Heterogeneity of maximal lobar emptying rates in dogs with compensatory lung growth

Five dogs underwent left pneumonectomy at 10 wk of age, whereas four littermates underwent a sham operation. At 26 wk of age the postpneumonectomy dogs had total lung vital capacity (VC) and lung weight similar to controls, but maximum expiratory flow was reduced. Pressure capsules were glued to right lower (RLL) and right cardiac (RCL) lobes, and alveolar pressures (PA) were measured during forced expiration. In postpneumonectomy dogs RLL and RCL both emptied more slowly than in control dogs, and emptying was especially delayed in RCL, which underwent the most growth. When both lobes deflated together, PA in RCL and RLL were similar in control dogs, but in postpneumonectomy dogs PA in RCL exceeded that in RLL by approximately 3 cmH2O from 80 to 20% VC. Because the higher driving pressure in RCL compensated for the relatively high resistance of RCL, the pattern of lobar emptying was relatively uniform over these lung volumes. This result was compatible with interdependence of lobar maximum expiratory flows. In addition, at PA of 6-10 cmH2O in postpneumonectomy dogs, maximum emptying rates of RCL were less when RCL deflated alone than when RCL and RLL emptied together, again demonstrating interdependence of lobar maximum expiratory flow.     

How is maximal expiratory flow reduced in canine postpneumonectomy lung growth?

Six dogs underwent left pneumonectomy (P) at 10 wk of age, while four littermates had a sham operation (C). All dogs were studied at 26 wk of age. Pressure capsules were placed on the right lung to measure lobar alveolar pressures and flows, and a Pitot-static tube was used to measure dynamic intrabronchial pressures. Vital capacity and lung elastic recoil did not differ between P and C. At all lung volumes studied, maximum expiratory flows (Vmax) in P were substantially lower than in C. Choke points in P were located more peripherally than in C. In central airways subjected to the same distending pressure, calculated cross-sectional area was significantly lower in P than in C, indicating different bronchial area-pressure behavior. In P, frictional resistances of the right lower, middle, and cardiac lobes were significantly higher than those in C. These results indicate that the reduction in Vmax in P was greater than would have been expected on the basis of reductions in central airway diameter alone. We calculated that, in the middle vital capacity range, approximately 60% of the decrease in Vmax was due to changes in dynamic central airways properties, and approximately 40% was due to increased lobar frictional resistance related to compensatory growth.     

Expiratory flow limitation in dogs with regional changes in lung mechanical properties

We examined maximum expiratory flow (Vmax) in two canine preparations in which regional changes in lung mechanical properties were produced. In one experiment serial bronchial obstructions were made to determine whether flow-limiting sites (choke points, CP) would occur in series. With the right lung tied off, constrictions were placed at the left lower lobar bronchus (LLL) and left main-stem bronchus. On deflation from total lung capacity, the obstructed LLL and nonobstructed left upper lobe (LUL) emptied into the obstructed left main-stem bronchus. Although a CP common to both lobes was identified at the main-stem obstruction, which limited total Vmax, we questioned whether there was also a CP at the lobar obstruction that fixed LLL flow. In that case the rate of LLL emptying would not be dependent on the presence of the common (i.e., central) CP and thus the flow contribution of the LUL. We found that when the LUL was removed, the LLL increased its rate of emptying. Thus a lobar CP did not fix LLL flow and CP did not occur in series. In a second experiment emphysema was produced in the left lung to reduce lung recoil, whereas the right lung was normal. CP were identified at approximately lobar bronchi of each lung, and the lungs were emptied at different rates. A CP common to both lungs was not identified. Our results indicate that in localized lung disease, if flows from the different regions are high enough, then wave speed is reached in proximal airways, and a CP occurs centrally rather than peripherally. On the other hand, if flows are low, then wave speed is reached peripherally and a CP common to all lung regions does not occur.     

Inhomogeneity during deflation of excised canine lungs. II. Alveolar volumes

We have previously demonstrated appreciable inhomogeneity of alveolar pressures measured by a capsule technique in excised canine lobes deflated at submaximal flows (J. Appl. Physiol. 65: 1757-1765, 1988). We further analyzed the results of these experiments by estimating alveolar volumes (VA) and regional flows from regional transpulmonary pressures, assuming that regional pressure-volume relationships were homogeneous. Deflation at submaximal flows of lungs suspended in air caused significant flow-dependent inhomogeneity of VA that increased as lung volume decreased. Immersion of lungs in stable foams that simulated the gradient of pleural pressure modified the pattern of emptying, but not always to a gravity-dependent sequence. Limitation of regional expiratory flow was often asynchronous during both air suspension and foam immersion. There was no evidence of a common regional flow-volume curve. Submaximal deflation is a complex heterogeneous process, with the interregional pattern of emptying determined by the interaction of factors that are both intrinsic and extrinsic to the lungs.     

Airway narrowing in excised canine lungs measured by high-resolution computed tomography.

The exact site of airway narrowing in asthma and chronic obstructive pulmonary disease is unknown. High-resolution computed tomography (HRCT) is a sensitive noninvasive imaging technique that can be used to measure airway dimensions. After determining the optimal computed tomographic parameters using a phantom, we measured lobe volume and airway dimensions of isolated canine lung lobes at a transpulmonary pressure of 25 cmH2O. These measurements were repeated after deflation and administration of aerosolized saline and carbachol (256 mg/ml). Lobe volume decreased with all treatments. The maximal lobar volume change was 26% at 6 cmH2O after carbachol. Average airway lumen area decreased with all treatments. After carbachol, at transpulmonary pressures of 25, 15, 10, 8, and 6 cmH2O, lumen area decreased by 7.3 +/- 4.1, 62.0 +/- 4.9, 77.5 +/- 3.0, 31.9 +/- 9.0, and 95.2 +/- 1.0% (SE), respectively. When the airways were divided into four categories on the basis of initial lumen diameter (less than 2, 2-4, 4-6, and greater than 6 mm), the greatest decreases in luminal area after carbachol were seen in intermediate-sized airways (2-4 mm, 56 +/- 4%; 4-6 mm, 59 +/- 3%). HRCT can be used to make accurate measurements of airway dimensions and airway narrowing in excised lungs. HRCT may allow measurement of airway wall thickness and determination of the site of airway narrowing in asthma.     

Surrounding structures affect pressure-diameter behavior of excised dog bronchi

The effects of adjacent large blood vessels, fibroelastic membrane, and parenchyma on pressure-diameter (P-D) behavior of intrapulmonary bronchi were studied in five dog lung lobes. Central lobar airways were inflated separately by blocking all branches with beads and inflating the distal lobar air spaces via pleural capsules. After bronchial P-D curves were obtained at fixed pleural pressures (Ppl) of -30, -10, and -5 cmH2O, the P-D properties of the isolated bronchi were measured in each of four stages of dissection: 1) lobar artery and vein were left attached to the bronchus, but parenchyma was removed to within 1-2 mm of the limiting membranes; 2) all remaining parenchyma was carefully removed; 3) the large vessels were removed, leaving the bronchial fibroelastic membrane intact; and 4) the fibroelastic membrane was peeled from the bronchus. From stage 1 it was deduced that in the intact lobes, peak peribronchial parenchymal stress (Px) averaged -29.2 cmH2O at Ppl = -30 cmH2O). In stage 2 bronchial recoil was reduced only approximately 5%. The major decrease (approximately 35%) occurred in stage 3, indicating that interaction between vessels and bronchi contributed significantly to bronchial stiffness. A final decrease of approximately 10% was seen in stage 4. We conclude that Px in the intact state is similar to Ppl at a transpulmonary pressure of 30 cmH2O and that stages 1 or 2 may provide a better basis for estimating Px than the commonly employed bronchus free of vessels and tissue.     

Effect of increased static lung recoil on bronchial dimesions of excised lungs.

We measured bronchial diameters and lengths during static deflation and inflation in eight excised dog lobes before and after static lung recoil (Pst(L)) had been significantly increased by cooling the lobe for 48 h at 4 degrees C and ventilating it for 3 h. In control lobes, bronchial diameters were the same at any volume even though Pst(L) was different during inflation and deflation. These results agree with those of Hughes et al. (J. Appl. Physiol. 32: 25-35, 1972). However, when Pst(L) was increased, diameters at a given volume were significantly increased over control values; diameters at a given pressure were nearly the same as the controls. Therefore, under these conditions, bronchial diameter did not conform to lung volume. The ventilation process appeared to alter the circumferential elastic properties of the bronchi because diameters at all pressures were slightly larger after ventilation. Bronchial length-volume relationships were the same in both control and ventilated lobes. Thus, when Pst(L) was markedly increased, diameter corresponded best to lung recoil and length to lung volume.     

Mechanical modulation of pressure-volume characteristics of contracted canine airways in vitro

In normal humans and dogs, the airways do not constrict to closure even when maximally stimulated. However, airway closure can be produced in isolated canine lobes and bronchial segments that are stimulated with maximal concentrations of bronchoconstrictors. These observations suggest that under normal conditions, physiological mechanisms to limit bronchoconstriction exist in vivo. In this investigation, we evaluated how mechanical factors that influence airway smooth muscle contractility contribute to the modulation of the pressure-volume characteristics of contracted canine intraparenchymal airways in vitro. Our results demonstrated that maximal and even submaximal contractile stimuli can produce airway closure in bronchi that are allowed to contract under isobaric conditions. However, the effectiveness of bronchoconstrictors is significantly reduced when the airways are subjected to tidal volume oscillations during contraction. In addition, airways contracted isovolumetrically at low volumes exhibit a markedly reduced sensitivity to submaximal concentrations of acetylcholine. This may limit bronchoconstriction at low lung volumes and transpulmonary pressures where the effectiveness of parenchymal stress in keeping the airways open is reduced. Together these factors could provide a mechanism by which bronchoconstriction is limited to low levels of airway resistance under normal conditions in vivo.     

Parenchymal interdependence and airway response to methacholine in excised dog lobes

The objective of this investigation was to determine the minimum transpulmonary pressure (PL) at which the forces of interdependence between the airways and the lung parenchyma can prevent airway closure in response to maximal stimulation of the airways in excised canine lobes. We first present an analysis of the relationship between PL and the transmural pressure (Ptm) that airway smooth muscle must generate to close the airways. This analysis predicts that airway closure can occur at PL less than or equal to 10 cmH2O with maximal airway stimulation. We tested this prediction in eight excised canine lobes by nebulizing 50% methacholine into the airways while the lobe was held at constant PL values ranging from 25 to 5 cmH2O. Airway closure was assessed by comparing changes in alveolar pressure (measured by an alveolar capsule technique) and pressure at the airway opening during low-amplitude oscillations in lobar volume. Airway closure occurred in two of the eight lobes at PL = 10 cmH2O; in an additional five it occurred at PL = 7.5 cmH2O. We conclude that the forces of parenchymal interdependence per se are not sufficient to prevent airway closure at PL less than or equal to 7.5 cmH2O in excised canine lobes.     

BRONCHIAL CARCINOMA—Lobar Distribution of Lesions in 250 Cases

In a study of the lobar distribution of tumors in 250 consecutive cases of primary bronchial cancer, it was noted that 130 of the tumors originated in the upper lobes, 11 in the right middle lobe, and 49 in the lower lobes. Some 40 arose in the main bronchi, and most of the remainder were either “hilar” or unspecified in anatomic location.There was no apparent correlation of the lobar site of these tumors with the lobar location of childhood pneumonic lesions as observed in another group of patients in the same hospital.     

Changes in airway length after unilateral pneumonectomy in weanling ferrets

We have previously shown that airway cross-sectional area increases 15-20% after pneumonectomy in weanling ferrets by measuring bronchial casts. We have now reanalyzed these same casts to quantitate changes in airway length after pneumonectomy. In each cast the distance from each of 120 airways to the terminal bronchiole along its axial pathway was measured. The relationship between the logarithm of this distance and that of the fraction of the lobe subtended by an airway could be described by a quadratic equation with a correlation coefficient greater than 0.85. Subsegmental and more distal airways of postpneumonectomy animals were 33-47% longer than those of controls. Overall the main axial pathway of airways in the left lower lobes was 12% longer in operated animals, but this increase was primarily accounted for by an increase in the length of the more peripheral airways. Central airways were little if any longer in operated animals. After pneumonectomy in weanling ferrets, subsegmental and peripheral airway lengths increase to a greater degree than lung volume and airway cross-sectional area, whereas central airway lengths increase to a lesser extent if at all. The mechanisms responsible for this difference between central and intralobar compensatory airway growth are unknown.     

Inhomogeneity during deflation of excised canine lungs. I. Alveolar pressures

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.     

Morphological hysteresis of the small airways

The resistance to airflow that develops in most obstructive processes takes place in the small airways. The aim of the present paper is to describe bronchial hysteresis morphometrically in a respiratory cycle model. As a working hypothesis, it is proposed that the changes that take place in the respiratory tract during the respiratory cycle are related to the bronchial size. Specimen rat lungs were organized into five groups: In the first group, the lungs were filled with a liquid fixative to 25 cm of H2O transpulmonary pressure. The following four groups were inflated with air and fixed through the pulmonary artery. Groups 2 and 3 were fixed at 10 and 20 cm transpulmonary pressure in inflation. The last two groups were fixed in deflation and, for this purpose, the transpulmonary pressure was increased to 27 cm and decreased to 20 and 10 cm, respectively. The lungs were processed for morphometrical study and the following variables were quantified: pulmonary volume, internal area, internal perimeter, wall area, internal area radius and bronchial wall radius. The diameter of the airways studied varied between 84.06 microm and 526.4 microm. The results were classified into three subgroups consisting of small, medium-sized and large bronchi. With a single exception--the internal area in the medium-sized bronchi inflated to 20 cm--all the results obtained in deflation were higher than those obtained in inflation. The internal area increased or decreased significantly upon raising or lowering the transpulmonary pressure respectively, in the small and medium-sized bronchi. The wall area in the large bronchi showed significant differences between inflation and deflation at 10 and 20 cm transpulmonary pressure. The wall area was modified significantly in the lungs fixed at 20 cm in the small bronchi and at 10 cm in medium-sized bronchi. The bronchial wall radius was significantly greater in the large bronchi and smaller in the small bronchi. The lumen of the medium-sized and small bronchi increases in inspiration and decreases in expiration. The wall thickness displayed differences between inflation and deflation. The most marked hysteresis was presented by the bronchial wall in the large bronchi. Our results suggest that the behavior of the bronchi varies according to their size.     

Longitudinal distribution of pulmonary vascular resistance with very high pulmonary blood flow

Dog left upper lobes (LUL) were perfused in situ via the left lower lobe artery. Lobe weight was continuously monitored. Increasing lobar flow from normal to 10 times normal had little effect on left atrial pressure, which ranged from 1 to 5 mmHg. There was a flow threshold (Qth) below which lobar weight was stable. Qth ranged from 1.1 to 1.55 l/min (mean 1.27) corresponding to four times normal LUL blood flow. Above Qth, step increases in lobar flow resulted in progressive weight gain at a constant rate that was proportional to flow. The effective pressure at the filtration site (EFP) at different flow rates was estimated from the static vascular pressure that resulted in the same rate of weight gain. From this value and from mean pulmonary arterial (PA) and left atrial (LA) pressures, we calculated resistance upstream (Rus) and downstream (Rds) from filtration site. At Qth, Rds accounted for 60% of total resistance. This fraction increased progressively with flow, reaching 83% at Q of 10 times normal. We conclude that during high pulmonary blood flow EFP is closer to PA pressure than it is to LA pressure, and that this becomes progressively more so as a function of flow. As a result, the lung accumulates water at flow rates in excess of four times normal despite a normal left atrial pressure.     

Effects of lung volume and alveolar surface tension on pulmonary vascular resistance

Utilizing the arterial and venous occlusion technique, the effects of lung inflation and deflation on the resistance of alveolar and extraalveolar vessels were measured in the dog in an isolated left lower lobe preparation. The lobe was inflated and deflated slowly (45 s) at constant speed. Two volumes at equal alveolar pressure (Palv = 9.9 +/- 0.6 mmHg) and two pressures (13.8 +/- 0.8 mmHg, inflation; 4.8 +/- 0.5 mmHg, deflation) at equal volumes during inflation and deflation were studied. The total vascular pressure drop was divided into three segments: arterial (delta Pa), middle (delta Pm), and venous (delta Pv). During inflation and deflation the changes in pulmonary arterial pressure were primarily due to changes in the resistance of the alveolar vessels. At equal Palv (9.9 mmHg), delta Pm was 10.3 +/- 1.2 mmHg during deflation compared with 6.8 +/- 1.1 mmHg during inflation. At equal lung volume, delta Pm was 10.2 +/- 1.5 mmHg during inflation (Palv = 13.8 mmHg) and 5.0 +/- 0.7 mmHg during deflation (Palv = 4.8 mmHg). These measurements suggest that the alveolar pressure was transmitted more effectively to the alveolar vessels during deflation due to a lower alveolar surface tension. It was estimated that at midlung volume, the perimicrovascular pressure was 3.5-3.8 mmHg greater during deflation than during inflation.     

Patient-Specific Modeling of Regional Antibiotic Concentration Levels in Airways of Patients with Cystic Fibrosis: Are We Dosing High Enough?

Background

Pseudomonas aeruginosa (Pa) infection is an important contributor to the progression of cystic fibrosis (CF) lung disease. The cornerstone treatment for Pa infection is the use of inhaled antibiotics. However, there is substantial lung disease heterogeneity within and between patients that likely impacts deposition patterns of inhaled antibiotics. Therefore, this may result in airways below the minimal inhibitory concentration of the inhaled agent. Very little is known about antibiotic concentrations in small airways, in particular the effect of structural lung abnormalities. We therefore aimed to develop a patient-specific airway model to predict concentrations of inhaled antibiotics and to study the impact of structural lung changes and breathing profile on local concentrations in airways of patients with CF.

Methods

In- and expiratory CT-scans of children with CF (5–17 years) were scored (CF-CT score), segmented and reconstructed into 3D airway models. Computational fluid dynamic (CFD) simulations were performed on 40 airway models to predict local Aztreonam lysine for inhalation (AZLI) concentrations. Patient-specific lobar flow distribution and nebulization of 75 mg AZLI through a digital Pari eFlow model with mass median aerodynamic diameter range were used at the inlet of the airway model. AZLI concentrations for central and small airways were computed for different breathing patterns and airway surface liquid thicknesses.

Results

In most simulated conditions, concentrations in both central and small airways were well above the minimal inhibitory concentration. However, small airways in more diseased lobes were likely to receive suboptimal AZLI. Structural lung disease and increased tidal volumes, respiratory rates and larger particle sizes greatly reduced small airway concentrations.

Conclusions

CFD modeling showed that concentrations of inhaled antibiotic delivered to the small airways are highly patient specific and vary throughout the bronchial tree. These results suggest that anti-Pa treatment of especially the small airways can be improved.     

Location of flow-limiting segments via airway catheters near residual volume in humans

Previous studies have demonstrated sites of flow limitation in the central airways of dogs and humans. At low lung volumes, however, during a forced expiration, it is not clear whether flow-limiting segments (FLS) move into the lung periphery. Using intrabronchial lateral pressure catheters, we located FLS in human subjects at all lung volumes between functional residual capacity (FRC) and residual volume (RV). Three individuals with severe intracranial hemorrhage maintained on ventilators were studied. Partial maximal flow-volume curves were generated from 1 liter above FRC to RV by lowering downstream pressure and using the interrupter technique. Sites of FLS were defined as the most downstream points where lateral pressure did not change with driving pressure. FLS were found in all subjects in the central airways. In one subject, FLS moved from segmental bronchi to the first subsegmental bronchus as RV was approached but not beyond. In the other two subjects, FLS remained fixed in location at all measured lung volumes. At constant volume, multiple FLS were located, all in parallel, e.g., fixed in left upper, left lower, and right middle lobar bronchi. In conclusion, sites of flow limitation remain in the central airways as lung volume approaches RV. FLS may move peripherally within the central airways but not beyond proximal subsegmental bronchi.     

Mechanism of lobar alveolar pressure decline during forced deflation in canine regional emphysema

Mink, S. N. Mechanism of lobar alveolar pressuredecline during forced deflation in canine regional emphysema.J. Appl. Physiol. 82(2): 632-643, 1997.A canine model of unilobar papain-induced emphysema was used toexamine the extent to which differences in alveolar pressures(PA) would develop between anemphysematous right lower lobe (RLL) and normal left lower lobe (LLL)during forced vital capacity (FVC) deflation. RLL and LLLPA(PA_RLL and PA_LLL,respectively) were measured by the alveolar capsule technique. Duringforced deflation, PA and lobarflows were determined between 95 and 20% FVC. A choke point common toboth lower lobes was observed at >40% FVC. The results showed thatdeflation compliance (C) was altered for the RLL such that <90%lobar vital capacity, C_RLL > C_LLL, whereas >90% lobar vitalcapacity, C_RLL < C_LLL. At 95 and 90% FVC, theinitial RLL PA decline wasgreater than that for the LLL (P < 0.05). However, large differences inPA were prevented because of theeffect of interdependence of regional expiratory flow (IREF). IREFcaused a relative decrease in RLL flows and increase in LLL flows thatlimited PA differences. Between 80 and 50% FVC, as C_RLL becamegreater than C_LLL, and because ofthe initial effect of IREF,PA_RLL was~PA_LLL.At 40% FVC, without IREF, lobar differences inPA widened. These findings indicate that IREF may affect the dynamics of flow limitation inregional lung disease.

     

Diagnostic morphometry in emphysema and chronic bronchitis

A morphometric technique of point counting was developed for macroscopic use in emphysematous lungs and microscopic use in bronchi to obtain actual areas and volumes, as opposed to ratios or percentages, of emphysema and submucosal glands. The results in emphysematous lungs showed that the volume of emphysema seen in one slice of one lung cannot be used to predict the volume in other slices, nor the volume of emphysema in one lung to predict the volume of emphysema in the other. The results in the airways showed that, if the volume of bronchial glands in each generation along an airway is expressed per unit of luminal surface area, a distinctive profile of gland distribution along the airway is obtained, as well as the mean volume per gland. These results are discussed in relation to the application of morphometry in individual cases for diagnostic purposes, revealing a need for a central repository of validated methods, so that each method is not repeatedly revalidated, and normal baseline data for the diagnostic morphometrist to use in deciding whether the findings in his or her individual patients are of diagnostic significance.