 14.4% saline vs 41 +/- 15% with 0.9% saline and 36 +/- 13% with control. We conclude that an increase in osmolarity of the airway surface liquid increases mucociliary clearance both in asthmatic and healthy subjects. These findings are in keeping with our previous suggestion that the increase in mucociliary clearance after isotonic hyperventilation with dry air is due to a transient hyperosmolarity of the airway surface liquid.

Inhaled mannitol improves lung function in cystic fibrosis

BACKGROUND The airways in patients with cystic fibrosis (CF) are characterized by the accumulation of tenacious, dehydrated mucus that is a precursor for chronic infection, inflammation, and tissue destruction. The clearance of mucus is an integral component of daily therapy. Inhaled mannitol is an osmotic agent that increases the water content of the airway surface liquid, and improves the clearance of mucus with the potential to improve lung function and respiratory health. To this end, this study examined the efficacy and safety of therapy with inhaled mannitol over a 2-week period. METHODS This was a randomized, double-blind, placebo-controlled, crossover study. Thirty-nine subjects with mild-to-moderate CF lung disease inhaled 420 mg of mannitol or placebo twice daily for 2 weeks. Following a 2-week washout period, subjects were entered in the reciprocal treatment arm. Lung function, respiratory symptoms, quality of life, and safety were assessed. RESULTS Mannitol treatment increased FEV(1) from baseline by a mean of 7.0% (95% confidence interval [CI], 3.3 to 10.7) compared to placebo 0.3% (95% CI, - 3.4 to 4.0; p < 0.001). The absolute improvement with mannitol therapy was 121 mL (95% CI, 56.3 to 185.7), which was significantly more than that with placebo (0 mL; 95% CI, - 64.7 to 64.7). The forced expiratory flow in the middle half of the FVC increased by 15.5% (95% CI, - 6.5 to 24.6) compared to that with placebo (increase, 0.7%; 95% CI, - 8.3 to 9.7; p < 0.02). The safety profile of mannitol was adequate, and no serious adverse events related to treatment were observed. CONCLUSIONS Inhaled mannitol treatment over a period of 2 weeks significantly improved lung function in patients with CF. Mannitol therapy was safe and well tolerated. TRIAL REGISTRATION (ClinicalTrials.gov) Identifier: NCT00455130.

Inhaled mannitol for the treatment of mucociliary dysfunction in patients with bronchiectasis: Effect on lung function, health status and sputum

Objective:  Inhaled mannitol increases mucus clearance in patients with bronchiectasis by an unclear mechanism. The effect of mannitol on lung function, health status and sputum properties was investigated.

Inhalation of dry-powder mannitol increases mucociliary clearance

Inhalation of hypertonic saline stimulates mucociliary clearance (MCC) in healthy subjects and those with obstructive lung disease. We investigated the effect of inhaling the osmotic agent mannitol on MCC. We used a dry-powder preparation of mannitol British Pharmacopea (BP) which was encapsulated and delivered using a Dinkihaler. MCC was measured for 75 min in six asthmatic and six healthy subjects on two occasions before and after the mannitol inhalation or its control, using 99mTc-sulphur colloid and a gamma camera. The inhaled dose of mannitol was 267+/-171 mg (mean+/-SD) and 400 mg and the percentage fall in forced expiratory volume in one second (FEV1) was 22+/-3 and 4+/-2% in the asthmatic and healthy subjects, respectively. The total clearance in the whole right lung for the 60 min from the start of inhalation of mannitol was greater by 263+/-11.9% in the asthmatic and 18.1+/-4.9% in the healthy subjects compared to the control. The total clearance over 75 min was 54.7+/-9.6% and 33.6+/-9.4% on the mannitol and control day (p<0.002), respectively, in the asthmatic subjects and 40.5+/-7.1% and 24.8+/-7.8% (p<0.002) in the healthy subjects. In conclusion, inhalation of dry-powder mannitol increases mucociliary clearance in asthmatic and healthy subjects and may benefit patients with abnormal mucociliary clearance.

Effect of increasing doses of mannitol on mucus clearance in patients with bronchiectasis

Bronchiectasis is characterised by hypersecretion and impaired clearance of mucus. A 400-mg dose of inhaled mannitol improves mucus clearance however, the effect of other doses is unknown. A total of 14 patients, aged 63.3±5.7 yrs, were studied on five visits. Mucus clearance at baseline and with mannitol (160, 320 and 480 mg) was measured using technetium-99m-sulphur colloid and imaging with a gamma camera over 45 min, followed by a further 30 min involving 100 voluntary coughs. A control study assessed the effect of cough provoked by mannitol during the intervention. Whole right lung clearance over 45 min was 4.7±1.2 and 10.6±2.6% on baseline and control days, respectively, and increased to 16.7±4.2, 22.8±4.2 and 31±4.7% with 160, 320 and 480 mg mannitol, respectively. Clearance over 45 min with 480 mg mannitol was greater than clearance with 320 and 160 mg. Total clearance over 75 min, after mannitol administration and voluntary coughs, was 36.1±5.5, 40.9±5.6 and 46.0±5.2% with 160, 320 and 480 mg mannitol, respectively, all significantly different from baseline (24.1±6.0%) and control (13.1±3.0%). Total clearance over 75 min with 480 mg mannitol was greater compared with 160 mg. In conclusion, mucus clearance increases with increasing doses of mannitol and can be further increased by cough in patients with bronchiectasis.

Phase 3 Randomized Study of the Efficacy and Safety of Inhaled Dry Powder Mannitol for the Symptomatic Treatment of Non-Cystic Fibrosis Bronchiectasis

BACKGROUND Inhaled dry powder mannitol enhanced mucus clearance and improved quality of life over 2 weeks in non-cystic fibrosis bronchiectasis. This studys objective was to investigate the efficacy and safety of dry powder mannitol over 12 weeks. METHODS Patients with bronchiectasis confirmed by high-resolution CT (HRCT) scan, aged 15 to 80 years, with FEV1≥50% predicted and ≥1 L participated in a randomized, placebo-controlled, double-blind study. Patients with a negative mannitol provocation test were randomized to inhale 320 mg mannitol (n=231) or placebo (n=112) bid for 12 weeks. To further assess safety, the same mannitol dose/frequency was administered to a patient subset in an open-label extension over 52 weeks. Primary end points were changes from baseline at 12 weeks in 24-h sputum weight and St. Georges Respiratory Questionnaire (SGRQ) score. RESULTS There was a significant difference of 4.3 g in terms of change in sputum weight over 12 weeks (95% CI, 1.64-7.00; P=.002) between mannitol and placebo; however, this was largely driven by a decrease in sputum weight in the placebo group. This was associated, in turn, with more antibiotic use in the placebo group (50 of 112 [45%]) than in the inhaled mannitol group (85 of 231 [37%]). There was no statistical difference between the groups (P=.304) in total SGRQ score (mannitol, -3.4 points [95% CI, -4.81 to -1.94] vs placebo, -2.1 points [95% CI, -4.12 to -0.09]). In a subgroup study (n=82), patients receiving mannitol showed less small airway mucus plugging on HRCT scan at 12 weeks compared with patients receiving placebo (P=.048). Compliance rates were high, and mannitol was well tolerated with adverse events similar to those of placebo. CONCLUSION Because the difference in sputum weights appears to be associated with increased antibiotic use in the placebo group, a larger controlled study is now required to investigate the long-term mannitol effect on pulmonary exacerbations and antibiotic use. TRIAL REGISTRY ClinicalTrials.gov; No.: NCT0027753; URL: www.clinicaltrials.gov.

Inhaled mannitol improves the hydration and surface properties of sputum in patients with cystic fibrosis.

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 FEV(1) (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 FEV(1) (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.

Local airway heat and water vapour losses

A previously developed time-dependent mathematical model of the heat and water vapour transport in the human respiratory tract for mouth breathing (Daviskas et al., J. Appl. Physiol. 69:362-372, 1990) was applied to calculate the local quantities of heat and water transfer. The results of the heat and water losses agreed with experimental data. The contribution of each airway to the conditioning of inspired air was found to depend on the inspired air conditions and the pattern of breathing as expected. The greater proportion of the total heat and water loss was calculated to occur within the upper airways. However, below the pharynx, the rate of water loss during hyperpnea was calculated at a much faster rate than in the resting state. The rate at which water is returned to the airways may not be adequate to keep the periciliary fluid isotonic. These findings support the proposal that the intrathoracic airways could become significantly dehydrated during hyperpnea. The use of calculated local heat and water transfer rates may help to predict the site of stimuli to exercise-induced asthma.

Regional mucociliary clearance in patients with cystic fibrosis.

This paper reports on a large retrospective analysis of mucociliary clearance (MCC) studies in a group of 59 patients with cystic fibrosis (CF) and 17 age-matched healthy subjects. As many of the CF patients were studied on multiple occasions, a total of 184 patient studies are presented. MCC was measured using a radioaerosol and gamma camera technique. In addition to whole lung clearance, MCC was measured from the central, intermediate, peripheral, basal, mid and apical regions of the lung. MCC was markedly decreased in the CF patient group. Not only was whole lung clearance (14.2 +/- 1.4% vs. 28.0 +/- 3.7%) impaired, but also clearance from the central (19.1 +/- 1.9% vs. 35.6 +/- 4.3%), intermediate (10.7 +/- 1.6% vs. 25.5 +/- 3.7%), apical (12.4 +/- 2.6% vs. 31.6 +/- 4.6%) and mid (14.0 +/- 1.9% vs. 30.4 +/- 4.0%) regions. Attempts were made to identify factors that may have influenced MCC in both the normal subjects and CF patients. Age, gender, body mass index, patient genotype, penetration index, spontaneous cough, and various lung function parameters were entered into a stepwise multiple regression model, but none of the factors proved to be statistically important in determining MCC. Both intrasubject repeatability and intersubject variability estimates are presented for the patients and normal subjects that had multiple studies. The values were found to be remarkably similar for both CF patients and normal subjects and for both intra- and intersubject repeatability. With marked deviation from normal ranges and good repeatability, the measurement of MCC in CF patients would seem to be a valuable outcome measure for clinical trials involving new pharmaceuticals and physical therapy designed to improve removal of secretions from the airways.

The protective effect of nedocromil sodium and other drugs on airway narrowing provoked by hyperosmolar stimuli: A role for the airway epithelium?

The airways of persons with asthma are sensitive to acute changes in airway osmolarity and to dehydration. In reviewing the literature it is clear that airway narrowing provoked by these stimuli is blocked acutely by inhaling aerosols of nedocromil sodium, cromolyn sodium, frusemide, bumetanide, and antihistamines and by chronic use of aerosol corticosteroids. The responses are unaffected by inhalation of amiloride and verapamil. We have previously proposed that increases in the osmolarity of airway surface liquid (ASL) occur as a result of the water lost by evaporation during hyperpnea with dry air. An increase or decrease in osmolarity of the ASL will also occur with deposition of hyperosmolar and hypoosmolar droplets. Changes in osmolarity of the ASL result in the movement of water out of (shrinkage) and into (swelling) the epithelial cell, and this necessitates regulatory volume increase or decrease by the cell. We propose that nedocromil sodium and cromolyn sodium can affect water transport into and out of the epithelial cell by an action on chloride ion channels. A unifying hypothesis to explain the protective effect of these drugs may be their capacity to affect regulatory volume increase or decrease in a variety of cell types.