Lung mucociliary transport in asymptomatic asthma: effects of inhaled histamine.

Bronchial mucociliary clearance (CB) and tracheal mucus velocity (TMV) were measured during the course of repeated inhalations of histamine in six subjects with asthma who had no symptoms in a double-blind, crossover study with a radioaerosol technique. Subjects inhaled a technetium 99m-labeled ferric oxide aerosol with an aerodynamic diameter of approximately 8 microns. CB was recorded for 2.5 hours with a gamma camera, and TMV measured with a multidetector probe situated over the extrathoracic trachea. Histamine was administered repeatedly in concentrations previously shown to produce a 20% fall in forced expired volume in 1 second and at intervals allowing 90% recovery of pulmonary function. Histamine produced a 28% increase in CB (p less than 0.001, analysis of variance) and an 87% increase in TMV (p less than 0.001, analysis of variance) above control values, which was not significantly different from that previously observed in normal subjects receiving significantly higher concentrations of histamine. We conclude that histamine stimulates the mucus transport mechanism in subjects with asthma and that there is a relative hypersensitivity to histamine when these subjects are compared with normal subjects.

The effect of inhaled histamine on human tracheal mucus velocity and bronchial mucociliary clearance.

The effect of inhaled histamine on human tracheal mucus velocity (TMV) and bronchial mucociliary clearance (CB) was investigated in six healthy subjects using radioaerosol techniques in a randomized double-blind crossover study. Subjects inhaled repeated doses of either phosphate-buffered saline (PBS) or histamine, immediately after the inhalation of a radioaerosol and during the subsequent 2.5-h clearance measurements. Histamine was administered in concentrations previously demonstrated to induce a 20% fall in FEV1 at intervals permitting 90% recovery (mean recovery time = 25 min). Both TMV and CB were significantly increased by inhaled histamine (p less than 0.001). Average TMV throughout the 2.5-h studies increased from 4.9 +/- 1.3 to 8.4 +/- 1.6 mm/min. The increase in TMV above control values became apparent from 5 to 20 min after the first histamine administration. The percentage of aerosol clearance in 60 min increased 33%. The enhancement of CB became statistically significant at 21 min and persisted throughout the 2.5-h measurements (p less than 0.05). The increase in CB could not be attributed to differences in aerosol deposition because measurements of aerosol penetration were not significantly different between PBS and histamine studies. These data indicate that the bronchoconstriction caused by histamine is accompanied by an increase in tracheal and bronchial mucus transport. Release of histamine, as part of an inflammatory response, may alter mucociliary clearance in humans.

Hand-rearing baboons for laboratory investigations.

To conduct laboratory studies in unsedated animals that were similar anatomically and physiologically to man, five full term baboons (four Papio cynocephalus anubis, one Papio cynocephalus cynocephalus) were hand-reared. These infants were used as unsedated animal models in short-term lung clearance studies conducted from birth to 2 years of age. The hand-rearing techniques described here encouraged the formation of an infant-human rearer bond that permitted us to control the level of expressed aggressive behavior as the infant matured. These techniques resulted in baboons which displayed subordinate behavior, showed positive reception to human contact (without evidence of negative stereotypic behavioral anomalies) and remained cooperative subjects for our investigations of short-term pulmonary clearance. The baboons generally were above average in weight in comparison to conspecifically-reared baboons of similar age, sex and species. Representative lung retention curves presented on one baboon demonstrate the feasibility of lung clearance studies in these hand-reared animals. Due to its suitability for unsedated studies, this baboon model may be considered for other types of laboratory investigations.

Aerosol penetration and mucociliary transport in the healthy human lung. Effect of low serum theophylline levels.

The effect of theophylline on the penetration of an inhaled radioaerosol in the lung, bronchial clearance, and tracheal mucociliary transport rate (TMTR) was investigated in 13 healthy volunteers. Following a randomized, double-blind, crossover protocol, subjects ingested 4 mg/kg twice daily of theophylline or placebo for three days which resulted in stable, low therapeutic serum levels. Aerosol penetration, assessed by the skew of the initial distribution of lung radioactivity, was more peripheral (p less than 0.025) with theophylline, indicating bronchodilation that was not detectable by standard pulmonary function tests. The TMTR increased in ten of 13 subjects after theophylline, but not to a significant level. Bronchial clearance was not significantly different with theophylline despite the longer clearance pathway created by the increased peripheral aerosol deposition. This finding suggests that mucus transport rates in the intrapulmonary airways were increased by theophylline.

Unsedated animal models of pulmonary mucociliary transport.

Measurements of the rate of mucociliary transport in the airways of the lower respiratory tract have been shown to be influenced by the techniques and protocols used. To avoid the effects associated with invasive techniques and anesthesia in animal models used to study the effect of maturation, drugs, disease, and inhaled pollutants on mucociliary transport we have developed unsedated dog and baboon models of mucociliary transport using radioaerosol techniques. As far as they have been tested these animal models of mucociliary transport react to drugs such as isoproterenol and atropine in the same manner as in man.

Clinical aerosols II. Therapeutic aerosols.

The current uses of clinical aerosols such as water, saline, mucolytics, bronchodilators, cromolyn sodium, corticosteroids, and antimicrobials have been reviewed. The benefits of water, saline, and detergent aerosols continue to be surrounded by uncertainty and controversy. Aerosolized mucolytic and proteolytic agents have not been conclusively shown to be of substantial value in the improvement of respiratory disorders. Favorable bronchodilator therapy is achieved with aerosols of certain sympathomimetic and anticholinergic agents. However, successful therapy depends on the dose administered and the site of aerosol deposition in the lung. The prophylactic use of cromolyn sodium in patients with asthma is another useful application of aerosols. Topically active corticosteroid aerosols are increasingly being used since they may reduce risks of systemic effects from corticosteroids. Research on uncommonly aerosolized agents has widened the spectrum of therapeutic applications of aerosols.

Clinical aerosols. I. Characterization of aerosols and their diagnostic uses.

Characterization of an aerosol is of major importance for the understanding of its pathogenic, diagnostic, or therapeutic effect. The parameters necessary for such characterization as well as the methods for obtaining them are reviewed. The factors that determine site of deposition in the human lung are discussed. Further, we have reviewed methods employed to produce aerosols for diagnostic, therapeutic, and clinical research uses. Basic and relatively simple knowledge of aerosol characterization can increase the usefulness of clinical aerosols. Using this knowledge, general principles for aerosol administration are developed. Finally, the application of aerosols in the diagnosis of respiratory diseases is presented; these aerosols include contrast agents, radioactive aerosols, and bronchospastic agents.

Mucociliary clearance of deposited particles from the human lung: intra- and inter-subject reproductivity, total and regional lung clearance, and model comparisons.

The intra- and inter-subject reproducibility of pulmonary mucociliary clearance was investigated in nine healthy male subjects following deposition of an aerosol of 7.9 microns aerodynamic diameter iron oxide particles labeled with TC-99m. The results have been analyzed for both total bronchial clearance and for clearance from areas representing central (Zone I), mid (Zone II), and peripheral (Zone III) regions of the lung. The observed clearance rates were compared to the predictions of a mathematical model for lung clearance based on Weibel's dicotomous branching system. The results for total bronchial clearance showed an average TB120 (percent cleared in 2 hr) of 57%, while the average TB120 for Zone I, II, and III was 56%, 62%, and 48%, respectively. The mean half-times (times required to clear 50% of the deposited activity) for the total bronchial clearance and for Zones I, II, and III were 1.90 hr, 1.97 hr, and 1.70 hr and 2.62 hr, respectively. Total bronchial and regional clearance was reproducible (P = .05) within subjects, but significant variation was observed among subjects. The predictions of the mathematical model for total bronchial clearance are in good agreement with the experimental results. However, the experimental clearance rate was slower in Zone I, and faster in Zone II and III than is predicted by the model. The implications of these results are discussed.

Respiratory neuromuscular response to CO2 rebreathing with inspiratory flow resistance in humans.

The effects of inspiratory flow resistance on mouth occlusion pressure (P0.15) and diaphragmatic EMG (EMGdi) responses to CO2 rebreathing were studied in normal subjects. Occlusion pressures were measured 150 msec after onset of an inspiratory effect; EMGdi was analyzed as a moving time average and quantified in terms of peak activity and rate of rise of activity. After a control CO2 response was obtained in each subject, rebreathing was repeated 30 min later with either of two inspiratory flow resistive loads, 5 cm H2O/L/sec (IR5) and 14 cm H2O/L/sec (IR14). With IR5 (6 subjects), the P0.15 response was decreased in two subjects, unchanged in two, and increased in two; peak EMGdi was unchanged in all, while rate of rise of EMGdi response decreased in 4 of the 6 subjects. With IR14 (6 subjects, 9 runs), the P0.15 response was not decreased in any subject, remained unchanged in 4, and increased in 5; peak EMGdi response to rebreathing in all runs was, again, unchanged by this load, but rate of rise of EMGdi was decreased in 3 and unchanged in 6. The inspiratory off-switch threshold as reflected by peak diaphragmatic activity was not changed by inspiratory flow resistance, whereas inspiratory neural drive as reflected by the the rate of rise of activity was decreased in some subjects. The decrease in inspiratory drive without change in inspiratory off-switch threshold resulted in prolongation of inspiration in an attempt to effect efficient lung expansion. However, the defense of ventilation during rebreathing with both resistances appeared to mainly depend on the response of inspiratory muscle force (P0.15), since in 7 of the 7 runs in which the P0.15 response was significantly increased from control, the ventilatory response was not decreased.

Calculated deposition of inhaled particles in the airway generations of normal subjects.

Detailed regional deposition of inhaled particles in the human lung is calculated for individual airway generations. The calculations are based on Landahl's deposition model as applied to the morphometric lung model of Weibel. We consider primarily deposition patterns of iron oxide particles with diameters ranging between 1 and 10 micrometers, but we also calculate patterns of deposition for bis(2-ethylhexyl) sebacate particles with diameters as small as 0.2 micrometers. We obtain good agreement between predicted values and observed values for alveolar retention of inhaled iron oxide particles with 64 and 20% of total deposition predicted to occur in nonciliated airways for 2- and 5-micrometer particles, respectively. This is compared with 48 +/- 9 and 27 +/- 10% for the measured values. Calculated values for total lung deposition of small bis(2-ethylhexyl) sebacate particles agree well with experimental data. The calculations show a minimum in deposition occurring for particle diameters of 0.5 micrometers, which is in agreement with observations. A calculation of surface concentration of deposited 7.9-micrometer aerodynamic particles reveals a very large concentration occurring at airway generation four. This observation is considered in light of observations that bronchial carcinomas occur in this vicinity of the lung.

Diaphragmatic EMG response to isocapnic hypoxia and hyperoxic hypercapnia in humans.

The EMGdi response to both isocapnic hypoxia and hyperoxic hypercapnia was studied in the same sitting in six normal subjects. Rebreathing methods achieving "open loop" conditions were used. EMGdi was quantified as a moving time average. In almost all subjects, during hypoxia changes in EMGdi were inversely and hyperbolically related to changes in PAO2. When EMGdi was plotted against extrapolated O2 saturation, the relationship was linear in all subjects. The EMGdi response to hypoxia was qualitatively similar to the concurrent responses VI and P.15. EMGdi was linearly related to PACO2 during CO2 rebreathing. The slopes of the EMGdi response to decreasing O2 saturation were positively correlated to the slopes of the EMGdi response to PACO2, so that subjects with a low hypoxic response also had a low CO2 response and vice versa. The couplings of neural to muscular and muscular to ventilatory events as assessed by the ratio of the slopes of EMGdi to P.15 and P.15 to VI, respectively, were similar for all subjects and were not related to the degree or type of chemostimulation. The following were our conclusions. (1) EMGdi can be used as an index of respiratory motoneuron drive during hypoxic or hypercapnic breathing in normal humans. (2) The relative degree of responsiveness to hypoxic and hypercapnia stimuli (chemosensitivity) appears to be similar in any given individual. (3) In normal subjects, changes in inspiratory muscle pressure and ventilation are proportionate to changes in inspiratory neural drive as assessed by EMGdi.

Relationship between mouth occlusion pressure and electrical activity of the diaphragm: effects of flow-resistive loading.

We determined the relationship between mouth occlusion pressure and diaphragmatic electromyography during CO2 rebreathing with and without inspiratory flow resistance. Diaphragmatic electromyography was measured as a moving time average; occlusion pressures were measured 150 msec after onset of an inspiratory effort against a closed airway (P.15). P.15 versus diaphragmatic electromyographic plots during CO2 rebreathing with and without inspiratory flow resistance were linear. In 3 subjects the slope of P.15 versus diaphragmatic electromyography was unchanged with inspiratory flow resistance whereas in 3 others the slope increased, indicating greater inspiratory force for a given degree of diaphragmatic activity. We concluded that under unloaded conditions P.15 is a reliable index of respiratory neural output but may no longer reflect only inspiratory motoneuron drive during mechanical loading.