Exhaled particles and small airways.

BACKGROUND: Originally, studies on exhaled droplets explored properties of airborne transmission of infectious diseases. More recently, the interest focuses on properties of exhaled droplets as biomarkers, enabled by the development of technical equipment and methods for chemical analysis. Because exhaled droplets contain nonvolatile substances, particles is the physical designation. This review aims to outline the development in the area of exhaled particles, particularly regarding biomarkers and the connection with small airways, i e airways with an internal diameter < 2 mm. MAIN BODY: Generation mechanisms, sites of origin, number concentrations of exhaled particles and the content of nonvolatile substances are studied. Exhaled particles range in diameter from 0.01 and 1000 µm depending on generation mechanism and site of origin. Airway reopening is one scientifically substantiated particle generation mechanism. During deep expirations, small airways close and the reopening process produces minute particles. When exhaled, these particles have a diameter of < 4 µm. A size discriminating sampling of particles < 4 µm and determination of the size distribution, allows exhaled particle mass to be estimated. The median mass is represented by particles in the size range of 0.7 to 1.0 µm. Half an hour of repeated deep expirations result in samples in the order of nanogram to microgram. The source of these samples is the respiratory tract ling fluid of small airways and consists of lipids and proteins, similarly to surfactant. Early clinical studies of e g chronic obstructive pulmonary disease and asthma, reported altered particle formation and particle composition. CONCLUSION: The physical properties and content of exhaled particles generated by the airway reopening mechanism offers an exciting noninvasive way to obtain samples from the respiratory tract lining fluid of small airways. The biomarker potential is only at the beginning to be explored.

Measures of bronchodilator response of FEV1, FVC and SVC in a Swedish general population sample aged 50-64 years, the SCAPIS Pilot Study.

BACKGROUND: Data are lacking from general population studies on how to define changes in lung function after bronchodilation. This study aimed to analyze different measures of bronchodilator response of forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC) and slow vital capacity (SVC). MATERIALS AND METHODS: Data were derived from the Swedish Cardiopulmonary Bioimage Study (SCAPIS) Pilot study. This analysis comprised 1,050 participants aged 50-64 years from the general population. Participants were investigated using a questionnaire, and FEV1, FVC and SVC were recorded before and 15 minutes after inhalation of 400 µg of salbutamol. A bronchodilator response was defined as the relative change from baseline value expressed as the difference in units of percent predicted normal. Predictors of bronchodilator responses were assessed using multiple linear regression models. Airway obstruction was defined as FEV1/FVC ratio below lower limit of normal (LLN) before bronchodilation, and COPD was defined as an FEV1/FVC ratio below LLN after bronchodilation. Physician-diagnosed asthma was defined as an affirmative answer to "Have you ever had asthma diagnosed by a physician?". Asymptomatic never-smokers were defined as those not reporting physician-diagnosed asthma, physician-diagnosed COPD or emphysema, current wheeze or chronic bronchitis and being a lifelong never-smoker. RESULTS: Among all subjects, the greatest bronchodilator responses (FEV1, FVC and SVC) were found in subjects with asthma or COPD. The upper 95th percentile of bronchodilator responses in asymptomatic never-smokers was 8.7% for FEV1, 4.2% for FVC and 5.0% for SVC. The bronchodilator responses were similar between men and women. In a multiple linear regression model comprising all asymptomatic never-smokers, the bronchodilator response of FEV1 was significantly associated with airway obstruction and height. CONCLUSION: When the bronchodilator response in asymptomatic never-smokers is reported as the difference in units of predicted normal, significant reversibility of FEV1, FVC and SVC to bronchodilators is ~9%, 4% and 5%, respectively.

Bronchial mucosal mast cells in asymptomatic smokers relation to structure, lung function and emphysema.

The pathologic mechanisms of chronic obstructive pulmonary disease (COPD) most certainly involves neutrophil granulocytes, cytotoxic T-cells, macophages and mast cells. The aim of this study was to investigate the relation between the number of mast cells in different compartments in bronchial biopsies of central proximal airways to structural changes, lung function tests and emphysema detected by high resolution computed tomography (HRCT). Twenty nine asymptomatic smoking and 16 never-smoking men from a population study were recruited. Central bronchial biopsies were stained to identify mast cells by immunohistochemistry. The number of mast cells in the epithelium, lamina propria and smooth muscle as well as epithelial integrity and thickness of the tenascin and laminin layer were determined. Smokers had increased numbers of mast cells in all compartments (P<0.001). Structural changes were correlated to mast cell numbers with the closest associations to mast cell numbers in the smooth muscle [epithelial integrity (R(S)=-0.48, P=0.008), laminin layer (R(S)=0.63, P=0.0002), tenascin layer (R(S)=0.40, P=0.03)]. Similar correlations between mast cells and lung function tests were seen [functional residual capacity (FRC) (R(S)=0.60, P=0.0006), total lung capacity (TLC) (R(S)=0.44, P=0.02) and residual volume (RV) (R(S)=0.41, P=0.03)]. No correlations could be detected between mast cells and FEV1 or to emphysema. Smoking is associated with an increase of mast cells in all compartments of the bronchial mucosa, including smooth muscle, and this is related to altered airway structure and function.

Improved red blood cell survival after cardiac operations with administration of urea during cardiopulmonary bypass.

The plasma hemoglobin and red blood cell survival (half-life of 51Cr) was studied in 48 patients undergoing single valve replacement or coronary artery bypass graft. Urea or placebo was administered during cardiopulmonary bypass in a prospective, randomized, double-blind manner to test the potential effect on mechanical hemolysis. The mean plasma hemoglobin level at the end of extracorporeal circulation was significantly lower in the urea-treated groups (coronary artery bypass 342 mg/L; valve replacement 364 mg/L) than in the control groups (coronary artery bypass 635 mg/L, p less than 0.05; valve replacement 518 mg/L, p less than 0.01). The half-life of 51Cr was significantly longer in the urea-treated patients (coronary artery bypass 18 days; valve replacement 16 days) than in the control groups (coronary artery bypass 12.4 days, p less than 0.01; valve replacement 12.7 days, p less than 0.001) but still below the normal reference value (29 +/- 4 days). The plasma hemoglobin returned to near normal values (50 mg/L) the day after operation (day 1) and remained low with no differences between control and urea-treated groups. The total blood hemoglobin was followed for 2 weeks after operation and showed significantly less anemia in the urea-treated group. The lowest mean blood hemoglobin level was noted between days 5 and 9-114 (coronary artery bypass) and 107 (valve replacement) gm/L in the urea-treated patients compared to 92.3 (coronary artery bypass, p less than 0.01) and 92.2 (valve replacement, p less than 0.01) gm/L in the control subjects. The reduction in the severity of the anemia led to less transfusion in the urea-treated patients (approximately 0.5 unit/patient) than in the control subjects (approximately 1 unit/patient, p less than 0.05) between days 3 and 14.

Reduction of alveolar-capillary diffusion after inhalation of endotoxin in normal subjects.

Normal subjects were exposed to an aerosol of Escherichia coli endotoxin. Carbon monoxide diffusion (Dco), spirometry, blood neutrophils, white blood cells, and platelets were determined at various times thereafter. A significant decrease in Dco and an increase in blood neutrophils was found, with a maximum effect 4 to 8 h after exposure. Exposure to distilled water caused a tendency for Dco to decrease and a significant increase in blood neutrophils. No effect on spirometry or body temperature was detected. It is suggested that the changes observed represent an inflammation at the alveolar level that appears at dose levels of endotoxin below those which cause bronchoconstriction and fever.

Vascular effects of topically applied bradykinin on the human nasal mucosa.

To evaluate the vascular effects of topically applied bradykinin on the human nasal mucosa, 13 asymptomatic hay fever patients and 11 non-allergic subjects were challenged with diluent or bradykinin in three increasing doses. Mucosal blood flow was determined with the 133Xenon wash-out method and expiratory peak flow measurements used to assess nasal airway resistance before and after challenge. Nasal symptoms were recorded. Nasal secretion quantity was measured from preweighed paper handkerchiefs. Bradykinin induced a slight increase in nasal airway resistance which was similar in both allergic and non-allergic subjects. Nasal secretion was clearly increased after challenge with bradykinin compared with challenge with diluent in both allergic and non-allergic subjects. Bradykinin did not, however, induce any change in mucosal blood flow in either group. The present findings could be explained by direct effects of bradykinin on the vascular bed without reflex activity. Bradykinin would then induce an increase in vascular permeability with subsequent oedema formation and increased amounts of fluid on the mucosal surface. In contrast to allergen challenge, bradykinin challenge had no effect on the resistance vessels, changes of which had previously been shown to be largely reflex-mediated.

Drug absorption from nifedipine hydrophilic matrix extended-release (ER) tablet-comparison with an osmotic pump tablet and effect of food.

The aim of the present study was to compare the bioavailability of nifedipine when administered as a hydrophilic matrix tablet (ER) and a push-pull osmotic pump tablet (XL) administrated after fasting, and to evaluate the effect of food for the hydrophilic matrix tablet. For this purpose, three separate studies were performed on healthy volunteers (n = 58) including gammascintigraphic monitoring of tablet erosion and localisation in the gastrointestinal tract for ER in one study. Both ER and XL provided almost constant drug delivery over 24 h, after administration under fasting conditions, and bioequivalence was obtained according to 90% confidence intervals of the difference between formulations within 80-125% for Cmax and AUC. Food significantly increased AUC for ER but no significant difference was obtained between ER and XL with food with respect to extent of bioavailability. The rate of absorption was increased to a higher degree for ER than for XL, as indicated by a Cmax which was almost twice as high for ER compared with XL. This finding was shown to be related to an increased tablet-erosion rate for ER, leading to more rapid drug release.

Respiratory resistance and impedance magnitude in healthy children aged 2-18 years.

Two hundred eighteen healthy children aged 2 to 18 years were studied using a modification of the forced oscillation technique. Reference values with height as predictor were determined for total respiratory resistance and impedance during inspiration, expiration, and throughout the whole respiratory cycle at an oscillation frequency of 4 Hz and, in a subpopulation of 61 children, at frequencies of 2 and 12 Hz. Mean total inspiratory resistance, determined at 4 Hz, decreased with growth from 1.3 kPa X 1(-1) X s at 2 years of age to 0.3 kPa X 1(-1) X s at 18 years. Variability in the results between individuals, expressed in terms of coefficient of variation, was found to be +27% and -21%, respectively, and within individuals, 9%. Resistance during expiration was on average 16% higher than during inspiration and the variability within individuals was 11%. A marked decrease in resistance was found in small children when the frequency was increased from 2 to 12 Hz. The frequency dependence of respiratory resistance observed in small children changes gradually with growth, in parallel with the reduction of total respiratory resistance, to an adult pattern in which no significant change in resistance can be noted between frequencies of 2 and 12 Hz.

Nasobronchial relationship after cold air provocation.

Provocation with cold air in the nose causes broncho-obstruction while warm air causes bronchodilation in patients with asthma, but not in healthy subjects. These findings have suggested the existence of a nasobronchial reflex. The present study aimed to block this effect and evaluate the mechanisms underlying the effect on lung function after cold stimulation of the nose. Lung function, as measured with specific conductance and forced expiratory flow, was reduced after cold stimulation of the nose, but this effect could not be blocked by anesthetizing the nose or by inhaling an anti-cholinergic drug before the provocation. These results confirm the presence of a nasobronchial relationship, but not of a nasobronchial reflex.

Ventilatory response to CO2 re-breathing before and after nocturnal nasal intermittent positive pressure ventilation in patients with chronic alveolar hypoventilation.

Long-term nocturnal nasal intermittent positive pressure ventilation (NIPPV) has beneficial effects on daytime PaCO2 in patients with chronic alveolar hypoventilation. Our aim was to investigate if these beneficial effects are related to improved respiratory drive as measured by ventilatory response to CO2. In 17 hypoventilated patients (mean age 62 years) we obtained daytime arterial blood gases, nocturnal transcutaneous oxygen saturation, nocturnal transcutaneous PaCO2 ventilatory response to CO2 re-breathing, spirometry and indices of respiratory muscle strength before and after 9 months of NIPPV. Patients served as their own controls. After 9 months of NIPPV day-time PaCO2 decreased from 7.1 kPa to 6.3 kPa, (P<0.001) and PaO2 increased from 8.1 kPa to 9.3 kPa, (P<0.01). The changes in morning and daytime PaCO2 and in nocturnal transcutaneous oxygen saturation were significantly correlated to the changes in several variables derived from the ventilatory response to CO2 re-breathing. In patients with substantial improvement in daytime PaCO2 we found significant improvements in ventilatory response to CO2 re-breathing. The present study confirms the beneficial effect of long-term NIPPV on daytime arterial blood gases. The results are consistent with the hypothesis that the improvement of daytime PaCO2 is related to improved respiratory drive observed after NIPPV.

Respiratory symptoms relate to physiological changes and inflammatory markers reflecting central but not peripheral airways. A study in 60-year-old 'healthy' smokers and never-smokers.

The aim of this study was to evaluate the relationship between respiratory symptoms, lung function and inflammatory markers in 'healthy' smokers. The study population was recruited from an epidemiological study with subjects of the same age, 60 years. Only smokers who considered themselves healthy (n=58) and a random sample of never-smokers (n=34) were investigated. All subjects underwent lung function tests--spirometry, carbon monoxide transfer (DLco) and the single-breath N2 method (N2 test)--together with high-resolution computed tomography (HRCT). A flexible bronchoscopy with a bronchoalveolar lavage (BAL) was performed in 30 smokers and 18 never-smokers. Bronchial biopsies were also taken. Smokers who reported non-specific respiratory problems, chronic bronchitis and wheezing in a symptom questionnaire had a lower forced expiratory volume in 1 sec (FEV1), FEV% and specific airway conductance (sGaw), lung function tests supposed to reflect the more central airways, than smokers without respiratory symptoms. A limited number of smokers with occasional non-specific respiratory problems also had more cytotoxic T cells (CD8) in bronchial biopsies. No differences were found in DLCO and the N2 test, lung function tests supposed to reflect the more peripheral airways including the alveoli, HRCT-diagnosed emphysema or inflammatory markers in blood and BAL between smokers with and without respiratory symptoms. It is concluded that even when smokers consider themselves 'healthy' they have mild symptoms that are related more to physiological changes and inflammatory markers that may reflect events in the central airways than to changes that may reflect events in the peripheral airways.

Emphysematous lesions and lung function in healthy smokers 60 years of age.

We aimed to study the occurrence of emphysematous lesions in symptom free smoking men of about 60 years of age and in a matching group of never-smoking men and the relationship between pulmonary changes at high resolution computed tomography (HRCT) and lung function tests. Our investigation included 57 smoking and 32 never-smoking healthy men from a randomized epidemiological study. HRCT was performed at full inspiration with a 1.5 mm slice thickness and a 3 cm inter-slice distance. Evaluation was made by two radiologists unaware of smoking history. Emphysematous lesions were scored visually. Pulmonary function tests were performed including spirometry and diffusion capacity test (DLCO). Emphysematous changes were demonstrated in 25 of 57 smokers but in only one never-smoker. DLCO/VA was the most sensitive test for early emphysematous lesions. It also correlated with radiographical scoring. Emphysematous lesions were evident in 44% of the healthy symptom free smokers. HRCT may reveal early emphysematous lesions in smokers before clinical symptoms have developed.

Neutrophil-associated activation markers in healthy smokers relates to a fall in DL(CO) and to emphysematous changes on high resolution CT.

Smoking is a risk factor for developing chronic obstructive pulmonary disease (COPD), but there are no good indicators for early identification of subjects who will develop symptomatic COPD. The aim of this study was to investigate inflammatory mechanisms related to changes in lung function and emphysematous changes on high resolution computed tomography (HRCT) in 'healthy' smokers. Subjects were 60-year-old men from a population study. Bronchoscopy was performed in 30 smokers and 18 who had never smoked. Blood tests, lung function measurements and HRCT were carried out in 58 and 34 subjects, respectively. In comparison with never-smokers, smokers had higher levels of myeloperoxidase (MPO), human neutrophil lipocalin (HNL), eosinophil cationic protein (ECP) and lysozyme in blood, higher levels of MPO, interleukin-8 (IL-8) and HNL in bronchial lavage (BL), and of IL-8, HNL and interleukin-lbeta (IL-1beta) in bronchoalveolar lavage (BAL). Smokers also had lower levels of Clara cell protein 16 (CC-16) in blood. HNL in BL and BAL showed strong correlations to other inflammatory markers (MPO, IL-8, IL-1beta). The variations in MPO in BL were explained by variations in HNL (R2 =0.69), while these variations in BAL were explained by variations in HNL and IL-1beta (R2 = 0.76). DL(CO) was the lung function variable most closely related to MPO and IL-8 in BL and BAL and to IL-1beta in BAL. In a multiple regression analysis, MPO, IL-1beta, IL-8 and CC-16 in BL and MPO in BAL contributed to the explanation of variations in DL(CO) to 41% and 22%. respectively, independent of smoking habits. In smokers with emphysematous lesions on HRCT, HNL in BAL correlated to emphysema score (r(s) = 0.71). We conclude that 'healthy' smoking men with a near normal FEV1 show signs of inflammation in the lower airways that are related to a decrease in DL(CO) and to emphysematous lesions on HRCT. This inflammation seems to be the result of both monocyte/macrophage and neutrophil activation.

Evaluation of attenuation corrections using Monte Carlo simulated lung SPECT.

SPECT (single photon emission computed tomography) images are distorted by photon attenuation. The effect is complex in the thoracic region due to different tissue densities. This study compares the effect on the image homogeneity of two different methods of attenuation correction in lung SPECT; one pre-processing and one post-processing method. This study also investigates the impact of attenuation correction parameters such as lung contour, body contour, density of the lung tissue and effective attenuation coefficient. The Monte Carlo technique was used to simulate SPECT studies of a digital thorax phantom containing a homogeneous activity distribution in the lung. Homogeneity in reconstructed images was calculated as the coefficient of variation (CV). The isolated effect of the attenuation correction was assessed by normalizing pixel values from the attenuation corrected lung by pixel values from the lung with no attenuation effects. Results show that the CV decreased from 12.8% with no attenuation correction to 4.4% using the post-processing method and true densities in the thoracic region. The impact of variations in the definition of the body contour was found to be marginal while the corresponding effect of variations in the lung contour was substantial.

In vitro and in vivo erosion of two different hydrophilic gel matrix tablets.

The aim of the present work was to establish in vivo predictive in vitro tests for the tablet erosion of two different compositions (A and B) of hydrophilic matrix tablets based on hydroxypropyl methylcellulose. The tablet erosion was studied in a modified USP II apparatus at different agitation intensities and ionic strengths according to 2(2) factorial design. The in vivo tablet erosion was studied in 8 healthy human volunteers by gamma scintigraphy after administration of the tablets together with breakfast. In vitro agitation intensity increased the erosion rate for both tablets whereas increased ionic strength caused a slower rate for tablet A and a faster rate for tablet B. The choice of in vitro testing conditions proved to be critical for the attainment of in vivo predictive results. The best in vitro/in vivo correlation for the two formulations was obtained at a paddle stirring rate of 140 rpm and a ionic strength of 0.14 obtained by addition of sodium chloride.

Long-term results with a simple surgical treatment of bilateral vocal cord paralysis.

Since 1979, we have treated patients suffering from bilateral vocal cord paralysis with laterofixation of one vocal cord, a simple and comparatively atraumatic method. To evaluate the long-term results of this method of laterofixation, 11 consecutive patients were examined at least 5 years postoperatively regarding breathing capacity, voice function, and swallowing ability. Breathing capacity was assessed by determination of orolaryngeal (upper) airway resistance and spirometry. Voice function was judged by two listening panels. Swallowing ability was studied by barium contrast radiography. Postoperative improvement of breathing capacity was, in most cases, found to be long lasting. Furthermore, there was no deterioration of voice function, nor were there aspiration problems during the postoperative follow-up period. We suggest this method of laterofixation as the treatment of choice in patients suffering from breathing difficulties due to bilateral vocal cord paralysis.

A simple operation for bilateral vocal cord paralysis.

To reduce the laryngeal obstruction in bilateral vocal cord paralysis, a new method of laterofixation was developed. The method is technically simple and less traumatic than previously published methods. No peroperative tracheostomy is needed. During surgery two needles are inserted through the thyroid cartilage. A nylon thread is passed through the needles and the needles are then withdrawn. The thread thus forms a permanent loop around the vocal cord. The effects of the laterofixation on breathing and on the voice are documented by assessment of upper airway resistance and by two listening panels respectively. Thirteen patients have been operated upon so far. In most cases the breathing was improved and the influence on the voice was moderate and adjustable. If needed the possibility to perform a more extensive surgical procedure still remains. We suggest our method of laterofixation to be the first treatment of choice in patients suffering from bilateral vocal cord paralysis.

Glucose and insulin infusion directly after cardiac surgery: effects on systemic glucose uptake, catecholamine excretion, O2 consumption, and CO2 production.

Systemic glucose uptake was studied in 31 patients during 4 hr starting 1 hr after open heart surgery, using the hyperinsulinemic "clamp" technique at different plasma insulin levels and at a glucose concentration of 6 or 10 mmol/liter. Possible metabolic side effects related to the glucose uptake were studied by measurements of urinary catecholamine excretion, O2 consumption, CO2 production, and arterial PCO2. A peak systemic glucose uptake of 7.0 +/- 0.4 mg/kg body weight/min was found at a plasma insulin concentration of 3192 +/- 150 mU/liter and a blood glucose concentration of 10.2 +/- 0.1 mmol/liter. No significant difference was found in urinary catecholamine excretion compared to control patients. O2 consumption was unaltered while a 15% increase in CO2 production was observed.

Influence of halo vest treatment on vital capacity.

Respiratory function (vital capacity) was studied in 20 consecutive patients with unstable cervical spine injuries treated with a halo vest. Eight patients were neurologically intact. Twelve patients had incomplete spinal cord injuries that were classified on a neurologic function scale (Sunny-brook) immediately and 3 months after injury. Spirometric tests were done within 1 week of halo vest fixation, after 3 months of treatment, and 1 week after dismounting of the halo vest. The results showed that initial vital capacity was smaller than predicted normal in all patients and 30% less in neurologically impaired patients. Both groups improved during the treatment and somewhat more after removal of the halo vest. In neurologically intact patients, the halo vest caused a respiratory restriction of 10%, which was fully regained after removal of the halo vest. The difference between the groups remained throughout the study. There was no evidence that the halo vest itself affects the vital capacity more in patients with incomplete cord lesions than in neurologically intact patients. All of the cervical spine injuries healed uneventfully.