Airway closure in humans does not result in overestimation of plethysmographic lung volume

Exercise Physiol. 52: 638-641, 1982) have shown in dogs that airway closure may induce rib cage deformation and nonhomogeneous alveolar pressure swings, and they have suggested that this could lead to thoracic gas volume (TGV) overestimation by body plethysmography. However, in humans the rib cage is less easy to distort than in dogs. In four healthy volunteers we measured TGV by plethysmography before (B) and during (D) the occlusion of the middle and lower right lobes by a balloon (attached to a double-lumen catheter) positioned in the intermediate right bronchus. Subjects were trained to perform panting maneuvers preferentially with intercostals and accessory muscles or the diaphragm. Five to eleven TGV measurements were made in each subject with each panting pattern B and D occlusion. Balloon inflation resulted in no change in TGV whether low [13.3 +/- 3.4 (SD) cmH2O] or high (46.8 +/- 8.4 cmH2O) transdiaphragmatic pressures (Pdi) were used: TGV 4.0 +/- 0.4 (B) vs. 4.0 +/- 0.4 liters (D) and 4.3 +/- 0.4 (B) vs. 4.3 +/- 0.4 liters (D) for low and high Pdi, respectively. Thus, in trained subjects performing maneuvers aimed to distort the rib cage, no pressure difference was observed between the occluded and the nonoccluded lung during panting against the closed shutter. We conclude that it is unlikely that the mechanism proposed by Brown et al. might explain errors in lung volume measurements by body plethysmography in humans.     

Airway resistance due to alveolar gas compression measured by barometric plethysmography in mice.

We developed a method for measuring airway resistance (R(aw)) in mice that does not require a measurement of airway flow. An analysis of R(aw) induced by alveolar gas compression showed the following relationship for an animal breathing spontaneously in a closed box: R(aw) = A(bt)V(b)/[V(t) (V(e) + 0.5V(t))]. Here A(bt) is the area under the box pressure-time curve during inspiration or expiration, V(b) is box volume, V(t) is tidal volume, and V(e) is functional residual capacity (FRC). In anesthetized and conscious unrestrained mice, from experiments with both room temperature box air and body temperature humidified box air, the contributions of gas compression to the box pressure amplitude were 15 and 31% of those due to the temperature-humidity difference between box and alveolar gas. We corrected the measured A(bt) and V(t) for temperature-humidity and gas compression effects, respectively, using a sinusoidal analysis. In anesthetized mice, R(aw) averaged 4.3 cmH(2)O.ml(-1).s, fourfold greater than pulmonary resistance measured by conventional methods. In conscious mice with an assumed FRC equal to that measured in the anesthetized mice, the corrected R(aw) at room temperature averaged 1.9 cmH(2)O.ml(-1).s. In both conscious mice and anesthetized mice, exposure to aerosolized methacholine with room temperature box air significantly increased R(aw) by around eightfold. Here we assumed that in the conscious mice both V(t) and FRC remained constant. In both conscious and anesthetized mice, body temperature humidified box air reduced the methacholine-induced increase in R(aw) observed at room temperature. The method using the increase in A(bt) with bronchoconstriction provides a conservative estimate for the increase in R(aw) in conscious mice.     

Functional residual capacity and ventilation homogeneity in mechanically ventilated small neonates.

A modification of a computerized tracer gas (SF6) washout method was designed for serial measurements of functional residual capacity (FRC) and ventilation homogeneity in mechanically ventilated very-low-birth-weight infants with tidal volumes down to 4 ml. The method, which can be used regardless of the inspired O2 concentration, gave accurate and reproducible results in a lung model and good agreement compared with He dilution in rabbits. FRC was measured during 2-4 cmH2O of positive end-expiratory pressure (PEEP) in 15 neonates (700-1,950 g), most of them with mild-to-moderate respiratory distress syndrome. FRC increased with body weight and decreased (P less than 0.05) with increasing O2 requirement. Change to zero end-expiratory pressure caused an immediate decrease in FRC by 29% (P less than 0.01) and gave FRC (ml) = -1.4 + 17 x weight (kg) (r = 0.83). Five minutes after PEEP was discontinued (n = 12), FRC had decreased by a further 16% (P less than 0.01). The washout curves indicated a near-normal ventilation homogeneity not related to changes in PEEP. This was interpreted as evidence against the presence of large volumes of trapped alveolar gas.     

Measurement of alveolar gas volume by ambient pressure changes in isolated lungs

Alveolar gas volume (AGV) may be measured in humans (Peslin et al., J. Appl. Physiol. 62: 359-363, 1987) by applying very slow sinusoidal variations of ambient pressure (delta Pam) around the body and studying the relationship between delta Pam and the resulting gas displacement at the mouth (delta Vaw): AGVapc = (PB.delta Vaw)/(delta Pam.cos phi), where AGVapc is AGV measured by ambient pressure changes, PB is barometric minus alveolar water vapor pressure, and phi is the phase angle between Pam and Vaw. The applicability of this method to excised lungs at various transpulmonary pressures was assessed in six rabbit lungs and three dog lobes by reference to AGV measurements by He dilution (AGVdil) and by a volumetric method (AGVvol). Except in one instance, AGVapc did not change significantly when the frequency of delta Pam was varied from 0.02 to 0.2 Hz. AGVapc was highly correlated (P less than 0.001) to both AGVdil and AGVvol. It did not differ significantly from AGVdil (81.4 +/- 50.6 vs. 80.2 +/- 44.2 ml) and was only marginally higher than AGVvol (64.6 +/- 26.9 vs. 62.4 +/- 24.4 ml, P less than 0.05). We conclude that the method usually provides accurate results in excised lung preparations. Its main advantages are that it does not require manipulating the lung or changing its volume and that the measurement takes less than 1 min.     

The D box asserts itself

New findings (Burton et al., 2005; Kraft et al., 2005) demonstrate the direct recognition of D and KEN boxes, short sequence elements in substrates of the anaphase-promoting complex/cyclosome (APC/C), by APC/C coactivators and indicate a special role for the D box in the assembly of catalytically active APC/C.     

Measurement of thoracic gas volume by low-frequency ambient pressure changes

When the whole body is exposed to sinusoidal variations of ambient pressure (delta Pam) at very low frequencies (f), the resulting compression and expansion of alveolar gas is almost entirely achieved by gas flow through the airways (Vaw). As a consequence thoracic gas volume (TGV) may be computed from the imaginary part (Im) of the delta Pam/Vaw relationship: TGV = PB/[2 pi f X Im(delta Pam/Vaw)], where PB is barometric minus alveolar water vapor pressure. The method was tested in 35 normal subjects and compared with body plethysmography. The subjects sat in a chamber connected to a large-stroke-volume reciprocating pump that brought about pressure swings of 40 cmH2O at 0.05 Hz. delta Pam and Vaw were digitally processed by fast Fourier transform to extract the low-frequency component from the much larger respiratory flow. Total lung capacities (TLC) obtained by ambient pressure changes and by plethylsmography were highly correlated (r = 0.959, p less than 0.001) and not significantly different (6.96 +/- 1.38 l vs. 6.99 +/- 1.38). TLC obtained by ambient pressure changes were not influenced by lowering the frequency to 0.03 Hz, adding an external resistance at the mouth, or increasing abdominal gas volume. We conclude that the method is practical and in agreement with body plethysmography in normal subjects.     

Modeling of respiratory system impedances in dogs

Mechanical impedances between 4 and 64 Hz of the respiratory system in dogs have been reported (A.C. Jackson et al. J. Appl. Physiol. 57: 34-39, 1984) previously by this laboratory. It was observed that resistance (the real part of impedance) decreased slightly with frequency between 4 and 22 Hz then increased considerably with frequency above 22 Hz. In the current study, these impedance data were analyzed using nonlinear regression analysis incorporating several different lumped linear element models. The five-element model of Eyles and Pimmel (IEEE Trans. Biomed. Eng. 28: 313-317, 1981) could only fit data where resistance decreased with frequency. However, when the model was applied to these data the returned parameter estimates were not physiologically realistic. Over the entire frequency range, a significantly improved fit was obtained with the six-element model of DuBois et al. (J. Appl. Physiol. 8: 587-594, 1956), since it could follow the predominate frequency-dependent characteristic that was the increase in resistance. The resulting parameter estimates suggested that the shunt compliance represents alveolar gas compressibility, the central branch represents airways, and the peripheral branch represents lung and chest wall tissues. This six-element model could not fit, with the same set of parameter values, both the frequency-dependent decrease in Rrs and the frequency-dependent increase in resistance. A nine-element model recently proposed by Peslin et al. (J. Appl. Physiol. 39: 523-534, 1975) was capable of fitting both the frequency-dependent decrease and the frequency-dependent increase in resistance. However, the data only between 4 and 64 Hz was not sufficient to consistently determine unique values for all nine parameters.     

Regional variations in lung expansion in rabbits: prone vs. supine positions

We studied the vertical gradient in lung expansion in rabbits in the prone and supine body positions. Postmortem, we used videomicroscopy to measure the size of surface alveoli through transparent parietal pleural windows at dependent and nondependent sites separated in height by 2-3 cm at functional residual capacity (FRC). We compared the alveolar size measured in situ with that measured in the isolated lungs at different deflationary transpulmonary pressures to obtain transpulmonary pressure (pleural surface pressure) in situ. The vertical gradient in transpulmonary pressure averaged 0.48 +/- 0.16 (SD) cmH2O/cm height (n = 10) in the supine position and 0.022 +/- 0.014 (SD) cmH2O/cm (n = 5) in the prone position. In mechanically ventilated rabbits, we used the rib capsule technique to measure pleural liquid pressure at different heights of the chest in prone and supine positions. At FRC, the vertical gradient in pleural liquid pressure averaged 0.63 cmH2O/cm in the supine position and 0.091 cmH2O/cm in the prone position. The vertical gradients in pleural liquid pressure were all less than the hydrostatic value (1 cmH2O/cm), which indicates that pleural liquid is not generally in hydrostatic equilibrium. Both pleural surface pressure and pleural liquid pressure measurements show a greater vertical gradient in the supine than in the prone position. This suggests a close relationship between pleural surface pressure and pleural liquid pressure. Previous results in the dog and pony showed relatively high vertical gradients in the supine position and relatively small gradients in the prone position. This behavior is similar to the present results in rabbits. Thus the vertical gradient is independent of animal size and might be related to chest shape and weight of heart and abdominal contents.     

Lung mechanics in hypervolemic pulmonary edema.

Extravascular thermal volume of the lung (ETVL) is a double indicator dilution technique of use in measuring pulmonary edema. ETVL and lung mechanics measurements were followed to find a less invasive monitor of pulmonary edema than the double indicator dilution technique. Pulmonary edema was induced by overloading the dogs' circulation with dextran. Phases of overload were defined on the basis of a previous electron microscopic study (Noble et al., Can. Anesthetists Soc. J. 21:275, 1974) of lung biopsies relating anatomic changes to physiologic measurements of ETVL and central blood volume (CBV). Congestion occurred when CBV was elevated and ETVL was not, interstitial edema when ETVL was elevated but smaller than 60% above control and alveolar edema when ETVL greater than 85% above control. Once the dogs were in alveolar edema, they were mechanically ventilated with 4, 8, 12, and 16 cmH2O end-tidal pressure (CPPV). Mean functional residual capacity (FRC) for all 15 dogs did not change up to the time CPPV was applied. Pulmonary resistance did not rise until alveolar edema was present. Once in pulmonary edema, lung compliance always fell as lung water increased. In individual dogs, the compliance fall was directly proportional to the rising lung water. However, the variations in slope and beginning point among dogs made it difficult to predict the amount of lung water from dynamic compliance values. PaO2 fell markedly in alveolar edema as a result of a widened A-a gradient. CPPV did not decrease lung water but did increase FRC and PaO2.     

Parenchymal stress affects interstitial and pleural pressures in in situ lung.

After resecting the intercostal muscles and thinning the endothoracic fascia, we micropunctured the lung tissue through the intact pleural space at functional residual capacity (FRC) and at volumes above FRC to evaluate the effect of increasing parenchymal stresses on pulmonary interstitial pressure (Pip). Pip was measured at a depth of approximately 230 microns from the pleural surface, at 50% lung height, in 12 anesthetized paralyzed rabbits oxygenated via a tracheal tube with 50% humidified O2. Pip was -10 +/- 1.5 cmH2O at FRC. At alveolar pressure of 5 and 10 cmH2O, lung volume increased by 8.5 and 19 ml and Pip decreased to -12.4 +/- 1.6 and -12.3 +/- 5 cmH2O, respectively. For the same lung volumes held by decreasing pleural surface pressure to about -5 and -8.5 cmH2O, Pip decreased to -17.4 +/- 1.6 and -23.8 +/- 5 cmH2O, respectively. Because Pip is more negative than pleural pressure, the data suggest that in intact pulmonary interstitium the pressure of the liquid phase is primarily set by the mechanisms controlling interstitial fluid turnover.     

Tome-1, wee1, and the onset of mitosis: coupled destruction for timely entry

In a recent issue of Cell, Ayad et al. (2003) report the identification of a novel F box protein Tome-1, which mediates the destruction of mitosis-inhibitory kinase wee1 via E3 ligase SCF. Tome-1 itself is targeted for degradation by APC in G1. This synergy of destructive action by APC and SCF has important implications for timely entry into mitosis.     

Estimation of alveolar pressure during forced oscillation of the respiratory system.

A method for obtaining a continuous estimate of alveolar pressure (PAlv) during periodic flow is described; it was developed to improve the precision of measurements of airway and respiratory tissue impedance using the improved resolution of relatively high-frequency (approximately 5 Hz) singlas. The respiratory system was modulated with a piston pump, and lung volume and the volume change due to compression and expansion of alveolar gas were measured plethysmorgraphically; these signals and an analog divider were used to obtain a continuous solution of Boyle's law during flow. The plethysmorgraph was of the "flow" type; with it volume changes at frequencies up to 10 Hz and with rates of change up to 6 l/s were measured without amplitude or phase distortion. The method permits control of frequency and flow amplitude during PAlv measurement and calibration of PAlv in the absence of an active chest wall. However, it is technically complex.     

Breath-by-breath alveolar gas exchange

A method is described for breath-by-breath measurement of alveolar gas exchange corrected for changes of lung gas stores. In practice, the subject inspires from a spirometer, and each expired tidal volume is collected into a rubber bag placed inside a rigid box connected to the same spirometer. During the inspiration following any given expiration the bag is emptied by a vacuum pump. A computer monitors inspiratory and expiratory tidal volumes, drives four solenoid valves allowing appropriate operation of the system, and memorizes end-tidal gas fractions as well as mixed expired gas composition analyzed by mass spectrometer. Thus all variables for calculating alveolar gas exchange, based on the theory developed by Auchincloss et al. (J. Appl. Physiol. 21: 810-818, 1966), are obtained on a single-breath basis. Mean resting and steady-state exercise gas exchange data are equal to those obtained by conventional open-circuit measurements. Breathing rates up to 30 X min-1 can be followed. The breath-to-breath variability of O2 uptake at the alveolar level is less (25-35%) than that measured at the mouth as the difference between the inspired and expired volumes, both at rest and during exercise up to 0.7 of maximum O2 consumption.     

Effect of detergent solutions upon distal lung phospholipids

Intratracheally injected acid detergent solutions induce in rabbits a predominantly bronchiolo-lobular process evolving in two steps, an epithelial and an epitheliomesenchymal one. When the acid detergent solution reached prominently the alveolar structures it determined a rapid release by exocytosis of phospholipid lamellated bodies from the large granular alveolocytes and the following engulfment by macrophages of released products (Eskenasy, 1982 b). Histochemically, the cells containing phospholipids increased in cellularized alveolar walls, the alveolar lining film appeared thickened and denser, and the accumulated free macrophages filled with phospholipid reactive granules (Landing et al. 's method). Glucose-6-phosphate-dehydrogenase activity is very intense in the cellularly thickened alveolar walls, in macrophages and in the newly formed (regenerated) bronchiolar cells. Lactate dehydrogenase activity becomes very intense in macrophages. These data complete the morphogenic events leading to the lobular pathology.     

Airway constriction measured from tantalum bronchograms in conscious mice in response to methacholine

A single-projection X-ray technique showed an increase in functional residual capacity (FRC) in conscious mice in response to aerosolized methacholine (MCh) with little change in airway resistance (Raw) measured using barometric plethysmography (Lai-Fook SJ, Houtz PK, Lai Y-L. J Appl Physiol 104: 521-533, 2008). The increase in FRC presumably prevented airway constriction by offsetting airway contractility. We sought a more direct measure of airway constriction. Anesthetized Balb/c mice were intubated with a 22-G catheter, and tantalum dust was insufflated into the lungs to produce a well-defined bronchogram. After overnight recovery, the conscious mouse was placed in a sealed box, and bronchograms were taken at maximum and minimum points of the box pressure cycle before (control) and after 1-min exposures to 25, 50, and 100 mg/ml MCh aerosol. After overnight recovery, each mouse was studied under both room and body temperature box air conditions to correct for gas compression effects on the control tidal volume (Vt) and to determine Vt and Raw with MCh. Airway diameter (D), FRC, and Vt were measured from the X-ray images. Compared with control, D decreased by 24%, frequency decreased by 35%, FRC increased by 120%, and Raw doubled, to reach limiting values with 100 mg/ml MCh. Vt was unchanged with MCh. The limiting D occurred near zero airway elastic recoil, where the maximal contractility was relatively small. The conscious mouse adapted to MCh by breathing at a higher lung volume and reduced frequency to reach a limit in constriction.     

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.     

The original presentation of Boyle's law.

The original presentation of what we know as Boyle's law has several interesting features. First, the technical difficulties of the experiment were considerable, because Boyle used a glass tube full of mercury that was nearly 2.5 m long, and the large pressures sometimes shattered the glass. Next, Boyle's table of results contains extremely awkward fractions, such 10/13, 2/17, 13/19, and 18/23, which look very strange to us today. This was because he calculated the pressure for a certain volume of gas by using simple multiplication and division, keeping the vulgar fractions. Boyle was not able to express the numbers as decimals because this notation was not in common use at the time. Finally, his contention that pressure and volume were inversely related depended on the reader's comparing two sets of numbers in adjacent columns to see how well they agreed. Today we would plot the data, but again orthogonal graphs were not in general use in 1662. When Boyle's data are plotted by using modern conventional methods, they strongly support his hypothesis that the volume and pressure of a gas are inversely related.     

Plethysmographic estimation of thoracic gas volume in apneic mice.

Electrical stimulation of intercostal muscles was employed to measure thoracic gas volume (TGV) during airway occlusion in the absence of respiratory effort at different levels of lung inflation. In 15 tracheostomized and mechanically ventilated CBA/Ca mice, the value of TGV obtained from the spontaneous breathing effort available in the early phase of the experiments (TGVsp) was compared with those resulting from muscle stimulation (TGVst) at transrespiratory pressures of 0, 10, and 20 cmH2O. A very strong correlation (r2= 0.97) was found, although with a systematically (approximately 16%) higher estimation of TGVst relative to TGVsp, attributable to the different durations of the stimulated (approximately 50 ms) and spontaneous (approximately 200 ms) contractions. Measurements of TGVst before and after injections of 0.2, 0.4, and 0.6 ml of nitrogen into the lungs in six mice resulted in good agreement between the change in TGVst and the injected volume (r2= 0.98). In four mice, TGVsp and TGVst were compared at end expiration with air or a helium-oxygen mixture to confirm the validity of isothermal compression in the alveolar gas. The TGVst values measured at zero transrespiratory pressure in all CBA/Ca mice [0.29 +/- 0.05 (SD) ml] and in C57BL/6 (N = 6; 0.34 +/- 0.08 ml) and BALB/c (N = 6; 0.28 +/- 0.06 ml) mice were in agreement with functional residual capacity values from previous studies in which different techniques were used. This method is particularly useful when TGV is to be determined in the absence of breathing activity, when it must be known at any level of lung inflation or under non-steady-state conditions, such as during pharmaceutical interventions.     

A model evaluation of estimates of breath-to-breath alveolar gas exchange

A mathematical model has been implemented for evaluation of methods for estimating breath-to-breath alveolar gas exchange during exercise in humans. This model includes a homogeneous alveolar gas exchange compartment, a dead space compartment, and tissue spaces for CO2 (alveolar and dead space). The dead space compartment includes a mixing portion surrounded by tissue and an unmixed (slug flow) portion which is partitioned between anatomical and apparatus contributions. A random sinusoidal flow pattern generates a breath-to-breath variation in pulmonary stores. The Auchincloss algorithm for estimating alveolar gas exchange (Auchincloss et al., J. Appl. Physiol. 21: 810-818, 1966) was applied to the model, and the results were compared with the simulated gas exchange. This comparison indicates that a compensation for changes in pulmonary stores must include factors for alveolar gas concentration change as well as alveolar volume change and thus implies the use of end-tidal measurements. Although this algorithm yields reasonable estimates of breath-to-breath alveolar gas exchange, it does not yield a "true" indirect measurement because of inherent error in the estimation of a homogeneous alveolar gas concentration at the end of expiration.     

A one-dimensional model for the propagation of transient pressure waves through the lung

The propagation of pressure waves in the lung has been investigated by many authors concerned with respiratory physiology, ultrasound medical techniques or thoracic impact injuries. In most of the theoretical studies, the lung has been modeled as an isotropic and homogeneous medium, and by using Hooke's constitutive law (see e.g. Ganesan et al. Respir. Physiol. 110 (1997) 19; Jahed et al. J. Appl. Physiol. 66 (1989) 2675; Grimal et al. C.R. Acad. Sci., Paris 329 (IIb) (2001) 655-662), or more elaborated material laws (see, e.g. Bush and Challener (Proceedings of the International Research Council on Biokinetics Impacts (IRCOBI), Bergish-gladbach, 1988); Stuhmiller et al. J. Trauma 28 (1988) S132; Yang and Wang, Finite element modeling of the human thorax. Web page: http://wwwils.nlm.nih.gov/research/visible/vhpconf98/AUTHORS/YANG/YANG.HTM.). The hypothesis of homogeneous medium may be inappropriate for certain problems. Because of its foam-like structure, the behavior of the lung-even if the air and the soft tissue are assumed to behave like linearly elastic materials-is susceptible to be frequency dependent. In the present study, the lung is viewed as a one-dimensional stack of air and soft tissue layers; wave propagation in such a stack can be investigated in an equivalent mass-spring chain (El-Raheb (J. Acoust. Soc. Am. 94 (1993) 172; Int. J. Solids Struct. 34 (1997) 2969), where the masses and springs, respectively, represent the alveolar walls and alveolar gas. Results are presented in the time and frequency domains. The frequency dependence (cutoff frequency, variations in phase velocity) of the lung model is found to be highly dependent on the mean alveolar size. We found that short pulses induced by high velocity impacts (bullet stopped by a bulletproof jacket) can be highly distorted during the propagation. The pressure differential between two alveoli is discussed as a possible injury criterion.