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Biomedical subjects

K Philipson

Publications and source records attributed to K Philipson.

At least 19 recordsLinked to original sources

Negligible clearance of ultrafine particles retained in healthy and affected human lungs.

Ambient particles are believed to be a specific health hazard, although the underlying mechanisms are not fully understood. There are data in the literature indicating fast and substantial systemic uptake of particles from the lung. The present authors have developed an improved method to produce ultrafine particles with more stable radiolabelling and defined particle size range. Fifteen subjects inhaled technetium 99m (99mTc)-labelled carbonaceous particles of 100 nm in size. Radioactivity over the lung was followed for 70 h. The clearance of these ultrafine particles from the lungs and specifically translocation to the circulation was tested. Lung retention for all subjects at 46 h was mean+/-sd 99+/-4.6%. Cumulative leaching of 99mTc activity from the particles was 2.6+/-0.96% at 70 h. The 24-h activity leaching in urine was 1.0+/-0.55%. No evidence of a quantitatively important translocation of 100-nm particles to the systemic circulation from the lungs was found. More research is needed to establish if the approximately 1% cleared activity originates from leached activity or insoluble translocated particles, and whether a few per cent of translocated particles is sufficient to cause harmful effects.

Administration, Inhalation↗

Long-term clearance from small airways decreases with age.

The prevalence of respiratory symptoms increases with age. Age has been found to be negatively associated with large airway clearance. The small airways region is considered important for development of airway disease. Clearance after the first 24 h was studied in 46 healthy subjects with a wide age distribution, (mean 42, range 19-81 yrs). All subjects inhaled monodisperse 6 microm Teflon particles labelled with 111In, with an extremely slow inhalation flow (0.05 L.s-1). The particles were mainly deposited in the small conducting airways. Lung retention was measured at 0 and 24 h, and at 7, 14 and 21 days after inhalation. Significant relationships were found for the individual 24 h "large" airway clearance in per cent of initial lung deposition with age, forced expiratory volume in one second and forced vital capacity. Age was negatively associated with "small" airway clearance after 24 h as estimated at 2, 7, 14 and 21 days. Using stepwise linear regression only age remained significantly associated to clearance. In conclusion, small airway clearance over 21 days was found to decrease with age. This might be one factor associated with the high prevalence of respiratory symptoms associated among the elderly.

Administration, Inhalation↗

Long-term clearance from small airways in patients with cystic fibrosis.

Impaired mucociliary clearance is a hallmark of cystic fibrosis (CF). Early morphological changes first appear in the small airways. Lung clearance was investigated in 11 young CF adults with mild-to-moderate lung disease using a method depositing particles mainly in the small airways. Radiolabelled Teflon particles (6 microm) were inhaled with an extremely slow inhalation flow, 0.05 L x s(-1). Lung retention was measured immediately following inhalations and, on four occasions up to 21 days. The results were compared with data from healthy subjects. The lung retention at 24 h in % of deposition was 67% (95% confidence interval 58-76) in the CF patients, compared to 48% (42-53) in the healthy subjects. Clearance on days 1-7 was larger in the CF patients, 22% (15-29) compared to the healthy subjects, 14% (12-16). No difference was observed between the CF patients and the healthy subjects in the slow clearance phase at day 7 to day 21, representing small airway clearance. Impaired mucociliary clearance in CF patients results in increased 24-h retention and a prolonged rapid clearance phase. The results of the study do not support the current authors' hypothesis that clearance from small airways is slower in cystic fibrosis patients compared to healthy subjects. Furthermore, the data suggest that mucociliary transport is not the dominant clearance mechanism in small airways.

Administration, Inhalation↗

Comparison of clearance of particles inhaled with bolus and extremely slow inhalation techniques.

Ten healthy nonsmokers inhaled 6-microm (aerodynamic diameter) Teflon particles labelled with 111In twice, once with the shallow bolus technique (volumetic lung depth 76+/-20 mL ([+/- SD]) and once with the extremely slow inhalation technique (0.05 L/s). The radioactivity in the lungs was measured at 1 and 24 hours as well as at 1, 2, and 3 weeks after both inhalations. The 24-hour lung retention a percentage of lung deposition was significantly lower for the bolus inhalation, 46%+/-9% (+/- SD) than for the extremely slow inhalation, 56%+/-11%. The retention after 21 days as a percentage of the 24-hour retention was 55%+/-9% for the shallow bolus inhalation and 56%+/-10% for the extremely slow inhalation. Also within the subjects, clearance was similar for the 2 modes of inhalation. Deposition of particles inhaled with the 2 modes of inhalation was calculated with 2 model, one being based on Monte (Carlo particle transport together with an asymmetric lung model. Deposition predicted with this model agreed well with the experimental data under the assumption that there are large retained fractions only in small ciliated airways (bronchioli) and not in large ones. For the bolus inhalation, the model predicted 43% to 50% deposition in the bronchial (BB) region of initial lung deposition, 33% to 38% in the bronchiolar (bb) region, and 16% to 22% in the alveolar region. For the extremely slow inhalation, the model predicted 31% to 34% deposition in the BB region, 45% to 47% in the bb region, and 21% to 22% in the alveolar region. In addition, it predicted about the same ratio between bb and alveolar depositions for the 2 modes of inhalation. Thus, both the experimental and theoretical data indicate that the shallow bolus particles to a considerable extent reach both the bb and the alveolar regions and that they do that at about the same extent as the particles inhaled extremely slow. This conclusion is concerning the experimental data based on the assumption that there are no large retained fractions in the BB region. Another interpretation of the similar clearance for the two modes of inhalation is that there are large retained fractions in both the BB and the bb regions and that individual charactristics of clearance of these fractions are of importance rather than the site of deposition.

Administration, Inhalation↗

Lung clearance in children with Duchenne muscular dystrophy or spinal muscular atrophy with and without CPAP (continuous positive airway pressure).

Bronchiolar clearance was studied in 7 boys in the age range of 8 to 17 years, 6 with Duchenne muscular dystrophy (DMD) and 1 with spinal muscular atrophy type II (SMA-II). These boys had healthy lungs but a severely reduced muscular strength (wheelchair dependent). In 6 of the boys, clearance was studied twice, at one occasion as a control and at the other occasion following treatment with continuous positive airway pressure (CPAP). A control group of healthy adults was used. In the clearance examinations, 6-microm Teflon particles, labeled with III In was inhaled extremely slowly, 0.05 L/s. This gives a deposition mainly in the bronchioles. Lung retention was measured after 0,24,48, and 72 hours. A model for deposition of particles in the adult lung was scaled down to represent the children in this study. Deposition in various airway generations was calculated to be similar in children and adults. Also the measured retentions were similar in the boys and the adults. In the clearance experiments during CPAP treatment, there was a significantly lower retention after 72 hours (but not after 24 and 48 hours) than in the control experiments. Theresults indicate that a severe reduction of muscular strength, and thereby a reduction of mechanical movement of the lung, does not affect clearance from large and small airways. However, some effect of clearance from small airways cannot be excluded due to the short measuring period. The small but significant effect of the CPAP treatment might have potential clinical importance and suggest that bronchiolar clearance can be affected by some form of mechanical force.

Adolescent↗

Does lung retention of inhaled particles depend on their geometric diameter?

Experiments with a bolus technique suggest that retained fractions in the airways are dependent on the geometric diameter of the particles. This view has been adopted by the International Commission on Radiological Protection (ICRP) in its new human respiratory tract model (HRTM). The aim of the present study was to test this view by the use of an inhalation technique, in which particles with an aerodynamic diameter of about 6 microns are inhaled extremely (0.05 l/s) and as a result, the particles are deposited mainly in small ciliated airways. Nine healthy subjects inhaled on one occasion monodisperse 111In-labelled polystyrene particles (geometric diameter 6.05 microns, aerodynamic diameter 6.2 microns) and on another occasion monodisperse 111In-labelled Teflon particles (geometric diameter 4.47 microns, aerodynamic diameter 6.5 microns). Both particles were inhaled at 0.045 L/s and radioactivity in the body was measured after 0, 24, 48, and 72 hours as well as after 1, 2, and, for some subjects, also 3 weeks. The retention in the lungs at 24 hours was slightly lower for the Teflon particles (47%) than for the polystyrene particles (51%). From earlier experimental data with different particle sizes as well as from predictions with theoretical lung models, this difference is reasonably explained by the somewhat larger aerodynamic diameter of the Teflon particles. Clearance of the 2 particle types between 1 day and 2 weeks was similar within each individual as well as in the whole group. The differences between the clearance of 4.5 microns and 6 microns geometric diameter particles observed in the present experiment are significantly different (P < .01) from the differences seen in earlier shallow bolus experiments as well as from the differences for such particles calculated with the HRTM, i.e., our experiment does not support the hypothesis that the fraction retained after 1 day is dependent on the geometric diameter in the size range studied.

Administration, Inhalation↗

Assessment of long-term bronchiolar clearance of particles from measurements of lung retention and theoretical estimates of regional deposition.

Twelve healthy nonsmokers inhaled monodisperse Teflon particles labelled with 51Cr (half-life 27.8 days) with an aerodynamic diameter (dae) of 6.1 microns, 5 at a normal flow, 0.5 L/s, and 7 at an extremely slow flow, 0.05 L/s. Lung retention after 24 hours was measured for about 6 months and could be well described by a 2-component exponential function. After the normal inhalation, 14% of the particles retained after 24 hours cleared with a half-time of 3.7 days and 86% with a half-time of 217 days. After the slow inhalation, 35% of the particles retained after 24 hours cleared with a half-time of 3.6 days and 65% with a half-time of 170 days. Deposition was calculated using 3 different models including the recent Human Respiratory Tract Model (HRTM), adopted by the International Commission on Radiological Protection (ICRP), and a model based on Monte Carlo particle transport, together with an asymmetric lung model. Generally, the 3 models agreed fairly well and predicted a considerably higher deposition in the bronchiolar region (generations 9-15) at the slow flow than at the normal flow. Together, the experimental data and the predictions of the deposition models indicate that about 40% of the particles deposited in the conducting airways during the slow inhalation were retained after 24 hours. They also strongly indicate that the particles which cleared with a half-time of about 4 days were mainly deposited in the bronchiolar region, and that about 25% of the particles deposited in the bronchiolar region cleared in this phase. The experimental data agreed quite well with the HRTM predictions made using its default parameter values for slow clearance in the bronchial tree.

Administration, Inhalation↗

Lung deposition and extremely slow inhalations of particles. Limited effect of induced airway obstruction.

Studies of lung deposition and clearance have focused on the large airways. Still, lung diseases affect also the small airways. We have developed a method for selective particle deposition in the smallest ciliated airways. Eight healthy subject inhaled 6-micron radiolabelled test particles on 3 occasions at 0.05 L/s and retention was measured for 72 hours. At one occasion, the subjects inhaled the particles at a normal airway resistance. At a second occasion, a 2-3-fold increase in airway resistance was induced by a cholinergic provocation before inhalation of the particles. At a third occasion, a corresponding provocation was induced after inhalation of the particles. The percentage lung depositions were 76 +/- 7, 68 +/- 7, and 73 +/- 8 (mean +/- SD) for "normal airway resistance," "provocation before," and "provocation after" exposures, respectively. The lower value for the "provocation before" exposure was probably a result of increased mucociliary clearance, due to cholinergic stimulation, before the first measurements of radioactivity. The retentions at 24 hours were 51 +/- 7, 52 +/- 9, and 51 +/- 8 in percent of initial lung deposition for "normal airway resistance," "provocation before," and "provocation after" exposures, respectively. We conclude that our inhalation technique is useful in studying conditions in the bronchioles, as deposition is rather independent of airway resistance.

Administration, Inhalation↗

Clearance in small ciliated airways in allergic asthmatics after bronchial allergen provocation.

BACKGROUND: Asthma tends to affect mucociliary clearance, as assessed from measurements in large airways. However, there is no knowledge about clearance in the smallest airways of the tracheobronchial region in acute exacerbation of asthma. OBJECTIVE: The aim of the study was to investigate clearance from the bronchiolar region in patients with allergic asthma in a situation resembling a mild acute exacerbation of the disease. We also aimed to compare clearance data with corresponding data found for healthy subjects and asthmatics on therapy. METHODS: Tracheobronchial clearance was studied twice in 9 patients with mild asthma of the allergic type after inhalation of 6 microm (aerodynamic diameter) monodisperse Teflon particles labelled with 111In. At one exposure, inhalation was performed 4 h after bronchial provocation with an allergen the patients were allergic to. The second exposure was a control measurement. The particles were inhaled at an extremely slow flow, 0.05 liter/s, which gives deposition mainly in the small ciliated airways (bronchioles). Lung retention was measured at 0, 24, 48 and 72 h. RESULTS: All patients demonstrated an early asthmatic reaction of varying degree after bronchial provocation. There was significant clearance of radioaerosol in each 24-hour period for both exposures, with the possible exception of the period between 24 and 48 h for the provocation exposure, with similar fractions of retained particles at all points of time. The retained fractions were significantly larger compared to a group of healthy subjects and asthmatics on regular treatment with anti-inflammatory drugs. CONCLUSIONS: Our results indicate that in allergic asthmatics a bronchial allergen provocation with an early asthmatic reaction does not significantly influence overall clearance from the bronchiolar region. However, in the present group of patients, retention in small ciliated airways was significantly higher compared to healthy subjects and asthmatics on regular treatment.

Adult↗

Tracheobronchial deposition and clearance in small airways in asthmatic subjects.

Asthma tends to impair mucociliary clearance, as assessed from measurements in large airways. However, very little is known about clearance in the smallest airways of the tracheobronchial region. Deposition and clearance was estimated in 11 subjects with stable asymptomatic asthma and 10 healthy subjects after inhalation of 6 microns (aerodynamic diameter) monodisperse Teflon particles labelled with 111In. The particles were inhaled at an extremely slow flow, 0.05 L.s-1. Theoretical calculations and experimental data in healthy subjects using this slow flow support an enhanced deposition in the tracheobronchial region, in particular in the small ciliated airways (bronchioles). Lung retention was measured at 0, 24, 48 and 72 h. Clearance was significant every 24 h both for asthmatic and healthy subjects, with similar fractions of retained particles at all time-points. The fractions of tracheobronchially-deposited particles were on average 41 and 47% for asthmatic and healthy subjects, respectively, as compared to a maximal deposition of 30% using a normal inhalation flow (0.5 L.s-1). No significant correlation was found between lung retention and lung function, either in asthmatics or in healthy subjects. Our results indicate that particles clear equally well from small ciliated airways in asthmatic and healthy subjects, maybe as a consequence of an optimal asthma therapy. Furthermore, our results show that it is possible to enhance tracheobronchial deposition both in healthy and asthmatic subjects, i.e. practically independent of airway dimensions, by inhaling rather large aerosol particles extremely slowly. This may be a useful therapeutic approach.

Administration, Inhalation↗

Oropharyngeal deposition of 3.5 microns particles inhaled through an elongated mouthpiece.

We previously studied the deposition of inhaled particles in the oropharynx of asthmatic patients, and found that a pharyngeal narrowing during inhalation seems to be one reason for high oropharyngeal deposition. In the present study, we investigated whether by-passing a larger part of the oral cavity by using an elongated mouthpiece would reduce deposition in the oropharynx, and increase deposition in the lungs. Deposition in the oropharynx and in the lungs was estimated in nine patients with obstructive airway diseases. In earlier investigations, three of these patients had repeatedly shown extremely high oropharyngeal deposition (> 70%). In the present study, the patients inhaled 3.5 microns (aerodynamic diameter) radiolabelled Teflon particles at 0.5 L.s-1, with and without an individually adapted elongated mouthpiece. Radioactivity was measured using a profile scanner. On average, oropharyngeal deposition was 27% (range 12-45%) and 30% (range 11-77%) of the total amount of particles deposited in the body, with and without elongated mouthpiece, respectively. There was no significant difference between these values (p > 0.05), nor between the values of lung deposition. However, oropharyngeal deposition was markedly reduced, with a corresponding increase in lung deposition, by the elongated mouthpiece in the one and only patient who still showed extremely high oropharyngeal deposition (> 70%). Our study shows that lengthening of the mouthpiece is not sufficient to reduce average deposition of aerosol particles in the oropharynx in patients with comparatively normal deposition values. This result, however, does not exclude a beneficial effect in patients with extremely high oropharyngeal deposition.

Administration, Inhalation↗

Added external resistance reduces oropharyngeal deposition and increases lung deposition of aerosol particles in asthmatics.

Mouth and throat, and regional lung deposition was estimated in fifteen asthmatic subjects for 3.6-microns (aerodynamic diameter) radiolabeled polytetrafluoroethylene (Teflon) particles inhaled at 0.5 L/s with and without added external resistance. Radioactivity was measured by a profile scanner. Behavior of the pharynx and larynx was assessed by fiberoptic laryngoscopy. Mean mouth and throat deposition was 22% (range, 13 to 47%) and 33% (range, 12 to 84%) with and without resistance (p < 0.05), respectively. A marked reduction in mouth and throat deposition (range, 20 to 44%), with a corresponding increase in lung deposition, was observed especially in the six subjects with mouth and throat deposition values > 30% at inhalation without resistance. Furthermore, a small (mean 8%) but significant (p < 0.05) increase in peripheral lung deposition, estimated as retention at 24 h, was found at inhalation with increased resistance. The fiberoptic examination showed wide intersubject variability in the pharynx and larynx, with tendencies toward higher mouth and throat deposition with pharyngeal narrowing, and significantly (p < 0.05) lower lung retention with laryngeal narrowing. Our results show that an external resistance reduces mouth and throat deposition and increases deposition and retention of aerosol particles in the lungs in asthmatic individuals.

Adult↗

Repeatability of airway deposition and tracheobronchial clearance rate over three days in chronic bronchitis.

Previous investigations on tracheobronchial clearance in chronic bronchitis or chronic obstructive pulmonary disease (COPD) have usually referred to measurements during a short time-period, i.e. a few hours. The purpose of this study, therefore, was to study regional particle deposition and tracheobronchial clearance during 72 h. In 14 patients with chronic bronchitis clearance of 111In-labelled 3.6 micrograms Teflon particles and lung function were measured on two occasions, with an interval of 2 weeks. Lung retention of test particles was measured at 0, 24, 48 and 72 h using a profile scanner. The weight of expectorated sputum samples was measured after the two clearance measurements. The particle retentions at all time-points were reproducible, as seen from the two measurements ( r > 0.90). The fast clearance phase was completed within 72 h. No correlation between sputum volume and clearance was seen. There was a significant negative correlation between airway resistance and the 72 h retention (r= -0.66), and an even better correlation between specific airway resistance and the 72 h retention (r = -0.82), indicating more central deposition in obstructed airways. There was no significant correlation between lung function tests reflecting smaller airways and the 72 h retentions. Deposition data agreed well with theoretical calculations and experimental data in healthy subjects. In spite of earlier findings that mucociliary transport is usually severely impaired in chronic bronchitis and COPD, the present results indicate that overall tracheobronchial mucus clearance in these patients is fairly effective, probably due to a productive cough. Alveolar deposition may be estimated by measurements of the 72 h retention in subjects with chronic obstructive pulmonary disease. The 72 h retention is dependent mainly on the calibre of larger airways. The present method of studying airway clearance during 3 days is highly reproducible.

Adult↗

Deposition of inhaled particles in the mouth and throat of asthmatic subjects.

We previously studied the deposition of inhaled particles in the mouth and throat of asthmatic patients, and found large, reproducible differences among subjects. In the present study, we examined whether anatomical and/or functional differences in the pharynx and larynx could underlie this interindividual variation. Deposition in the mouth and throat, and in the lung was estimated in 16 asthmatic subjects after inhalation of 3.6 microns (aerodynamic diameter) monodisperse Teflon particles labelled with 111In. The particles were inhaled at a flow rate of 0.5 l.s-1 with maximally deep breaths. Radioactivity was measured by external scanning over head and neck, lungs and stomach, immediately after the inhalation. Radioactivity in the lungs was also measured 24 h later. A measure of the total amount of particles deposited in the mouth and throat was obtained from the added activities in mouthwash, head and neck, and stomach, immediately after the inhalation of the test particles. Pharynx and larynx function was examined by fibreoptic laryngoscopy performed during a corresponding inhalation procedure. Deposition in the mouth and throat varied widely among the subjects, ranging 9-76% (median 12%). We found two subpopulations, 13 subjects in the range 9-34%, and 3 subjects with > 70% deposition. Deviations in pharyngeal configuration during inhalation were significantly related to high mouth and throat deposition, whereas functional differences in the larynx were not. Our study shows that mouth and throat deposition may be extremely high in some asthmatics, and that pharyngeal configuration affects deposition of particles in the mouth and throat.

Adult↗

Deposition in asthmatics of particles inhaled in air or in helium-oxygen.

Ten subjects with asthma inhaled 3.6 micron particles labeled with 111In in air and in a helium-oxygen mixture (He-O2) at 0.5 and at 1.2 L/s. Lung retention was measured after zero and after 24 h, and the percentage 24-h retention (Ret24) was taken to represent the fraction deposited in the alveolar part of the lung. For both inhalation rates, Ret24 was significantly higher when particles were inhaled with He-O2 than with air. The increase in Ret24 seemed to be larger in subjects with asthma than in healthy persons earlier studied. Ret24 was correlated with changes in both large and small airways, especially when the particles were inhaled with He-O2. Our data suggest that inhalation of drugs in He-O2 might be of therapeutic value when treating patients with severely obstructed airways.

Administration, Inhalation↗

Regional deposition of 3.6-micron particles and lung function in asthmatic subjects.

In a group of moderately severe asthmatic subjects, regional deposition of 3.6-microns (aerodynamic diameter) monodispersed Teflon particles labeled with 111In was studied twice. The particles were inhaled with maximally deep inhalation at 0.5 l/s. Lung retention was measured at 0, 6, 24, and 48 h by use of a profile scanner equipped with two 13 x 5-cm NaI crystals. The retentions at 24 (Ret24) and 48 h were highly correlated (r = 0.96 with a slope of the regression line close to 1). There was a poor correlation between retention at 6 h and Ret24 (r = 0.54). The Ret24 values at the two exposures were well correlated (r = 0.86). There were significant correlations between airway resistance as well as single-breath nitrogen test phase III and Ret24 (r = 0.70 and 0.67, respectively). The correlation between single-breath nitrogen test phase III and Ret24 persisted also when only subjects within a narrow interval of airway resistance were included. The study indicates that regional deposition can be studied by measurements of Ret24 in subjects with moderately severe asthma and that it is dependent on changes in both large and small airways.

Administration, Inhalation↗

Tracheobronchial clearance in asthma-discordant monozygotic twins.

Tracheobronchial clearance and bronchial reactivity were studied in 6 asthma-discordant monozygotic twin pairs, and in 3 concordant pairs as controls. Clearance of 6-microns Teflon particles labeled with 99mTc was followed for 2 h. The results indicate that clearance in the larger airways is usually not severely impaired in mild to moderate asthma, and that it may be increased as well as decreased. Bronchial reactivity correlated with clearance in the nonasthmatics.

Administration, Inhalation↗

Individual differences in regional deposition of 6-micron particles in humans with induced bronchoconstriction.

The effect of induced bronchoconstriction on regional lung deposition of 6 microns aerodynamic diameter 99mTc-labeled Teflon particles was studied in eight healthy non-smokers. The Teflon particles were inhaled at 0.5 l/s from a 25-l glass bulb with 8-12 maximally deep breaths on four consecutive days. For three exposures, various degrees of bronchoconstriction were induced using an aerosol of methacholine bromide before the inhalation of the Teflon particles. For the fourth (control) exposure, bronchoconstriction was induced after the inhalation of the Teflon particles. The degree of bronchoconstriction was quantified by measurements of airway resistance (Raw) using a whole-body plethysmograph. The fraction of alveolarly deposited particles in the lung (FAD) was estimated by measurements of radioactivity in the lung immediately after inhalation of the Teflon particles and 6 h later. Earlier studies have shown that when the mucociliary transport is stimulated with the cholinergic aerosol used in this study, the 6-h retention values (Ret6) are similar to the 24-h values. Within the subjects there was a close relationship between Raw and Ret6 with a decrease of Ret6 with increased Raw. This decrease varied markedly among the subjects. The relationship between Raw and Ret6 calculated from the model by the Task Group on Lung Dynamics, in which the airway diameters were varied, agreed with our experimental data. On an average, airway resistance of 1 and 2 cm H2O.s/l correspond to FAD of about 50% and 25%, respectively.

Administration, Inhalation↗