Chronic diffuse interstitial fibrosis of the lung in uranium miners.

Many uranium miners have been disabled by and died of pulmonary fibrosis that was not recognized as an occupational disease. A review of animal studies, complications from whole body irradiation, pulmonary function, and mortality studies of uranium miners led us to suspect radiation-induced chronic diffuse interstitial fibrosis in miners who had inhaled excessive radon progeny. A selected group of uranium miners (22) with severe respiratory disease (but no rounded nodules in chest films) were studied. Lung tissue from five disclosed severe diffuse interstitial fibrosis, with "honeycomb lung" in all. Some also had small anthrasilicotic nodules and birefringent crystals. Although quartz crystals probably contributed, we concluded that the predominant injurious agent in these cases was alpha particles from radon progeny. This disease, after a long latent period, usually results in pulmonary hypertension, shortness of breath, and death by cardiopulmonary failure.

Cardiac output and mixed venous oxygen content measurements by a tracer bolus method: theory.

We present a bolus method of inert-gas delivery to the lungs that facilitates application of multiple inert gases and the multiple inert-gas-exchange technique (MIGET) model to noninvasive measurements of cardiac output (CO) and central mixed venous oxygen content Reduction in recirculation error is made possible by 1) replacement of sinusoidal input functions with impulse inputs and 2) replacement of steady-state analyses with transient analyses. Recirculation error reduction increases the inert-gas selection to include common gases without unusually high (and difficult to find) tissue-to-blood partition coefficients for maximizing the systemic filtering efficiency. This paper also presents a practical method for determining the recirculation contributions to inert expired profiles in animals and determining their specific contributions to errors in the calculations of CO and from simulations applied to published ventilation-perfusion ratio (V/Q) profiles. Recirculation errors from common gases were found to be reducible to the order of 5% or less for both CO and whereas simulation studies indicate that measurement bias contributions from recirculation, V/Q mismatch, and the V/Q extraction process can be limited to 15% for subjects with severe V/Q mismatch and high inspired oxygen fraction levels. These studies demonstrate a decreasing influence of V/Q mismatch on parameter extraction bias as the number of inert gases are increased. However, the influence of measurement uncertainty on parameter extraction error limits improvement to six gases.

Long-term effect of almitrine bismesylate in patients with hypoxemic chronic obstructive pulmonary disease.

A long-term evaluation of the therapeutic efficacy and safety of oral almitrine bismesylate (AB) (50 mg twice daily) was made on 25 patients with COPD and moderate hypoxemia residing at an altitude of 1,500 m in a double-blind placebo-controlled study. Thirteen patients receiving AB (baseline PaO2, 54.3 +/- 4.9 mm Hg; mean +/- SD) and 12 patients receiving placebo (baseline PaO2, 53.0 +/- 4.1 mmHg) were periodically followed by arterial blood gas and other pulmonary function studies and plasma levels of AB. Eight patients receiving AB and nine patients receiving placebo were followed for 1 yr; all patients were followed for at least 90 days. AB administration resulted in an increase in PaO2 to 62.2 +/- 9.3 mm Hg (p less than 0.01) on Day 28. The increase was maintained until Day 360 (63.8 +/- 4.6 mm Hg; p less than 0.01). The mean plasma concentration of AB on Day 28 was approximately one-half that on Day 90 when the plasma level reached a near maximum. AB was associated with weight loss (five of 13 patients receiving AB lost more than 10% of their baseline body weight) and peripheral paresthesias of the lower extremities (three patients), both occurring at the peak plasma levels of the drug. We conclude that AB causes a long-term improvement in arterial oxygenation in hypoxemic patients with COPD residing at an altitude of 1,500 m. Our data suggest that lower doses of AB might produce the same effect on PaO2 with less adverse associated effects, and this should be tested in future studies.

Large airway size, lung size, and maximal expiratory flow in healthy nonsmokers.

It has been postulated that airway size and lung size may be dissociated because of developmental differences between the tracheobronchial tree and the pulmonary parenchyma (dysanapsis). To test this hypothesis, we compared measurements of airway size (diameters, cross-sectional area, length and volume of the trachea, diameter and cross-sectional area of the mainstem bronchi) and lung size (total lung capacity, thoracic diameters, lung length), as determined from plain chest radiographs in 79 male and 86 female healthy nonsmokers. In both groups of subjects, the correlation between indexes of airway size and lung size was low. Airway size was not significantly different between men and women, when standardized for lung size. Tracheal diameter and length tended to increase with age. To assess the value of airway size measurements in the prediction of maximal expiratory flow, we compared tracheal and bronchial size with FVC, FEV 0.5, FEV1, and mean forced expiratory flow during the middle half of VC. The correlation between airway size and spirometric indexes was very low. Multiple regression analysis showed that the use of airway size variables in addition to the age and height variables did not substantially improve the prediction of maximal expiratory flow. Our results are consistent with the dysanapsis hypothesis, but they suggest that the introduction of radiologic estimates of large airway size in the prediction equations relating maximal expiratory flow to age and height is not justified, at least in the general population.

Informative value of simple multibreath nitrogen washout measurements for clinical and research purposes.

Some simple multibreath nitrogen washout indexes quantifying inspired gas distribution and ventilatory efficiency were obtained in a group of patients with mild to advanced chronic obstructive pulmonary disease (COPD) and studied in their relationships with routine pulmonary function tests. The indexes (lung clearance index (LCI), mixing ratio (MR) and data obtained by graphic analysis of the washout curve) were correlated with spirometric, pulmonary mechanics and arterial blood gas measurements, but only 8-38% of the interindividual variation in these indexes was explained by the above routine tests. An additional 5-13% of the variation was explained by the washout tidal volume (VT); this finding may reflect changes in gas distribution with VT and/or the influence of the dead space on ventilatory efficiency. Our data indicate that, in patients with COPD, nitrogen washout indexes tend to change in parallel with routine pulmonary function tests, reflecting the severity of the disease; these indexes also contain specific information (in addition to that provided by routine physiologic tests), presumably related to the distribution and efficiency of ventilation. Nitrogen washout measurements may thus represent a helpful adjunct to routine pulmonary function testing; LCI and MR appear to be particularly convenient for practical purposes because of their simplicity, and an informative content comparable with that of more complex indexes.

Effect of right-to-left shunting on alveolar dead space.

Right-to-left shunting decreases the efficiency of carbon dioxide excretion and increases the alveolar dead space (physiological dead space minus anatomical dead space). The theoretical effects of shunting on alveolar dead space were studied, using a human blood nomogram, for different values of inspired oxygen fraction (FIO2), respiratory quotient (R), and arterial-venous oxygen content difference. An equation developed to define the relationship between alveolar dead space and shunt could be closely fitted to the nomogram data. With high levels of shunt, FIO2 and R, alveolar dead space can substantially increase above normal levels. The conditions needed for this increase are unusual but lie within the range observed in critically ill patients. A rise in dead space of this magnitude can be clinically important in the absence of effective compensatory mechanisms.

Granulocyte adherence in pulmonary and systemic arterial blood samples from patients with adult respiratory distress syndrome.

The accumulation of granulocytes in lung capillaries, caused by increased granulocyte adherence in response to circulating inflammatory mediators, is proposed as one mechanism of pulmonary vascular injury in the adult respiratory distress syndrome (ARDS). The adherence characteristics of granulocytes from humans with this syndrome have, however, not been described. We assayed the granulocyte adherence to nylon fiber columns using whole blood samples collected from the pulmonary artery of 14 patients within 24 h of satisfying criteria for ARDS. The mean value was 83% of that of normal subjects, and granulocyte adherence was less than or equal to control in samples from 10 of 14 patients. Eight of 12 plasma samples, including 7 of 10 from patients with decreased or normal whole blood granulocyte adherence, contained an activity that increased the adherence of granulocytes isolated from normal subjects. These data suggest that granulocytes may become desensitized to a circulating adherence-promoting mediator or that granulocytes with different functional characteristics circulate in some patients with ARDS. Granulocyte adherence varied directly with the circulating platelet number, indicating that adherence may be influenced by cell-cell interactions as well as by humoral mediators. The granulocyte adherence was a mean of 75% of control samples in samples from 3 patients with increased lung uptake of indium-labeled leukocytes, suggesting that granulocyte accumulation in the lung can occur in the absence of markedly enhanced adherence of circulating cells. These data also suggest that alterations in lung endothelial cells, or the local elaboration of inflammatory mediators, may be important determinants of granulocyte accumulation in the pulmonary microvasculature in established ARDS.

Gas-blood Pco2 and Po2 equilibration in a steady-state rebreathing dog preparation.

Alveolar gas and mixed venous blood PCO2 and PO2 were compared in a steady-state rebreathing dog preparation, during spontaneous breathing and mechanical ventilation, by a new null-balancing method that removes potential biases in the comparison of measurements in the blood and gas phases and includes an inert gas test to verify the equilibration between the rebreathing lung and the bag. No systematic PCO2 and PO2 differences were observed under equilibrium conditions. However, inert gas studies suggested that a high percentage of measurements obtained during spontaneous breathing were unreliable because of inadequate equilibration between blood and rebreathing bag (attributable to reduced ventilation or perfusion) and that all mechanical ventilation measurements were acceptable. The present data support the view that no PCO2 or PO2 gradients exist when the pulmonary capillary blood and alveolar gas are in equilibrium; the data also suggest that the steady-state rebreathing dog preparation may not be completely stable and that the time course of PCO2 and PO2 in the rebreathing bag may not be reliable as a means of assessing the equilibration between blood and bag.

Mechanical and gas-distribution behavior of a collateral ventilation model.

We extended the theoretical analysis of Otis et al. (J. Appl. Physiol. 8: 427-443, 1956) to study the effects of collateral ventilation on lung mechanics and gas distribution. Equations were developed to express the effective compliance, the effective resistance, and the distribution of airflow and tidal volume in a two-compartment model incorporating a collateral communication. The analysis of the model showed that, in general, collateral ventilation tends to attenuate the degree of frequency dependence of compliance and resistance, the magnitude of this effect being dependent on the mechanical properties of the model, including collateral resistance. The influence of collateral ventilation is important when the model simulates the mechanical characteristics of the emphysematous lung (marked time-constant inequality with regionally high airway resistance, and relatively low collateral resistance). Under these conditions, a large fraction of the tidal volume of the high airway resistance lung compartment is contributed by the collateral communication. The effects of collateral ventilation on the mechanical behavior of the model are negligible when collateral resistance largely exceeds airway resistance (simulating experimental findings in normal lungs). The present theoretical data suggest that the use of equations based on a model incorporating collateral ventilation is justified, at least in predicting the mechanical and gas-distribution behavior of the lung in emphysema.

Bronchocentric granulomatosis associated with rheumatoid arthritis.

A 49-year-old woman with biopsy-proved bronchocentric granulomatosis (BCG) had repeated exacerbations of seronegative rheumatoid arthritis and vasculitis of the skin concurrent with BCG. To our knowledge, there have been no prior reports of this form of systemic involvement in BCG. While its pathogenesis remains obscure, this case, along with another recent report of eye involvement, suggests that BCG is part of a widespread immunologic response and is not a distinct entity.

Antinuclear antibodies in Utah coal miners.

Antinuclear antibodies (ANA) were detected using a mouse kidney substrate in 69 of 238 (29 percent) underground Utah coal miners at a titer of 1:16. At titers of 1:4 and higher, 52 percent were positive. The majority had a speckled pattern and were not directed against any previously characterized antigens. Fifteen of 28 with high titer ANA had reduced complement. The ANA was more apt to be present in those with coal workers' pneumoconiosis (CWP), and as ANA titer increased, the percentage with CWP increased. The ANA increased with both age and coal mine dust exposure. It is hypothesized that ANA and CWP both result from long-term dust exposure, but that there is insufficient evidence to implicate ANA in the pathogenesis of CWP.

Functional and metabolic activity of granulocytes from patients with adult respiratory distress syndrome. Evidence for activated neutrophils in the pulmonary circulation.

Although it has been proposed that the circulating granulocyte (PMN) is an effector cell that causes pulmonary vascular injury in the adult respiratory distress syndrome (ARDS), the functional status of PMNs from patients with this disorder has not been previously defined. In the present study we found that PMNs in samples of pulmonary artery blood from patients with ARDS are in a functionally and metabolically activated state. The mean chemotactic index of PMNs from ARDS patients was 172 +/- 22 SEM compared with a mean chemotactic index of 79 +/- 8 of PMNs from normal subjects (p = 0.0001), a 227 +/- 24% increase over the control value. Respiratory burst activity of PMNs, as assessed by the chemiluminescence response (CL), was 151 +/- 12% of control (mean peak CL of PMNs from patients with ARDS, 166 +/- 31 cpm X 10(3); mean peak CL of normal PMNs, 105 +/- 16 cpm X 10(3); p = 0.04), suggesting that granulocytes from patients with ARDS are likely to generate increased quantities of active oxygen metabolites when stimulated. The chemotactic and chemiluminescence responses of PMNs from patients with ARDS were much greater than those of critically ill patients without ARDS, were enhanced in the absence of concurrent bacterial infection, and did not appear to be blunted by recent administration of glucocorticoids. The PMNs from patients with ARDS had increased ratios of intracellular cyclic GMP to cyclic AMP (165 +/- 5% of control, p = 0.0002), which may be related to the enhanced metabolic activity. Release of superoxide anion, a potential mediator of endothelial injury, was increased over that of control by PMNs from 4 of 8 patients with ARDS (mean, 205 +/- 71% of normal). The results suggest that the circulating PMN is in an activated state in patients with ARDS and may be more likely to release active oxygen species and other inflammatory mediators when perturbed, potentially contributing to pulmonary vascular injury and alveolitis.

Predictors of survival in subjects with chronic airflow limitation.

In a study of chronic airflow limitation, we followed 140 subjects living in Utah at altitudes of 1,300 to 1,500 meters for seven to 13 years. Twelve-year survival probabilities were determined and compared with an age- and sex-matched Utah population. The lowest 12-year survival probability was 0.40 for those patients with a forced expiratory volume in one second/forced vital capacity (FEV1/FVC) of less than or equal to 0.40, indicating that there is much variability in survival. Other indicators of a lower survival probability (and increased death risk ratio) were an FEV1 percent predicted less than or equal to 50, an FEV1 less than or equal to 1.5 liters, male gender, partial pressure of oxygen (PO2) [exercise] less than or equal to 50 mm Hg, partial pressure of carbon dioxide (PCO2) [rest] greater than 39 mm Hg, PCO2 (exercise) greater than 39 mm Hg, FVC percent predicted less than or equal to 80, PO2 (rest) less than or equal to 55 mm Hg, and a carbon monoxide diffusing capacity (DLCO) percent predicted less than or equal to 80. Current smokers had a poorer survival probability than the reference population and an increased death risk when compared with the nonsmokers in the study. Pack/years of smoking also affected survival. Other variables associated with reduced survival were a diagnosis of chronic bronchitis combined with emphysema, more rapid annual declines in the FEV1 and/or FVC, low alpha 1-antitrypsin levels, a 20 percent improvement in FEV1 following the use of a bronchodilator aerosol, and a lower socioeconomic class. Differences between these findings and those noted in other studies are in the main due to differences in the characteristics (such as age, diagnosis, and extent of disease) of the patients in the study populations. The findings have relevance in estimating a patient's prognosis and for developing guidelines for disability determination purposes.

Pulmonary resistance and dynamic compliance as functions of respiratory frequency.

The behavior of pulmonary resistance (RL) and that of dynamic compliance (Cdyn) as functions of respiratory frequency (f) were compared in normal subjects and in patients with chronic obstructive pulmonary disease (COPD). Although both RL and Cdyn varied with f in most COPD patients and in some normal subjects, Cdyn appeared to be more sensitive than RL to variations of frequency; no significant changes in RL could be demonstrated in subjects in whom Cdyn was frequency dependent. The degree of frequency dependence of Cdyn was correlated with the severity of respiratory impairment (as quantified by conventional pulmonary function tests); in contrast, RL was not detectably frequency dependent in some subjects with advanced COPD. Compared with Cdyn, RL was more commonly nonlinearly related to respiratory frequency, often increasing at high breathing rates. Our results indicate that changes in RL with frequency are less predictable and more difficult to detect than the corresponding changes in Cdyn.

A copper-deficient, zinc-supplemented diet produces emphysema in pigs.

A mild form of emphysema was produced in pigs raised on a copper-deficient, zinc-supplemented diet. The copper-requiring enzyme, lysyl oxidase, catalyzes the cross-linking of tropoelastin into mature elastin. Zinc further inhibits the activity of lysyl oxidase. Lungs from animals raised on copper-deficient, zinc-supplemented diets of demonstrate perforations in alveolar walls and diminished amounts of elastin bronchi and pulmonary arteries. Mean linear intercepts are greater and alveolar internal surface areas are less than those in control animals, fulfilling the generally accepted definition of emphysema. Physiologic confirmation is provided by a leftward shift of the saline volume-pressure curves when compared with those in control animals. Ultrastructurally, the alveolar walls are effaced and pores of Kohn are enlarged. There are areas in which elastin is absent leaving remnant microfibrils, and there are other changes consistent with active elastin synthesis. Biochemical data demonstrate no difference in elastin content as micrograms/ml of fat-free dry weight but do demonstrate increased collagen content in experimental animal lungs compared with that in control lungs. Ultrastructural similarities to enzyme-induced models of emphysema suggest the presence of elastin degradation in our model. We speculate that although the copper-deficient, zinc-supplemented state may stimulate protein synthesis in general, elastin is being degraded by endogenous means, but collagen is not.

Hypocapnia and measurement of airflow resistance and dynamic compliance as functions of respiratory frequency.

Measurements of lung mechanical behaviour as a function of respiratory frequency may be associated with significantly increased ventilation at high breathing rates. It follows that these measurements may be influenced by hypocapnia which has been shown to increase airflow resistance and to decrease dynamic compliance. To examine this possibility we continuously monitored the end-tidal CO2 tension during the determination of pulmonary resistance and dynamic compliance as functions of frequency and we compared measurements obtained by the standard method and by a technique designed to prevent the development of hypocapnia at high breathing rates. We studied 11 patients with chronic obstructive pulmonary disease and also two smokers with normal spirometry and resistance. Although conventional measurements at frequencies higher than 40-45 breaths/min were associated with a significant decrease in end-tidal CO2, no systematic differences were found between the values of pulmonary resistance and dynamic compliance obtained by the two techniques. Our data indicate that the development of hypocapnia at high breathing rates does not significantly affect measurements of resistance and compliance as functions of frequency, at least when the duration of each period of hyperventilation is limited to the minimum necessary for a single determination, which was less than 30 seconds in the present study. A comparison of our results with previously published data suggests that the time factor may be critical with respect to the possible effects of hypocapnia on these measurements.

Effects of bronchodilators on the behavior of pulmonary resistance and dynamic compliance as functions of respiratory frequency.

The effects of bronchodilator treatment (intravenous atropine or inhaled metaproterenol) on the behavior of pulmonary resistance (RL) and dynamic compliance (Cdyn) as functions of respiratory frequency were studied in patients with chronic obstructive pulmonary disease and in apparently normal smokers. No systematic changes in the frequency-dependent behavior of RL and Cdyn were observed after bronchodilator treatment; the degree of frequency dependence increased in some subjects, and decreased or remained unchanged in others. The present results suggest that the effects of bronchodilators on the relationships between lung mechanical properties and respiratory frequency are not based on a single mechanism, but probably reflect the interaction of multiple factors possibly associated with the bronchodilator treatment.