J.E. Agnew

Inhaled aerosols: lung deposition and clinical applications

Although aerosol deposition in the lungs is often considered in the context of industrial hygiene, aerosols also play an important clinical role. Three principal mechanisms (inertial impaction, gravitational sedimentation and Brownian diffusion) account for the majority of aerosol deposition in the lungs. Deposition depends upon the mode of inhalation, the nature of the particles and physical characteristics of the subject inhaling the particles. Radioaerosols are widely employed in measurements of total and regional deposition, and topographical distribution may also be determined. Aerosols play an important role in the treatment of various forms of respiratory disease, with bronchodilators for the therapy of asthma being particularly important. On average only 10% of the therapeutic aerosol dose actually reaches the lungs. The rate of removal of insoluble radioaerosols deposited in the lungs may be used as an index of mucociliary transport. Aerosols are also used in a variety of other diagnostic and research procedures, particularly for ventilation scanning, alveolar clearance, measurement of alveolar permeability, and for measuring the size of pulmonary air space.

Effect of oral N-acetylcysteine on mucus clearance.

Oral N-acetylcysteine has been advocated as a mucolytic agent for use in chronic bronchitis. We have investigated the effects of regular use of this drug at a dose of 200 mg thrice daily for 4 weeks in nine patients with chronic bronchitis on lung function, lung mucociliary clearance and sputum viscosity in a controlled, double-blind, crossover study. No significant differences were found in lung function, mucociliary clearance curves or sputum viscosity following treatment with N-acetylcysteine compared to control or placebo measurements.

Quantitative comparison of 99Tcm-aerosol and 81Krm ventilation images

Quantitative indices are described for assessing the distribution of ventilation imaging agents (radioaerosols, in particular) within the lung. They have been applied to images obtained with 99Tcm aerosol particles (0.5-2.0 micrometer diameter) and with 81Krm gas in 12 patients with a wide range of lung function. In patients with normal lung function aerosol distribution was similar to that of 81Krm. In patients with airways obstruction, the aerosol tended to penetrate less well than 81Krm to the lung periphery and to show a less homogeneous distribution there. Quantitative analysis confirms that the aerosol technique is an effective substitute for 81Krm in patients with normal lung function. When lung function is impaired aerosol images may still be valuable particularly in confirming a diagnosis of pulmonary embolism though they must be interpreted with caution in attempting to exclude that diagnosis. We conclude that small particle radioactive aerosols provide a readily available ventilation technique for clinical ventilation-perfusion imaging.

The effect of unproductive coughing/FET on regional mucus movement in the human lungs

The study was designed to ascertain the movement of mucus from proximal and peripheral regions within the human lungs during cough and the forced expiration technique (FET). Mucus movement was measured using a radioaerosol technique. Seven patients (mean +/- SEM age: 63 +/- 3 years) with airways obstruction (% predicted FEV1: 44 +/- 4) participated in the study. Each patient underwent three assessments in a randomized manner: control/cough/FET. Peak expiratory flow rate (PEFR) was measured at the mouth during cough and FET. None of the patients produced sputum during the assessment periods. Both cough and FET compared with control increased, on average, mucus clearance from all regions; statistical significance was achieved only for central lung regions with cough (P less than 0.05). There was no significant correlation between PEFR during cough/FET and regional lung clearance.

Effect of terbutaline administered from metered dose inhaler (2 mg) and subcutaneously (0.25 mg) on tracheobronchial clearance in mild asthma

Tracheobronchial mucus clearance was measured in nine mild asthmatics, using an objective radioaerosol technique, on 3 separate days at intervals of 1 week. Immediately after radioaerosol inhalation, drug or placebo was administered via subcutaneous injection (SC) plus metered dose inhaler (MDI)--2 puffs. Three randomized treatments were used: saline placebo SC plus 2 mg terbutaline by MDI (1 mg per puff); 0.25 mg terbutaline SC plus placebo (propellants and surfactant only) by MDI; and double placebo. Changes in lung mucociliary clearance showed an inverse relationship to baseline clearance of both proximal and distal ciliated airways following inhaled terbutaline, whereas terbutaline SC related inversely only to baseline clearance of the distal ciliated airways. This may reflect the surface concentrations of drug, established by each route.

Effect of oral antibiotics on lung mucociliary clearance during exacerbation of chronic obstructive pulmonary disease

It has been well established that lung mucociliary clearance is depressed in patients with chronic obstructive pulmonary disease. This study examines whether oral antibiotics have a detectable effect on this clearance mechanism during exacerbation in patients with such disease. Twelve patients with a mean +/- SE age of 63 +/- 2 years participated in a randomized, double-blind, parallel group study to assess the effect of 1 week of treatment with amoxycillin (500 mg t.d.s.) or ciprofloxacin (500 mg b.d.) on lung mucociliary clearance during exacerbation. Lung mucociliary clearance rates were measured by a non-invasive radioaerosol technique. Both drugs on average resulted in small, non-significant, enhancement of mucociliary clearance. Following treatment, the numbers of coughs were reduced in both groups and significantly (P < 0.05) after treatment with ciprofloxacin. Sputum production was also significantly reduced (P < 0.01) in both groups. The magnitude of improvement in lung mucociliary clearance was relatively modest following 1 week of treatment with either antibiotic. Since the number of coughs was significantly less after ciprofloxacin treatment the measured enhancement of lung mucociliary transport is probably, however, an underestimate.

Effect of Four-Week Treatment with Oxitropium Bromide on Lung Mucociliary Clearance in Patients with Chronic Bronchitis or Asthma

The effect of oxitropium bromide on lung mucociliary clearance, pulmonary function and viscoelastic properties of sputum was investigated in 10 asthmatics and 10 chronic bronchitics. A controlled, double-blind, crossover study was performed. Following a baseline (B) measurement the patients were, in a random order, allocated placebo (P) or oxitropium bromide (O; 0.1 mg/puff), administered from metered dose inhalers, which they used for 4 weeks at a dose of 2 puffs t.d.s. This test medication was used in conjunction with their normal medication. At the end of the treatment period the patients were assessed, the treatments were then crossed over and a final assessment made 4 weeks later. The administration of oxitropium bromide resulted in (1) small but statistically significant increases in pulmonary function (less than 10% vs. placebo); (2) increased penetrance of radioaerosol into the lungs (mean +/- SEM alveolar deposition: 35 +/- 3, 26 +/- 3 and 24 +/- 3% for the O, P and B runs respectively; p less than 0.025); (3) no significant change in particle clearance rate from the lungs despite their deeper penetration (mean +/- SEM area under the tracheobronchial clearance curves between 0 and 6 h: 317 +/- 26, 324 +/- 25 and 287 +/- 25%.h for the O, P and B runs respectively; p greater than 0.1); (4) no alteration in sputum production, and (5) no significant changes in apparent viscosity (mean +/- SEM: 640 +/- 162, 446 +/- 79 and 557 +/- 115 mPa.s for the O, P and B runs, respectively; p greater than 0.1) and elasticity (mean +/- SEM: 3,682 +/- 1,383, 1,779 +/- 353 and 2,061 +/- 366 mPa for the O, P and B runs, respectively; p greater than 0.1) of sputum. When the two groups, i.e. the chronic bronchitics and asthmatics, were studied separately, no significant differences in any parameter measured (other than radioaerosol penetrance which was significantly enhanced on oxitropium bromide in chronic bronchitics) were noted between the three assessments.

No effect of gender on lung mucociliary clearance in young healthy adults

Lung mucociliary clearance (LMC) depends on age and it is adversely affected by cigarette smoking. When using the radioaerosol technique for measuring LMC the initial site of deposition of the radioaerosol within the lungs affects its rate of removal. Whether there is a difference in gender for LMC is still an open question. Forty-one (20 female, 21 male) healthy, non-smoking subjects had their lung mucociliary clearance measured using an objective, non-invasive radioaerosol technique. The male and female groups were closely matched for initial distribution of the radioaerosol. There was no statistical significant difference between males and females in the rate of clearance of inhaled radioaerosol over a 6 h observation period. When comparing the LMC of two groups although it is important to match them for age, smoking habits and initial topographical distribution of the tracer radioaerosol it does not seem essential to also match the two groups for gender.

Aerosol particle impaction in the conducting airways

Modelling of inhaled particle deposition in the lungs potentially offers data relevant to assessing hazards from toxic inhaled particles, to studying mucus clearance or lung permeability by aerosol techniques, and to achieving better utilisation of drugs administered as aerosols. Analysis of published modelling studies is complicated by differing approaches to the quantitative estimation of physical factors determining deposition and by differing choices of anatomical data. Published formulae for predicting aerosol particle impaction are compared by applying them to the deposition of 5 micron particles in the human conducting airways using the morphological data of Weibel together with information from other sources about airways branching angles. The results indicate the range of deposition estimates that may be obtained from currently available impaction formulae. All but one of the formulae considered agree in indicating maximum deposition by impaction in, or close to, the segmental or subsegmental bronchi. Data are presented to indicate how the principal physical determinants of deposition depend on particle size, inhalation flow rate and lung volume during inhalation.

Krypton-81 m and 5-μm radioaerosol images in asymptomatic asthma: a blind marking assessment

Gamma camera images recorded during tidal breathing of krypton-81m (81mKr) and after slow inhalation of 99mTc-labelled monodisperse 5-μm polystyrene particles were assessed by three independent observers. Results from 20 symptom-free asthmatic subjects, all with a forced expiratory volume in 1 s (FEV1) at least equal to 75% of the predicted value, were compared with those from 16 healthy non-smoking volunteers. Blind marking scores for the 81mKr images of the asthmatic subjects related significantly to small airways function. Radioaerosol abnormalities in the asthmatic subjects included excessive deposition of the radioaerosol in the central airways and related significantly to small airways function. Radioaerosol imaging performed better than 81mKr imaging at differentiating asthmatic from normal subjects. Radioaerosol abnormalities in patients with poor small airways function probably reflect (1) uneven distribution of ventilation to different regions of the lung periphery and (2) changed patterns of airflow in the bronchial tree. Image abnormalities detected in routine clinical ventilation imaging-with 81mKr or radioaerosol-may sometimes be caused by small airways fysfunction even when the patients FEV1 is normal.