Pressure, flow, and density relationships in airway models during constant-flow ventilation

Adequate CO2 elimination and normal arterial PCO2 levels can be maintained in dogs during apnea by delivering a continuous flow of inspired gas at high flow rate (1-3 l.min-1.kg-1) through tubes placed in the main-stem bronchi. However, during constant-flow ventilation (CFV) the mean alveolar pressure is increased, causing increased lung volume despite low pressures in the trachea. We hypothesized that the increased dynamic alveolar pressures during CFV were due to momentum transfer from the high-velocity jet stream to resident gas in the lung. To test this, we simulated CFV in straight tubes and in a branched airway model to determine whether changes in gas flow rate (V), gas density (rho), and tube diameter (D) altered the pressure difference (delta P) between alveoli and airway opening in a manner consistent with that predicted by conservation of momentum. Momentum analysis predicts that delta P should vary with V2, whereas measurements yielded a dependence of V1.69 in branched tubes and V1.9 in straight tubes. Substitution of heliox (80% He-20% O2) for air significantly reduced lung hyperinflation during CFV. As predicted by momentum transfer, delta P varied with rho 1.0. Momentum analysis also predicts that delta P should vary with D-2.0, whereas measurements indicated a dependence on D-2.02. The influence of V and rho on depth of penetration of the jet down the airway was explored in a straight tube model by varying the flow rate and gas used. The influence of geometry on penetration was measured by changing the ratio of jet-to-airway tube diameters.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of flow direction on collateral ventilation in excised dog lung lobes

We determined the effect of flow direction on the relationship between driving pressure and gas flow through a collaterally ventilating lung segment in excised cranial and caudal dog lung lobes. He, N2, and SF6 were passed through the lung segment distal to a catheter wedged in a peripheral airway. Gases were pushed through the segment by raising segment pressure (Ps) relative to airway opening pressure (Pao) and pulled from the segment by ventilating the lobe with the test gas, then lowering Ps relative to Pao. Driving pressures (Ps - Pao) between 0.25 and 2 cmH2O were evaluated at Pao values of 5, 10, and 15 cmH2O. Results were similar in cranial and caudal lobes. Flow increased as Ps - Pao increased and was greatest at Pao = 15 cmH2O for the least-dense gas (He). Although flow direction was not a significant first-order effect, there was significant interaction between volume, driving pressure, and flow direction. Dimensional analysis suggested that, although flow direction had no effect at Pao = 10 and 15 cmH2O, at Pao = 5 cmH2O, raising Ps relative to Pao increased the characteristic dimension of the flow pathways, and reducing Ps relative to Pao reduced the dimension. These data suggest that at large lobe volumes, airways (including collateral pathways) within the segment are maximally dilated and the stiffness of the parenchyma prevents any significant distortion when Ps is altered. At low lobe volumes, these pathways are affected by changes in transmural pressure due to the increased airway and parenchymal compliance.     

Effects of recruitment/derecruitment dynamics on the efficacy of variable ventilation

Variable (or noisy) ventilation (VV) has been demonstrated in animal models of acute lung injury to be superior to constant (or conventional) ventilation (CV), in terms of improved gas exchange and mitigation of lung injury, for reasons that are not entirely clear. We hypothesized that the efficacy of VV is related to the fact that recruitment and derecruitment of lung units are dynamic processes. To test this hypothesis, we modeled the lung computationally as a symmetrically bifurcating airway tree terminating in elastic units. Each airway was fully open or completely closed, at any point in time, according to its pressure history. The model is able to accurately mimic previous experimental measurements showing that the lungs of mice injured by acid aspiration are better recruited after 60 min of VV than CV. The model also shows that recruitment/derecruitment dynamics contribute to the relative efficacy of VV, provided lung units open more rapidly than they close once a critical opening or closing pressure threshold has been crossed. We conclude that the dynamics of recruitment and derecruitment in the lung may be important factors responsible for the benefits of VV compared with CV.     

Effect of a regional increase in alveolar pressure on pulmonary blood flow.

We examined whether wedging a catheter (0.5 cm OD) into a subsegmental airway in dog (n = 6) or pig lungs (n = 5) and increasing pressure in the distal lung segment affected pulmonary blood flow. Dogs and pigs were anesthetized and studied in the prone position. Pulmonary blood flow was measured by injecting radiolabeled microspheres (15 microns diam) into the right atrium when airway pressure (Pao) was 0 cmH2O and pressure in the segment distal to the wedged catheter (Ps) was 0, 5, or 15 cmH2O and when Pao = Ps = 15 cmH2O. The lungs were excised, air-dried, and sectioned. Blood flow per gram dry weight normalized to cardiac output to the right or left lung, as appropriate, was calculated for the test segment, a control segment in the opposite lung corresponding anatomically to the test segment, the remainder of the lung containing the test segment (test lung), and the remainder of the lung containing the control segment (control lung). The presence of the catheter reduced blood flow in the test segment compared with that in the control segment and in the test lung. Blood flow was not affected by increasing pressure in the test segment. We conclude that, in studies designed to measure collateral ventilation in dog lungs, the presence of the wedged catheter is likely to have a greater effect on blood flow than the increase in pressure associated with measuring collateral airway resistance.     

Lung gas mixing during expiration following an inspiration of air

The airway system of the lung from the mouth to the pulmonary membrane is modelled by matching a cylindrical model of a pathway through the respiratory region of the lung onto a one-dimensional trumpet model for the conducting airways. The concentration of O₂ in gas expired from this model airway system is investigated following an inspiration of air at two different flow rates (10 litres/min and 85 litres/min). In each case, expiration occurs at the same constant flow rate as that during the previous inspiration. The inspirations, which are studied in an earlier paper, are each of 2 sec duration and begin at a lung volume of 2300 ml and a lung oxygen tension of 98 mm Hg. The equations are solved numerically and plots of expired O₂ concentration against time and against expired volume are shown. It is found that at 85 litres/min, gas mixing in the lung is complete after about 0.7 sec of expiration whereas at 10 litres/min, about 2.6 sec of expiration is required for complete equilibration. It is suggested that the experimental alveolar plateau slope is not in general caused by a slow approach to equilibrium of gas concentrations; except at very low flow rates in the early part of the concentration/time plateau.     

Dynamic model of the bronchial tree

We present a distributed model of the bronchial tree which simulates the global dynamic characteristics of the lung. Local mechanical characteristics of each airway are represented by RCL circuits and parameters of the electrical components are determined from local physiological data. The bronchi geometry is described by Weibel's symmetric model, the flow in each airway is assumed laminar and mixing effects at the bifurcations are neglected; the transpulmonary pressure is assumed to be sinusoidal. In simulations of quiet breathing the resistance to airflow is found to be dominant, the flow amplitude decreasing as breathing frequency increases, but remaining almost constant in all the generations. Simulations of ventilation through obstructed lungs show frequency dependence of the dynamic characteristics in very compliant lungs. The global resistance to airflow and the dynamic compliance of the bronchi decrease as the forced oscillation frequency increases in a pattern similar to in vivo measurements in diseased lungs. This may be an outcome of the RCL properties of the network rather than due to uneven distribution of mechanical properties of the lung.     

Airway pressures in an asymmetrically branched airway model of the dog respiratory system

A computer model of the mechanical properties of the dog respiratory system based on the asymmetrically branching airway model of Horsfield et al. (11) is described. The peripheral ends of this airway model were terminated by a lumped-parameter impedance representing gas compression in the alveoli, and lung and chest wall tissue properties were derived from measurements made in this laboratory. Using this model we predicted the respiratory system impedance and the distribution of pressures along the airways in the dog lung. Predicted total respiratory system impedances for frequencies between 4 and 64 Hz at three lung volumes were found to compare quite closely to measured impedances in dogs. Serial pressure distributions were found to be frequency-dependent and to result in higher pressures in the lung periphery than at the airway opening at some frequencies. The implications of this finding for high-frequency ventilation are discussed.     

Resistance of intrathoracic airways of healthy subjects during periodic flow.

The resistance and reactance of lower airways were measured as functions of the frequency and amplitude of periodic flow in three healthy subjects by relating flow, produced with a piston pump, to the difference between lateral tracheal and alveolar pressure, estimated plethysmorgraphically. Resistance consistently increased with frequency; reactance was small never exceeding resistance. This result cannot be explained by distortion of velocity profiles by inertia because, in long pipes, resistance increases only when inertial forces are large and reactance exceeds resistance. Theoretical analyses of airway resistance suggested that the results reflected inhomogeneity. In lung models which considered airway wall distensibility and inertial reactance of airways, resistance increased with frequency and inertial reactance was small. These results imply that in health, as in lung disease, resistance is determined by the distribution of resistance and reactance within the lung and is not simply the total resistance of the individual airways. As flow amplitude increased at constant frequency, flow-pressure relationships became distorted and resistance increased, due probably to motion of airway walls and further distortion of velocity profiles     

Measuring airway exchange of endogenous acetone using a single-exhalation breathing maneuver.

Exhaled acetone is measured to estimate exposure or monitor diabetes and congestive heart failure. Interpreting this measurement depends critically on where acetone exchanges in the lung. Health professionals assume exhaled acetone originates from alveolar gas exchange, but experimental data and theoretical predictions suggest that acetone comes predominantly from airway gas exchange. We measured endogenous acetone in the exhaled breath to evaluate acetone exchange in the lung. The acetone concentration in the exhalate of healthy human subjects was measured dynamically with a quadrupole mass spectrometer and was plotted against exhaled volume. Each subject performed a series of breathing maneuvers in which the steady exhaled flow rate was the only variable. Acetone phase III had a positive slope (0.054+/-0.016 liter-1) that was statistically independent of flow rate. Exhaled acetone concentration was normalized by acetone concentration in the alveolar air, as estimated by isothermal rebreathing. Acetone concentration in the rebreathed breath ranged from 0.8 to 2.0 parts per million. Normalized end-exhaled acetone concentration was dependent on flow and was 0.79+/-0.04 and 0.85+/-0.04 for the slow and fast exhalation rates, respectively. A mathematical model of airway and alveolar gas exchange was used to evaluate acetone transport in the lung. By doubling the connective tissue (epithelium+mucosal tissue) thickness, this model predicted accurately (R2=0.94+/-0.05) the experimentally measured expirograms and demonstrated that most acetone exchange occurred in the airways of the lung. Therefore, assays using exhaled acetone measurements need to be reevaluated because they may underestimate blood levels.     

Modeling stochastic and spatial heterogeneity in a human airway tree to determine variation in respiratory system resistance

Asthma is a variable disease with changes in symptoms and airway function over many time scales. Airway resistance (Raw) is variable and thought to reflect changes in airway smooth muscle activity, but just how variation throughout the airway tree and the influence of gas distribution abnormalities affect Raw is unclear. We used a multibranch airway lung model to evaluate variation in airway diameter size, the role of coherent regional variation, and the role of gas distribution abnormalities on mean Raw (Raw) and variation in Raw as described by the SD (SDRaw). We modified an anatomically correct airway tree, provided by Merryn Tawhai (The University of Auckland, New Zealand), consisting of nearly 4,000 airways, to produce temporal and spatial heterogeneity. As expected, we found that increasing the diameter variation by twofold, with no change in the mean diameter, increased SDRaw more than fourfold. Perhaps surprisingly, Raw was proportional to SDRaw under several conditions-when either mean diameter was fixed, and its SD varied or when mean diameter varied, and SD was fixed. Increasing the size of a regional absence in gas distribution (ventilation defect) also led to a proportionate increase in both Raw and SDRaw. However, introducing regional dependence of connected airways strongly increased SDRaw by as much as sixfold, with little change in Raw. The model was able to predict previously reported Raw distributions and correlation of SDRaw on Raw in healthy and asthmatic subjects. The ratio of SDRaw to Raw depended most strongly on interairway coherent variation and only had a slight dependence on ventilation defect size. These findings may explain the linear correlation between variation and mean values of Raw but also suggest that regional alterations in gas distribution and local coordination in ventilation amplify any underlying variation in airway diameters throughout the airway tree.     

Effect of chest strapping on regional lung function.

We studied lung mechanics and regional lung function in five young men during restrictive chest strapping. The effects on lung mechanics were similar to those noted by others in that lung elastic recoil increased as did maximum expiratory flow at low lung volumes. Chest strapping reduced the maximum expiratory flow observed at a given elastic recoil pressure. Breathing helium increased maximum expiratory flow less when subjects were strapped than when they were not. These findings indicated that strapping decreased the caliber of airways upstream from the equal pressure point. Regional lung volumes from apex to base were measured with xenon 133 while subjects were seated. The distribution of regional volumes was measured at RV, and at volumes equal to strapped FRC and strapped TLC; no change due to chest strapping was observed. Similarly, the regional distribution of 133Xe boluses inhaled at RV and strapped TLC was unaffected by chest strapping. Closing capacity decreased with chest strapping. We concluded that airway closure decreased during chest strapping and that airway closure was not the cause of the observed increase in elastic recoil of the lung. The combination of decreased slope of the static pressure-volume curve and unchanged regional volumes suggested that strapping increased the apex-to-base pleural pressure gradient.     

Influence of airway diameter and cell confluence on epithelial cell injury in an in vitro model of airway reopening.

Recent advances in the ventilation of patients with acute respiratory distress syndrome (ARDS), including ventilation at low lung volumes, have resulted in a decreased mortality rate. However, even low-lung volume ventilation may exacerbate lung injury due to the cyclic opening and closing of fluid-occluded airways. Specifically, the hydrodynamic stresses generated during airway reopening may result in epithelial cell (EpC) injury. We utilized an in vitro cell culture model of airway reopening to investigate the effect of reopening velocity, airway diameter, cell confluence, and cyclic closure/reopening on cellular injury. Reopening dynamics were simulated by propagating a constant-velocity air bubble in an adjustable-height parallel-plate flow chamber. This chamber was occluded with different types of fluids and contained either a confluent or a subconfluent monolayer of EpC. Fluorescence microscopy was used to quantify morphological properties and percentage of dead cells under different experimental conditions. Decreasing channel height and reopening velocity resulted in a larger percentage of dead cells due to an increase in the spatial pressure gradient applied to the EpC. These results indicate that distal regions of the lung are more prone to injury and that rapid inflation may be cytoprotective. Repeated reopening events and subconfluent conditions resulted in significant cellular detachment. In addition, we observed a larger percentage of dead cells under subconfluent conditions. Analysis of this data suggests that in addition to the magnitude of the hydrodynamic stresses generated during reopening, EpC morphological, biomechanical, and microstructural properties may also be important determinants of cell injury.     

Demonstration of airway closure in man.

After partial equilibration of the lung with a N2O gas mixture absorption of N2O by the pulmonary circulation results in a flow of gas into the lungs during breath holding. A bolus of 133Xe introduced at the mouth at the beginning of the breath hold is carried in by the gas flow and distributed according to regional perfusion. In three subjects, breath holding at FRC, apex-to-base distribution of a 133Xe bolud delivered by N2O absorption (Xecar) was similar to that of a bolus injected intravenously (Xeiv). Near RV however, much less of Xecar penetrated into dependent zones than expected from the distribution of Xeiv. In fact, distribution of Xecar did not differ from that of a slowly inhaled bolus. Correction for Compton scatter in the chest wall, measured in one subject, accounted only in part for the radioactivity recorded over dependent lung regions. The findings indicate that near RV some but not all of the dependent airways must be closed. Furthermore, the distribution of airway closure completely accounts for the distribution of a bolus inhaled from RV.     

Flow and volume dependence of respiratory mechanical properties studied by forced oscillation

The influence of inspiratory and expiratory flow magnitude, lung volume, and lung volume history on respiratory system properties was studied by measuring transfer impedances (4-30 Hz) in seven normal subjects during various constant flow maneuvers. The measured impedances were analyzed with a six-coefficient model including airway resistance (Raw) and inertance (Iaw), tissue resistance (Rti), inertance (Iti), and compliance (Cti), and alveolar gas compressibility. Increasing respiratory flow from 0.1 to 0.4 1/s was found to increase inspiratory and expiratory Raw by 63% and 32%, respectively, and to decrease Iaw, but did not change tissue properties. Raw, Iti, and Cti were larger and Rti was lower during expiration than during inspiration. Decreasing lung volume from 70 to 30% of vital capacity increased Raw by 80%. Cti was larger at functional residual capacity than at the volume extremes. Preceding the measurement by a full expiration rather than by a full inspiration increased Iaw by 15%. The data suggest that the determinants of Raw and Iaw are not identical, that airway hysteresis is larger than lung hysteresis, and that respiratory muscle activity influences tissue properties.     

Late phase bronchial obstruction following nonimmunologic mast cell degranulation

Immunologic degranulation of airway mast cells after antigen inhalation produces early and late airway obstructions in allergic sheep. In this study we determined whether nonimmunologic degranulation of airway mast cells by inhalation of compound 48/80 had similar effects. In five sheep, pulmonary flow resistance (RL), thoracic gas volume (Vtg), and arterial O2 tension (Pao2) were determined prior to and at predetermined times after inhalation of 48/80 aerosol. Immediately after challenge mean specific lung resistance (sRL = RL X Vtg) increased by 259% and mean Pao2 decreased by 29%. All values returned to normal by 3 h. By 5-h postchallenge sRL again increased significantly; this second increase in sRL (92% above base line) was maximal at 7 h and was accompanied by a 17% drop in Pao2. In these same sheep inhalation of Ascaris suum antigen produced comparable early changes in sRL, but the onset of the late response was somewhat delayed and more pronounced. In a second group of sheep (n = 5), pretreatment with the mast cell stabilizer cromolyn sodium prevented both early and late responses by compound 48/80. Pretreatment with the histamine H1-antagonist chlorpheniramine had no significant effect on either response, whereas pretreatment with FPL 55712, an antagonist of slow-reacting substance of anaphylaxis (SRS-A), slightly but not significantly attenuated the early response and completely prevented the late response. We conclude that, like immunologic stimuli, nonimmunologic mast cell degranulation produces early and late bronchial obstructions in allergic sheep; that these responses are mediator dependent; and that while histamine and SRS-A contribute to the early response, it is the early appearance of SRS-A which is an important prerequisite for the late response.     

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.     

Significance of airway resistance for the pattern of breathing and lung volumes in exercising humans

The effects of increased airway resistance on lung volumes and pattern of breathing were studied in eight subjects performing leg exercise on a cycle ergometer. Airway resistance was changed 1) by increasing the density (D) of the respired gas by a factor of 4.2 and changing the inspired gas from O2 at 1.3 bar to air at 6 bar and 2) by increasing airway flow rates by exposing the subjects to incremental work loads of 0-200 W. Increased gas D caused a slower and deeper respiration at rest and during exercise and, at work loads greater than 120 W, depressed the responses of ventilation and mean inspiratory flow. Raised airway resistance induced by increases in D and/or airway flow rates altered respiratory timing by increasing the ratio of inspiratory time (TI) to total breath duration. Furthermore, analyses of the relationships between tidal volume and TI and between end-inspiratory volume and TI revealed elevation of Hering-Breuer inspiratory volume thresholds. We propose that this elevation, and hence exercise-induced increases of tidal volume, can largely be explained by previous observations that the threshold of the inspiratory off-switch mechanisms depends on central inspiratory activity (cf. C. von Euler, J. Appl. Physiol. 55: 1647-1659, 1983), which in turn increases with airway resistance (Acta Physiol. Scand. 120: 557-565, 1984).     

Inhibition of neuronal nitric oxide synthase by 7-nitroindazole attenuates acute lung injury in an ovine model

Nitric oxide (NO) has been shown to play a major role in acute lung injury (ALI) after smoke inhalation. In the present study, we developed an ovine sepsis model, created by exposing sheep to smoke inhalation followed by instillation of bacteria into the airway, that mimics human sepsis and pneumonia. We hypothesized that the inhibition of neuronal NO synthase (nNOS) might be beneficial in treating ALI associated with this model. Female sheep (n = 26) were surgically prepared for the study and given a tracheostomy. This was followed by insufflation of 48 breaths of cotton smoke (40 degrees C) into the airway of each animal and subsequent instillation of live Pseudomonas aeruginosa [5 x 10(11) colony forming units (CFU)] into each sheep's lung. All sheep were mechanically ventilated using 100% O2. Continuous infusion of 7-nitroindazole (7-NI), an nNOS inhibitor, NG-monomethyl-l-arginine (l-NMMA), a nonspecific NOS inhibitor, or aminoguanidine (AG), an inducible NOS inhibitor, was started 1 h after insult. The administration of 7-NI improved pulmonary gas exchange (PaO2/FiO2; where PaO2 is arterial PO2 and FiO2 is fractional inspired oxygen concentration) and pulmonary shunt fraction and attenuated the increase in lung wet-to-dry weight ratio seen in the nontreated sheep. Histologically, 7-NI prevented airway obstruction. The increase in airway blood flow after injury in the nontreated group was significantly inhibited by 7-NI. The increase in plasma concentration of nitrate and nitrite (NOx) was inhibited by 7-NI as well. Posttreatment with l-NMMA improved the pulmonary gas exchange, but AG did not. The results of the present study show that nNOS may be involved in the pathogenesis of ALI after smoke inhalation injury followed by bacterial instillation in the airway.     

Airway stability and heterogeneity in the constricted lung.

The effect of bronchoconstriction on airway resistance is known to be spatially heterogeneous and dependent on tidal volume. We present a model of a single terminal airway that explains these features. The model describes a feedback between flow and airway resistance mediated by parenchymal interdependence and the mechanics of activated smooth muscle. The pressure-tidal volume relationship for a constricted terminal airway is computed and shown to be sigmoidal. Constricted terminal airways are predicted to have two stable states: one effectively open and one nearly closed. We argue that the heterogeneity of whole lung constriction is a consequence of this behavior. Airways are partitioned between the two states to accommodate total flow, and changes in tidal volume and end-expiratory pressure affect the number of airways in each state. Quantitative predictions for whole lung resistance and elastance agree with data from previously published studies on lung impedance.