Kenneth R. Lutchen

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.

The difference in ventilation heterogeneity between asthmatic and healthy subjects quantified using hyperpolarized 3He MRI

In this pilot study, algorithms for quantitatively evaluating the distribution and heterogeneity of human ventilation imaged with hyperpolarized (HP) (3)He MRI were developed for the goal of examining structure-function relationships within the asthmatic lung. Ten asthmatic and six healthy human subjects were imaged with HP (3)He MRI before bronchial challenge (pre-MCh), after bronchial challenge (post-MCh), and after a series of deep inspirations (post-DI) following challenge. The acquired images were rigidly coregistered. Local voxel fractional ventilation was computed by setting the sum of the pixel intensity within the lung region in each image to 1 liter of inhaled (3)He mixture. Local ventilation heterogeneity was quantified by computing regional signal coefficient of variation. Voxel fractional ventilation histograms and overall heterogeneity scores were then calculated. Asthmatic subjects had a higher ventilation heterogeneity to begin with (P = 0.025). A methacholine challenge elevated ventilation heterogeneity for all subjects (difference: P = 0.08). After a DI postchallenge, this heterogeneity reversed substantially toward the baseline state for healthy subjects but only minimally in asthmatic subjects. This difference was significant in absolute quantity (difference: P = 0.007) as well as relative to the initial increase (difference: P = 0.03). These findings suggest that constriction heterogeneity is not a characteristic unique to asthmatic airway trees but rather a behavior intrinsic to all airway trees when provoked. Once ventilation heterogeneity is established, it is the lack of reversal following DIs that distinguishes asthmatics from non-asthmatics.

How heterogeneous bronchoconstriction affects ventilation distribution in human lungs: a morphometric model.

AbstractConvective dependent flow heterogeneities associated with airways proximal to the acini are the dominant cause of abnormal ventilation distribution during induced bronchoconstriction (Verbanck, S., D. Schuermans, A. Van Muylem, M. Paira, M. Noppen, and W. Vincken. Ventilation distribution during histamine provocation. J. Appl. Physiol. 83:1907–1916, 1997). We applied a morphometric model of the human lung to predict flow distributions among the acini during heterogeneous bronchoconstriction and relate these distributions to impairments in the mechanical properties of the lung. The model has an asymmetrical branching airway system. Heterogeneous constriction was invoked by defining an airway constriction distribution with a mean (μ) and coefficient of variation (CV) and either a Gaussian or log normal distribution. The lung resistance (RL) and elastance EL were most sensitive to severely heterogeneous constriction that produced a few highly constricted or closed airways dispersed randomly throughout the periphery. Ventilation distribution in the healthy lung was effectively homogeneous over the frequency range of 0.1–5.0 Hz. With homogeneous or mildly heterogeneous constriction (CV⩽20%) ventilation remained fairly homogeneous at low frequencies (≤0.1 Hz) but rapidly became heterogeneous as frequency increased. Conversely, a low mean but severely heterogeneous constriction that produced random airway closure produced abnormal ventilation distribution in most acini at all frequencies, and some acini received up to 25 times the normal ventilation. This suggests that certain forms of heterogeneity can lead to shear induced lung injury even at common mechanical ventilation rates.

Pseudorandom signals to estimate apparent transfer and coherence functions of nonlinear systems: applications to respiratory mechanics

For pseudorandom (PRN) input stimuli, general expressions are derived for the apparent transfer (Z) and coherence ( gamma /sup 2/) functions of nonlinear systems that can be represented by a Volterra series. To avoid the problems that are shown here to be associated with harmonic distortions and to minimize the influence of crosstalk, a family of pseudorandom signals which are especially suited for the estimation of Z and gamma /sup 2/ in mechanical measurement of physiological systems at low frequencies is proposed. The components in the signals cannot be reproduced as linear combinations of two or more frequency components of the input. In a second-order system, this completely eliminates the bias, while in higher order but not strongly nonlinear systems, the interactions among the components are reduced to such a level that the response can be considered as if it were measured with independent sine waves of an equivalent amplitude. It is also shown that the values of gamma /sup 2/ are not appropriate for assessing linearity of the system. The theory is supported by simulation results and experimental examples.<<ETX>>

Tidal stretches do not modulate responsiveness of intact airways in vitro

Studies on isolated tracheal airway smooth muscle (ASM) strips have shown that length/force fluctuations, similar to those likely occurring during breathing, will mitigate ASM contractility. These studies conjecture that, solely by reducing length oscillations on a healthy, intact airway, one can create airway hyperresponsiveness, but this has never been explicitly tested. The intact airway has additional complexities of geometry and structure that may impact its relevance to isolated ASM strips. We examined the role of transmural pressure (Ptm) fluctuations of physiological amplitudes on the responsiveness of an intact airway. We developed an integrated system utilizing ultrasound imaging to provide real-time measurements of luminal radius and wall thickness over the full length of an intact airway (generation 10 and below) during Ptm oscillations. First, airway constriction dynamics to cumulative acetylcholine (ACh) doses (10(-7) to 10(-3) M) were measured during static and dynamic Ptm protocols. Regardless of the breathing pattern, the Ptm oscillation protocols were ineffective in reducing the net level of constriction for any ACh dose, compared with the static control (P = 0.225-0.793). Next, Ptm oscillations of increasing peak-to-peak amplitude were applied subsequent to constricting intact airways under static conditions (5.0-cmH(2)O Ptm) with a moderate ACh dose (10(-5) M). Peak-to-peak Ptm oscillations < or = 5.0 cmH(2)O resulted in no statistically significant bronchodilatory response (P = 0.429 and 0.490). Larger oscillations (10 cmH(2)O, peak to peak) produced modest dilation of 4.3% (P = 0.009). The lack of modulation of airway responsiveness by Ptm oscillations in intact, healthy airways suggests that ASM level mechanisms alone may not be the sole determinant of airway responsiveness.

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.

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

AbstractWe 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.

Physiological interpretations based on lumped element models fit to respiratory impedance data: use of forward-inverse modeling

Respiratory impedance (Z/sub rs/) data at lower (<4 Hz) and higher (>32 Hz) frequencies require more complicated inverse models than the standard series combination of a respiratory resistance, inertance, and compliance. A forward-inverse modeling approach was used to provide insight on how the parameters in these more complicated inverse models reflect the true physiological system. Forward models are set up to incorporate explicit physiological and anatomical detail. Simulated forward data are then fit with identifiable inverse models and the parameter estimates related to the known detail in the forward model. It is shown that inverse fitting of low-frequency data alone will not allow a distinction between frequency dependence due to airway inhomogeneities and frequency dependence due to tissue viscoelasticity. With higher frequency data, a forward model based on an asymmetric branching airways network was used to simulate Z/sub rs/ from 0.1-128 Hz with increasing amounts of nonuniform peripheral airway obstruction. Hence, inverse modeling is more amenable to sensibly separating estimates of airway and tissue properties.<<ETX>>

Assessment of time-domain analyses for estimation of low-frequency respiratory mechanical properties and impedance spectra

Time-domain estimation has been invoked for tracking of respiratory mechanical properties using primarily a simple single-compartment model containing a series resistance (Rrs) and elastance (Ers). However, owing to the viscoelastic properties of respiratory tissues,Rrs andErs exhibit frequency dependence below 2 Hz. The goal of this study was to investigate the bias and statistical accuracy of various time-domain approaches with respect to model properties, as well as the estimated impedance spectra. Particular emphasis was placed on establishing the tracking capability using a standard step ventilation. A simulation study compared continuous-timeversus discrete-time approaches for both the single-compartment and two-compartment models. Data were acquired in four healthy humans and two dogs before and after induced severe pulmonary edema while applying sinusoidal and standard ventilator forcing.Rrs andErs were estimated either by the standard Fast Fourier Transform (FFT) approach or by a time-domain least square estimation. Results show that the continuous-time model form produced the least bias and smallest parameter uncertainty for a single-compartment analysis and is quite amenable for reliable on-line tracking. The discrete-time approach exhibits large uncertainty and bias, particularly with increasing noise in the flow data. In humans, the time-domain approach produced smooth estimates ofRrs andErs spectra, but they were statistically unreliable at the lower frequencies. In dogs, both the FFT and time-domain analysis produced reliable and stable estimates forRrs orErs spectra for frequencies out to 2 Hz in all conditions. Nevertheless, obtaining stable on-line parameter estimates for the two-compartment viscoelastic models remained difficult. We conclude that time-domain analysis of respiratory mechanics should invoke a continuous-time model form.

Probing airway conditions governing ventilation defects in asthma via hyperpolarized MRI image functional modeling.

Image functional modeling (IFM) has been introduced as a method to simultaneously synthesize imaging and mechanical data with computational models to determine the degree and location of airway constriction in asthma. Using lung imaging provided by hyperpolarized (3)He MRI, we advanced our IFM method to require matching not only to ventilation defect location but to specific ventilation throughout the lung. Imaging and mechanical data were acquired for four healthy and four asthmatic subjects pre- and postbronchial challenge. After provocation, we first identified maximum-size airways leading exclusively to ventilation defects and highly constricted them. Constriction patterns were then found for the remaining airways to match mechanical data. Ventilation images were predicted for each pattern, and visual and statistical comparisons were done with measured data. Results showed that matching of ventilation defects requires severe constriction of small airways. The mean constriction of such airways leading to the ventilation defects needed to be 70-80% rather than fully closed. Also, central airway constriction alone could not account for dysfunction seen in asthma, so small airways must be involved.