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Maximal inspiratory pressure (MIP) was assessed in 4,443 ambulatory participants of the Cardiovascular Health Study, 65 yr of age and older, sampled from four communities. Maximal expiratory pressure (MEP) was also measured in 790 participants from a single clinic. Positive predictors of MIP included male sex, FVC, handgrip strength, and higher levels of lean body mass (or low bioelectric resistance). Negative predictors were age, current smoking, self-reported fair to poor general health, and waist size. Both participant and technician learning effects were noted, but there was no independent effect of race, hypertension, cardiovascular disease, or diabetes. A healthy subgroup was identified by excluding current smokers, those with fair to poor general health, or an FEV1 less than 65% of predicted. Mean values determined from the healthy group were 57/116 cm H2O (MIP/MEP) for women, and 83/174 for men. Lower limits of the normal range (fifth percentiles) were 45 to 60% of the mean predicted values. The reference equations derived from this group of healthy 65 to 85-yr-olds may be used by pulmonary function laboratories and respiratory therapists who evaluate the respiratory muscle strength of elderly patients.

This animal model of emphysema exhibits the same abnormalities in respiratory mechanics as those seen in human emphysema. The histologic and radiographic findings also closely resemble changes of panacinar disease. Moreover, the progressive hypoxemia preceding hypercarbia also parallels the clinical course seen in human disease. Drawbacks of this model include the long time period required to develop significant changes and the cost of maintaining the animals for such a time period. Large cystic areas were not noted in our animals and one would have to turn to another model to address the problem of giant bullous emphysema. There is no ideal animal model of pulmonary emphysema, and the usefulness of an experimental model should be judged on how well it answers the specific questions. Significant information has been obtained using various animal models of emphysema in lung transplantation, diaphragmatic function, pulmonary hemodynamics, and in several other areas. The dog appears to be a suitable model for thoracic surgical research on emphysema.

Objective. —To determine whether a program incorporating smoking intervention and use of an inhaled bronchodilator can slow the rate of decline in forced expiratory volume in 1 second (FEV1) in smokers aged 35 to 60 years who have mild obstructive pulmonary disease. Design. —Randomized clinical trial. Participants randomized with equal probability to one of the following groups: (1) smoking intervention plus bronchodilator, (2) smoking intervention plus placebo, or (3) no intervention. Setting. —Ten clinical centers in the United States and Canada. Participants. —A total of 5887 male and female smokers, aged 35 to 60 years, with spirometric signs of early chronic obstructive pulmonary disease. Interventions. —Smoking intervention: intensive 12-session smoking cessation program combining behavior modification and use of nicotine gum, with continuing 5-year maintenance program to minimize relapse. Bronchodilator: ipratropium bromide prescribed three times daily (two puffs per time) from a metered-dose inhaler. Main Outcome Measures. —Rate of change and cumulative change in FEV1over a 5-year period. Results. —Participants in the two smoking intervention groups showed significantly smaller declines in FEV1than did those in the control group. Most of this difference occurred during the first year following entry into the study and was attributable to smoking cessation, with those who achieved sustained smoking cessation experiencing the largest benefit. The small noncumulative benefit associated with use of the active bronchodilator vanished after the bronchodilator was discontinued at the end of the study. Conclusions. —An aggressive smoking intervention program significantly reduces the age-related decline in FEV1in middle-aged smokers with mild airways obstruction. Use of an inhaled anticholinergic bronchodilator results in a relatively small improvement in FEV1that appears to be reversed after the drug is discontinued. Use of the bronchodilator did not influence the long-term decline of FEV1. (JAMA. 1994;272:1497-1505)

Functional residual capacity (FRC) and quasi-static deflation pressure-volume (PV) curves of the total respiratory system, lung, and chest wall were measured in eight trained dogs lying supine, first awake and then anesthetized with halothane. Two of the eight dogs were repetitively examined 10 times during a 15-mo period. FRC decreased with anesthesia in six of the eight dogs and incresed with anesthesia in the remaining two dogs. There was a significant mean anesthesia-induced reduction in FRC of 16.9% (P 〜 0.05). FRC change with anesthesia varied between studies in one of the two dogs repetitively examined. Mean PV curves of the total system, lung, and chest wall of the six dogs whose FRC decreased with anesthesia were shifted to the right by anesthesia. PV curves from the two dogs whose FRC increased with anesthesia were shifted to the left. Anesthesia produced a significant reduction (P 〜 0.05) in mean lung compliance and significant increases (P 〜0.05) in mean chest wall and total system compliances.

Three consecutive dose-response curves to aerosolized histamine were obtained in 11 anesthetized dogs. All dogs showed desensitization (i.e., tachyphylaxis) to high doses of histamine. Tachyphylaxis was highly reproducible. No tachyphylaxis occurred with inhaled acetylcholine or methacholine. Beta-Adrenergic blockade with propranolol or muscarinic blockade with atropine given intravenously had no effect on the histamine tachyphylaxis. Duration of thiamylal anesthesia did not alter the histamine responsiveness. Histamine tachyphylaxis was also seen with chloralose-urethan anesthesia. Since tachyphylaxis is not observed with acetylcholine, it cannot be attributed to a general decline in muscle contractility. We conclude that histamine tachyphylaxis in vivo is not explained by effects of cholinergic reflexes, catecholamine release, duration of anesthesia, or, probably, type of anesthetic agent.

Factors both intrinsic and extrinsic to the lung may cause inhomogeneity of alveolar pressures during deflation. Wilson et al. (J. Appl. Physiol. 59: 1924-1928, 1985) predicted that any such inhomogeneity would be limited by interdependence of regional expiratory flows. To test this hypothesis and to explore how the pleural pressure gradient might affect inhomogeneity of alveolar pressures, we deflated at submaximal flows excised canine lobes that first were suspended in air and then were immersed in foams that simulated the vertical gradient of pleural pressure. Interregional inhomogeneity of regional transpulmonary pressures was measured with use of an alveolar capsule technique. Flow-dependent inhomogeneity of alveolar pressures was present, with differences in alveolar pressure quickly relaxing to a constant limiting value at each flow. Foam immersion increased inhomogeneity at a given flow. We conclude that factors intrinsic to the lung cause significant inhomogeneity of alveolar pressures at submaximal expiratory flows and that this inhomogeneity is enhanced by the extrinsic gradient of pleural pressure. These observations are consistent with the interdependence of flow proposed by Wilson et al.

Left pneumonectomy was performed in nine rabbits at 10 wk of age. Detailed pulmonary mechanics studies were performed at 14 wk of age in these rabbits and in nine littermate controls. Lung weight, total lung capacity, and static lung pressure-volume curves of the pneumonectomized rabbits were not different from those of the controls, but the forced vital capacity was smaller (P less than 0.05). Tantalum bronchograms of excised right lungs revealed no difference between controls and pneumonectomized rabbits in terms of bronchial diameter or pressure-area behavior of central or peripheral airways. Airways of pneumonectomized rabbits lengthened in accordance with the increase in lung volume. Over the midvolume range, the flow-limiting site moved from the trachea in controls to the right main bronchus in pneumonectomized rabbits. Maximal expiratory flow on air and on 80% He-20% O2 in the pneumonectomized rabbits average 70% of that in controls. This difference in flow was consistent with predictions based on the wave-speed theory of flow limitation.

Bronchographic studies were performed on 22 normal human lungs at transpulmonary pressures between 20 and 0 cmH2O. Pressure-diameter behavior of 322 bronchi was evaluated. In younger (less than 40 yr) subjects, the airways of males showed greater recoil than those of females. No difference between sexes was seen in older (greater than 40 yr) subjects. Bronchi less than 2.1 mm diam had a significant decrease in recoil with increasing age in males but not in females. Small bronchi had greater recoil than large bronchi in both sexes in the younger group but not in the older group. The younger group had evidence of anisotropic behavior of the bronchi not seen in the older group. The percentage decrease in lung volume for a given decrease in transpulmonary pressure was less in the older than in the younger subjects in both sexes. Measurements of the cube root of lung volume, bronchial length, and the position of markers attached to the pleura indicated that the lungs deflated in an overall, isotropic manner down to a pressure of 3 cmH2O.

Estimations were made of the vertical gradient of transpulmonary pressure (VGTP) from measurements of esophageal pressure in nine head-up dogs at functional residual capacity (FRC) when alive, when dead, and after total bilateral pneumothorax. The VGTP of 0.4 cmH2O/cm height in the alive state was abolished by pneumothorax, and roentgenograms showed that the heart moved in a caudal-dorsal direction. There was a small but significant increase in the VGTP on going from FRC to near total lung capacity (TLC) in alive head-up dogs. In eight dead head-up dogs heart weight was increased by replacing various amounts of heart blood with Hg. The VGTP was significantly increased from 0.28 to 0.51 cmH2O/cm height. The fractional increase in the VGTP was similar to the fractional increase in heart weight. In five dogs extrapolation to zero heart weight gave an average VGTP of 0.14 cmH2O/cm height. We conclude that the lungs help support the heart in the head-up dog and that the VGTP is in part determined by the pressure distribution required for this support.

The diagnosis of emphysema has been associated with changes in the appearance of the pressure-volume (P-V) curve: reduced maximal recoil pressure, increased lung volume, and a shift in the position of the curve to the left. In our clinical practice, we have observed that patients with chronic obstructive lung disease (COPD) commonly had P-V curves with reduced maximal elastic recoil that are difficult to classify according to the classic description of the P-V curve in emphysema. In order to study the variability of P-V curves, we studied 39 cigarette smokers attending a pulmonary clinic (age, 61 +/- 1 yr; smoking history, 45 +/- 3 pack-years; mean +/- SEM) and compared them with 20 patients with alpha-1-antitrypsin deficiency (AATD) (age, 41 +/- 2 yr; 13 smokers with a smoking history of 17 +/- 2 pack-years, and seven nonsmokers). Subjects underwent spirometry, lung volume, and diffusing capacity measurements as well as static deflation P-V curves. To characterize the P-V curves, we used transpulmonary pressure at 90% of TLC (PL90) as a measure of overall recoil and specific compliance (Csp) as a measure of the slope of the initial part of the P-V curve. The curves of non-AATD smokers were classified into three groups: 13 had PL90 greater than or equal to 80% predicted (Group I), 13 had PL90 less than 80% predicted and Csp greater than or equal to 0.08 (Group II), and 13 had PL90 less than 80% predicted and Csp less than 0.08 (Group III).(ABSTRACT TRUNCATED AT 250 WORDS)

Saline-filled wick catheters were inserted intraparenchymally in the loose connective tissue separating the bronchus and pulmonary artery of unperfused isolated dog lobes. Px, the difference between perivascular pressure and pleural surface pressure (which was atmospheric pressure), was measured by the wick for arterial pressures (Pa) of 10 and 25 cmH2O at lobe transpulmonary pressures (Ptp) of 25, 15, 10, 5, and 2 cmH2O during a deflation pressure-volume maneuver. The response time of Px to step changes in Pa was relatively short, a pressure plateau always occurring in less than 3 min. For Pa of 25 cmH2O, mean Px in five lobes was -2 cmH2O at Ptp of 2 cmH2O and decreased almost linearly to -9 cmH2O at Ptp of 25 cmH2O. Reducing Pa from 25 to 10 cmH2O resulted in a mean decrease in Px of 1 cmH2O at Ptp of 2 cmH2O and 2 cmH2O at Ptp of 25 cmH2O. These results are generally consistent with predictions from a continuum-mechanics analysis of pulmonary vascular interdependence and do not support the concept that perivascular interstitial fluid pressure is different from surface pressure.

The effects on lung mechanics of equal (37%) reduction in total lung capacity (TLC) by rib cage or abdominal restriction were studied in 10 healthy males. Lung recoil pressure (Pst) was simultaneously measured from three sites in the esophagus. This also provided an estimate of the vertical pleural pressure gradient (PPG). Deformation of the right hemithorax was quantified by roentgenograms in three subjects. At the same lung volume, abdominal restriction decreased lung height and increased anteroposterior diameter compared with the control case, whereas rib cage restriction had opposite effects. Maximum expiratory flow increased equally with both types of restriction, and average Pst increased equally with both types of restriction. There was a significant correlation between degree of TLC reduction and increase in Pst that was similar for both types of restriction. This study indicates that changes in lung mechanics depend primarily on the amount of volume reduction and not on the type of deformation producing the volume decrease.

We created a model of airway obstruction that avoids long-term toxic exposure. Bronchial injury was induced in 7 dogs by exposure to nebulized 1% nitric acid (HNO3) on alternate days for 4 wk. Lung mechanics were measured prior to exposure and after 2 and 4 wk. Both TLC and VC decreased and the FRC/TLC ratio increased. Expiratory flows decreased while breathing air and an 80% helium-20% oxygen mixture; the volume of isoflow increased. Pulmonary resistance increased and dynamic compliance decreased. On single-breath nitrogen washout, there were increases in the slope of phase III and in closing capacity. Histologically, there was widespread chronic airway inflammation, slight epithelial changes, slight peribronchiolar fibrosis, and an increase in smooth muscle. Pathologic scores were significantly higher in the HNO3-exposed group than in the control group. Scores for peripheral and central airway pathology were correlated with results of tests of airway obstruction.

Total respiratory resistance (Rrs) was studied by the forced oscillation technique at a frequency of 3 cps in 76 normal subjects (36 men, 40 women), ages 21 to 64 years. Slopes (equivalent to specific conductance) assuming a linear relationship with zero intercept between 1/Rrs and thoracic gas volume (TGV) were computed. In women, expiratory slopes were significantly less than inspiratory slopes; moreover, slopes decreased significantly with height and were significantly less in current smokers. For men, there were no consistently significant relationships between slopes and phase, age, height, weight, or smoking habits. Predicted resistance and estimates of the 5th and 95th percentiles of inspiratory, expiratory, and average resistance are presented for all men combined and for currently nonsmoking women. The fact that, in contrast to men, asymptomatic, current women smokers showed an elevation in Rrs when compared to nonsmoking women merits further study.

An entomologist developed an illness with typical features of hypersensitivity pneumonitis. On-site investigations indicated that on the days of his attacks he was exposed to dust laden with several species of mold, especially Penicillium spp., as well as to mists generated by reservoir-type humidifiers. Serologic tests to more than 40 antigens prepared from organisms and sources known to cause hypersensitivity pneumonitis showed strong reactions to Penicillium and to antigens prepared from the scum of a large industrial humidifier and from his laboratory humidifier. PFTs revealed a significant reduction in DLCO, Following a 4-mo period without laboratory exposure, he experienced no further episodes, a return to his previous exercise tolerance, and a normal DLCO, BP studies with extracts of Penicillium casei and humidifier water from his laboratory (H1) resulted in objective evidence, both clinically and by hematologic and pulmonary function testing, of hypersensitivity to Penicillium spp. and possibly also to the H1 preparation.

Changes in the anterior-posterior (AP) and lateral diameters of the rib cage and abdomen were assessed by magnetometry in seven anesthetized supine dogs during spontaneous respiration (SR) and mechanical ventilation after muscle paralysis (MV). Regional distribution of inspired gas was measured for both modes of ventilation by determining regional 133Xe clearances. Marked differences in chest wall motion were observed between SR and MV: during MV, the changes in lateral rib cage diameter from FRC to end inspiration were larger, and the changes in both abdominal diameters smaller than during SR. AP rib cage diameter changes were similar for both modes of ventilation. Inward motion of the lateral rib cage during initial inspiration was observed in four dogs during SR; it disappeared consistently with MV. Regional 133Xe clearances were not significantly different: there was no cephalocaudal gradient, and the vertical gradient in regional ventilation was similar with MV and SR. We conclude that significant changes in chest wall motion and shape are not necessarily associated with detectable differences in the distribution of regional ventilation.

There is a large variability in maximal expiratory flow (V) and density dependence (DD) in normal humans. Lung mechanics and flow-volume curves were obtained in 40 normal males while they breathed air or helium-oxygen (80%-20%). Static lung recoil (Pst) at 50% vital capacity, total lung capacity, and pulmonary resistance each correlated (P < 0.05) with airflow at 50% vital capacity. The relationship of V and Pst was described by Pst = 1/2 p V2/A2 + RV, where p is gas density, A is the critical area at the flow-limiting site, and R is peripheral resistance. At constant Pst and R, this simplified equation predicts an inverse relation between DD and airflow, which was found at recoil pressures of 8 and 7 cmH2O (P < 0.05). If peripheral losses are small, subjects with smaller flow-limiting airways would have lower airflows but higher DD than subjects with larger airways. Our findings are consistent with concept of dysanaptic growth and suggest that the central airways play a significant role in determining V and DD in normal humans.

Lung volumes, static pressure-volume curves, maximal expiratory flow-volume curves, right-to-left intrapulmonary shunts (Qs/Qt), and distributions of ventilation and perfusion relative to the alveolar ventilation and perfusion ration (VA/Q) were determined in seated normal men before chest strapping while breathing air (Cair) and during chest strapping while breathing air (Sair) or 100% oxygen (So2). With Sair and So2, mean vital capacity was reduced by 44% from control. Elastic recoil pressure [Pst(L)] of the lung at 50% control total lung capacity (TLC) increased significantly (P less than 0.05) from 4.64 +/- 0.39 cmH2O (mean +/- SE) to 7.00 +/- 0.47 cmH2O with Sair and to 7.24 +/- 0.70 cmH2O with So2. Maximal expiratory flow at 50% of control TLC increased significantly (P less than 0.05) from 3.22 to 0.25 l/s (mean +/- SE) to 5.84 +/- 0.69 l/s with Sair and to 5.50 +/- 0.68 l/s with So2. With Sair, no significant increase in Qs/Qt from control was observed. With So2, mean Qs/Qt increased significantly (P less than 0.05) from 0 to 2.2 +/- 0.9% of the cardiac output. It is therefore unlikely that the development of atelectasis, as indicated by an increase in Qs/Qt, accounts for the increase in Pst (L) with Sair and So2. Current evidence suggests that either change in alveolar surface compliance or distortion of the lung or both are responsible for the increased recoil pressure but that neither mechanism alone appears to explain it totally.

The pulmonary mechanics and bronchoscopic findings in 5 patients with relapsing polychondritis were studied to evaluate the mechanism of obstruction. Two of the patients did not have clinical symptoms referable to the respiratory tract: pulmonary function was normal in 1 patient and was suggestive of mild restriction in the other. Three patients had dyspnea; pulmonary function studies revealed expiratory and inspiratory obstruction in all 3. The maximal flow-static recoil curves demonstrated that the expiratory obstruction was due predominantly to airway abnormality and not to loss of elastic recoil forces of the lung. The bronchoscopic appearance of the extrathoracic airway during quiet breathing did not accurately reflect pulmonary function results. One patient had a visually normal upper airway but greatly reduced maximal inspiratory flow rates, whereas another patient had pronounced narrowing of the upper airway but only a modest reduction of maximal inspiratory flow rates. The bronchoscopic appearance of the intrathoracic airway during quiet breathing did relate well to maximal expiratory flow rates. We conclude that in our group of patients the predominant mechanism of expiratory obstruction in relapsing polychondritis is due to airway abnormality. Although the bronchoscopic and radiographic findings are useful, spirometry is more important in determining functional abnormality.

Tracheal Na+-K+-ATPase activity is positively correlated with in vivo airway responsiveness to histamine. We wondered whether this were a chance association or whether it was directly related to the mechanism of hyperreactivity. Therefore, we obtained dose-response curves to aerosols of histamine and ouabain in guinea pigs to determine whether an in vivo relationship existed between the excitatory effects of histamine and the enzyme-inhibiting effect of ouabain. Airway responsiveness to ouabain was measured as the ouabain concentration producing a 30% decrease in specific airway conductance (ED30) or that producing a half-maximal response (ED50). Responsiveness to histamine was measured either as ED30 or as ED50. Significant positive correlations were noted between the log ED50 of ouabain and log histamine ED30 or ED50 (r = 0.81 and 0.83, respectively; P less than 0.001), and between log ouabain ED30 and log histamine ED30 and ED50 (r = 0.76 and 0.77, respectively; P less than 0.002). Pretreatment with ouabain increased airway responsiveness to histamine (P less than 0.05). We suggest that in hyperreactive airways Na+-K+-ATPase serves a homeostatic function of preventing Na+ and Ca2+ loading of the cell and that it is not directly responsible for the hyperreactivity.

Pressure-volume (PV) and conductance-volume (GV) curves were obtained in trained dogs awake and then anesthetized with thiopental sodium, in the prone left lateral decubitus, and supine positions. By paired analyses, induction of anesthesia had no significant effect on lung volumes, static PV curves of the lung or chest wall, or static compliance of the lung or chest wall. In addition, change of posture had little effect on these variables in either the awake or the anesthetized state. Frequently, however, individual dogs showed changes in lung PV curves after induction of anesthesia or change of posture. These PV curve shifts were not accompanied by predictable changes in GV relations. Therefore, we concluded that such changes in the lung PV curve reflect either local artifacts or local deformation of the respiratory system.

Static lung volumes and static elastic recoil pressure (Pel) were measured in normal subjects breathing air and 80% helium plus 20% oxygen (He+O2). In 22 subjects, He+O2 produced small but significant increases in total lung capacity (TLC) (mean 0.11 liter, P less than 0.001) and residual volume (mean 0.10 liter, P less than 0.01) without change in vital capacity or functional residual capacity. The mechanisms for this change are obscure. In 10 subjects, breathing He+O2 had no significant effect on Pel (paired t-test) at any lung volume measured (50–80% TLC). In one subject, Pel at 70 and 80% TLC was significantly higher on air than on He+O2 (unpaired t-test, P less than 0.05). Because changes in lung volumes and lung recoil were small, we concluded that these effects do not negate the clinical utility of He+O2 flow-volume curves.

Abnormalities in small airways appear to be important in the evolution of chronic obstructive pulmonary disease. Patients with these pathologic lesions may have normal values for airway resistance and forced expiratory volume in one second. Two new tests, the closing volume (CV) and the dependence of maximal flow on density, are believed to be sensitive to abnormalities in the peripheral airways. The CV test detects an increased nonuniformity of changes in volume of pulmonary units. Reduced dependence of flow on density is believed to result from an increase in the peripheral component of the losses of driving pressure which determine maximal expiratory flow. Both tests differentiate smokers with normal conventional spirometric data from age-matched nonsmokers. Although this evidence suggests that these tests can be used to detect abnormalities in small airways, there is very little pathologic confirmation of this belief. The clinical significance of abnormalities in the results of either of these tests in an otherwise normal person has not yet been determined.

In 10 normal volunteers, total lung capacity determined from a single-breath N2 washout was not significantly different from that determined by body plethysmography. However, in patients who underwent clinical pulmonary function tests, total lung capacity was substantially underestimated by the single-breath N2 washout, compared with that determined by either body plethysmography or the 7-min open-circuit N2 washout method. The single-breath N2 washout underestimated total lung capcity in patients who had a normal slope of Phase III, and the error was even greater in patients who had steeper Phase III slopes or low maximal mid-expiratory flow values. Total lung capacity determined by 5 vital capacity breath N2 washout method was comparable to that determined by the 7-min N2 washout method, provided that expired N2 did not exceed 10 per cent during the fifth vital capcity maneuver. By extending the washout beyond 5 vital capacity maneuvers when necessary to achieve a peak expired N2 of less than 10 per cent, a mean total lung capacity within 1 per cent of that determined by the 7-min washout method was obtained. The multiple vital capacity maneuver was well tolerated by patients and saved considerable time.

Esophageal elastance was measured in trained dogs placed in the prone, supine, and left lateral postures before and during sodium thiopental anesthesia. Esophageal elastance was measured from static pressure-volume curves and during spontaneous breathing at functional residual capacity. There was a significant decrease in esophageal elastance, estimated from the pressure-volume curves, during anesthesia in both prone and lateral positions but not in the supine posture. Changes in vagal tone produced by stimulation of the vagal nerves did not alter esophageal elastance. Therefore, underlying mechanisms for these changes in esophageal elastance are not fully understood. There was an increase in esophageal elastance when lung volumes increased from 55 to 80% total lung capacity. However, we did not find a significant change in esophageal elastance between awake and anesthetized conditions or between positions during spontaneous breathing at functional residual capacity.

Pulmonary mechanics were studied in 22 patients with chronic obstructive pulmonary disease (COPD) who had no evidence of asthma. Eleven of the 22 patients had a density dependence of maximal expiratory flow within the reported normal range. Patients with normal density dependence (responders) were not different from those with decreased density dependence (nonresponders) in mean age, smoking history, symptoms of cough or dyspnea, maximal expiratory flow at 75, 50, and 25% of the vital capacity during air breathing, total lung capacity, or static elastic lung recoil at 50% of the vital capacity. The nonresponders had smaller vital capacity values, larger ratios of residual volume to total lung capacity, higher resistance, and lower static recoil at total lung capacity. There was a correlation between diffusing capacity for CO and density dependence. There was an inverse relationship between the change in density dependence after inhalation of isoproterenol and initial density dependence. Dysanaptic lung growth and increased compliance of the central airways are potential mechanisms for normal density dependence in these patients. The prevalence of normal density dependence in these patients with established COPD raises serious questions concerning the usefulness of density dependence in the early detection of COPD. The differences in density dependence may indicate differences in pathogenesis of the airflow obstruction and hence may be of prognostic significance.

Chest cage restriction was produced in 13 normal male subjects. We could not detect trapped air during restriction by comparing lung volumes determined by nitrogen washout with those determined by plethysmography. However, 3 subjects did have definite evidence of trapping because they released small amounts of air (mean, 61 ml) when the restriction was removed. Two subjects had suggestive evidence of trapping. Yet there was no correlation between trapping and the degree of increase in static lung recoil associated with restriction. Seven subjects had chest restriction produced while they were breathing air and again while they were breathing 100 per cent oxygen, in an attempt to reveal the presence of airway closure. In only one subject was oxygen breathing clearly associated with a greater then expected increase in lung recoil after restriction; suggestive changes were seen in 2 other subjects. However, there was no definite correlation between unusual increases in lung recoil induced by restriction while breathing oxygen and the presence of air trapping. We conclude that trapping, hence airway closure, is not required for the increase in static lung recoil that occurs with chest cage restriction.

Further studies of ascitic fluid production and related factors in dogs with constriction of the vena cava above the diaphragm are reported. Whole dog plasma given intravenously to such animals produces a rise in circulating plasma protein to normal levels, but increases the output of ascitic fluid with a loss of protein via the ascites equivalent to 72, 76, and 65 per cent respectively, of the injected protein. Forced ingestion of water in excess of the test animal's normal needs and desires produces no significant changes in the circulating plasma protein level or in ascitic fluid production. Amino acid growth mixtures given intravenously in distilled water cause weight loss, elevation of circulating plasma proteins, a slightly negative nitrogen balance, but no ascitic fluid production. Amino acid growth mixtures given intravenously in normal saline cause depression of the circulating plasma proteins, negative nitrogen balance, and significant ascitic fluid production. Ascitic fluid given intravenously to the test animals causes a marked depression of circulating plasma proteins, a marked increase in ascitic fluid production containing the equivalent of 116 and 98 per cent of the injected protein, and a negative nitrogen balance. Ascitic fluid given orally produces a marked depression of circulating plasma proteins, and a marked increase in ascitic fluid secretion, containing the equivalent of 66, 66, and 54 per cent respectively, of the ingested protein. Sodium chloride is a dominant factor in some of these experiments where abundant ascites production is recorded. Protein levels and intake are important, but take second place to sodium. Ascitic fluids show electrophoretic patterns which are almost identical to the plasma patterns. The A/G ratios are often equal in ascitic fluid and plasma, sometimes even lower in the ascitic fluid. This emphasizes the ease with which globulins pass cell or other membrane barriers in these experiments.