Semiautomatic segmentation of ventilated airspaces in healthy and asthmatic subjects using hyperpolarized 3He MRI.

A segmentation algorithm to isolate areas of ventilation from hyperpolarized helium-3 magnetic resonance imaging (HP (3)He MRI) is described. The algorithm was tested with HP (3)He MRI data from four healthy and six asthmatic subjects. Ventilated lung volume (VLV) measured using our semiautomated technique was compared to that obtained from manual outlining of ventilated lung regions and to standard spirometric measurements. VLVs from both approaches were highly correlated (R = 0.99; P < 0.0001) with a mean difference of 3.8 mL and 95% agreement indices of -30.8 mL and 38.4 mL. There was no significant difference between the VLVs obtained through the semiautomatic approach and the manual approach. A Dice coefficient which quantified the intersection of the two datasets was calculated and ranged from 0.95 to 0.97 with a mean of 0.96 ± 0.01 (mean ± SD). VLVs obtained through the semiautomatic algorithm were also highly correlated with measurements of forced expiratory volume in one second (FEV1) (R = 0.82; P = 0.0035) and forced vital capacity (FVC) (R = 0.95; P < 0.0001). The technique may open new pathways toward advancing more quantitative characterization of ventilation for routine clinical assessment for asthma severity as well as a number of other respiratory diseases.

Impact of positive end-expiratory pressure during heterogeneous lung injury: insights from computed tomographic image functional modeling.

Image Functional Modeling (IFM) synthesizes three dimensional airway networks with imaging and mechanics data to relate structure to function. The goal of this study was to advance IFM to establish a method of exploring how heterogeneous alveolar flooding and collapse during lung injury would impact regional respiratory mechanics and flow distributions within the lung at distinct positive end-expiratory pressure (PEEP) levels. We estimated regional respiratory system elastance from computed tomography (CT) scans taken in 5 saline-lavaged sheep at PEEP levels from 7.5 to 20 cmH(2)O. These data were anatomically mapped into a computational sheep lung model, which was used to predict the corresponding impact of PEEP on dynamic flow distribution. Under pre-injury conditions and during lung injury, respiratory system elastance was determined to be spatially heterogeneous and the values were distributed with a hyperbolic distribution in the range of measured values. Increases in PEEP appear to modulate the heterogeneity of the flow distribution throughout the injured lung. Moderate increases in PEEP decreased the heterogeneity of elastance and predicted flow distribution, although heterogeneity began to increase for PEEP levels above 12.5-15 cmH(2)O. By combining regional respiratory system elastance estimated from CT with our computational lung model, we can potentially predict the dynamic distribution of the tidal volume during mechanical ventilation and thus identify specific areas of the lung at risk of being overdistended.

Airway smooth muscle dynamics: a common pathway of airway obstruction in asthma.

Excessive airway obstruction is the cause of symptoms and abnormal lung function in asthma. As airway smooth muscle (ASM) is the effecter controlling airway calibre, it is suspected that dysfunction of ASM contributes to the pathophysiology of asthma. However, the precise role of ASM in the series of events leading to asthmatic symptoms is not clear. It is not certain whether, in asthma, there is a change in the intrinsic properties of ASM, a change in the structure and mechanical properties of the noncontractile components of the airway wall, or a change in the interdependence of the airway wall with the surrounding lung parenchyma. All these potential changes could result from acute or chronic airway inflammation and associated tissue repair and remodelling. Anti-inflammatory therapy, however, does not "cure" asthma, and airway hyperresponsiveness can persist in asthmatics, even in the absence of airway inflammation. This is perhaps because the therapy does not directly address a fundamental abnormality of asthma, that of exaggerated airway narrowing due to excessive shortening of ASM. In the present study, a central role for airway smooth muscle in the pathogenesis of airway hyperresponsiveness in asthma is explored.

Relationship between airway narrowing, patchy ventilation and lung mechanics in asthmatics.

Bronchoconstriction in asthma results in patchy ventilation forming ventilation defects (VDefs). Patchy ventilation is clinically important because it affects obstructive symptoms and impairs both gas exchange and the distribution of inhaled medications. The current study combined functional imaging, oscillatory mechanics and theoretical modelling to test whether the degrees of constriction of airways feeding those units outside VDefs were related to the extent of VDefs in bronchoconstricted asthmatic subjects. Positron emission tomography was used to quantify the regional distribution of ventilation and oscillatory mechanics were measured in asthmatic subjects before and after bronchoconstriction. For each subject, ventilation data was mapped into an anatomically based lung model that was used to evaluate whether airway constriction patterns, consistent with the imaging data, were capable of matching the measured changes in airflow obstruction. The degree and heterogeneity of constriction of the airways feeding alveolar units outside VDefs was similar among the subjects studied despite large inter-subject variability in airflow obstruction and the extent of the ventilation defects. Analysis of the data amongst the subjects showed an inverse relationship between the reduction in mean airway conductance, measured in the breathing frequency range during bronchoconstriction, and the fraction of lung involved in ventilation defects. The current data supports the concept that patchy ventilation is an expression of the integrated system and not just the sum of independent responses of individual airways.

Heterogeneous airway versus tissue mechanics and their relation to gas exchange function during mechanical ventilation.

We have advanced a commercially available ventilator (NPB840, Puritan Bennett/Tyco Healthcare, Pleasanton, CA) to deliver an Enhanced Ventilation Waveform (EVW). This EVW delivers a broadband waveform that contains discrete frequencies blended to provide a tidal breath, followed by passive exhalation. The EVW allows breath-by-breath estimates of frequency dependence of lung and total respiratory resistance (R) and elastance (E) from 0.2 to 8 Hz. We hypothesized that the EVW approach could provide continuous ventilation simultaneously with an advanced evaluation of mechanical heterogeneities under heterogeneous airway and tissue disease conditions. We applied the EVW in five sheep before and after a bronchial challenge and an oleic acid (OA) acute lung injury model. In all sheep, the EVW maintained gas exchange during and after bronchoconstriction, as well as during OA injury. Data revealed a range of disease conditions from mild to severe with heterogeneities and airway closures. Correlations were found between the arterial partial pressure of oxygen (PaO2) and the levels and frequency-dependent features of R and E that are indicative of mechanical heterogeneity and tissue disease. Lumped parameter models provided additional insight on heterogeneous airway and tissue disease. In summary, information obtained from EVW analysis can provide enhanced guidance on the efficiency of ventilator settings and on patient status during mechanical ventilation.

Relation between structure, function, and imaging in a three-dimensional model of the lung.

Previous studies have reported morphometric models to predict function relations in the lung. These models, however, are not anatomically explicit. We have advanced a three-dimensional airway tree model to relate dynamic lung function to alterations in structure, particularly when constriction patterns are imposed heterogeneously inspecific anatomic locations. First we predicted the sensitivity of dynamic lung resistance and elastance (RL and EL) to explicit forms of potential constriction patterns. Simulations show that severe and heterogeneous peripheral airway constriction confined to a single region in the lung (apex, mid, or base) will not produce substantial alterations in whole lung properties as measured from the airway opening. Conversely, when measured RL and EL are abnormal, it is likely that significant (but not necessarily homogeneous) constriction has occurred throughout the entire airway tree. We also introduce the concept of image-assisted modeling. Here positron emission tomographic imaging data sensitive to ventilation heterogeneity is synthesized with RL and EL data to help identify which airway constriction conditions could be consistent with both data sets. An ultimate goal would be personalized predictions.

How does airway inflammation modulate asthmatic airway constriction? An antigen challenge study.

During the late-phase (LP) response to inhaled allergen, mediators from neutrophils and eosinophils are released within the airways, resembling what occurs during an asthma attack. We compared the distribution of obstruction and degree of reversibility that follows a deep inspiration (DI) during early-phase (EP) and LP responses in nine asthmatic subjects challenged with allergen. Heterogeneity of constriction was assayed by determining frequency dependence of dynamic lung resistance and elastance, airway caliber by tracking airway resistance during a DI, and airway inflammation by measuring inflammatory cells in induced sputum postchallenge. Despite a paucity of eosinophils in the sputum at baseline (<1% of nonsquamous cells), asthmatic subjects showed a substantial EP response with highly heterogeneous constriction and reduced capacity to maximally dilate airways. The LP was associated with substantial airway inflammation in all subjects. However, five subjects showed only mild LP constriction, whereas four showed more marked LP constriction characterized by heterogeneous constriction similar to EP. Bronchoconstriction during LP was fully alleviated by administration of a bronchodilator. These findings, together with the impaired bronchodilatory response during a DI, indicate a physiological abnormality in asthma at the smooth muscle level and indicate that airway inflammation in asthma is associated with a highly nonuniform pattern of constriction. These data support the hypothesis that variability in responsiveness among asthmatic subjects derives from intrinsic differences in smooth muscle response to inflammation.

Tracking variations in airway caliber by using total respiratory vs. airway resistance in healthy and asthmatic subjects.

An index of airway caliber can be tracked in near-real time by measuring airway resistance (Raw) as indicated by lung resistance at 8 Hz. These measurements require the placing of an esophageal balloon. The objective of this study was to establish whether total respiratory system resistance (Rrs) could be used rather than Raw to track airway caliber, thereby not requiring an esophageal balloon. Rrs includes the resistance of the chest wall (Rcw). We used a recursive least squares approach to track Raw and Rrs at 8 Hz in seven healthy and seven asthmatic subjects during tidal breathing and a deep inspiration (DI). In both subject groups, Rrs was significantly higher than Raw during tidal breathing at baseline and postchallenge. However, at total lung capacity, Raw and Rrs became equivalent. Measured with this approach, Rcw appears volume dependent, having a magnitude of 0.5-1.0 cmH2O. l-1. s during tidal breathing and decreasing to zero at total lung capacity. When resistances are converted to an effective diameter, Rrs data overestimate the increase in diameter during a DI. Simulation studies suggest that the decrease in apparent Rcw during a DI is a consequence of airway opening flow underestimating chest wall flow at increased lung volume. We conclude that the volume dependence of Rcw can bias the presumed net change in airway caliber during tidal breathing and a DI but would not distort assessment of maximum airway dilation.

Spatial distribution of human respiratory system transfer impedance.

Transfer impedance (Ztr) of the respiratory system provides specific information on airways and tissues, but little is known about its spatial distribution in the different thoracoabdominal regions. To study Ztr distribution on the chest wall surface we analyzed five healthy subjects in the supine position by applying a sinusoidal forcing pressure (4, 8, and 12 Hz) at the mouth and measuring airway opening pressure and flow. Three-dimensional positions of 68 reflective markers placed on the chest wall over selected reference points were simultaneously measured by an optoelectronic motion analyzer. A subset of ten points placed on the midline were used to measure chest wall movements in the craniocaudal direction. While the motion of rib cage markers was synchronous, the abdominal markers demonstrated surface waves propagating caudally. The amplitude and phase of these waves were strongly dependent on position and frequency. We used a new method to measure total and local chest wall volume variations to compute the distribution of Ztr over the chest wall. Above 4 Hz we found that Ztr was inhomogeneously distributed and strongly dependent on position and frequency, mainly in the abdomen where the phase was often more more than 180 degrees with high values of modulus. For this reason, we conclude that above 8 Hz Ztr represents rib cage mechanics almost exclusively.

Exact morphometric modeling of rat lungs for predicting mechanical impedance.

We have developed a computational approach that allows for one-to-one mapping of the airway anatomy when predicting the overall lung mechanical properties and their response to explicit constriction patterns imposed on the airway tree. Specifically, we have exploited the database from Raabe et al. (LF-53 Albuquerque, NM: Lovelace foundation for radical Education and Research), to build the first anatomically based computational model of the rat. The model was then used to predict the response to homogeneous and heterogeneous peripheral airway constriction. Unlike in humans, the inherent asymmetry in the airway tree of rats is predicted to be a dominant contributor to the frequency dependence of lung resistance and elastance even if the constriction is imposed homogeneously. A similar approach would, in principal, be applicable for humans, but the Raabe data is not sufficiently complete to permit this.

Hysteresivity of the lung and tissue strip in the normal rat: effects of heterogeneities.

We measured lung impedance in rats in closed chest (CC), open chest (OC), and isolated lungs (IL) at four transpulmonary pressures with a optimal ventilator waveform. Data were analyzed with an homogeneous linear or an inhomogeneous linear model. Both models include tissue damping and elastance and airway inertance. The homogeneous linear model includes airway resistance (Raw), whereas the inhomogeneous linear model has a continuous distribution of Raw characterized by the mean Raw and the standard deviation of Raw (SDR). Lung mechanics were compared with tissue strip mechanics at frequencies and operating stresses comparable to those during lung impedance measurements. The hysteresivity (eta) was calculated as tissue damping/elastance. We found that 1) airway and tissue parameters were different in the IL than in the CC and OC conditions; 2) SDR was lowest in the IL; and 3) eta in IL at low transpulmonary pressure was similar to eta in the tissue strip. We conclude that eta is primarily determined by lung connective tissue, and its elevated estimates from impedance data in the CC and OC conditions are a consequence of compartment-like heterogeneity being greater in CC and OC conditions than in the IL.

Airway constriction pattern is a central component of asthma severity: the role of deep inspirations.

Measurements of lung resistance and elastance (RL and EL) from 0.1 to 8 Hz reflect both the mean level and pattern of lung constriction. The goal of this study was to establish a relation between a deep inspiration (DI) and the heterogeneity of constriction in healthy versus asthmatic subjects. Constriction pattern was assessed from measurements of the RL and EL from 0.1 to 8 Hz in seven healthy subjects and in 12 asthmatics. These data were acquired before and after a DI and before and after a standard methacholine challenge versus a modified challenge in which a DI is prohibited. Generally, avoidance of a DI increased responsiveness. In healthy subjects and in those with mild-to-moderate baseline asthma a bronchial challenge, especially during self-inhibited DI, produced a heterogenous pattern of constriction inclusive of randomly distributed airway closures or near closures. Nevertheless, such subjects were able to reopen their airways via a DI. In contrast, in subjects with severe baseline asthma, there is a more extreme heterogeneous constriction pattern with random airway closures even at baseline. Further, there is no residual bronchodilatory effect of a DI either before or after bronchial challenge. We conjecture that inflammation and wall-remodeling facilitate a dangerous degree of heterogeneous constriction inclusive of airway closures or near closures, and contribute to the prevention of a DI from having a residual bronchodilatory effect.

Selected contribution: airway caliber in healthy and asthmatic subjects: effects of bronchial challenge and deep inspirations.

In 9 healthy and 14 asthmatic subjects before and after a standard bronchial challenge and a modified [deep inspiration (DI), inhibited] bronchial challenge and after albuterol, we tracked airway caliber by synthesizing a method to measure airway resistance (Raw; i.e., lung resistance at 8 Hz) in real time. We determined the minimum Raw achievable during a DI to total lung capacity and the subsequent dynamics of Raw after exhalation and resumption of tidal breathing. Results showed that even after a bronchial challenge healthy subjects can dilate airways maximally, and the dilation caused by a single DI takes several breaths to return to baseline. In contrast, at baseline, asthmatic subjects cannot maximally dilate their airways, and this worsens considerably postconstriction. Moreover, after a DI, the dilation that does occur in airway caliber in asthmatic subjects constricts back to baseline much faster (often after a single breath). After albuterol, asthmatic subjects could dilate airways much closer to levels of those of healthy subjects. These data suggest that the asthmatic smooth muscle resides in a stiffer biological state compared with the stimulated healthy smooth muscle, and inhibiting a DI in healthy subjects cannot mimic this.

Inspiratory lung impedance in COPD: effects of PEEP and immediate impact of lung volume reduction surgery.

Frequency-dependent characteristics of lung resistance (RL) and elastance (EL) are sensitive to different patterns of airway obstruction. We used an enhanced ventilator waveform (EVW) to measure inspiratory RL and EL spectra in ventilated patients during thoracic surgery. The EVW delivers an inspiratory flow waveform with enhanced spectral excitation from 0.156 to 8.1 Hz. Estimates of the coefficients in a trigonometric approximation of the EVW flow and transpulmonary pressure inspirations yielded inspiratory RL and EL spectra. We applied the EVW in a group with mild obstruction undergoing various thoracoscopic procedures (n = 6), and another group with severe chronic obstructive pulmonary disease undergoing lung volume reduction surgery (n = 8). Measurements were made at positive end-expiratory pressure (PEEP) of 0, 3, and 6 cmH(2)O. Inspiratory RL was similar in both groups despite marked differences in spirometry. The chronic obstructive pulmonary disease patients demonstrated a pronounced frequency-dependent increase in inspiratory EL consistent with severe heterogeneous peripheral airway obstruction. PEEP appears to have beneficial effects by reducing peripheral airway resistance. Lung volume reduction surgery resulted in increased inspiratory RL and EL at all frequencies and PEEPs, possibly due to loss of diseased lung tissue, pulmonary edema, increased mechanical heterogeneity, and/or an improvement in airway tethering.

Fast, robust identification of nonlinear physiological systems using an implicit basis expansion.

Because the number of parameters required by a Volterra series grows rapidly with both the length of its memory and the order of its nonlinearity, methods for identifying these models from measurements of input/output data are limited to low-order systems with relatively short memories. To deal with these computational and storage requirements one can either make extensive use of the structure of the Volterra series estimation problem to eliminate redundant storage and computations (e.g., the fast orthogonal algorithm), or apply a basis expansion, such as a Laguerre expansion, which seeks to reduce the number of model parameters, and hence, the size of the estimation problem. The use of an appropriate expansion basis can also decrease the noise sensitivity of the estimates. In this paper, we show how fast orthogonalization techniques can be combined with an expansion onto an arbitrary basis. We further demonstrate that the orthogonalization and expansion may be performed independently of each other. Thus, the results from a single application of the fast orthogonal algorithm can be used to generate multiple basis expansions. Simulations, using a simple nonlinear model of peripheral auditory processing, show the equivalence between the kernels estimated using a direct basis expansion, and those computed using the fast, implicit basis expansion technique which we propose. Running times for this new algorithm are compared to those for existing techniques.

Effects of collagenase and elastase on the mechanical properties of lung tissue strips.

The dynamic stiffness (H), damping coefficient (G), and harmonic distortion (k(d)) characterizing tissue nonlinearity of lung parenchymal strips from guinea pigs were assessed before and after treatment with elastase or collagenase between 0.1 and 3.74 Hz. After digestion, data were obtained both at the same mean length and at the same mean force of the strip as before digestion. At the same mean length, G and H decreased by approximately 33% after elastase and by approximately 47% after collagenase treatment. At the same mean force, G and H increased by approximately 7% after elastase and by approximately 25% after collagenase treatment. The k(d) increased more after collagenase (40%) than after elastase (20%) treatment. These findings suggest that, after digestion, the fraction of intact fibers decreases, which, at the same mean length, leads to a decrease in moduli. At the same mean force, collagen fibers operate at a higher portion of their stress-strain curve, which results in an increase in moduli. Also, G and H were coupled so that hysteresivity (G/H) did not change after treatments. However, k(d) was decoupled from elasticity and was sensitive to stretching of collagen, which may be of value in detecting structural alterations in the connective tissue of the lung.

Parametric and nonparametric nonlinear system identification of lung tissue strip mechanics.

Lung parenchyma is a soft biological material composed of many interacting elements such as the interstitial cells, extracellular collagen-elastin fiber network, and proteoglycan ground substance. The mechanical behavior of this delicate structure is complex showing several mild but distinct types of nonlinearities and a fractal-like long memory stress relaxation characterized by a power-law function. To characterize tissue nonlinearity in the presence of such long memory, we investigated the robustness and predictive ability of several nonlinear system identification techniques on stress-strain data obtained from lung tissue strips with various input wave forms. We found that in general, for a mildly nonlinear system with long memory, a nonparametric nonlinear system identification in the frequency domain is preferred over time-domain techniques. More importantly, if a suitable parametric nonlinear model is available that captures the long memory of the system with only a few parameters, high predictive ability with substantially increased robustness can be achieved. The results provide evidence that the first-order kernel of the stress-strain relationship is consistent with a fractal-type long memory stress relaxation and the nonlinearity can be described as a Wiener-type nonlinear structure for displacements mimicking tidal breathing.

Technique to determine inspiratory impedance during mechanical ventilation: implications for flow limited patients.

We present the design of an enhanced ventilator waveform (EVW) for routine measurement of inspiratory resistance (R) and elastance (E) spectra in ventilator-dependent and/or severely obstructed flow-limited patients. The EVW delivers an inspiratory tidal volume of fresh gas with a flow pattern consisting of multiple sinusoids from 0.156 to 8.1 Hz and permits a patient-driven exhalation to the atmosphere or positive end-expiratory pressure. Weighted least-squares estimates of the coefficients in a sinusoidal series approximation of the EVW inspirations yielded inspiratory R and E spectra. We first validated the EVW approach using simulated pressure and flow data under different physiological conditions, noise levels, and harmonic distortions. We then applied the EVW in four intubated patients during anesthesia and paralysis: two with mild airway obstruction and two with severe emphysema and flow limitation. While the level of inspiratory R was similar in both groups of patients, the inspiratory E of the emphysematous patients demonstrated a pronounced frequency-dependent increase consistent with severe peripheral airway obstruction. We conclude that the EVW offers a potentially practical and efficient approach to monitor lung function in ventilator-dependent patients, especially those with expiratory flow limitation.

Airway remodeling in asthma amplifies heterogeneities in smooth muscle shortening causing hyperresponsiveness.

Although airway remodeling and inflammation in asthma can amplify the constriction response of a single airway, their influence on the structural changes in the whole airway network is unknown. We present a morphometric model of the human lung that incorporates cross-sectional wall areas corresponding to the adventitia, airway smooth muscle (ASM), and mucosa for healthy and mildly and severely asthmatic airways and the influence of parenchymal tethering. A heterogeneous ASM percent shortening stimulus is imposed, causing distinct constriction patterns for healthy and asthmatic airways. We calculate lung resistance and elastance from 0.1 to 5 Hz. We show that, for a given ASM stimulus, the distribution of wall area in asthmatic subjects will amplify not only the mean but the heterogeneity of constriction in the lung periphery. Moreover, heterogeneous ASM shortening that would produce only mild changes in the healthy lung can cause hyperresponsive changes in lung resistance and elastance at typical breathing rates in the asthmatic lung, even with relatively small increases in airway resistance. This condition arises when airway closures occur randomly in the lung periphery. We suggest that heterogeneity is a crucial determinant of hyperresponsiveness in asthma and that acute asthma is more a consequence of extensive airway wall inflammation and remodeling, predisposing the lung to produce an acute pattern of heterogeneous constriction.

Airway and lung tissue mechanics in asthma. Effects of albuterol.

We examined the partitioning of total lung resistance (RL) into airway resistance (Raw) and tissue resistance (Rti) in patients with mild to moderate asthma (baseline FEV1, 54 to 91% of predicted) before and after albuterol inhalation. An optimal ventilator waveform was used to measure RL and lung elastance (EL) in 21 asthmatics from approximately 0.1 to 8 Hz during tidal excursions. Analysis of the RL and EL provided separate estimates of airway and lung tissue properties. Eleven subjects, classified as Type A asthmatics, displayed slightly elevated RL but normal EL. Their data were well described with a model consisting of homogeneous airways leading to viscoelastic tissues before and after albuterol. The other 10 subjects, classified as Type B asthmatics, demonstrated highly elevated RL and an EL that became highly elevated at frequencies above 2 Hz. These subjects required the inclusion of an airway wall compliance in the model prealbuterol but not postalbuterol. This suggests that the Type B subjects were experiencing pronounced constriction in the periphery of the lung, resulting in shunting of flow into the airway walls. Spirometric data were consistent with higher constriction in Type B subjects. Both groups demonstrated significant (p < 0.05) decreases in Raw and tissue damping after albuterol, but tissue elastance decreased only in the Type B group. The percent contributions of Raw and Rti to RL were similar in both groups and did not change after albuterol. We conclude that in asthma, Raw comprises the majority (> 70%) of RL at breathing frequencies. The relative contributions of Raw and Rti to RL appear to be independent of the degree of smooth muscle constriction.