Comparison of bronchodilator responses and deposition patterns of salbutamol inhaled from a pressurised metered dose inhaler, as a dry powder, and as a nebulised solution.

The lung dose and deposition patterns of drug delivered by dry powder inhaler are not known. The effects of inhaling 400 micrograms salbutamol delivered by dry powder inhaler (two 200 micrograms salbutamol Rotacaps), by pressurised metered dose inhaler, and by Acorn nebuliser were studied in nine subjects with chronic stable asthma. Technetium-99m labelled Teflon particles were mixed with micronised salbutamol in the pressurised metered dose inhaler and in the capsules; technetium-99m labelled human serum albumin was mixed with the salbutamol solution for the nebuliser study. The pressurised metered dose inhaler deposited 11.2% (SEM 0.8%) of the dose within the lungs; this was significantly more than the dose deposited by the dry powder inhaler (9.1% (0.6%], but did not differ significantly from the dose delivered by the nebuliser (9.9% (0.7%]. Distribution within the peripheral third of the lung was significantly greater with the nebuliser than with the other two systems; FEV1 improved to a significantly greater extent after inhalation of 400 micrograms salbutamol from the pressurised metered dose inhaler (35.6% from baseline) than from the nebuliser (25.8%) or dry powder inhaler (25.2%). Thus after inhalation of similar doses of salbutamol a larger proportion of drug was deposited within the lungs when it was inhaled from a metered dose inhaler than from a dry powder system; the nebuliser achieved the greatest peripheral deposition. The bronchodilator response seems to depend on the amount of drug within the lungs rather than its pattern of distribution.

Influence of breathing pattern on lung deposition and bronchodilator response to nebulised salbutamol in patients with stable asthma.

The influence of breathing pattern on lung deposition and bronchodilator response to nebulised salbutamol is uncertain. Three different breathing patterns were assessed in eight patients with chronic stable asthma. Salbutamol solution (2.5 mg in 4 ml) mixed with technetium-99m labelled human serum albumin was nebulised by an Acorn nebuliser at a flow rate of 6 litres a minute. Particles with a mass median aerodynamic diameter of 4.8 microns were produced for inhalation by (a) tidal breathing, (b) six tidal breaths followed by three deep breaths, and (c) six tidal breaths followed by three deep breaths with a five second breath hold after each breath. Each breathing pattern was continued for four minutes. There was no significant difference in the percentage of radioaerosol deposited in the lung or in the distribution of radioaerosol within the lung as assessed by gamma camera imaging. Changes in bronchodilator responses as measured by peak expiratory flow rate (PEF), forced expiratory volume in one second (FEV1), and forced vital capacity (FVC) 30, 45, and 60 minutes after inhalation were similar for the three studies. The mean (SEM) maximum percentage change in FEV1 was 44 (7.1), 47 (9.2), and 51 (8.4) for studies 1, 2, and 3 respectively. The percentage of nebulised solution deposited in the body was also similar for the three breathing patterns--that is, 11-13%, of which 98% entered the lung. This study shows that inhaling a nebulised aerosol by tidal breathing, the simplest method, is as effective as tidal breathing with deep breaths with or without a breath hold.

Effect of particle size of bronchodilator aerosols on lung distribution and pulmonary function in patients with chronic asthma.

The particle size of bronchodilator aerosols may be important in determining the site of deposition in the lung and their therapeutic effect. The distribution of aerosols (labelled with technetium-99m diethylene triamine pentacetic acid) of two different particle sizes has been studied by gamma camera imaging. The particles had mass median aerodynamic diameters (geometric standard deviations) of 1.4 (1.4) and 5.5 (2.3) micron, and they were administered from a jet nebuliser to eight patients with chronic severe stable asthma. There was no significant difference in peripheral lung deposition with the two aerosols in any patient. The bronchodilator effect of the two aerosols was determined from cumulative dose-response studies. To avoid large doses that might mask possible differences in effect due to aerosol size, small, precisely determined incremental amounts of salbutamol (25-250 micrograms total lung dose) were used. The two doses were given via a nebuliser on separate occasions and the bronchodilator response was measured from FEV1, forced vital capacity, and peak expiratory flow 30 minutes after each dose. Bronchodilatation was similar with the two aerosols at each dose of salbutamol. There was therefore no difference in distribution within the lung or any difference in bronchodilator effect between an aerosol of small (1.4 micron) particle size and an aerosol of 5.5 microns in patients with severe but stable asthma.

Experimental human muscle damage: morphological changes in relation to other indices of damage.

The effects of eccentric exercise have been examined in human calf and biceps muscles. Release of muscle creatine kinase and uptake of technetium pyrophosphate have been followed for up to 20 days after the exercise and the results are related to the morphological changes seen in needle biopsy samples. The response to exercise was variable, all subjects developing pain and tenderness in the exercised muscles after 1-2 days and this was followed, in most subjects, by a large increase in plasma creatine kinase 4-6 days after the exercise. This was paralleled by an increased uptake of technetium pyrophosphate into the exercised muscle. Biopsies of the affected muscles showed little or no change in the first 7 days after the exercise but later degenerating fibres were seen, as well as infiltration by mononuclear cells and eventually, by 20 days, signs of regeneration. Very extensive changes were seen in the calf muscle of one subject; changes in the biceps were qualitatively similar but not so severe. In the severely affected calf muscle type II fibres were preferentially damaged. Mononuclear cell infiltration both between and within degenerating fibres was maximal well after the time of peak plasma creatine kinase and it is likely that in eccentrically exercised muscle infiltrating mononuclear cells act to scavenge cellular debris rather than to cause damage to the muscle.

Pulmonary epithelial permeability: vascular background effects on whole lung and regional half-time values.

Pulmonary epithelial permeability was first measured by Jones et al. We have adapted their technique for use with a gamma camera. Both regional half-time values and background correction factors vary from apex to base in the lung. Examination of two methods of background correction show: that inter-segmental half-time comparison is possible without applying individual correction factors to regions. the use of a region of interest with similar vascular supply to that of the lung eliminates the need for a background correction technique that relies upon an intravenous injection of radioisotope. The inter-renal area provides such a vascular area.

Skeletal muscle damage: a study of isotope uptake, enzyme efflux and pain after stepping.

We have studied the occurrence of skeletal muscle uptake of 99mtechnetium pyrophosphate (Tc-PYP), creatine kinase (CK) release and muscle pain in normal subjects after exercise. Five subjects stepped on and off a high bench in such a way that one leg stepped up and the other down. Pain only developed in the muscles used for descending: quadriceps, adductors and gluteal muscles of one leg and the calf muscle of the other. A large rise in plasma CK occurred in four subjects but no increased Tc-PYP muscle uptake was seen in the quadriceps. In the four subjects with high CK effluxes, increased isotope uptake was seen in the thigh adductors used when stepping down; in the two subjects with the largest CK effluxes there was extensive uptake into the gluteal muscles. Muscle pain preceded and was not well correlated with either the magnitude of the enzyme release or the amount and distribution of increased muscle isotope uptake. We conclude that delayed onset muscle pain, the cause of which remains unknown, is a poor indicator of muscle damage as indicated by circulating muscle enzymes and muscle isotope uptake. Tc-PYP uptake by skeletal muscle can provide useful information about the localisation and time course of muscle damage.

Regional distribution of pulmonary epithelial permeability in normal subjects and patients with asbestosis.

The overall and regional clearance of an inhaled isotope labelled solute from the lungs was examined on the basis of a 15 minute period of data collection, for which a technique was developed that does not require intravenous injection to correct for blood-tissue background activity. The technique was applied to 52 normal subjects (31 non-smokers and 21 smokers) and to 37 patients with asbestosis (21 non-smokers and 16 smokers). In normal smokers solute clearance was faster in the upper and middle zones, with a mean ratio of T1/2 LB (half time solute clearance from lungs to blood) in the upper two thirds to the lower one third of the lungs of 0.66 (0.28-1.33), compared with 1.24 (0.43-2.77) in normal non-smokers (p less than 0.002). In patients with asbestosis solute clearance was accelerated throughout the lungs even though radiographic abnormalities were limited to lower or lower to middle zones. Regional distribution of clearance was not affected by posture in normal subjects. Overall solute clearance was significantly faster in normal current smokers and in patients with asbestosis than in normal non-smokers (p less than 0.001 respectively). Among patients with asbestosis, smokers had faster overall clearance than non-smokers (p less than 0.01). Among normal non-smokers T1/2 LB was not significantly different between those who had never smoked and ex-smokers. Regional abnormalities in pulmonary epithelial permeability may offer insight into the pathogenesis of interstitial lung diseases and smoking related disorders.

Clearance of 99m-technetium-labelled DTPA in asbestos-exposed subjects without clinical or radiological evidence of interstitial lung disease.

The half-time clearance of an inhaled aerosol of 99m-technetium-labelled diethylene triamine pentacetate from lung to blood (T1/2LB) was measured using a gamma camera in 20 non-smoking subjects (mean age 54, range 40-69 years) with previous occupational asbestos exposure, but no clinical or radiological evidence of asbestosis, and 20 non-smoking normal subjects (mean age 54, range 40-62). Mean T1/2LB was 44.7 minutes (range 12-102) in exposed subjects, significantly less than 57.2 minutes (range 30.5-109) in normal subjects (P less than 0.05). There was no correlation between age and T1/2LB in either group. In exposed subjects T1/2LB showed a weak rank correlation with the membrane component of DLco (Dm) (r = 0.40, P less than 0.05) but no significant correlation with FVC, TLC, DLco, Kco, resting Pao2 or change in Pao2 on exercise. In six exposed subjects T1/2LB was shorter than in any of the normal subjects. These six did not differ from the other 14 exposed subjects in any physiological variables. T1/2LB is abnormal in some asbestos-exposed subjects without clinical, radiological or physiological evidence of asbestosis. Follow-up will show whether it is an early indicator of development of interstitial lung disease.

Direct labelling of ipratropium bromide aerosol and its deposition pattern in normal subjects and patients with chronic bronchitis.

A technique for the direct labelling of ipratropium bromide with bromine-77, with reconstitution of the drug in a metered dose inhaler so as to be identical to the commercial product, was used to study drug deposition patterns in seven normal subjects and seven patients with chronic bronchitis (mean FEV1 32% (SD 12.2%) predicted normal). The gamma camera image of the thorax was divided into a middle zone--the mediastinal zone--and the lung itself into a central zone comprising its medial third and a peripheal zone, the lateral two thirds. Measurements after 10 inhalations of labelled ipratropium bromide showed similar results for the two groups of subjects. The total lung dose inhaled was 11.2% of 203 micrograms and 11.7% of 186 micrograms in the normal subjects and the patients respectively. In contrast to the deposition patterns seen in aerosol studies using steady state inhalation methods, there was no difference in deposition pattern--that is, the distribution between the central and the peripheral lung zones--between the normal subjects and the patients with airways obstruction.