Evaluation of bronchodilator responses in patients with "irreversible" emphysema.

Given the emerging physiological and clinical rationale for pharmacological lung-volume reduction, assessment of volume responses to bronchodilators is likely to be highly relevant in chronic obstructive pulmonary disease (COPD). The authors examined the magnitude of lung-volume reduction after acute bronchodilator treatment in patients with advanced emphysema. Eighty-four stable patients with emphysema (mean+/-SEM forced expiratory volume in one second (FEV1): 32+/-1% predicted) performed spirometry and body plethysmography before and 15-30 min after 200 microg salbutamol. Only irreversible patients with a postbronchodilator change in FEV1 <10% pred were considered in this study. Postsalbutamol, the majority of subjects (83%) had significant improvements in one or more lung volumes: on average, residual volume (RV), functional residual capacity (FRC), inspiratory capacity (IC), forced vital capacity and slow vital capacity changed by -18+/-2, -10+/-1, 8+/-1, 9+/-1 and 7+/-1% pred (p<0.0005 each). Total lung capacity (TLC) decreased 0.12+/-0.04 L (p<0.01). Change in IC reflected change in FRC (r=-0.60, p<0.0005), but more strongly in the 57% of patients with no significant change in TLC (r=-0.93, p<0.0005). The magnitude and frequency of volume responses were greatest in patients with the most severe COPD; for example, RV decreased by 0.51+/-0.09 L (23+/-4% pred) and 0.27+/-0.04 L (14+/-2% pred) in severe and moderate subgroups, respectively. Significant reductions in lung hyperinflation occurred in the absence of a change in forced expiratory volume in one second after low-dose salbutamol in a majority of patients with advanced emphysema; the greatest changes occurred in those with the most severe disease.

A new method to perform quantitative measurement of bronchoscopic images.

Bronchoscopy is a commonly used clinical tool that provides a direct image of the bronchial lumen. However, bronchoscopy has seen little use as a quantitative measurement tool, mainly because of the wide-angle lens which distorts the image. The present authors have tested the ability of numerical algorithms and commercial software to correct for this distortion. Test objects of known size were imaged with four different bronchoscopes. Commercial image analysis software was used to measure the size of features in the images before and after applying distortion correction algorithms. The technique was then applied by measuring airway narrowing in anaesthetized pigs during vagal stimulation. Without correction, object size near the edge of the field of view is underestimated by approximately 40%. The error in measured diameter of concentric circles was dependent on the radius of the circle, increasing to 25% for circles occupying 90% of the field. Third order polynomial functions were required to correct these errors. After correction, errors were independent of object size or location in the image. Correction for lens distortion was independent of the distance between bronchoscope and object. The authors conclude that modern image processing software can correct for the distortion produced by wide-angle bronchoscope lenses.

Quantitative videobronchoscopy: a new technique to assess airway caliber.

Quantitative assessment of airway caliber is generally confined to indirect physiologic methods or to radiographic techniques. Fiberoptic bronchoscopy provides a direct view of airways, permitting quantification of airway caliber by image analysis. We investigated the characteristics of a bronchoscopic imaging system, determined its limitations in quantification and the corrections necessary for accurate assessment of image dimension, validated the methodology with airway models, and applied the technique to airways in vivo. The system comprised a bronchoscope, videocamera, videocassette recorder (VCR), computer with a frame grabber, and image-analysis program. Image quantification was affected by two sources of distortion: (1) Distance distortion: a loss of image resolution with increasing distance between the object and bronchoscope, requiring determination of the operational distance range. (2) Radial distortion: a progressive reduction in image size from the center to the periphery of the bronchoscopic field of view (FOV), requiring correction of airway dimension according to airway size and location in FOV. Validation of the methodology with different sized airway models indicated an underestimation of measured diameters, which normalized with distortion correction. We provide an example of quantitative videobronchoscopy with measurements of in vivo airway narrowing due to vagal stimulation in the anesthetized dog. Measurements of airway narrowing made with videobronchoscopy were also compared with those made with high-resolution computer-assisted tomography (HRCT) which suggested that the two technologies provide unique but complementary perspectives on airway dimensions. We conclude that videobronchoscopy and image analysis provide a novel and accurate method for the quantification of airway caliber.

Trichloroethylene induces pulmonary fibrosis in mice.

Trichloroethylene elicits acute pulmonary cytotoxicity in mice, which involves Clara cells of bronchioles. In this study, we have examined the effects of an acute dose of trichloroethylene in lungs of mice over 3 months. Pulmonary fibrosis was first detected at 15 days and was progressive with time elapsed after trichloroethylene exposure. Diffuse interstitial fibrosis was observed in the alveolar zone, resulting in thickening of alveolar septa and distortion of lung structure. The fibrosis was most pronounced at 90 days after treatment, resulting in deposition of connective tissue in the alveolar septa. Levels of total lung hydroxyproline were not significantly different in control and treated mice at 30 and 60 days after trichloroethylene treatment, but were significantly increased at 90 days. Proline content remained unchanged during the course of this study. The increase in collagen deposition at 90 days coincided with a significant increase in lung elastic recoil. Our results show that a single acute dose of trichloroethylene causes structural and functional abnormalities that are progressive for at least 3 months.

Breathlessness during acute bronchoconstriction in asthma. Pathophysiologic mechanisms.

The purpose of this study was to examine potential contributing factors to breathlessness during bronchoconstriction, in particular, to evaluate the role of lung hyperinflation. We also wished to elucidate qualitative aspects of the unpleasant sensory experience and to identify factors that contribute to intersubject variability in subjective and objective assessments of airflow obstruction. We studied sensory-mechanical interrelationships during and after induced bronchoconstriction in 21 subjects with mild stable asthma. Breathlessness (Borg scale), spirometry, and inspiratory capacity (IC) were measured after each dose during methacholine bronchoprovocation to a maximal change (delta) in FEV1 of 50%. Breathing pattern, specific airway resistance (SRaw), plethysmographic thoracic gas volume, and maximal inspiratory mouth pressure (MIP) were recorded at baseline, at maximal response, and at full symptom recovery. End-expiratory lung volume (EELV) was derived from IC. Borg increased from 0.4 +/- 0.1 (very, very slight) at baseline to 5.0 +/- 0.5 (severe) at maximal bronchoconstriction (mean +/- SEM, p < 0.001). FEV1 fell significantly (p < 0.001) to 48% predicted at maximal response. Of the 21 subjects, 19 reported increased inspiratory rather than expiratory difficulty and predominantly described sensations of reduced inspiratory capacity and unrewarded inspiratory effort. Stepwise multiple regression analysis using delta Borg (outcome variable) versus changes in spirometry, SRaw, IC, and breathing pattern components, selected delta IC as the principal contributing factor: delta Borg = 0.09 (delta IC, %fall); n = 193, r = 0.86, p < 0.001. delta IC continued to contribute significantly (p < 0.001) to the variance in Borg ratings after accounting for delta FEV1, and it was the strongest predictor of symptom recovery (p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of vagal stimulation on the distribution of inspired gas in the lungs.

We investigated the direct effects of efferent vagal activity on the distribution of inspired gas by stimulating the vagus nerve of one lung and measuring the topographic distribution of a radioactive tracer (133Xe) to both lungs. The distribution of inspired (133Xe) boli was measured with NaI scintillation detectors placed apex-base over each posterior lung of intubated, paralyzed, anesthetized dogs. In 7 supine dogs vagal stimulation reduced the distribution of rapidly insufflated 133Xe boli (flow greater than 2.5 L/s) to the test lung (P less than 0.02), but not when boli were insufflated slowly (flow less than 0.5 L/s), suggesting that vagal stimulation affects pulmonary gas distribution primarily by increasing airway resistance and not through changes in lung compliance. The effect of vagal stimulation on the regional apex-base distribution of inspired gas (greater than 2.5 L/s) was measured in 7 supine and 5 upright dogs. In the supine position, vagal stimulation did not change the uniform apex-base bolus distribution, whereas in the upright position less of the bolus was distributed to the middle and lower lung regions (P less than 0.043), compared to control measurements. This indicates that the regional effects of vagal stimulation on the distribution of inspired gas are uniform in the supine position, but that vagal stimulation alters the distribution of inspired gas when the apex-base pleural pressure gradient is increased.

Oxygenation in patients with chronic airflow obstruction after cessation of exercise.

Although oxygenation has been widely investigated in patients with chronic airflow obstruction both at rest and during exercise, very little is known about their oxygenation in the postexercise recovery period. Recently, it has been shown that PaO2 may in fact be higher during the initial 20 to 120 seconds recovery phase, compared to rest and peak exercise levels. Since it is not established to what extent this improvement persists, we investigated the changes in oxygenation during this phase in patients with CAO. We measured arterial blood gas values, expired gases and ventilation at rest, peak exercise and during the first seven minutes of recovery in 18 male patients with moderate-severe CAO. Mean rest PaO2 (77 mm Hg) and peak exercise PaO2 (76 mm Hg) did not change significantly. Compared to peak exercise, PaO2 was significantly higher during recovery at one minute (93 mm Hg, p = 0.005) and at four minutes (91 mm Hg, p = 0.005), but not at seven minutes (86 mm Hg, p = 0.155) after exercise. All of the recovery PaO2 levels were significantly higher than resting PaO2. These results indicate that during the postexercise recovery period, oxygenation is better than at peak exercise or at rest. Regression analysis of the data predicts that oxygenation may return to resting levels 8 to 9 minutes after cessation of exercise.

Influence of the menstrual cycle on airway function in asthmatic and normal subjects.

Investigations of premenstrual asthma (PMA) have been based on studies of asthmatics already aware of a deterioration of asthma premenstrually. Little is known, therefore, about relationships between the menstrual cycle and airway function in asthmatics who do not complain of PMA or in normal subjects. We investigated airway function in both of these groups for three or four consecutive menstrual cycles. Daily records of asthma symptoms and peak expiratory flow rates were maintained by 11 asthmatics and 29 normal control subjects. Standard spirometry and serum estradiol and progesterone levels were measured during the follicular, midluteal, and late luteal phases of the menstrual cycle. Airway reactivity to methacholine was tested during the follicular and luteal phases. The normal group showed no significant changes in symptoms, peak flow rates, spirometric parameters, or airway reactivity. Although the asthmatic group also demonstrated no significant changes in spirometry and airway reactivity, asthma symptoms (shortness-of-breath, cough, wheeze, and chest tightness) deteriorated significantly (p less than 0.001) from the follicular to the luteal phase, as did the morning peak flows of the asthmatics (p = 0.045). Airway function and reactivity were not related to hormone levels in either group. This study indicates that asthmatics not previously aware of PMA will record a premenstrual worsening of asthma symptoms and peak expiratory flow rates. These changes are not related to a deterioration in spirometry and airway reactivity or to the absolute levels of circulating progesterone and estradiol.

The relationship between lung volume and standard scalar ECG parameters in normal subjects.

Although the relationship between abnormalities in the ECG and lung volumes has been well described in patients with chronic obstructive lung disease, little is known about this relationship in normal subjects. We investigated this relationship in normal, supine subjects at lung volumes ranging from residual lung volume to total lung capacity. We found that there was a significant right shift in the frontal axis with increasing lung volume. Over the precordium, R wave amplitude decreased mainly at the lateral leads and S wave amplitude increased chiefly at the anterior leads. These results are consistent with a normal vertical shift and clockwise rotation of the heart with increasing lung volume.

Intraregional gas mixing in humans during high frequency oscillations.

We measured the effect of high frequency oscillation (HFO) on gas mixing in the human lung. In seven healthy, seated subjects the alveolar slope of the single breath nitrogen washout was used to assess the effects of HFO on gas mixing. A reduction in slope was interpreted as reflecting improved gas mixing within topographical lung regions. The alveolar slope was measured after 0, 10, 20 and 30 sec of control breathhold or HFO applied at the subject's TLC. We found that HFO reduced the alveolar slope more than did control breathhold. The difference in the slopes was greater with longer durations, increased stroke volume (SV) and frequency (f) of oscillations. The reduction in alveolar slope correlated better with SV than with f. We conclude that to the extend that a change in the slope in the alveolar plateau reflects intraregional mixing, this mixing is more dependent on SV than on f.

Interregional gas mixing and gas transport during high frequency oscillations.

We investigated gas mixing between lung regions and its relationship to gas transport out of the lungs during high frequency oscillation (HFO) in eight, healthy male volunteers. Gas mixing within the lung during HFO was assessed by measuring changes in the regional concentration of 133Xenon with scintillation detectors positioned over the posterior chest, 5, 15 and 25 cm below each lung apex. Gas transport out of the lungs was assessed by measuring changes in 133Xenon concentration at the mouth during HFO. Mixing between topographic lung regions from the apex to base was increased by both the stroke volume (P less than 0.05) and the frequency (P less than 0.05) of HFO. This mixing correlated best with the product of f X SV1.5 (r = 0.99 P less than 0.001). Changes in regional gradient with HFO showed a strong positive correlation with changes in mouth concentration (r = 0.94, P less than 0.025). We conclude that gas mixing between lung regions in man is increased more by stroke volume than frequency during HFO. This mixing is closely related to gas transport out of the lungs.

Lung injury and repair: DNA synthesis following 1,1-dichloroethylene.

Injury and cellular proliferation in the lung were examined following administration of 1,1-dichloroethylene (1,1-DCE) or vinylidene chloride. C57BL/6 male mice were treated orally with 200 mg/kg of 1,1-DCE prior to a single pulse of tritiated thymidine [( 3H]TdR). Necrosis and exfoliation of Clara cells of bronchiolar epithelium were evident by 1 day after chemical administration, and increased in severity by 2 days. A regenerative response was observed at 3 days after 1,1-DCE administration, and by 7 days the epithelium was substantially restored. At 30 days after 1,1-DCE, re-epithelization was achieved and areas devoid of epithelium were not observed. Changes in cellular proliferation were calculated from measurements of [3H]TdR incorporation into total pulmonary DNA. Activity of [3H]TdR was significantly inhibited at 1 day after chemical administration and thereafter increased: a peak of synthesis occurred between 3 and 5 days. At 7 days after 1,1-DCE administration, incorporation of [3H]TdR decreased to levels that were not significantly different from those of control animals. Autoradiographic examination of 0.5 micron thick plastic-embedded lung sections showed that [3H]TdR was incorporated into the DNA of bronchiolar epithelial cells, macrophages, interstitial, endothelial and Type II alveolar cells. However, the majority of the label was taken up by the nonciliated bronchiolar epithelial cells. The increased [3H]TdR incorporation into whole lung correlated with repopulation of bronchioles which was observed following injury. The results demonstrated that 1,1-DCE-induced damage to Clara cells of the bronchiolar epithelium was severe and rapid; re-epithelization was achieved in a relatively short time whereas differentiation was a prolonged process.

The effect of lung volume on regional gas transport during high frequency oscillations.

Boluses of 133Xenon entrained in oscillating flow during high frequency oscillation (HFO) were used to study the effects of lung volume on the distribution of gas to topographical lung regions. The distribution of the tracer was measured with scintillation detectors positioned 5, 15 and 25 cm below each lung apex of subjects seated in a plethysmograph, while they maintained a patent glottis and constant breathhold. An index of HFO gas transport was obtained by measuring the 'wash-in' time for Xenon count rates to attain 0.25-0.75 of their final magnitude within each region. The distribution of gas was determined at 5 Hz with similar oscillatory volumes at FRC + 1 L, FRC, FRC - 1 L, and RV. Above FRC wash-in times were similar from apex to base. From FRC to RV, wash-in times at the bases became progressively longer. The results indicate that the regional distribution of HFO gas transport is dependent on lung volume.

Static lung function in puppies after pneumonectomy.

We performed left pneumonectomy on eight puppies at 9 wk of age; seven littermates underwent a sham operation and functioned as controls. All were studied at 20 wk of age, at which time the remaining lung in the animals with pneumonectomy had the same volume, weight, and surface areas as both lungs of the controls. Total lung capacity (TLC) was the same in controls and postpneumonectomy dogs, but in the latter, the ratio of functional residual capacity to TLC (FRC/TLC) and that of residual volume to TLC (RV/TLC) were larger. Lung pressure-volume curves also differed, postpneumonectomy dogs demonstrating slightly greater recoil at lung volumes below TLC. Therefore, the increased FRC and RV of postpneumonectomy animals could not be ascribed to changes in lung recoil and must have been caused by increased chest wall recoil perhaps related to differences in shape between lung and chest wall. Studies of regional lung function revealed reduced aerated lung in the left hemithorax of the postpneumonectomy dogs and increased FRC/TLC and RV/TLC at the left base. The abnormal distribution of regional volumes did not account entirely for the increase in overall FRC and RV. Comparison of excised lung pressure-volume curves in those measured in intact animals revealed better agreement in postpneumonectomy dogs than in controls.

Effect of regional chest wall restriction on regional lung function.

The effect of impeding regional chest wall excursion on regional lung function was assessed. Fourteen subjects were studied while seated in a volume-displacement plethysmography. The lower rib cage and epigastrium were restricted with an inextensible binder. Because such restriction increases lung recoil and diminishes functional residual capacity (FRC), all measurements were made at the unstrapped FRC (FRCus). Regional excursion of the chest wall was measured with magnetometers placed anteroposteriorly at the sternomanubrial angle, the xyphoid, and umbilicus and transversely at the level of the xyphoid at the midaxillary line. Regional lung function was assessed by measuring the distribution of inspired boluses and washout of 133Xe with scintillation detectors positioned against the subject's back at the apical, middle, and basal regions. Restriction of the lower chest wall impeded expansion of the lower rib cage and diminished the distribution of inspired gas to and washout of the lung bases. The upper rib cage expanded normally and was associated with an increased distribution of inspired gas and normal distribution of washout to the apices. These results suggest that regional lung function was dependent on regional rib cage excursion.

Pathophysiology of pulmonary contusion in dogs.

We produced a localized right lower lobe (RLL) contusion in 14 anesthetized ventilated dogs, 7 of which were treated with positive end-expiratory pressure (PEEP group). We measured gas exchange, pulmonary mechanics, and regional function before and 5 h after the contusion. Arterial PO2 decreased by 20 Torr and venous admixture doubled in both groups during air breathing. The shunt fraction (Qs/Qt) was minimally increased, despite a large lobar Qs/Qt (0.43) in the contused RLL. These results were explained by reduced ventilation per unit volume (VA/V), and ventilation-to-perfusion ratios of the contused RLL measured with 133Xe technique. We conclude that pulmonary contusion causes a leak of blood and plasma, flooding 25% of the air spaces of the RLL at FRC, reducing the compliance of adjacent air spaces, and resulting in a reduced VA/V and a large RLL Qs/Qt. These results are consistent with the observed reduction in regional volume and perfusion in the contused RLL, and suggest that Qs/Qt was not increased because blood flow was markedly reduced to flooded air spaces. PEEP reduced the hypoxemia, but increased the contusion.

Airway closure and closing volume.

Using boluses of radioactive Xe we compared regional N2O uptake with regional perfusion distribution during open glottis breath hold in five seated men. Measurements were made near residual volume, at closing volume (CV), above CV and when possible, between CV and residual volume (RV). At low lung volumes basal N2O uptake was small whereas basal blood flow was not. This discrepancy was interpreted as evidence of airway closure and was quantitated. All subjects showed extensive basal closure near RV. At closing volume four of five subjects demonstrated closure and some closure was evident in these subjects at volumes in excess of CV. The increase in airway closure with decreasing lung volume was much greater below CV than above it. Conventional CV tracings were obtained using helium boluses; the height of phase IV was positively correlated with the change in airway closure between CV and RV as assessed by the N2O technique. The slope of phase III did not correlate with the amount of airway closure measured at CV. We concluded that the conventionally measured CV is not the volume at which airway closure begins but that the onset of phase IV reflects an increase in basal airway closure and the height of phase IV reflects the amount of basal closure between CV and RV.