Effect of oral bronchodilators on lung mucociliary clearance during sleep in patients with asthma.

BACKGROUND: Lung mucociliary clearance rates are reduced during sleep in patients with asthma. Methylxanthines and beta 2 agonists have been shown to enhance rates of lung mucociliary clearance. This study examined whether oral slow release bronchodilators may also have an effect on this clearance mechanism during sleep in patients with asthma. METHODS: Nine patients with asthma with a mean(SE) age of 65(5) years and percentage predicted forced expiratory volume in one second (FEV1 of 61(9)% participated in a double blind, placebo controlled, within subject crossover study to assess the effect of two weeks of treatment with salbutamol (Volmax; 8 mg twice daily) or theophylline (Phyllocontin; 350 mg twice daily) on lung mucociliary clearance during sleep. Lung mucociliary clearance rates were measured by a radioaerosol technique. RESULTS: The observation period for radioaerosol clearance was approximately 0.3 hours before sleep, 6.0 hours during sleep and 0.6 hours after sleep. Mean mucociliary clearance rates for theophylline, placebo and salbutamol before sleep were: 39, 39, and 32%/hour respectively; during sleep: 11, 10, and 9%/hour respectively; and after sleep: 39, 32, and 35%/hour respectively. CONCLUSION: During sleep lung mucociliary clearance in stable asthma was reduced, which is in agreement with the group's previous findings. Treatment with controlled/slow release oral bronchodilators had no effect on this reduced rate of clearance associated with sleep.     

Nasal mucociliary clearance in coal mine workers

OBJECTIVE: The purpose of this study was to analyze the effect of coal dust particles on nasal mucociliary function in coal mine workers. METHOD: Using the saccharin method, nasal mucociliary clearance was determined for 77 subjects, of which 39 who worked in a coal mine were actively exposed to coal dust whereas 38 were unexposed control subjects. The measurements were performed in the coal mine, at the level of 170 m below sea level. RESULTS: The average saccharin nasal transit time in coal mine workers, 12.61 (SD: 4.30) minutes, is longer than that of the control subjects, 10.97 (SD: 3.22). CONCLUSION: Although the findings of this study demonstrate that the coal particles affect the nasal mucociliary clearance, the difference in saccharin nasal transit time between the two groups (exposed vs unexposed) is not statistically significant (P = 0.063).     

Relationship between rhinosinusitis symptoms and mucociliary clearance time.

OBJECTIVE: To determine the correlation between rhinosinusitis symptoms as assessed by the Sino-Nasal Outcomes Test-20 (SNOT-20) and mucociliary clearance as assessed by the saccharin method. STUDY DESIGN AND SETTING: This was a cross-sectional study of 50 adult volunteers. Subjects completed the SNOT-20, and mucociliary clearance was determined with the saccharine method. Correlation coefficients (Spearman's Rho) were calculated for the global SNOT-20 score. RESULTS: The SNOT-20 scores varied from 20 to 54 (mean 30.28) with a possible range of 20 to 100. Clearance times varied from 418 to 2865 seconds (mean 999). There was no significant correlation between global SNOT-20 score and clearance time (r = 0.196). CONCLUSIONS: There is no significant correlation between rhinosinusitis symptoms as assessed by SNOT-20 scores and mucociliary clearance. SIGNIFICANCE: Mucociliary clearance is important for the health of the sinonasal cavities, but clearance time does not appear to be associated with symptom severity in the population studied. EBM rating: A-1b.     

Halothane inhibition of ion transport of the tracheal epithelium. A possible mechanism for anesthetic-induced impairment of mucociliary clearance.

Significant depression of mucociliary function occurs during general anesthesia. One possible mechanism to account for this effect is a change in ion and water transport across airway epithelium. To determine if anesthetics alter epithelial cell function, we used electrophysiologic techniques to measure the effects of halothane on ion transport of in vitro canine tracheal epithelial. Epithelial tissues were mounted in an Ussing chamber and the short-circuit current (Isc) (a measure of active ion transport) and transepithelial resistance were determined in the absence and presence of halothane. Halothane induced a rapid and reversible decrease in Isc that was dose-dependent. Four percent halothane reversibly decreased Isc from 90 +/- 11 to 39 +/- 6 microA/cm2 (n = 12; P = 0.001) and increased transepithelial resistance. Isoproterenol is a well-known activator of chloride secretion that acts via beta-adrenergic receptors and cyclic adenosine monophosphate (cAMP). Pretreatment with isoproterenol or dibutyryl cAMP (a cell permeable analogue of cAMP) increased the percent inhibition of Isc by 4% halothane. These effects are consistent with preferential inhibition of chloride secretion by halothane but rule out a primary action of halothane on the beta-adrenergic system. In the presence of indomethacin, which eliminates the contribution of chloride secretion to Isc, 4% halothane induced a much smaller but still significant inhibition. This suggests that sodium absorption is also affected. We conclude that halothane significantly decreases ion and water transport in canine epithelia and that impaired fluid secretion may contribute to decreased mucous clearance in the perioperative period.     

The effect of injection immunotherapy on mucociliary clearance in allergic patients.

OBJECTIVE: To assess the effect of injection immunotherapy on mucociliary clearance in allergic patients with the use of the saccharin test. METHODS: In this prospective cohort study, mucociliary clearance in 42 allergic patients treated with injection immunotherapy was determined with the saccharin test. Of these patients, 23 were retested 1 year later to assess changes in mucociliary clearance times. Mean results for historical controls were determined in a review and meta-analysis of the existing literature. RESULTS: Saccharin clearance times (SCTs) were initially prolonged in allergic patients who received injection immunotherapy when compared to historical controls (one-sided P value < 0.05). However, after 1 year of immunotherapy, there was a significant reduction in SCTs in our patient population. This finding was independent of other evaluated patient characteristics, with the exception of nasal steroid use, which was also significantly associated with a decrease in SCT. CONCLUSIONS: After 1 year of injection immunotherapy, there was a significant reduction in mean SCT in our patient population. Of the other factors studied, only nasal steroid was associated with decreased mucociliary clearance times. To our knowledge, this is the first report in the literature documenting the beneficial effect of injection immunotherapy on mucociliary clearance as measured by saccharin clearance times. Nevertheless, further research is warranted, given the confounding effect of nasal steroid use.     

Pathophysiology and treatment of airway mucociliary clearance. A moving tale

Airway hygiene depends largely on mucociliary clearance (MCC) which in turn depends upon the movement of viscoelastic mucus along the airway by the beating of the ciliary appendages of airway epithelial cells. Failure to keep the airways sterile by MCC results in a host inflammatory response to the persistent microorganisms which, if it becomes chronic, causes damage to the airway wall and upregulation of mucus production manifest clinically as bronchiectasis, sinusitis and otitis. There are three principal disorders of MCC. Firstly, primary ciliary dyskinesia (PCD), a rare genetic deficiency of the ultrastructural apparatus required to propel the cilium, in which nasal nitric oxide is very low due to a deficiency of inducible nitric oxide synthase. Secondly, secondary ciliary dyskinesia due principally to microbial toxin-induced dysfunction of the energy pathways required for ciliary beating. Thirdly, abnormalities in the physicochemical properties of mucus, including reduced salt content/osmolality which results in it being unsuitable in quality for cilia to move it. Methods of rectifying this defect promise to restore MCC to normal and interfere in the vicious circle of inflammatory lung damage.     

Transit-time analysis of the forced expiratory spirogram during clinical remission in juvenile asthma.

The mean transit time (MTT), coefficient of variation (CoV), and index of skewness (IoS) of transit times of the forced expiratory flow/time curve have been compared with maximal mid-expiratory flow (MMEF), flow at 75, 50, and 25% of vital capacity (V75, V50, and V25), and the ratio of forced expiratory volume in 1 second (FEV1) to vital capacity (VC) in 51 asthmatic children judged on clinical grounds to be in remission. In 19 children all eight indices were normal. Of the remaining 32, MTT was normal in 5, V50 in 11, V75 in 12, and FEV1/VC and MMEF in 13 each. MTT was significantly more sensitive in detecting abnormality when other indices were normal, and abnormalities in MTT were of significantly greater magnitude when present. In 12 patients with at least one abnormal index given salbutamol aerosol, MTT was not more sensitive than MMEF, V25, FEV1/VC, or V50 in detecting change.     

Increase in mucociliary clearance in normal man induced by oral high frequency oscillation.

Data on the effect on mucociliary clearance of oral high frequency oscillation is conflicting. By means of a technique to superimpose high frequency oscillation on tidal breathing, changes in mucociliary clearance during high frequency oscillation were studied in seven normal non-smokers by monitoring the clearance of inhaled radiolabelled aerosol from the lungs. After inhalation of 5 microns technetium 99m labelled particles under controlled conditions, whole lung clearance was monitored by scintillation counters half hourly for six hours with a final count at 24 hours, from which tracheobronchial deposition and clearance could be calculated. Control and high frequency oscillation studies were performed on separate days in random order. Oral high frequency oscillation was applied by a bass loudspeaker through a mouthpiece to superimpose sinewave oscillations (RMS input pressure 1.2 cm H2O, mean pressure zero) on normal breaths. On high frequency oscillation days 30 minutes of oscillation alternated with 30 min of rest. Between 3 and 4.5 hours mucociliary clearance with high frequency oscillation exceeded control by about 10% (p less than 0.05). The mean time taken to eliminate 90% of deposited radioaerosol from the tracheobronchial tree fell from 4 hours 50 minutes (range 1 h 52 min-6 h 50 min) during control to 3 hours 43 minutes (range 2 hr 28 min-5 hr 54 min) during the high frequency oscillation run (p less than 0.05). Possibly this comfortable, simple technique would be of therapeutic benefit to patients with chronic sputum retention and merits further investigation.     

Effect of cigarette smoking on nasal mucociliary clearance and ciliary beat frequency.

Despite the in vitro ciliotoxicity of tobacco smoke and the abnormal mucociliary clearance found in smoking related chronic bronchitis, studies of mucociliary clearance in healthy smokers have produced variable results. The nasal mucociliary clearance of saccharin and the in vitro nasal ciliary beat frequency were studied in healthy smokers and non-smokers. One of 29 smokers had a nasal mucociliary clearance time of over 60 minutes; in the remaining 28 the mean (SD) clearance time was 20.8 (9.3) minutes, which was significantly longer (p less than 0.001) than the mean time of 11.1 (3.8) minutes in 27 lifelong non-smokers. There was no significant difference between the mean nasal ciliary beat frequency of 10 smokers and 10 non-smokers. There were no significant differences in mean ciliary beat frequency or mean nasal mucociliary clearance time after 10 healthy non-smoking volunteers had smoked two cigarettes each, exhaling the smoke through their nostrils. Unless there is a prompt reversal of any ciliotoxic effect of tobacco smoke when cilia are removed for in vitro examination, the defective clearance seen in chronic cigarette smokers seems unlikely to be due to slowed ciliary beat frequency. It may be due to reduction in number of cilia or to change in the viscoelastic properties of mucus. The failure to detect any acute effect of tobacco smoke is in keeping with this hypothesis.     

Imaging of the airways by bronchoscintigraphy for the study of mucociliary clearance.

A method for functional imaging of the large airways (bronchoscintigraphy) has been developed. It is based on the administration of aerosolised albumin labelled with technetium-99m using a special inhalation technique to produce central airway deposition. The method was evaluated as a measure of mucociliary clearance by recording the movement of radioactivity in the airways of 11 healthy, non-smoking subjects on two separate days. A series of bronchoscintigrams was acquired at five minute intervals for two hours after termination of the inhalation. After the first bronchoscintigram 1.25 mg terbutaline or placebo was administered from a metered dose inhaler (five puffs) according to a randomised, double blind, crossover design. The scintigrams were evaluated blind. After terbutaline the segmental bronchi were no longer visible after a median time of 10 minutes, the lobar bronchi after 20 minutes and the main bronchi after 30 minutes. In six cases the trachea was cleared after two hours. After placebo the segmental bronchi disappeared after a median of 15 minutes, but at two hours half the lobar bronchi remained visible. In only two cases was it no longer possible to see the main bronchi or the trachea. It is concluded that bronchoscintigraphy can be used to examine regional mucociliary clearance in healthy subjects and that terbutaline significantly increases the clearance of the deposited radioactive aerosol.     

Effect of ipratropium bromide on mucociliary clearance and pulmonary function in reversible airways obstruction.

The effects of (a) regular use for one week and (b) a single dose of a synthetic anticholinergic (ipratropium bromide) on lung mucociliary clearance and as a bronchodilator was ascertained in a controlled, double-blind, cross-over study in 12 patients with reversible airways obstruction (mean increase in FEV after isoprenaline: 17% range 10-50%). Two puffs from a metered dose inhaler of either placebo (propellants only) or drug (40 microgram) were administered four times a day for one week (regular use), and mucociliary clearance was measured, by radioaerosol tracer, at the end of each treatment period and after a control period in which no treatment was given. On the mornings of the measurements after the placebo and drug periods one final dose (single dose) of ipratropium (40 microgram) or placebo was given 2.5 hours before the start of the test. There was no statistically significant difference between the three mean mucociliary clearance curves (control, placebo, and drug) for the group; however, there was a significantly greater penetration towards the periphery of the lung of the tracer in the test after drug administration compared with the other two. This increased penetration was attributed to bronchodilatation caused by the drug. Ipratropium bromide does not appear to impair mucociliary clearance, and it acts an effective bronchodilator.     

The effect of saline solutions on nasal patency and mucociliary clearance in rhinosinusitis patients.

OBJECTIVE: To compare the effect of two saline nasal sprays on nasal patency and mucociliary clearance in patients with rhinosinusitis. STUDY DESIGN: Randomized double-blind trial. SUBJECTS AND METHODS: Eighty patients with rhinosinusitis at a tertiary care academic center had nasal patency and mucociliary clearance measured. Each patient was then treated with either physiological or hypertonic saline. Nasal patency and mucociliary clearance measurements were repeated after treatment. Subjective evaluation was also performed. RESULTS: Both solutions improved saccharine clearance times (P < 0.0001). Buffered physiological saline significantly affected nasal airway patency (P = 0.006). Both solutions improved symptoms of nasal stuffiness (P < 0.0001) and nasal obstruction (P < 0.0001). Buffered hypertonic saline caused increased nasal burning/irritation compared with buffered physiological saline (P < 0.0001). CONCLUSIONS: Buffered physiological and buffered hypertonic saline nasal sprays both improve mucociliary clearance, which is beneficial for treatment of rhinosinusitis. Additionally, buffered physiological saline improves nasal airway patency, whereas buffered hypertonic saline has no effect. Both solutions provide symptomatic relief, but buffered hypertonic saline is more irritating.     

Effect of four weeks'' high dose ipratropium bromide treatment on lung mucociliary clearance.

In a randomised, double blind crossover study the effect of high dose ipratropium bromide (200 micrograms three times daily given by metered dose inhaler for four weeks) on lung mucociliary clearance and on the wet weight and mean apparent viscosity of sputum was compared with that of placebo. Six smokers, six ex-smokers, and three non-smokers (12 men and three women, median age 60 years) were studied. Eight subjects had chronic obstructive lung disease (median FEV1 46% predicted) and seven had asthma (FEV1 70% predicted). Seven subjects produced sputum regularly, two of whom had asthma. Clearance of secretions was measured by an inhaled radioaerosol technique. The number of coughs and the wet weight, radioactive content, and mean apparent viscosity of sputum produced during the six hour observation period were recorded, as was the mean wet weight of sputum produced during the last two 24 hour periods ending each treatment. Comparison with placebo showed that treatment with high dose ipratropium bromide was associated with a significant increase in the penetration index of inhaled particles, but there was no significant change in alveolar deposition of particles or in tracheobronchial clearance, uncorrected or corrected for sputum expectorated. The wet weight of sputum produced, its radioactive content, and mean apparent viscosity were similar after treatment with ipratropium bromide and placebo. These results show that high dose inhaled treatment with the synthetic anticholinergic bronchodilator ipratropium bromide for four weeks is not associated with detectable modification of the clearance of secretions from the lungs, or of sputum volume or viscosity.     

Effects of buffered saline solution on nasal mucociliary clearance and nasal airway patency.

OBJECTIVE: To compare the effects of buffered hypertonic and buffered normal saline nasal spray on mucociliary clearance and nasal airway patency. STUDY DESIGN AND SETTING: Double-blind trial with subjects acting as their own controls. Tertiary care academic medical center. RESULTS: Buffered hypertonic saline and buffered normal saline both improved saccharine clearance times ( P < 0.0001 for buffered hypertonic and P = 0.002 for buffered normal saline). Buffered hypertonic saline improved saccharine clearance times more than buffered normal saline (39.6% vs 24.1%, P = 0.007). Neither buffered hypertonic nor buffered normal saline significantly affected nasal airway patency. CONCLUSIONS: Both buffered hypertonic and buffered normal saline nasal spray significantly improved saccharine clearance times without affecting nasal airway patency. Buffered hypertonic saline affected saccharine clearance times to a greater degree than buffered normal saline. CLINICAL SIGNIFICANCE: Buffered hypertonic and buffered normal saline sprays both improve mucociliary clearance and should therefore be beneficial in conditions such as rhinitis and sinusitis, which are associated with disruption of mucociliary clearance. However, these sprays do not appear to affect the nasal airway. Patients may therefore benefit from other treatments for "nasal congestion." EBM rating: B-2.     

Nasal mucociliary clearance and ciliary beat frequency in cystic fibrosis compared with sinusitis and bronchiectasis.

Nasal ciliary function and mucociliary clearance were studied in patients with cystic fibrosis and in three control groups. Ciliary beat frequency and nasal clearance time were measured in groups of 10 subjects with cystic fibrosis, sinusitis and bronchiectasis and age and sex-matched control subjects. Ciliary beat frequency was also measured in normal subjects matched as bronchiectasis controls. Cystic fibrosis patients and their controls, patients with sinusitis, and the bronchiectasis controls did not differ in ciliary beat frequency, but it was slower in the patients with bronchiectasis (p less than 0.05). Nasal mucociliary clearance in cystic fibrosis and bronchiectasis was slower than in the cystic fibrosis controls (p less than 0.001) and in patients with sinusitis (p less than 0.01). The finding of a normal beat frequency in cystic fibrosis cilia studied in vitro together with abnormal nasal mucociliary clearance measured in vivo in the same patients suggests the existence of an abnormality of mucus in vivo. The innate function of cystic fibrosis cilia, as measured in vitro by beat frequency, is normal.     

Impaired tracheobronchial clearance in patients with mild stable asthma.

Tracheobronchial mucociliary clearance was measured with the radioaerosol technique in 25 patients with stable, mild asthma, none of whom was taking systemic corticosteroids. The results were compared with those obtained from a control group of 25 healthy subjects matched for age and sex. All patients and healthy subjects were non-smokers. Ventilatory function was significantly impaired in the asthmatic group, which resulted in a more central initial tracheobronchial deposition of inhaled radioaerosol than in the control group. Despite the shorter transit path along the ciliated airways for the tracer radioaerosol in the asthmatic group, mucociliary clearance was found to be significantly poorer than in the healthy control group. This may be important with respect to bronchial mucus plugging.     

Tracheobronchial injuries in children.

Five patients with tracheobronchial injuries secondary to blunt thoracic trauma were reviewed over a 9-year period. Bronchial disruption occurred in four cases and tracheal disruption in one. Of the four patients with bronchial disruption, a major airway injury was suspected early because of a large air leak or persistent pulmonary atelectasis. However, definitive diagnosis by bronchoscopy was delayed from 4 to 16 days due to initial response to conservative management. Bronchial repair was achieved in every case: additional lobectomy was required in only one instance. Postoperative bronchial stenosis occurred in one patient and responded well to dilatation. The child with a blowout perforation of the trachea was diagnosed early by bronchoscopy and was successfully managed without surgery. Tracheobronchial injury is one of the most severe injuries caused by blunt trauma and requires a high index of suspicion for early diagnosis and surgery. Bronchial repair is successful in most instances.     

Effect of selective and non-selective beta blockade on pulmonary function and tracheobronchial mucociliary clearance in healthy subjects.

A controlled, double blind, crossover study was carried out to ascertain the effect of single doses of selective (100 mg atenolol) and non-selective (160 mg propranolol) beta blocker on pulmonary function and tracheobronchial mucociliary clearance. The study group comprised 12 healthy, young subjects. Adequate and comparable blockade was achieved with both drugs, the administration of which resulted in significantly lower pulse rates (at least up to eight hours after administration of the drug) and systolic blood pressures (three hours after drug administration) than were found with placebo. Small (of the order of 5%) but nevertheless statistically significant falls in FEV1 and forced vital capacity accompanied the administration of both beta blockers (but not the placebo) and were measurable up to eight hours after administration of the drug. Indices of pulmonary function had returned to normal by the next day. Peak expiratory flow and indices of small airways function remained unaltered after beta blockade. Mean tracheobronchial mucociliary clearance was depressed after administration of both beta blocking drugs, although the reduction was significant (p less than 0.05) only when propranolol was compared with placebo.     

Exhaled nitric oxide predicts asthma relapse in children with clinical asthma remission

BACKGROUND: Nitric oxide in exhaled air (FE(NO)) is a marker of eosinophilic airway inflammation. A study was undertaken to determine whether FE(NO) predicts asthma relapse in asymptomatic asthmatic children in whom inhaled corticosteroids are discontinued. METHODS: Forty children (21 boys) of mean age 12.2 years on a median dose of 400 mug budesonide or equivalent (range 100-400) were included. FE(NO) was measured before and 2, 4, 12, and 24 weeks after withdrawal of steroids. A relapse was defined as more than one exacerbation per month, or need for beta agonist treatment on 4 days per week for at least 2 weeks, or diurnal peak flow variability of >20%. FE(NO) measurements were performed online with an expiratory flow of 50 ml/s. RESULTS: Nine patients relapsed. Two and 4 weeks after withdrawal of steroids geometric mean FE(NO) in children who were about to relapse was higher than in those who did not relapse: 35.3 ppb v 15.7 ppb at 2 weeks (ratio 2.3; 95% CI 1.2 to 4.1; p = 0.01) and 40.8 ppb v 15.9 ppb at 4 weeks (ratio 2.6; 95% CI 1.3 to 5.1). An FE(NO) value of 49 ppb at 4 weeks after discontinuation of steroids had the best combination of sensitivity (71%) and specificity (93%) for asthma relapse. CONCLUSION: FE(NO) 2 and 4 weeks after discontinuation of steroids in asymptomatic asthmatic children may be an objective predictor of asthma relapse.